Breast C a n c e r R e s e a r c h a n d T r e a t m e n t , 3, 303-325 (1983) © 1983, M a r t i n u s N i j h o f f Publishers, Boston. P r i n t e d in the N e t h e r l a n d s
Abstracts
1
A RANDOMIZED COMPARISON OF OBSERVATION VS. CMFP VS. CMFPT A D J U V A N T CHEMOHORMONE THERAPY OF NODE POSITIVE POSTMENOPAUSAL BREAST CANCER: AN ECOG TRIAL. ::]EOlson*, SG Taylor IV, LA Kalish, Mary Imogene Bassett Hospital, Cooperstown, NY, Rush Medical College, Chicago, IL 60612 and Sidney r'arber Cancer Institute, Boston, MA 021 l 5. 265 node positive post-menopausal breast cancer patients ~ 66 years were randomized following surgery to either observation (Obs) or Cyclophosphamide, Methotrexate, 5-Fluorouracil an~ Prednisone (CMrP) or ~MFP+Tamo×ifen (CMFP~). C 100 mg/M ~ p.o. d½-1#,M 00 mg/M IV dl and 8, F 6 0 0 m g / M IVdl a n d g , pt~0 mg/M p.o. d l - I # and T 20 mg p.o. dl-2g were to be repeated every 28d for 12 cycles. Patients were entered between 3/7g and 7/81. 222 patients were eligible and evaluable with 36 months median followup. There are no significant differences between the CMFP and the CMFPT groups in relapse (p-.26) or survival (p:.gl). Comparison of observation vs. the combined chemotherapy regimens over time shows:
PROGNOSTIC% NED - l YR. GROUP Obs CMFP/T All pts. ER+ ERl-3Nodes > 3 Nodes
% NED - 2 YR. O ' b s CMFP/T
% NED 3 YR. Obs CMFP/T
75 85
9/4. 92
6¢4 77
73 72
52 *
51
58
92
#5
74
*
*
7g 71
96 71 79 * * 90 57 66 * * ~Too early to analyze. The relapse rate for CMFP/CMFPT is lower than the relapse rate for Obs during the first year (p <.001) but not after that (p=.53), suggesting only transient eHect by the chemohormone therapy regimens. Survival is similar in the Obs and CMFP/CMFPT groups (p:.68). Similar conclusions are reached by comparing Obs to CMFP or CMFPT individually. Definitive conclusions regarding long-term results will require additional follow-up. However, at this time there is no indication of a long-term benefit from adjuvant CMFP or CMFPT treatment.
THE E F F E C T OF P R I O R A D J U V A N T C H E M O T H E R A P Y ON S U R V I V A L IN M E T A S T A T I C BREAST CANCER. J. coburn*, F.R. Ahmann, T. Moon and S.E. Jones. U n i v e r s i t y of A r i z o n a Cancer Center, Tucson, A r i z o n a 85724 Adjuvant c h e m o t h e r a p y has become w i d e l y used for many women with operable b r e a s t c a n c e r b e c a u s e of improved d i s e a s e - f r e e and overall survival. Even so, some of these p a t i e n t s d e v e l o p recurrent breast cancer, and little is known r e g a r d i n g the effect of prior adjuvant c h e m o t h e r a p y or other p r o g n o s t i c factors on response to subsequent treatment. AS part of an ongoing adjuvant breast cancer trial since 1974, 144 p a t i e n t s who received A d r i a m y c i n e y c l o p h o s p h a m i d e adjuvant c h e m o t h e r a p y have relapsed. The m e d i a n d i s e a s e - f r e e interval was 24 m o n t h s (21 months for 67 stage II and 51 stage ZII patients) and 34 m o n t h s for 7 stage I patients. Initial t r e a t m e n t strategies at the time of relapse were: i) C h e m o t h e r a p y (36 patients), 2) Sequential hormono-chemotherapy (37 patients), 3) c o m b i n e d hormono-chemotherapy (39 patients), and other (13 patients). The overall objective response rate (CR + PR) was 56%. The overall m e d i a n survival from onset of stage IV disease was 61 weeks compared w i t h a m e d i a n survival of 124 weeks in 222 p r e v i o u s l y u n t r e a t e d p a t i e n t s w i t h stage IV b r e a s t c a n c e r treated d u r i n g the same time period. At this time a relapse t r e a t m e n t strategy of either combined or sequential h o r m o n o - c h e m o t h e r a p y appeared to r e s u l t in a superior survival than that a c h i e v e d with c h e m o t h e r a p y alone. Other p o t e n t i a l p r o g n o s t i c factors at the time of relapse are being used in a Cox M u l t i v a r i a t e analysis model to d e t e r m i n e their effect on survival. In summary, p r i o r adjuvant therapy appears to a d v e r s e l y affect the survival of p a t i e n t s who d e v e l o p r e c u r r e n t b r e a s t cancer when c o m p a r e d to o t h e r p a t i e n t s with stage IV d i s e a s e not p r e v i o u s l y treated.
ADJUVANT CHEMOTHERAPY FOR OPERABLE BREAST CANCER WITH POSITIVE AXILLARY NODES. S. R i v k i n * , H. Glucksberg, M. Foulkes~ Tumor I n s t i t u t e o f Swedish H o s p i t a l , S e a t t l e , WA 98104, Southwest Oncology Group S t a t i s t i c a l Center, Houston, TX 77030 f o r Southwest Oncology Group, San Antonio, TX 78229. Women w i t h operable breast cancer with h i s t o l o g i c a l l y p o s i t i v e a x i l l a r y nodes were randomized to receive e i t h e r combination (CMFVP) or s i n g l e agent (melphalan) chemotherapy a f t e r a m o d i f i e d or r a d i c a l mastectomy. A l l p a t i e n t s had a normal bone scan. S t r a t i f i c a t i o n included menopausal status and number o f p o s i t i v e nodes ( I - 3 , > 4). CMFVP: C~toxan (60 mg/M z po qd x l y r . ) ; 5 - F i u o r o ~ r a c i l (-300mg/M IV wkly x l y r . ) ; Methotrexate (15 mg/M 2 IV wkly x l y r . ) ; V i n c r i s t i n e (0.625 mg/M 2 IV wkly x lO w k s . ) ; Prednisone (30 mg/M 2 days 1-14; 20 mg/M z days 15-28; lO mg/M z days 29-42 po). MeIphalan: 5 mg/M 2 qd x 5 days every 6 wks. x 2 y r s . 359 evaluable and p a r t i a l l y evaluable women on study had a median f o l l o w - u p o f 72 months and a minimum o f 60 months. l l 9 o f 166 women t r e a t e d w i t h CMFVP versus 95 o f 183 t r e a t e d w i t h Melphalan are c u r r e n t l y d i s e a s e - f r e e (p:.O02). Diseasef r e e i n t e r v a l a t 5 years is 70% f o r CMFVP and 48% f o r Melphalan (p=.O02). Total s u r v i v a l at 5 years is 74% f o r CMFVP and 58% f o r Melphalan (p=.O02). Disease-free s u r v i v a l times were s i g n i f i c a n t l y longer w i t h CMFVP than with Melphalan in the f o l l o w i n g subgroups: premenopausal (p=.O02) I - 3 a x i l l a r y nodes (p=.O06), and 4 or more involved a x i l l a r y nodes (p=.O02). There is a s i g n i f i c a n t d i f f e r e n c e in overa l l s u r v i v a l in f a v o r o f CMFVP compared to Melphalan (p=.O02) and i n the f o l l o w i n g subgroups: premenopausal ( p = . O l ) , postmenopausal (p=.03), and g r e a t e r than 3 involved a x i l l a r y nodes (p=.O02). There have been no relapses i n the past 2 years among p a t i e n t s with less than 4 i n v o l v e d a x i l l a r y nodes t r e a t e d w i t h CMFVP. These r e s u l t s show t h a t c o n t i n uous CMFVP is s u p e r i o r to i n t e r m i t t e n t Melphalan in decreasing recurrences increasing s u r v i v a l in both pre- and postmenopausal p a t i e n t s . (Supported i n part by NCI #CA20319.)
CORRELATION OF TUMOR BURDEN TO ANTIGEN r A N T I BODY AND IMMUNE COMPLEXES tN BREABT CARCINOMA. *P A Balinas, K H Wee, J Ragaz & H S i l v e r , Cancer Control Agency of B. C. and University of B r i t i s h Columbia, V a n c o u v e r , B . C . , VBZ 3J3, Canada. We have Further examined the n o n - d i a g n o s t i c clinical significance of how a n t i b o d y , antigen and c i r c u l a t i n g immune complexes ( C I C ) relate to stage of disease and prognosis in selected breast carcinoma ( B C ) patients (pts). BC associated antigens ( B C A A ) have been isolated from serum samples b y i m m u n o a f f i n i t y using sepharose beads coated with monoclonal antibodies (Mc) prepared against human mammary epithelial antigen of milk fat globule membranes (HMFG Mc-3 & Mc-8, PNAS 79: 5420, 1982, c o u r t e s y of Dr. R . L . Ceriani, Oakland, CAT. Upon 5DSPAGE, isolated antigen depicted heterogeneous moeities of M 33 66 and 105 Kdattons which c o r r o b o r a t e o u r t ' r e p o r t e d BCAA M 34 and 68 Kdaltons meeities isolated by the Raji-eell metl~od (Proc. ASCO 2: 103, 1983). I n t e r action of BCAA with autologous pts sera grouped ( G p ) according to tumor b u r d e n , resulted in generation of 8-11S smaller CIC from 20-25S. We observed a similar CIC size reduction d u r i n g melanoma associated antigen and autoIogous sera interaction ( P r o t . Biol. Fluids Coll. 3 t , 1983). A d m i x t u r e of Mc-3 & Mc-8 with BC sera resulted in a drastic reduction (90-95~) in CIC levels f o r Gp I and III, with a lesser (73%) reduction f o r Gp II pts. Also, the amount of Mc that achieved maximal serum CIC change correlated (p<0.001) with tumor b u r d e n d e p e n d e n t antigen: a n t i b o d y concentration as shown by Gp I and II r e q u i r i n g B- and 6 - f o l d more Mc than Gp III. Analysis of antigen, a n t i b o d y and CIC interaction to effect changes of CIC concentration and size p r o v i d e s improved assessment of pts clinical disease stage ( t u m o r b u r d e n ) than CiC q u a n t i t a t i o n alone. ( S u p p o r t e d in p a r t by N C I ( C ) g r a n t ) .
304 5
Abstracts
INFLUENCE OF THE LH-RN AGONIST, ICI 118630 ON THE ENDOCRINE ENVIRONMENT OF HUMAN BREAST TUMOURS. R I Nicholson*and K J Walker, Tenovus I n s t i t u t e f o r Cancer Research, Welsh National School of Medicine, Heath Park, C a r d i f f , CF4 4XX, U.K. ICI I18630 (D-Ser(But)6AzglylO_LH_RH) is a potent LH-RH agonist which when administered at pharmacological dose levels blocks f o l l i c u l a r maturation, decreases plasma levels of oestradiol and reduces the size of oestrogendependent tissues, including oestrogen receptor positive DMBA-induced mammary tumours (Nicholson et a l . , 1982) in female rats. Such observations have led to phase I c l i n i cal t r i a l s investigating the use of ICI I18638 in the treatment of hormone dependent breast cancer in premenopausal women. Following a single i n j e c t i o n of ICI 118630 (I000 wg) plasma levels of LH and FSH were elevated. On continued d a i l y i n j e c t i o n s , however the drug did not maintain this response and was associated with a rapid decline in plasma progesterone levels. Plasma oestradiol concentrations equivalent to those seen in oophorectomised or postmenopausal women were eventually produced in all patients treated with ICl 118630. Persistent f o l l i c u l a r a c t i v i t y was however seen in some patients up to two months following the i n i t i a t i o n of therapy. No appreciable side effects of the drug were observed. These data indicate that ICI 118630 produces a ' c a s t r a t i o n - l i k e ' response in patients with breast cancer, Extended c l i n i c a l t r i a l s are now necessary to assess tumour response to the drug.
6 ESTROGEN RECEPTOR IMMUNOCYTOCHEMICAL ASSAY NITH MONOCLONAL ANTIBODIES. CORRELATION NITH BIOCHEMICAL ASSAY IN 103 CASES AND WITH CLINICAL RESPONSE TO ENDOCRINE THERAPY IN 32 CASES. L P Pertsehuk,* K B Eisenberg, A C Carter and S A Dayan, Downstate Medical Center, 8UNY, Brooklyn, New York 11203. Specimens from 103 women with breast cancer were examined for estrogen receptors utilizing D547 and D?5 monoclonal rat antibodies to estrophilin and the estrogen receptor immunoc~tochemical assay (ERICA) of Greene and King (G Greene, In, Biochemical Actions of Hormones, Vol i[, 1983) in which frozen tissue sections are fixed in picrie acid/paraformaldehyde, incubated with antibody, reacted with goat anti~rat IgG and then with rat peroxidase anti-peroxidase. Positive staining appeared only in the nucleus and heterogeneity was common. Results of ERICA were compared with those of dextran-coated charcoal assay (DOC) and were in accord in 87%. Analysis with the Kappa statistic (K) gave a value of .73, p < . O O i , indicating an excellent level of agreement. In a retrospective study of 32 cases with Stage IV disease where the results of endocrine therapy were known and tissue available, a positive ERICA had a predictive value for response or disease stabilization of 81% while a negative ERICA had a predictive value for treatment failure of 87% (sensitivity 87%, specificity 82%, p<.O01). These results indicate that ERICA, a method capable of performance and interpretation at the community hospital level will be a valuable adjunct in enabling prediction of tumor hormone response. Supported by USPHS grant CA23623 from NCI.
7
DIFFERENCES BETWEEN ESTRADIOL- AND MONOHYDROXYTAMOXIFE~ NUCLEAR ESTROGEN RECEPTOR COMPLEXES FROM MCF-7 BREAST CANCER CELLS. V C Jordan,* R K Burr and A C Tate. The University of Wisconsin, Madison, Wisconsin 53792. Tamoxifen (TAM) has proved useful in the treatment of the majority of patients with estrogen receptor (ER) positive breast tumors, however the precise mechanism of action of the antiestrogen is not known. We have investigated the effects of estradiol (E2) and monohydroxytamoxifen (OH-TAM, a metabolite of TAM with high a f f i n i t y f o r the ER) on progesterone receptor (PgR) and nuclear estrogen receptor (ERn) levels in MCF-7 cells Zm v ~ o . E2 (l-lO0 nM) induced up to a 4-fold increase in PgR, whereas OH-TAM (l-IO0 nM) produced only s l i g h t increases in PgR. The concentration and sedimentation characteristics of ERn were determined a f t e r incubation of cells f o r ½, I , 6 and 24 h with either 20 nM [~H]E 2 or [3H]OH-TAM. [~H]Em decreased ERn from 3.4 to 1.2 pmol/mg BNA within 6 h. This has been referred to as "processing" (Horwitz & McGuire, J Biol Chem 253:2223, 1978). [~H]OH-TAM caused an accumulation of ERn to 4.0 pmol/mg DNA within 6 h. The ERn forms were compared on sucrose density gradients. [3H]OH-TAM - ERn sedimented at 5S and [3H]E2 - ERn usually sedimented at 4S. In 20% of experiments, [3H]E~ ~ ERn sedimented as a mixture of 4S and 5S forms, and both were recognized by the monoclonal antibody D547 raised to the ER. We conclude t h a t , in this cell l i n e , differences e x i s t in the i n t e r a c t i o n of estrogens and antiestrogens with the ERn that may help explain antiestrogen action. The monoclonal antibody D547 was generously provided by G L Greene, University of Chicago, Chicago, I l l i n o i s .
8
A POTENTIAL ESTRADIOL-BASED AFFINITY LABEL FOR STUDYING ESTROGEN RECEPTORS IN HUMAN BREAST CANCER. GCA Reiner,* and B S Katzenellenbogen, Department of Physiology and Biophysics, U n i v e r s i t y of l l l i n o i s and College of Medicine, Urbana. I l l i n o i s 61801, We have studied the estrogen receptor interactions of an estradiol-based a f f i n i t y label (EAL). The apparent r e l a t i v e binding a f f i n i t y of EAL f o r rat uterine estrogen receptor measured by competitive binding assay is 70%, where the a f f i n i t y of estradiol (E2) is considered I00%. Incubations of cytosol estrogen receptor preparations from MCF-7 c e l l s or rat uteri with EAL at 21°C resulted in a concentration and time dependent decrease in receptor content measured by exchange assay with 3H-E2. I n a c t i v a t i o n of 80-95% of the receptors (presumed due to covalent attachment) occurs within lh at 21°C by exposure to 5 or 20 nM EAL with 2 nM giving 30% inactivation. The receptor i n a c t i v a t i o n is f u l l y prevented by preincubation with 2000 nME2 indicating that the decrease in assayable receptor content is due to i n t e r a c t i o n at the 2 binding s i t e . Covalent receptor interaction is alsoE~een in whole rat uteri incubated in v i t r o . MCF-7 cells incubated with 20 nM EAL show a loss of cytoplasmic receptor sites and no accumulation of receptors detectable by exchange assay in the nucleus, while 20 nME2 shows nuclear translocation of receptor. The EAL stimulates the growth of MCF-7 cells and increases c e l l u l a r progesterone receptor content, being equipotent with E2 on a molar basis, indicating that i t is a good estrogen agonist. This compound appears to be an e f f e c t i v e a f f i n i t y label and may be useful in elucidating estrogen receptor dynamics and actions in human breast cancer c e l l s . (Supported by Max Kade Fellowship and NIH CA 18119 and CA 31870).
Abstracts
9
AN UPDATE ON THE PROPERTIES OF ANT1ESTROGEN BINDING SITES IN HUMAN BREAST CANCER CELLS. RL Sutherland,* CKW Watts, and LC Murphy, Ludwig Institute for Cancer Research (Sydney Branch), University of Sydney, NSW 2006, Australia. Properties of the high affinity antiestrogen binding site (AEBS) recently described by this group have been further investigated in MCF 7 human breast cancer cells. Differential centrifugation of cell homogenates into nuclear, mitoehondrial, microsomal and eytosol fractions revealed that AEBS was confined almost entirely to the microsomal fraction. Futhermore, when the relative specific activity of AEB5 was compared with a number of marker enzymes in these 4 fractions the profiles for AEBS and NADPH-cytoehrome c reductase, marker for endopiasmic reticulum, were identical. Scatchard analysis demonstrated a single population of binding sites for tamoxifen (Kd = 1.5 + 0.2 nM, C = 4.5 + 0.7 pmol/mg microsomal protein). The interaction between tamoxifen and this site was influenced by changes in pH, ionic strength, temperature and pretreatment with enzymes. Binding activity was reduced following incubation with proteases, phospholipases and lipase. The alkylaminoether side chain of the triphenylethylene antiestrogens appeared to be the major structural determinant of binding to AEBS. Analogues lacking a basic amino group in the alkyl side chain had little or no affinity while some bibenzyl derivatives with aminoethoxy side chains had moderate affinity. It is concluded that the AEBS is located in the endoplasmic reticulum of MCF 7 cells.
10
TAMOXIFEN VS. LYl56758 FOR TREATMENT OF HUMAN BREAST AND PROSTATE CANCER IN VITRO. I. Wiznitzer* and C. Benz, Yale U n i v e r s i t y School of Medicine, New Haven, CT. 06510. We compared the i n h i b i t o r y effects of the new estrogen antagonist LYl56758 (courtesy L i l l y Res. Labs) to tamoxifen (TAM) in 3 human carcinoma cell lines in v i t r o . The three cell lines included the mammary carcinomas MCF-7 and 47-DN, and the prostate adenocarcinoma DU-145. All 3 cell lines demonstrated specific high a f f i n i t y estradiol (E2) binding using a whole cell ligand binding assay. Specific binding was analyzed by Scatchard plots to determine E2 binding sites (fmol/lO6cells) and a f f i n i t y (Kd). Antiestrogen s e n s i t i v i t y was measured by monolayer growth i n h i b i t i o n a f t e r continuous exposure to O.l-lO~M LY or TAM. Differences in antiestrogen s e n s i t i v i t y were found to correlate with E2 binding a f f i n i t y (Kd), but not with absolute number of binding sites. MCF-7 was most s e n s i t i v e , and the prostate carcinoma DU-145 required 6-fold higher doses of LY or TAM to achieve 50% growth i n h i b i t i o n (IDBo).Growth i n h i b i t i n g doses of LY and TAM were comparable f o r each cell l i n e , c o n f l i c t i n g with evidence f o r t h e i r d i f f e r e n t biological effectiveness in immature r a t uteri (L.J.Black, e t . a l . ; 1 9 8 2 ) . We conclude that LY is active against human mammary and prostatic carcinoma cells in v i t r o and that c l i n i c a l evaluation of LY in hormonally responsive cancers is warranted. These preliminary studies also suggest that e f f e c t i v e c l i n i c a l treatment of some endocrine sensitive tumors may require much higher doses of antiestrogen than r o u t i n e l y used to t r e a t breast cancer.
MCF-7 47-DN DU-145
1 ENDOGENOUS BIOLOGICAL FACTORS A F F E C T I N G HORMONE R E C E P T O R BINDING ACTIVITIES. Y M Chen and C B Vaughn, Department of Oncology, Providence Hospital, Southfield, MI 48075. The endogenous biological factors affecting hormone r e c e p t o r - h o r m o n e binding reaction was demonstrated by using pooled cytosols of tumor-tumor and tumor-immature rabbit uterus combinations. The resulted activation and/ or inhibition upon one eytosol by another was evaluated by comparing the observed and calculated values of the mixed cytosol. In an experiment u t i l i z i n g five mixed powderized human breast tumors with relatively low activity, the fresh rabbit uterus (FR) p r e p a r a t i o n greatly activated the fresh tumor (FT) receptors from 1.7 to 9 folds for ER (estrogen receptor) and 12 to 45 folds for PgR (progestin receptor) or from little or n o n - d e t e c t a b l e (ND) activity to high activity for both ER and PgR. A significant a c t i v a t i o n or inhibition for both receptors in tumor-tumor c o m b i n a t i o n was also observed. In a second experiment utilizing thirteen human breast tumors, the FR cytosol caused an a c t i v a t i o n up to 1.4 folds for ER and from i0 to 17 folds or from ND activity to high activity for PgR upon the FT cytosol. A considerable inhibition of the FR ER activity by FT p r e p a r a t i o n was also revealed. Further, in another two experiments u t i l i z i n g two and four day old cytosols from many human tumors, great activation of both tumor ER and PgR activities by FR cytosol in many cases has occurred. It appears that the fresh eytosol with high receptor activity from rabbit uterus and tumor contains a c t i v a t o r and/or inhibitorinactivator for activation and tumor with low or ND activity contains inhibitor for inhibition.
305
12
IO50(~M ) TAM LY 0.8 0.6 2.5 4.0 5.0 3.0
Specific E2 binding fmol/lO6cells Kd(nM) 15 0.] 33 1.3 ]2 4.0
ENDOGENOUS STEROID HORMONES IN BREAST C A N C E R TISSUE; A A J van Landeghem, J Poortman ~ and J H H Thijssen, Department of Endocrinology, U n i v e r s i t y Hospital, 1 0 1 C a t h a r i j n e singel, 3500 GV Utrecht, The Netherlands. D a t a on ~he plasma concentrations of androgens and oestrogens in relation to human b r e a s t cancer are i n c o n c l u s i v e As steroids exert their influence at the cellular level, we thought it more relevant to study the concentration of steroid sex hormones in mammary cancer tissue and in control tissue. A method was d e v e l o p e d to measure androgens and oestrogens in the cytosol and in the nuclear compartment separately. In llJ b r e a s t tissue specimens (including mammary cancer, benign, h y p e r t r o f i c and several control tissues) we m e a s u r e d oestrone (El), o e s t r a d i o l (E2) , dehydroepiandrosterone (D), d e h y d r o e p i a n d r o s t e r o n e - s u l p h a t e (DS) and 5-androstene-3beta, 17beta-diol (Adiol). The c o n c e n t r a t i o n of E 2 was significantly h i g h e r in malignant tissues than in non-malignant, there were no differences in E 2 cocentration b e t w e e n tissues of pre- and postmenopausal women and there was no relation of the E 2 concentration to E 2 - r e c e p t o r content. For E l there were no differences b e t w e e n m a l i g n a n t and n o n - m a l i g n a n t tissues. Neither for DHEA nor for Adiol significant differences were found between m a l i g n a n t eazd n o n - m a l i g a n t tissues. The DHEA-S concentration in the cytosol was significantly higher in n o n - m a l i g n a n t than in m a l i g n a n t tissue. For DHEA and Adiol h i g h concentrations were found in the nuclear fraction, both of m a l i g n a n t and n o n - m a l i g n a n t tissues. The ratio of Adiol to E 2 was identical in normal and m a l i g n a n t b r e a s t tissue.
306
Absn'acts
13ADJUVANT CHEMOTHERAPYAND HORMONAL THERAPY FOR OPERABLE BREAST CANCER WITH POSITIVE AXILLARY NODES. S.E. Rivkin,* W.S. Knight, M. Foulkes. Tumor I n s t i t u t e of Swedish Hospital, Seattle, WA 98104, University of Texas Health Sciences Center at San Antonio, TX 78284, and Southwest Oncology Group S t a t i s t i c a l Center, Houston, TX 77030 Women with operable breast cancer with h i s t o l o g i c a l l y positive a x i l l a r y nodes were randomized on the basis of estrogen receptor status, menopausal status, and number of involved a x i l l a r y nodes (I-3 and >4). All patients were c l i n i c a l l y staged and had a normaT bone scan. Patients receiving a r a d i c a l , modified radical or tylectomy with primary radiation were randomized and i n i t i a t e d on therapy within 42 days a f t e r surgery, CMFVP: Cytoxan (60 mg/M2 po qd]; 5-FU (400 mg/M2 IV w k l y . ) ; Methotrexate (15 mg/M2 IV wkly); V i n c r i s t i n e (0.625 mg/M2 IV wkly. x lO weeks); Prednisone (30 mg/M2 days 1-14; 20 mg/M2 days 15-28; lO mg/ M2 days 29-42 po and discontinued t h e r e a f t e r ) . Tamoxifen: lO mg po bid for one year. A total of 614 f u l l y evaluable patients have been randomized since July 1979. Pre- and Postmenopausal, ERF. EVAL. RELAPSES T r t . #1 CMFVP x l year 145 27 T r t . #2 CMFVP x 2 years 144 21 Premenopausal, ER+ Trt. #3 CMFVP x l year 37 6 T r t . #4 Ooph. + CMFVP 33 2 Postmenopausal, ER+ Trt. #5 CMFVP + Tamoxifen 83 7 T r t . #6 Tamoxifen x 1 year 87 9 Trt. #7 CMFVP x 1 year 85 9 This is preliminary data and the study continues to accrue patients. However, i t appears that estrogen receptor negat i v e patients have a higher relapse rate than estrogen receptor positive patients (p = 0.025). (Supported in part by NCI Grant CA 20319.)
5
A RANDOMIZED COMPARATIVE STUDY OF DOXORUBICIN VS. 4'-EPIDOXORUBICIN IN PREVIOUSLY TREATED REFRACTORY BREAST CANCER. A. Aboud, H. Yap, G. Blumenschein, and G. Bodey. M.D. Anderson Hospital, Houston, Tx. 77030. To compare the therapeutic efficacy and toxicity of doxorubicin vs. 4'-epidoxorubicin: patients with no prior anthracycline therapy or who had no previous response to doxorubicin-containing regimen and have showed no resistance to doxorubicin were randomly allocated to treatment (Rx) with: Rx i, 48-hour continuous infusion doxorubicin 60-70 mg/m2: Rx 2& 4'-epidoxorubicin 48-hour continuous infusion 90-105 mg/m ~, or Rx 3, 4'-epidoxorubicin 90-105 mg/m 2 bolus injection. In this continuing study, 36 patients have thus far been entered, and the results are: ~x 1-9 pts. evaluable and 1 had achieved CR (14%), 2 pts. had less than PR (24%), and 3 pts. had stable disease (38%) and the remainder had PD. Rx 2-11 pts were evaluable: 5 PR (38%) and 1 P D (8%). Rx 3-10 pts. were evaluable: 5 PR (50%), 4 SD (40%), and i PD (10%). All pts. treated had normal ejection fraction and grade 1 cardiac toxicity or less on endomycardial biopsy. The median doses of prior doxorubicin were 405 mg/m 2 (range 310-450), 395 mg/m 2 (range 350-450), 350 mg/m 2 (ran~ 40-450) for Rx I, 2 and 3, respectively. To date, the additional median dose of doxorubicin was 365 mg/m 2 (range 120-540) for Rx I; the median doses of 4'-epidoxorubicin was 305 mg/m 2 (range 90-508): and 180 mg/m 2 (range 90-540) for Rx 2 and 3. Three pts. (i from each Rx arm) developed evidence of cardiac dysfunction following additional 360 mg/m 2 of doxorubicin and 485 mg/m 2 of 4'-epidoxorubicin continuous in 190 mg/m 2 bolus. All three pts. had prior doxorubicin 450 mg/m 2. GI toxicity was less marked with continuous infusion 4'-epidoxorubicin and doxorubicin, and there were no difference in hematologic toxicity between doxorubicin and 4'-epidoxorubicin. In conclusion, these preliminary results suggest comparable activity between doxorubicin and 4'-epidoxorubicin.
OF ADJUVANT CYTOTOXIC, ENDOCRINE AND I~MUNOLOGIC 1 4 T EVALUATION H E R A P Y FOR STAGE IT BREAST CANCER PATIENTS. NH Gordon*, CA Kubay*, SP Guyton*, OH Pearson +, JS Marshall +, WL McGuire ~ and Participa$ing Investigators. From The Departments of Surgery and Medicine + , Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44106 and The University of Texas Health Science Center ~, San Antonio, Texas 78284. A prospective, randomized study of adjuvant therapy with cyclophospbamide, methotrexate, 5-fluorouracil (CMF); CMF with Nolvadex (CMFN); and CMFN with Bacillus CalmetteGuerin vaccination (CMFNBCG) was carried out with 312 women having Stage II breast cancer. Accession of patients spanned 5 years ending June, 1979. Patients were stratified according to the number of positive lymph nodes PLN (1-3 and 4 or more) and the estrogen receptor (ER) content (ER- if EN < 3.0 fm/mg; ER+ if ER > 3.0 fm/mg). The data were analyzed using the Cox proportional hazards linear model with the Breslow modification for tied data. Treatment regimen (TR), tumor diameter (TD), body weight and height, number of PLN treated as a continuous variable, ER value treated as a dichotomous variable, race, age, menopausal status and weight-height index were variables. PLN (p < .0001), TD (p = .010) and TR (p = .017) were the most important indicators of disease-free survival. ER appeared less important. After controlling for PLN and TD, no significant difference was found between CMFN and CMFNHCG. However, the addition of Nolvadex to CMF (i.e. CMF vs. CMFN & CMFNBCG) signific@ntly increases the diseasefree Survival interval (p = .013). Statistical interaction appeared between TR and ER and between TR and menopausal status. The addition of Nolvadex to CMF appeared to benefit ER+ patients (p for TR to enter the model is .030); whereas, it is of no benefit to ER- patients (p for TR to enter is .59). Moreover, addition of Nolvadex to CME benefited postmenopausal patients (p to enter is .055l but only marginally benefited premenopausal patients (p to enter is .12). We conclude that the addition of Nolvadex to CMF treatment benefited ER+ and postmenopausal patients.
16
P~3LIFERATIVE A C T M T Y AND ESTIKDGEN RECEPTOR IN HUMAN Pp,MARY BREAST CANCER. P.F. Conte", A. Alama", R. Favoni", G. Fraschini', B. Drewinko'. Istituto Nazionale Ricerca Cancro", Genova 16132, Italy and MD Anderson Hospital and Tumor Institute', Houston, Texas 77030. The proliferative activity of ttmottrs can be an important parameter to precise the patients' prognosis and to select the approl~date treatment. In fifty cases of primary breast cancer subnitted to radical surgery or surgical biopsy, the thymidine labeling index (LI) and the estrogen re ceptor status (ER) were determined. The median LI for the-total population was 1.11% (range 0.68-8.61%) ; the median LI was I .2% (range 0.68-5.99%) for ER + ttmmurs and 1.62% ~ange 0.94-8.61%) for ER- ttm~urs. In view of their worse prognosis, the subset of patients with ER- inoperable breast cancer was treated with diethylstilbestrol (DES) Img total dose p.o. daily for 4-7 days. The aim was to recruit the noncycling tturour cells into the proliferative pool in order to increase their sensitivity to a subsequent administered polichemotheraty (CT). Serial tru-cut tt~rour biopsies were performed before, during DES a ~ i n i s t r a t i o n and after CT. Turnout recruitment was evaluated by LI end the primer DNA dependent DNA polymerase (PDP) , which expresses the percentage of actively cycling cells indipendent of their pesition in the cell cycle. The mean LI was I. 64% (range 0.94-2.57%) before therapy, 4.29% (range 1.10-11.819 during DES and 0.95% range 0.74-I .35%) after CT. The mean PDP index was 2.98% (range 1.71-4.76%) before theralmy , 9.55% (range 4.36-20.74%) during DES and 1.59% ~ange 0.872.42%) after CT. These preliminary data suggest that low doses of oral estrogens are able to stimulate the proliferative activity of ER- breast cancer and that the proliferating cancer cells can be inhibited by subsequent CT. (supported by grants 8200441.11-CNR-Italy,CA23272,NCI,USA).
Abstracts
17
CLINICAL STUDY NF STEROID HORMONERECEPTORS IN CHINESE PATIENTS WITH BREAST CANCER. T J L i u , * C W Chi and L H Wu, Division of General Surqery, Department of Surgery, Veterans General Hospital, Taichung, Taiwan, R.O.C. The d i s t r i b u t i o n and the prognostic value of cytosol estrogen receptor(ERc),progesterone receDtor(PgR),androoen receptor(AR) and intranuclear estrogen receptor(ERn) were studied in 230 Chinese patients with breast cancer. Positive incidence of ERc was 42.17%,PgR was 43.12%, ERn was 37.75% and AR was 51.72%. The r e l a t i o n s h i p of receptor levels to menstrual condition demonstrated an even d i s t r i b u t i o n of PgR and AR, however, postmenooausal women had higher ERc and ERn value than premenopausal women. The results of endocrine theraoy response rate in ERc(+) patients was 50% (13/26), ERc(-) was 25% (5/20), PgR(+) was 83.33% {lO/12) and PgR(-) was 17-.64% (3/17). When beth receptors were positive in nat i e n t s , the response rate was 90% ( 9 / I 0 ] and when negative was 14.28% ( I / 7 ) . The level between ERc and PgR showed a l i near correlation (p<.OOl). ERn and AR determination combined with ERc and PgR r e s p e c t i v e l y did not improve predict a b i l i t y of response to therapy. In v i t r o tissue culture study have demonstrated that ERc(+) cells decreased s i g n i f i c a n t l y (D<.05) a f t e r estrogen priming. The PgR o o s i t i v e incidence increased , however, the mean value of PqR did not change from pre and post culture status. Cells from 3 of 4 patients with ERc(+) PgR(-) that showed an increase in PgR levels a f t e r estrogen priminq in culture benefited c l i n i c a l l y from endocrine therapy.Another patient whose cells remained in the negative PgR range f a i l ed to respond. We have concluded that e f f e c t of estrogen priming in v i t r o on PgR formation may provide a better method f o r prediction the therapeutic response of hormone manioulation in breast cancer patients.
18
9
INSULIN EFFECTS ON METHOTREXATE POLYGLUTAMATE (MTXGn) SYNTHESIS IN CULTURED HUMAN BREAST CANCER CELLS. RL SCHTLSKY* and F ORDWAY. Research Service, Harry S Truman VA Hospital and Department of Medicine, University of Missouri Health Sciences Center, Columbia, Missouri 65212 A number of human tissues, includin~ breast cancer cells, synthesize polyglutamate derivatives of methotrexate (MTX). These compounds bind to dihydrofolste r e d u c t a s e are retained intraeellularly, and mrolon~ the cytotoxle effects of the drug. Previous studies have demonstrated that insulin enhances transport of MTX into MC~7 cells and increases the susceptibility of these cells to MTX toxicity. We have therefore examined the effect of insulin on MTXGn synthesis in two human breast cancer cell lines, MCF7 and MDA-MB-231. Cells were oasssged 3 times in media + 10% charDoal-treated fetal calf serum prior to exposure to 2.5xi0- M insulin for 48 hour~. Cells were then incu bated another 24 hours with 2uM [ H ] MTX and insulin and were analyzed for MTXGn content by NPLC. After insu!in treatment, MCF7 cells contained 25.0 + 2.8 nmol/R MTXqn compared to 19.2 ~ 1.9 nmol/z in control cells (p <0.O25) and MDA-231 cells contained 4.26 + .47 nmol/g MTXNn compared to 3.44 + .63 nmol/~ MTXGn in control (p
20
307
5'-NUCLEOTIDE PHOSPHODIESTERASE ISOZYME-V AS A MARKER FOR LIVER METASTASES IN BREAST CANCER PATIENTS. K C Tsou,* R H Creech, W Y Inouye, and K W Lo, the University of Pennsylvania School of Medicine, Philadelphia, PA 19104. A two year prospective study testing 258 breast cancer patients for the presence of 5'-nucleotide phosphodiesterase isozyme-V (5'-NPD-V) as a marker for liver metastases was undertaken. Despite the difficulty associated with such a study in obtaining data from biopsy (only 12 patients) and autopsy (only 18 patients), the 5'-NPD-V test correctly predicted confirmed liver metastases in 39/41 patients (95%). Of this group, 25 patients had abnormal liver scans at the time the 5'-NPD-V test was positive (64%). In 11/39 patients 5'-NPD-V was found postive before liver scans. The majority of patients had their 5'-NPD-V fluctuate between positive and negative during follow-up. While such transiently positive values may be related to treatment, conservatively they should be interpreted as liver proliferation until confirmed otherwise. Throughout the study only seven patients with nonmalignant hepatic diseases had consistent positive values (2.7%). As an indicator of liver metastases 5'-NPD-V is more specific than other liver function tests. It is also important to note that fourteen patients received early chemotherapy because attention was directed towards the diagnosis of liver metastases by this test. Isoelectric focusing of 16/18 breast cancer patients' sera for 5'-NPD also found a common isozyme with pI = 5.5 of this group. Whether this is a new marker related to breast cancer deserves further study. (This work supported by NCI grant CA25376).
DEMONSTRATION OF COLLATERAL SENSITIVITY IN PRIMARY HUMAN BREAST CANCER. D D Von Hoff, G Clark, C K Osborne, 3 F Sandbach, The University of Texas Health Science Center, San Antonio, Texas 7828% Austin Diagnostic Clinic, Austin, Texas, 78765. The term collateral sensitivity describes tumor cells which are resistant to one drug but which exhibit sensitivity to another drug. The study of collateral sensitivities of human tumors might lead to more optimal design ol drug combinations. Utilizing the human tumor cloning system, we have tested 232 primary breast cancers for sensitivity to Adriamycin, 5Iluorouracil, methotrexate, cyclophosphamide, vinblastine, mitomycin C, mitoxantrone, and Bisantrene. For selected pairs of drugs the following collateral sensitivities were noted. n Resistant to % with collateral sensitivity to_(drug) 5FU 6 (CTX) 77 50 5FU lO (MTX) 70 Adria 13 (SFU) 77 Adria 9 (CTX) 36 Adria 14 (Mito C) 21 Adr ia 10 (Bis) 10 Adria 10 (DHAD) 32 5FU 22 (VLB) 27 MTX 26 (VLB) 53 Adria 17 (VLB) 23 5FU 17 (Mito C) I8 5FU 17 (Bis) 24 MTX i7 (Mito C) 18 CTX 17 (DHAD) The drugs most frequently utilized to treat patients with breast cancer (CMF or CAP) have infrequent collateral sensitivity to other drugs in the combinations. Thus, these drugs might not be optimally suited for use in combination. The results do suggest that use o£ vinblastine or mitomycin C in combination with these agents should be considered for clinical trial. Supported by Medical Oncology Program Project POl CA 30195.
308
Abstracts
2 1 EPITHELIAL FOCUS ASSAY FOR DETECTION OF ALTERED MAMMARY EPITHELIAL CELLS FROM BALB/c MICE EXPOSED TO LOW DOSES OF DMBA AND/OR GAMMARADIATION. *LM ADAMS AND RL ULLRICH, THE UNIVERSITY OF TEXAS SYSTEM CANCER CENTER, SMITHVILLE, TEXAS 78957 AND OAK RIDGE NATIONAL LABORATORY, OAK RIDGE, TENNESSEE, 38730.
22
Current assays for estrogen receptors (ER) in cancer cells do not distinguish hormone binding by clonogenic cells from that by non-clonogenic cells. Because receptor status of clonogenie cells may differ from that of the entire tumor, yet be more relevant to therapy, we developed a method to detect hormone binding by clonogenic cells, employing cell "suicide" by labelled hormone.
Carcinogen altered e p i t h e l i a l cells have been isolated from mammary glands of mice exposed to low doses of 7,12dimethylbenz(a)anthracene (DMBA) and/or to 137Cs~ r a d i ation. An e p i t h e l i a l focus (EF) assay was used to ident i f y cells which exhibited an increased p r o l i f e r a t i v e c a p a b i l i t y in v i t r o . Under conditions non-permissive for normal ( c o n ~ o ~ m m a r y cell growth, carcinogen exposed cells formed e p i t h e l i a l foci which p r o l i f e r a t e d in primary culture f o r at least 4 wks (EF). Some of these EF could be subcoltured more than 3 times (EFs). Eight adult mice per treatment were exposed to one of the following: 50 tad, I00 rad, 75~g DMBA ( i . g . ) or 50 r a d ~ 7 5 ~ g DMBA ( i . g . ) . Mammary glands from each mouse were enzymatically dissociated at 24 hr, I wk, 4 wks or 16 wks a f t e r treatment. Cells were plated at 5xlO4/60mm dish in complete Ham's F-12 or MCCoy's 5A ~ insulin (10~g/ml). At 24 hr, I wk and 4 wks EF were obtained a f t e r DMBA but not a f t e r r a d i ation. At 16 wks, EF were obtained in approximately equal frequencies a f t e r radiation and/or DMBA. Of these f o c i , those reaching- 2cm in diameter were subcultured. Percent EFs were for 50 rad (0%), I00 rad (40%), DMBA (75%) and 50 rad + OMBA (100%). This difference in subc u l t u r a b i l i t y given similar EF frequencies suggests a q u a l i t a t i v e difference in the focus forming c e l l s . Furt h e r , these data show that cells exposed t o Y r a d i a t i o n as well as to DMBA e x h i b i t enhanced p r o l i f e r a t i o n in v i t r o but that a longer time in situ following exposure is important for the expresslon of radiation altered c e l l s .
23
SUPPRESSIONOF PROLACTIN (Prl) GROWTH STIMULATION IN HUMAN BREAST CARCINOMA BY BUSERILIN (Bus) AND PERGOLIDE (Perg) IN VITRO. I. Wiznitzer* and C. Benz, Yale Univers i t y School of Medicine, New Haven, CT. 06510. We studied the LHRH analogue buserilin (courtesy Hoechst) and the dopamine agonist pergolide (courtesy L i l l y Res. Labs) to determine whether these two drugs,with known prolactin antagonistic actions at the level of the p i t u i t a r y , have peripheral a c t i v i t y on a human mammary carcinoma cell l i n e , 47-DN. 47-ON cells showed a bell shaped, growth stimulatory response to Prl when grown in chemically defined medium (ITS, Collaborative Res.). Human Prl (courtesy NIAODK) produced 50% growth stimulation at a concentration of I00 ng/ml. Growth i n h i b i t o r y and s t i mulatory effects were determined by cell counts a f t e r 7 days of continuous exposure to Bus (O.l-lO ~g/ml) and Perg (O.I-IO~M) in the presence or absence of Prl I00 ng/ ml. Growth stimulation of Prl was prevented by 0.I ug/ml Bus and O.I~M Perg. Bus and Perg in the absence of Prl had minimal growth i n h i b i t o r y effects. These preliminary studies suggest that Bus and Perg may have peripheral growth i n h i b i t o r y effects when used in the treatment of breast cancer, and that t h e i r prolactin antagonistic act i v i t y is not r e s t r i c t e d to i n h i b i t i o n of p i t u i t a r y hormone release.
CYTOTOXICITY ASSAY FOR ESTROGEN BINDING OF HUMAN TUMOR CLONOGENIC CELLS. Dana BW, Oregon Health Sciences Univ. Portland, OH 97201
Cell suspensions from two human tumor cell lines, and four primary human cancers (breast-3; ovary-l) were exposed for 60' to 10-8M 3H-estradiol (E2) in the presence or absence of unlabelled 10-6M diethylstilbestrol (E2+DES) in charcoal-stripped media. Cells were washed twice with stripped media, then plated routinely in the soft-agar assay using unstripped media. Colonies () 20 cells} were counted at 14-21 days. Reduced clonogenicity (< 80% of controls) in the presence of E2, which was abrogated by DES, was seen in 4/6 cell suspensions, including MCF-7 breast cancer cells and 3/3 primary breast tumors. No change in clonogenicity was seen in Colo 205 colon cancer cells or a primary ovarian tumor. Of the cells showing reduced elonogenicity, 3/4 contained cytoplasmic ER by standard assay; one primary breast cancer contained no ER. No reduced elonogenicity was seen in MCF-7 cells when they were kept at 4Oc during the E2 incubation. We conclude that E2-induced cell "suicide" may allow detection of estrogen binding by clonogenic cells of human tumors.
24
COMBINED EFFECT OF CIS-DIA~INEDICHLOROPLATINUM (CIS-DDP) AND HYPERTHERMIA (HT) ON TA3Ha MOUSE MAMMARY CARCINOMA CELLS M.S. Murthy, J.D. Travis, H.N. Keer, J.D. Khandekar, E.F. Seanlon. Evanston Hospital/Northwestern University Medical School, Evanston, IL 60201 Cytotoxicity of Cis-DDP on tumor cells is enhanced at elevated temperatures (41-43°C). However, it is not known if a combination of HT and Cis-DDE is of benefit in treating tumors that are resistant to either treatment alone. Therefore, we studied the effect of Cis-DDP and HT on TA3Ha parental cells and metastases at the renal lymph node (RLN) and lumbar lymph node (LLN) areas of mice injected with TA3Ha cells in the tail. The cells were treated with varying concentrations of Cis-DDP at either 37°C or 43°C, and their colony forming ability in soft agar determined. Cis-DDP TA3Ha
~ 37~C 43°C
O , 89±6 42±2
0.i 70±4 26±4
0.2 46±3 23±3
0.4 15±3 17+2
1.0 19±2 16±3
RLN
37°C 43°C
23±2 9±2
12±1 9±2
9±1 6±2
7±2 7±i
5±i 4+1
LLN
37°C 43°C
26±i 24+2
22±I 17±2
21+2 11±4
15±2 9±i
5±1 5±2
* Numher of colonies: mean iS.D. The results showed that the cells resistant to HT were resistant to Cis-DDP also. However, when the treatments were combined, the cytotoxicity was augmented especially against the cells moderately (TA3Ha parental) and highly resistant (LLN) to HT and Cis-DDP. Combination treatment offered only marginal benefit over HT alone on heat sensitive (RLN) cells. This beneficial effect depends on the concentration of CisDDP. In vivo studies have confirmed these findings. Supported by Peter Garard Mem. Fund,Butz Found.,& Dee&Moody Funds.
Abstracts 5 C O M B I N E D EFFECTS OF ALTERATIONS IN ESTRADIOL AND DIETARY LIPID ON RAT MAMMARY TUMOR GROWTH AND THE PROLACTIN BINDING CAPACITY OF HEPATIC MICROSOMES. W.T.Cave,Jr.* and J.J. Jurkowski,Endocrine Unit & Cancer Center, Univ. of Rochester School of Med.,St. Mary's Hospital, Rochester, N.Y. 14611. The purpose of these studies was to determine the effect of quantitative differences in dietary lipid on the prolactin (PEL) binding capacity of tissue obtained from animals maintained on varying levels of estrogen and to observe how such alterations might be correlated with mammary tumor growth. In an initial experiment, female Buffalo rats were divided into 4 treatment groups: a)ovary intact, b)ovariectomized(ovex), c)ovex + .2mg estradiol valerate(E.V.) given subcutaneously every i0 days, d)ovex + 2mg E.V.; and placed on either a 0.5% corn oil diet(LF) or a 20% corn oil diet (HF). Ten weeks later the animals were killed and their hepatic microsomes were found to have the following mean BRL binding capacities (femtomoles/mg protein): LF: a) 27.5, b)ll.5, c)53.7, d) 42.8; HF: a)46.3, b) 21.1, c)90.3, d) 66.9. In a subsequent experiment, female Buffalo rats were again assigned to the same HF and LF diets and, following the sequential administration of the carcinogen nitrosomethylurea, were further divided into 4 treatment groups: a)ovary intact, b)ovex, c) ovex + .04 mg E.V., d)ovex + .4 mg E.V. All animals were killed when their mammary tumors exceeded 2 cm. in diameter with the following results for mean age of death (days): L F: 0 1 4 9 , b) 175; c)147, d) 160; H F: a)140, b) 172, c)137, d) 153; and tumor number: LF: a) 3.2, b)0.9, c)3.8, d) 2.2; HF: a) 5.9, b) l.9, c)4.2, d) 2.6. We conclude from these data that both insufficient and excessive estrogen can inhibit optimal growth in this tumor model regardless of dietary lipid, but that this inhibition of tumor growth is greatest in the LF group. Additionally, the hepatic mierosome data suggest that the observed differences in mammary tumor growth may be a reflection of dietary and estrogenic effects on PRL binding.( NIH GR# CA30629)
27
T-ANTIGEN IN BENIGN AND MALIGNANT BREAST TUMORS. AD Keramopoulos,* 1st Dept. of Obstetrics and Gynecology, University o[ Athens, Athens, Greece. Sera of normal individuals (AB- blood group), known to contain anti-T antibodies~ were used for indentiIication of T antigen on breast tumors. Immunoperoxidase procedures were employed for demonstrating the bound anti-T antibody. All malignant breast carcinomas (2g cases) were found to express the T antigen. Similarly adjacent areas of atypic ceils, presumably in a premalignant stage, were also shown to express T antigen. In contras% benign breast tumors (27 cases) were devoid of such an antigen on their surfaces. Isolated anti-T antibodies from AB serum, following absorption and elution from neuraminidase-treated red ceils, were as efficient in T cell antigen identification as the whole AB serum. The antibodies were found to belong primarily in the IgM class. These studies strongly suggest that this marker (T-antigen) can be used for immunohistologic identification of breast carcinomas and their differentiation from benign tumors. Moreover~ they suggest that anti-T antibodies may have useful applications in the early diagnosis of tumors by radiographic or radioisotopic techniques as well as their t r e a t m e n t following targeting and conjugation of anti-T antibodies with chemotherapeutic agents or toxins. Work in these areas is now in progress.
26
28
309
DISSOCIATION KINETICS OF THE 8S ESTROGEN RECEPTOR. L e V e r n e C. L e R o y * ¢ J o h n G. C h o s a y , A n d r e w C. H u a n g , B o r g e s s M e d i c a l C e n t e r , Kalamazoo, Michigan 49001. The d i s s o c i a t i o n constants o f 4S a n d 5S e s trogen receptor have been reported, b u t t h e 8S dissociation value is still in doubt. The e s t r o gen receptor e x i s t s in s e v e r a l d i f f e r e n t forms (i.e. 8S, 4S, a n d 5S). The majority of c y t o s o l s from human breast cancer contained b o t h the 8S a n d t h e 4S f o r m s . T h e n a t i v e 8S f o r m is p r e d o m i n a n t ( g r e a t e r t h a n 60% f r o m o u r d a t a ) ~ its contribution to the d i s s o c i a t i o n rate, using scatchard analysis w i l l be s i g n i f i c a n t . Using Sepharose with attached heparin, a supporting matrix is f o r m e d to s e l e c t i v e l y bind and immobilize the 8S r e c e p t o r . This provides a simple and easily controlled in v i t r o m o d e l f o r s t u d y i n g (H a ) estradiol dissociation kinetics f r o m t h e 8S e s t r o gen receptor. The dissociation rate constant (k = .031 m i n -~) w a s m e a s u r e d by e x c h a n g e w i t h unlabeled estradiol at 4OC. The dissociation measurement was corrected for r e s i d u a l 4S a b s o r p t i o n to the m a t r i x a n d r e l e a s e of the 8S m o l e c u l e from the matrix. T h e h i g h salt c o n c e n t r a t i o n , molybdate, and temperature have a noticeable e f f e c t on the 8S d i s s o c i a t i o n rate. The dissocia t i o n r a t e for the e s t r o g e n receptor, derived from the scatchard a n a l y s i s m a y be i n v a l i d a t e d by the existence of two r e c e p t o r s with different dissociation rates.
COMPARISION B E T ~ ] I ~ CONCE~fRATION OF TRACE ELEME}~fS IN NORMAL AND NEOPLASTIC HUMAN BREAST TISSUE. S.L.Rizk and H.H. Sky-Peck*: Rush Presbyterian-St. Luke's Medical Center, Chicago, lllinois~ 60612. Histologically normal and neoplastic human breast tissues obtained from 18 patients at the time of masteetomy were homogenized (2@0mg/ml) in distilled water and 5ul aliquots dried on formvar films prior to analysis for trace elements by energy dispersive X-ray fluorescence. The elements determined were calcium, vanadium, copper, zinc, iron, chromium, manganese, nickel : selenium, molybdenum, bromine, rubidium, strontium, mercury, arsenic, and lead. In general, significantly large increases (P
Abstracts
310
29
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IN VITRO SYNERGISM BETWEEN AN ANTINEOPLASTIC AGENT DERIVED FRO~ BOVINE AORTA (A-10) A/~D ADRIAMYCIN (ADR) OR RADIATION (RT) IN MURINE TA3Ha MAMMARy ADENOCARCINOMA (MCa).*M Haid ~ , R Eisensteln'',J Cohen',G Mazarieges',S Murtby',J Travis', S G Prasad',R Garces" ('= Evanston Hosp./Northwestern Univ. 2650 N. Ridge, Evanston IL 60201;''=Mt. Sinai Med. Ctr., Milwaukee WI 53211). Supported by Dee & Moody Fund, grant # 3706. A-10 is an aortic extract of molecular weight 6N-10K Daltons which contains an antiprotease probably identical to Trasylol (T) as well as antineoplastic and antineovascnlariaing activity, A-10 was tested on TAgNa zells Jn tJs~la culture (TCU) and found to have a dose response curve (50 mcg/ml = optimal).Using a weighted score reflecting the # and size of tumor colonies grown in TCU, A-10 (50 mcg/ml) was tested in two runs (A and B) singly and with ADR (0.25 mcg/mi). The mean scores and analysis of variance were: CONTROL ADR RUN A 1757 718 RUN B 219 23
A-IO 1331 91
ADR + A-10 499 12
ADR + A-10 versus (vs) ADR ALONE A-10 ALONE p < 0.002 p < 0.0005 p < 0.002 p < 0.0005
A-10 was tested alone and with 60Cobalt RT (7500 fads was the LD 5 _0 in our system and thus the dose used). The mean scores and analysis of variance were:
RUN A RUN B
CONTROL RT 173 37 159 56
A-10 76 73
RT + A-10 19 27
-
coneentra
RT + A-10 vs RT ALONE A-10 ALONE p < 0.002 ~ < 0.0005p < 0.002 p < 0.0005
T had no tumor inhibiting effect, ADR + A-10 were more effective than either single agent alone.A-10 potentiated RT by a factor of 1.47 and 1.51 in runs A and B respectively. Anima~ studies are ongoing.
2
IDENTIFICATION OF OCCULT BREAST CANCER BY TWO DIT~IENSIONAL PROTEIN ELECTROPHORESIS. K.M. Anderson,* P. Bonomi, J. Baranowski, D. Pessis, S.G. Economou. Depts. of Medicine, Surgery, Urology & Biochemistry, Rush Medical College, Chicago, II. 60612 The identification of patients with metastases from an occult primary breast carcinoma is important because frequently significant palliation can be achieved. A 60 year old woman presented with 3+ left leg" edema, bilateral ing`uinal masses, bilateral ureteral obstruction, and multiple sclerotic bone lesions. Extensive search for a primary, including` mammography revealed no abnormalities. Biopsies of the groin masses were interpreted as undifferentiated malignant neoplasm, and electron microscopy was consistent with an epithelial tumor. The estrog`en receptor level was 696 and the progesterone receptor level was 35 fro/rag` protein. Comparison of Coomassie blue R 2SO-stained proteins from a biopsy of the groin analyzed by two-dimensional protein electrophoresis with representative patterns from identified breast, uterine and ovarian carcinomas indicated the greatest homolo~'y w i t h primary breast eancer. Tamoxifen was initiated. Nine weeks later the left breast became red and edematous~ leg edema remained, anemia developed, and cancer cells were found in the bone marrow. Tamoxifen was stopped, and CMFF begun. Breast erythema and leg edema cleared, hemoglobir}ros% and a 3 x 3 em mass became evident in the left breast, which biopsy showed infiltrating dueta] carcinoma. The pattern of proteins found on 2Delectrophoresis of the metastasis, the very high ER and positive PR, sclerotic bone lesions and response to chemotherapy were all consistent with the initial diagnosis of metastatic breast cancer. Further application of 2D-protein eleetrophoresis to the problem of histologically indeterminate metastatic cancers is needed to assess its ultimate usefulness, which appears very promising. (Supported by CA-3~]05 from the NPCTF, NCI).
FROZEN SECTION DIAGNOSIS (FSD) IN 4436 CONSECUTIVE~REA&T ~IOPSIES (i.I.1978-12.31.Ig82}: ACCORACyEVALUATION.B.Ghiringhgl]o.L.Fessia, G-3otta,R.Arisio,G.Gordini,V.Aimone~ Servizio di Anatomia Patologica 0 Ricerche Cliniche,Osped~le Spec.Ostetrico Ginecologico SantIAnna , 10126 7orino , Italy. The diagnosis of 4436 consecutive breast biopsies examined by Frozen section were checked against the deflnltive pathological report.On the whole aeries (1389 cancers and 3047 benign lesions),FSD was correct (CO) in 4284 cases {
[email protected]%) and fa]sely n~gative (FN) in 74 {l.66%);the diagnosis was deferred (DO) to paraffin section in 78 (1,75%);n0 false pos i t i v e occurred. Excluding 00 from computation,the predictive value for posit}co r~sults I~as I~C~Ca~¢'f¢~ n~gative results 37.5%; the speciflcity was i00~, the sensitivity g4.6~ and accuracy 3B 2~, In the 82 minimal in situ cancers(CIS)(26 duct~1 and 56 lobular),FSD s e n s i t i v i t y was 10.37% (9 CO, 10 DO, 83 FN).In the gl minimal invasive cancers (invasion ~ 10% or mean diameter ~ 0.9 cm),FSO s e n s i t i v i t y rose to 80.21% (73 CO, 10 DO, 8 FNJ. In hhe 12~5 non minlm~l invasive cancers s e n s i t i v i t y was 39.42% (1200 CD, 4 00, 3 FN). A revision of DD shows that the greatest d l f f i c u l t y ~as ercountered in papil]ary leslons (pBpilloma,cistoadenoma,florid epitheliosis) and in sclerotic lesions with ~pitheliaI p r o l i f e r a t i n g areas ( i n f ~ i t r a t i n g ep~the]iosis,sclerosing p~pilloma);in these lesions,Fine and histochemistry is often needed for diagnosis.
cytological de~ai]s
In FN diagnosis the main problem were lobular CIS and microductal CIS, because they can easl]y escape macroscoplcal sampling . Preoperative need]e |ocalization or intraoperative spec~nen radiogra~y (nEither used in ~ur series) could perhaps p a r t l a l l y decrease FN diagnosis; because of sampling lim~tatic:n of tke technique and ] i m i t for microscopic intErpretation,the surgeon (and the patient) must consider a FSD as p r e l i minary ,since a small percentage of FN is inevitable .
Abstracts
33
5
BREAST CANCER PROGNOSIS AND DETECTION OF THE FIRST SYMPTOM. *P. Cohen, Department of Clinical Epidemiology, Tel Hashomer 52621, Israel. In an epidemiological study on female breast cancer, conducted in Israel from 1960 through 1966, 2741 patients were found presenting with a lump as their first symptom. Time seriesanalysis revealed a clear seasonal pattern in the symptomatology of the disease.Peaksoccurred in the spring, troughs in the autumn. Analysis by age and spread of the tumor showed that the pattern was confined primarily to a subgroup of patients under 55 years of age with a non-localized tumor at time of diagnosis. The repetative character of the seasonaIity in this subgroup could be shown by graphing the monthly distribution as 3month moving averagesfor each of the sevenyearsstudied. To maintain such a rhythmic pattern the input of synchronizing environmental physical stimuli is necessary.As these stimuli may havedifferent effects when acting at different times along the circannual scale a survival study was conducted according to the period of the year of patient detection of a mass in the breast. A statistically significant median survival difference of 33 months was found for the two consecutive half year periods with the highest self-detection differences: March-August (274 cases) versus September-February (211), and April-September (268) versus October-March (217), after a follow-up of minimal 10 years (p = 0.013, and 0.028 respectively).Analysis by quarters revealed a steady decreaseof median survival from April-June through JanuaryMarch (97.9, 70.9, 61.6 and 48.1 months) suggesting time related response. Furthermore, comparing subgroups under 55 years of age with patient detection time of first symptom known versus unknown, the latter had a better survival. This holds for localized (69.6% vs. 75.6%, p = 0.024) as well as for non-localized tumors (41.2% vs. 48.0%, p = 0.050). Therefore, in composing homogenous therapeutic trial groups, detection particularsshould be taken into account.
POST M A S T E C T O M Y P R O P H Y L A C T I C VERY L O W DOSE R A D I A T I O N M A Y P R E V E N T M E T A S T A T I C BONE D I S E A S E IN B R E A S T CANCER. * A . H e r c b e r g s , A. W e r n e r and H. Brenner, The Dept. of Oncology, Sheba Medical Center, Tel-Hashomer, Israel.52621 A r e t r o s p e c t i v e study of 118 women with m e t a s t a t i c breast c a n c e r to m u l t i p l e bone sites was m a d e c o v e r i n g the years 1971-1981. 62 women (Group A) had r e c e i v e d our standard post m a s t e c t o m y irradiation for Stage II b r e a s t carcinoma (310 reds x 3 w e e k l y for three weeks) which included a parasternal portal. 56 women (Group B) had not r e c e i v e d a paresternal portal as part of their i m m e d i a t e postm a s t e c t o m y management. Those who had r e c e i v e d the parasternal i r r a d i a t i o n had s i g n i f i c a n t l y fewer m e t a s t a s e s in the dorsal v e r t e b r a e D5,6,7,8, w h i c h had of course been i r r a d i a t e d unintentionally. In G r o u p A 8/62 (13%) d e v e l o p e d m e t a s t a s e s in one or m o r e of the dorsal v e r t e b r a e D5678, w h e r e a s in G r o u p B 29/56 (52%) d e v e l o p e d metastases. All other m e t a s t a t i c skeletal sites were c o m p a r a b l e in their m e t a s t a t i c d i s t r i b u t i o n and showed no significant difference. The dose of r a d i a t i o n (from a 250 kv. Phill~ps machine) which the "protected" v e r t e b r a e r e c e i v e d was c a l c u l a t e d to be b e t w e e n 1 2 0 0 - 1 4 0 0 reds over three weeks. This is a very l o w dose. This would a p p e a r to be the first report in the l i t e r a t u r e that i n d i c a t e s that very l o w dose r a d i a t i o n a d m i n i s t e r e d a f t e r m a s t e c t o m y for p r i m a r y m a m m a r y c a r c i n o m a can p r e v e n t the o u t g r o w t h o f p o t e n t i a l distant bone metastases.
34
36
311
OPTIMAL TIMING OF RADIATION AND CHEMOTHERAPY IN THE PRIMARY TREATMENTOF BREAST CANCER. PL Weiden,* AB Einstein, and R Rudolph, The V i r g i n i a Mason Medical Center, Seattle, Washington 98111 An adverse e f f e c t of radiotherapy (RT) on disease free survival following mastectomy has been reported f o r patients (pts) receiving adjuvant chemotherapy (chemo) including cyclophosphamide, methotrexate and f l u o r o u r a c i l (CMF). RT has been reported both to and not to decrease the dose of chemo administered. Delay in s t a r t i n g chemo and decrease in drug dosage may contribute to the higher frequency of relapse in RT pts. Because of these observations and the fact that the r i s k f o r survival in pts with Stage II breast carcinoma is occult metastatic disease (rather than local recurrence), we i n i t i a t e d the following protocol: All pts undergo excisional biopsy with margins of resection h i s t o l o g i c a l l y free of tumor and limited a x i l l a r y node dissection. Adjuvant chemo including CMF is i n i t i a t e d within 2 weeks of surgery and planned f o r 12 mos. RT to the breast, internal mammary and supraclavicular nodes is administered during mos 7 and 8; methotrexate is omitted during RT. To date, o f 9 pts (age 28-74): 5 have completed and 2 are receiving therapy as planned. A f t e r RT, pts received 68-102 (mean 90) % o f chemo doses received before RT. One pt discontinued chemo a f t e r 8 mos. One pt with a 2 cm medial, ER neg, node neg tumor relapsed in the breast a f t e r 5 mos and is well following mastectomy and a l t e r n a t i v e chemo. These preliminary results indicate the f e a s i b i l i t y of delaying primary RT u n t i l a f t e r 6 mes of chemo. Any delay or decrease in chemo related to RT during the c r i t i cal i n i t i a l mos is avoided. Recurrence in the breast can be treated e f f e c t i v e l y and may be an important in vivo indicator of the need f o r a l t e r n a t i v e chemo,
A "PSYCHOSOClAL" PROGRAMTO HELP WOMENBEFORE DIAGNOSIS AND TREATMENTAT ALL STAGES OF BREAST CANCER. Rose Kushner. Breast Cancer Advisory Center, Kensington, MD. 20895. Most existing "psychosocial" programs f o r breast cancer patients are concerned with helping them a f t e r primary treatment, and l i t t l e attention is paid to t h ~ i e t y and stress they must endure before diagnosis. According to the National Cancer I n s t i t u t ~ u t 114,000 new cases w i l l be discovered in 1983 in the United States. Since about I0 per cent of a l l breast masses are malignant, approximately 1.4 m i l l i o n women must undergo the t e r r o r and dread of expecting a positive diagnosis: a l l of them, including those with benign lesions, s u f f e r equa--aTly until the pathology report is received. Their q u a l i t y of l i f e , and that of t h e i r f a m i l i e s , is destroyed f o r a traumatic period that can l a s t f o r weeks or months. After primary treatment, about half of them w i l l need some kind of adjuvant therapy, and these women are faced with a vast array of controversial options regarding cytotoxic or hormonal substances. The time of receiving adjuvant therapy i s , emotionally, more d i f f i c u l t than the time surrounding primary treatment: the various medications frequently have t o x i c s i d e - e f f e c t s , and there is no way f o r the women to know whether or not they are being helped by the substances. "Is i t worth i t ? , " is a common question in t h e i r minds, and they must rely on busy nurse oncologists f o r information and support. Women being treated f o r metastatic disease also need help. There is no organized "psychosocial" program f o r these c r i t i c a l int e r v a l s , and the need is great. Knowledge and emotional support can overcome feelings of confusion and helplessness Since September 1975, the Breast Cancer Advisory Center (BCAC) in Kensington, Md. has provided both via a telephone ~hot1~ne" and mail service. Grateful l e t t e r s from about 15,~00 women, a~d many of t h e i r physicians, are the,;only 'data ~ ~hew~nq that the BCAC is successful.
312
A bslracts
: 3 7 GROUP PSYCHOTSERAPY WITH COUPLES FOLLOWING MASTECTOMY. L. Baider* and E.L. Edelstein, Department of Radiation and Clinical Ontology and Department of Psychiatry, Hadassah University Hospital, Jerusalem, Israel 91120.
38
Short term group psychotherapy was carried out with a nonrandomized group of couples where the wife had undergone mastectomy during the previous 24 months. This preliminary mode of intervention had the following objectives: to provide a setting for mutual observation of single and couple's mode of behavior; to observe and experience their own resistance and the different adaptable and nonadaptable mechanisms in husband and wife, their own affinities and mutuality. Previous unpublished research (Baider) assessing different aspects of adjustment (PAIS), (BSI) and family relationships (MOOS) in 20 postmastectomy couples. showed an increase in psychological distress (anxiety, hostility) significantly greater in husbands than in wives, one to three years after surgery. These findings confirm some of our conclusions about the group dynamics. Husbands and wives share almost the same amount of tension and distress, with the husband using adaptable mechanisms which often enough are not congruent with the wife's needs and expectations. These findings highlight two basic points: That husbands of postmastectomy patients are as vulnerable as the women. Thus, one should not regard them as the natural support system of the patients, but as people in stress.
~9
SERUM PROLACTIN LEVELS (SPRL) IN WOMENWITH BREAST CANCER. I. Wiznitzer*, C.C. Benz, L.R. Farber, W.B. Lundberg, A.L. Levy, S.N. Bobrow. Yale University School of Medicine, New Haven,CT. 06510. Prolactin influences the growth and development of rodent mammary gland tumors, as well as s e l e c t i v e l y stimul a t i n g the growth of the 47-DN human mammary carcinoma cell l i n e in v i t r o . Although i t s association remains controvers i a l , some studies have implicated hyperprolactinemia with aggressive mammary carcinoma and a poor prognosis. We studied SPRL in 59 women with breast cancer. SPRL were determined by RIA with normal values ranging between 5-25 ng/ml. Patients on mediation or with diseases known to elevate SPRL were excluded from the study. 25 patients with a mean age of 50 ± 11 years were receiving adjuvant chemotherapy and had SPRL of 5.9 * 2.8 ng/ml. The remaining 34 patients with a mean age of 57 ± g years had metast a t i c disease and SPRL of 12.6 ± 13.5 ng/ml. These d i f f e r ences were suggestive but not s t a t i s t i c a l l y s i g n i f i c a n t . SPRL did'not correlate with patient age, menopausal status, estrogen receptor status, CEA, or disease a c t i v i t y . The highest SPRL (77 and 35 ng/ml) were found in the only 2 patients in this study with brain metastases. In this limited study we were unable to i d e n t i f y any subgroup of breast cancer patients with hyperprolactinemia. Future studies should address the r e l a t i v e incidence of hyperprolactinemia in patients with primary and metastatic central nervous system tumors.
40
pLASMA PROLACTIN CONCENTRATIONS IN DIEFERENT STAGES OF BREAST CANCER, IN BENIGN BREAST DISEASE AND MALIGNANT TUMORS. *W Holtkamp, D yon Heyden, H F Rauschecker, G.A. Nagel, Medical University Clinics, ]:)-3400 Goettingen, West Germany. From the literature there is evidence that hyperprolactinemia (HyPRL) is an indicator of poor prognosis in breast cancer. In order to further substantiate such preliminary communications plasma PRL determinations were done in 377 patients (pts) with breast cancer (bc), 151 pts with benign breast disease and 119 pts with solid tumors. 7 % of 204 pts with metastatic bc showed a HyPRL (> 1.080 mIU/1, 30.8 ng/ ml) in the measurements of morning plasma prolactin levels. The incidence of HyPRL was significantly higher in patients with metastatic bc than in 173 pts with non metastatic be (p < 0.001), in 151 pts with mastopathy (p = 0.01), in 63 pts with local (p = 0.001) and 56 pts with advanced solid tumors of different histolgoy without prolactin stimulating medication (p = 0.0Ol). After 5 measurements with a median interval of 2 months elevated prolactin levels over 1.000 mIU/l were found at least once in 35 % of the pts with metastatic bc. These findings confirm that HyPRL is associated with tumor progression and a poor prognosis of metastatic bc. 93 % of the women with hyperprclactinemic bc showed a progression at time of measurements, non in remission; on the other hand pts with advanced bc and normal prolactin levels had in 14 % of the cases a remission.
THE EVOLUTION OF A BREAST REHABILITATION SERVICE. RK Snyderman,* AE Synderman, The University of Medicine and Dentistry of New 3ersey-Rutgers Medicai School, Academic Health Science Center, CN 19, New Brunswick, New Jersey 08903. Originally, the Breast Rehabilitation Service of the Rutgets MedicaI School was organized to help patients who had undergone mastectomy, deal with the many problems which arose from the diagnosis of breast cancer and treatment by mastectomy. Because increasing numbers of women who had mastectomy sought breast reconstruction, it had become difficult for plastic surgeons to devote enough time to each patient. The needs o£ the patient were recognized to be both physical and emotional, The Breast Rehabilitation Service was designed so that each patient who came in to discuss breast reconstruction could be seen by a counselor especially sensitized to the problems of breast cancer patients and their £amilies. Following breast reconstruction, another session was to be held with the same counselor. At that tim% Yurther evaluation of patient needs and further counseling was suggested if necessary. However, it became clear that because breast cancer treatment often involved more than surgical intervention, interaction with oncotogists, radiation therapists, nurses and more was necessary to help the patient with bre~.s'~ pr'ek~l#ms and breast cancer. Thus we see that there is a need for a Comprehensive Breast Center. This would be a facility where woman would be able to receive in one place and in a shortened period of time, all the information and the support services which would help her and her family with their proble~ns concerning her breasts.
Abstracts 1 PRECISION TRAINING BY BREAST SELF-EXAMINATION FOR LUMP DETECTION. G e r a l d H. S t e i n , M a r k K a n e Goldstein, a n d H.S. P e n n y p a c k e r . Manual breast examination remains the most widely used procedure for the detecton of b r e a s t cancer. Its p o t e n t i a l for reducing mortality relies on the effectiveness of technology to optimize manual s k i l l in d e t e c t i n g small breast lesions. We have developed a realistic synthetic breast model and psychophysical search method which results in u n i f o r m d e t e c t o n of v e r y s m a l l simulated (-2mm.)(Cancer 40:364, 1977). This discovery w a s a p p l i e d to t h e d e t e c t i o n of r e a l b r e a s t m a s s e s in a c o n t r o l l e d series of experiments with the results that a significant larger n u m b e r of in v i v o m a s s e s w e r e d e t e c t e d after experimental training than before such exposure (Cancer 46:408, 1980). A training unit has been designed to i n c o r p o r a t e nodularity, tissue complexity and multiple synthetic t u m o r s in a l i f e like breast simulation. A more efficient search procedure was also discovered using a "strip" method of searching repeated vertical adjacent strips yeilding higher detection rates than circular or concentric search procedures. The findings suggest the early manual detection of v e r y small breast lesions can be improved b y an e n g i n e ered technology which will produce uniform and rapid acquisition of palpation skill resulting in a d e g r e e of p r o f i c i e n c y never before achieved.
43
BREAST CANCER RISK ANALYSIS: A NEW CLINICAL SERVICE. P.T. Kelly, and E.H. Rosanbaum, Mount Zion Hospital and Medical Conter, San Francisco, California 94120 A new service for assessing breast cancer risk has been made possible by recent studies which provide more accurate information about risk than was available before. These studies show that not all women who have a personal or family history of breast cancer are at the same high misk. Women with similar appearing family histories can have very different risks. A summary of risks due to a family history of breast cancer, breast and other cancers, and other risk factors will be presented. Analysis of 168 patients seen for breast cancer risk analysis suggests that women with a family history of breast cancer may have special needs for information, counseling, and breast health care. Sixteen per cent of the study population had less than one breast examination by a physician each year and 20% did not practice breast self examination. Nearly 75% held erroneous beliefs about their breast cancer risks. The effects of beliefs about risks and emotional reactions to familial disease (anger, fear, guilt and low self-esteem) will be discussed. The cancer risk analysis service appears to help reduce the anxiety many women feel about breast cancer and encourages them to set up and maintain appropriate breast health regimens. Physicians use risk analysis to determine which patients need closer surveillance due to high risk. The service has been especially helpful in making the most up-to-date genetic and epidemiologic risk factors available to physicians.
42
313
NCI COMMUNITY BASED CANCER CONTROL PROGRAM: BREAST SELF EXAM (BSB) TRAINING IN LOS ANGELES. C.Z.LEE, Memorial Hospital Medical Center. PO Box 1428,Long Beach,CA 90801. The program demonstrated that a large number of women can be recruited to learn BBE and once learned a large percentage continue to practice for at least one year. Community Cancer Control of Los Angeles funded five hospital based Breast Examination Training Centers for the purpose of individually training high risk women how to do BSE. When the demonstration program concluded, the five Centers had operated 154 months, individually trained 25,147 women, referred 2,161 symptomatic women to their physician, and detected 48 breast cancers. The program was offered at both the Center and offsite at local businesses, industries, churches, service groups, government agencies, etc. The two part training consisted of a group didactic session about breast disease followed by an individual BSE practice/feedback session with a nurse. Once the nurse was confident the woman was competent in BSE, the nurse performed a complete breast physical. It was at this time abnormalities were identified and women were referred to their physician. The program's follow up evaluation consisted of a random telephone interview of 2500 women one year after learning BSE. The interview was a series of tracked open end questions designed to determine the frequency and adequacy of BSE practice and technique. This self report from the five Centers indlcates 75% continued to practice BSE with 70% reporting at least monthly practice. The correctness of the technique varied from Center to Center which is probably due to the mixed population and teaching styles. The hospitals each served communities with diverse demographic, economic and social variables and varied in size from a 307 bed community hospital to an 848 bed teaching hospital.
44
NEW THROMBOTIC MATERIALS FOR _ _ ~ R A N S C A ~ ARTERIAL CHEM0I~v~3OLIZATION. Akio Sugitachi*, Yuichi Takatsuka and Izt~ni Sakamoto. Dept. of Surgery, Osaka National Hospital 2-1, Hoenzaka-machi, Higashi-ku, Osaka 540, Japan. Preoperative induction therapy plays an inioortant role in treatment of malignant neoplasms. In our clinic, preoperative transcatheter arterial che~o-e~oolization(~lACE), using our newly devised materials, is being prescribed as a pert of converging therapy for locally advanced breast cancer, Anticancer drugs, Adriamycin(ADM) or Mitcrmycin(MYC) were inmobilized on absorbable gelatin materials together with a blood clotting factor, Factor XIII and thrombin to provide a new type of throrabotic agent for TACE. The functions of this preoperative TACE are: i) to make the target lesions ischemic by ~ l e t e occlusion of the feeder vessels, 2) to ensure high concentrations of anticancer drugs in the ttmor tissues, 3) to prevent tumor dissemination during surgery, and 4) to reduce postoperative recurrence by the pharmacological effects of the antineoplastic drugs delivered from the carriers, slowly and continuously. In in vitro studies, accumulation of fibrin on the materials was remarkable and release of the inrsobilized ADM or continued for a long period. Clinical studies confirmed that the TACE with our materials strongly enhanced occlusive effects on the feeders of the mass and local supply of the ADM or ~ was highly concentrated. Plasma concentrations of ever low doses AIIM or ~ C were maintained for a long term. C~mp].ic~'~oluq due to the TACE were nil and the clinical efficacy of the procedures were excellent. Presurgical TACE with these materials shows great promise as induction therapy for neopla~ns.
314 ~
Abstracts TRANSCATHETER ARTERIAL CHEMO-EMBOLIZATION FOR BREAST CANCER. Y.Takastuka* a n d A. S u g i t a c h i , Dept. of Surgery, Osaka National Hospital, 2-1, Hoenzaka-machi, Higashi-ku, O s a k a 540, J a p a n .
46
Transcatheter arterial embolization is in current use for treating various neoplasms, howe v e r , l i t t l e is k n o w n o f t h e e f f e c t s in c a s e o f breast cancer. We have been prescribing transcatheter arterial chemo-embolization(TAC-E), using chemoembolic materials w e d e v i s e d as p a r t o f i n d u c tion of multi-modality treatments for locally advanced breast cancer. About 2 weeks after TAC-E,regresslon of the primary lesions was remarkable. Currative surgery and following adjuvant therapies w e r e fav o r a b l y c a r r i e d o u t f o r all p a t i e n t s and untoward effects were never observed. The primary lesions completely necrotized and viable cancer c e l l s w e r e n i l in t h e r e g i o n a l lymph nodes. Pharmacokinetic studies showed significantly high concentrations of Adriamyein in both tumor tissues and regional lymph nodes. All patients a r e d o i n g w e l l a n d to d a t e t h e r e is no e v i d e n c e of recurrence. Pre-operative T A C - E is e x p e c t e d to p l a y a n important role in treatment of locally advanced breast cancer.
A7
REGIONAL INTRA-ARTERIAL CHEMOTHERAPY INFUSION IN INOPERABLE 4 ~ BREAST CANCER. RD Carter,* Tulane Medical Center, New Orleans, Louisiana 70112 Locally advanced breast cancers greater than 5 cm in size, usually with skin and/or chest wall involvement are generally considered inoperable. Fourteen patients with locally advanced tumors were administered intra-arterial chemotherapy (IACT) through the internal mammary artery or subclavian artery, for a total of 18 infusions. 3/14 patients received a mean dose of 500 mg 5-fluorouracil for 5 days. 12/14 also received an average of 10.8 mg methotrexate for 5 days. 2/14 received thioTEPA for 4 days, and 1 patient received 70 mg adriamycin and 350 mg Cytoxan. 10/14 patients partially responded to one course of IACT, and were then considered operable. They went on to have mastectomies and further treatment. Of the 4 initial nonresponders, 2 became operable after a second course of IACT. Two patients were considered to be non-responders overall. Out of the 18 total IACT infusions given, there were only 2 instances of infection. Other toxicities were drug related and were not significant. The average survival from time of diagnosis was 24.5 months. IACT infusion in this manner is considered to be a relatively safe, non-toxic method of converting previously considered inoperable breast cancer to operability.
INTRA-ARTERIAL I N F U S I O N C H E M O T H E R A P Y IN THE TREATMENT OF L O C A L L Y A D V A N C E D OR LOCALLY RECURRENT BREAST CANCER. *C M Chen, T J L i u , W Y L u L and F K P ' e n g , D i v i s i o n of GeneralSurgery, D e p a r t m e n t of S u r g e r y , National Y a n g - M i n g M e d i c a l C o l l e g e , and V e t e r a n s G e n e r a l H o s p i t a l , T a i p e i l lZ, R e p u b l i c of C h i n a . Since O c t o b e r 1981, s i x p a t i e n t s w i t h a d v a n c e d b r e a s t c a n c e r and t e n p a t i e n t s w i t h l o c a l l y r e c u r r e n t b r e a s t c a n c e r w e r e s u b j e c t e d to i n t r a - a r t e r i a l i n f u s i o n chemotherapy. It w a s p e r f o r m e d t h r o u g h the s u b c l a v i a n artery via brachial artery. A d r i a m y c i n (ADM) and M i t o m y c i n C (MMC) w e r e i n f u s e d i n t e r m i t t e n t l y e v e r y four weeks. 5-FIuoroUraeil (5-FU) was infused daily f r o m one to f o u r w e e k s c o n t i n u o u s l y o r i n t e r m i t t e n t l y . The p l a s m a and t i s s u e c o n c e n t r a t i o n of A D M w e r e c h e c k e d w i t h F l u o r o m e t r i c m e t h o d ° AII s i x p a t i e n t s w i t h a d v a n c e d b r e a s t c a n c e r r e s p o n d e d to the t h e r a p y 100% permitting subsequent modified radical masteetomy. H i s t o l o g i c a l e x a m i n a t i o n of the r e s e c t e d s p e c i m e n s h o w e d e x t e n s i v e n e c r o s i s of the t u m o r t i s s u e . T h e s i d e e f f e c t s a p p e a r to be l e s s s e v e r e w h e n c o m p a r e d to s y s t e m i c chemotherapy. However, peripheraIneuropathy developed in two p a t i e n t s . S i x of the t e n p a t i e n t s w i t h l o c a l l y b r e a s t c a n c e r a l s o r e s p o n d e d g i v i n g an o v e r a l l r e s p o n s e r a t e of i Z / 1 6 (75%). B a s e d on t h e s e s t u d i e s , i n t r a - a r t e r i a l i n f u s i o n c h e m o t h e r a p y c a n have a b e n e f i c i a l r o l e in the m a n a g e merit of l o c a l l y a d v a n c e d o r l o o a l l y r e c u r r e n t b r e a s t cancer.
HORMONE RECEPTORS AND TUMOR DIFFERENTIATION IN BREAST CANCER WITH AXILLARY NODE INVOLVEMENT. AE Papatestas*, PI Tartter, G Lesnick, D Pertsemlidis, AH Aufses Jr. Department of Surgery, Mount Sinai Medical Center) New York) NY 10029. Estrogen receptors (ER) have been associated with tumor diflerentiation (TD). Breast tumors with poor TD are more frequently associated with positive axillary nodes but there is no association between ER and node involvement (NI). In the current study the relationship of ER to TD, reported as Well and Moderate ('W&M) or poor, was evaluated in 188 primary tumors after stratificatrion for NI. A similar evaluation for progesterone receptors (PR) was performed in 106 patients. Positive receptors were values > 10Imoles/mg cytosol protein. . NEGATIVE NODES POSITIVE NODES ER ER + _%+ _ ER_.2 ER + %+ TD (W&M) 17 4# 72% i 11 /~8 87% TD Poor 9 12 57% i5 12 40% X2=1.62 p> 0.25 X2=I 1.96 p<0.001 PR PR + _ %+ _ PR___= PR + %+ TD(W&M) 10 23 70% 7 26 7996 TD Poor 7 9 56% 16 7 3096 X2=0.86 p>0.25 X2=13.09 p<0.001 ER-orPR- ER+IPR+ 96+ iER-orPR_ _ ER%PR+ %+ TD (W&M) 10 23 70% 6 23 8296 TD Poor 8 8 50% 17 6 26% X2=1.80 p>0.1 X2=16.73 p <0.001 The results indicate that the association between TD and receptors is significant only among women with positive nodes. In this group tumors with W&M TD have more frequent positive receptors and tumors with poor TD, more freqeunt negative receptors compared to women without NI. The combined use of hormone receptors and tumor histology may help in selecting appropriate adjuvant therapy.
Abstracts
49
THE P R O G N O S T I C SIGNIFICANCE OF THE STEROID R E C E P TOR C O N T E N T O P P R I M A R Y BREAST C A N C E R . DM Barnes, ~ J M T Howat, R Swindell, and M Harris, Christie Hospital and Holt Radium Institute, Manchester, England. R e c u r r e n c e and survival r a t e s were studied in 175 w o m e n with p r i m a r y b r e a s t c a n c e r who, until r e c u r r e n c e , r e c e i v e d no t r e a t m e n t other than a modified radical (Patey) m a s t e c t o m y and in whom the o e s t r o g e n (REc) and p r o g e s t e r o n e (RPc) r e c e p t o r c o n t e n t of the t u m o u r was m e a s u r e d by t h e D e x t r a n - c o a t e d c h a r c o a l method. At the median follow-up of 24 months ( r a n g e 18-47) t h e r e was a s t a t i s t i c a l l y significant increase in r e l a p s e - f r e e s,arvival (RFS) for those who possessed REc (P = 0.02). This d i f f e r e n c e was most m a r k e d in p a t i e n t s with 1-3 axillary lymph nodes containing t u m o u r (P = 0.057; there was no b e n e f i t in any other subgroup (No, N4+). As t i m e passed this a d v a n t a g e disapeared and a t a median follow-up of ¢¢ months ( m a x i m u m 75 months) there was no d i f f e r e n c e b e t w e e n the RFS of REc+ve and R E c - v e p a t i e n t s (P = 0.076). In 163 p a t i e n t s who had R P c measured, RFS was u n a f f e c t ed by R P c s t a t u s r e g a r d l e s s of the node i n v o l v e m e n t or length of follow-up (at 44 months P = 0.g). At 4# months the overall survival of REc+ve p a t i e n t s was significantly b e t t e r when c o m p a r e d with those who lacked this r e c e p t o r (P = 0.002), but there was no d i f f e r e n c e in any subgroup based on axillary nodes. O v e r a l l survival was more f a v o u r a b l e for R P c + v e p a t i e n t s than for those with Rpc-ve t u m o u r s (P = 0.002) and this d i f f e r e n c e was most m a r k e d a m o n g s t node n e g a t i v e p a t i e n t s (P = 0.01). This study failed to c o n f i r m t h a t m e a s u r e m e n t of steroid r e c e p t o r s can p r e d i c t an early relapse in p a t i e n t s with b r e a s t c a n c e r . The a p p a r e n t increase in survival of r e c e p t o r positive p a t i e n t s m a y merely r e f l e c t their response to hormonal therapy given when m e t a s t a s e s occurred.
1 INITIAL CHEMOTHERAPY OH IN STAGE I,II & I I I CARCINtNA OF THE BREAST. C I . J A C Q U I L L A T ° , @.AUCLERC ° , F . B A I L L E T ,J.BLONDON °° , J P . L E F R A N C ° ° , C . M A Y L I N ~ , J . N A R A L ° , M.WEIL a o: Service d'Oneologie M6dicale,°°: C h i r u r g i e - G y n @ c o l o g i que : Hop. de la Salp6tri6re 75651 PARIS CEDEX 13 FRANCE ;~ : Service de Radioth6rapie, Hop. Necker,75730 PARIS CEDEX 15 - FRANCE 80 % of people with localized carcinoma of the breast die within 20 years(y.) ; and only 30 % of Tl or N- patients (pts) survive to 30 y.The studies of NISSEN-MEYER in 1967 have shown the advantage of early CH. These have led us to administer CH before any local therapy since 1980. 79 pts were admitted to one study of which 34 were stoped as T4 or inflammatory disease (ID). D e p e n d i n g on the clinical extent of disease (ED). T r e a t m e n t (Tt) consisted of 3 to 6 courses of Vinblastine, Thiotepa, Methotrexate, 5 fluoro-uraeil and Prednisone (VTMFP) strengthened with A d r i a m y e i n (VTMFAP) in cases and T3>7 om,T4,ID. Local Tt consisted of either radical mastectomy (RM)(21 pts) or only radiotherapy (RT) with external RT (45 Gy) and interstitial RT (25-30 Gy) (58 pts). RT was a d m i n i s t e r e d in the classical way except for pts receiving VTNFAP into received h y p o f r a c t i o n a t e d RT. M a i n t e n a n ce CH was given with the same drugs for 5-17 months (m) d e p e n d i n g of the initial ED. Tumors r e g r e s s i o n (TR) of greater than 50 % was seen after initial CH in 8 1 % , p a r t i c u l a r l y in pts with T4 or ID (34/38) after RT there was complete TR at 6 m.. Toxicity after VTMFP was digestive (68 %) or h a e m a t o l o g i c a l (H)(g4 %). After VTMFAP toxicity was : v o m i t i n g (46 % ) , a l o p e c i a (i00 %) & H ( 5 1 % ) . In no case was Tt suspended for toxicity. The median follow-up is 12 m. for RM group & 14 m. for RT group. We observe 6 relapses (RM at 8 m.,17 m.,l at 17 m. & at 18 m. ; RT : 1 at 9 m.,& at 27 m.). We present here the results in almost i00 pts with a median followup of~18 m.
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A N D R O G E N SUPPRESSION BY K E T O C O N A Z O L E IN PATIENTS WITH METASTATIC P R O S T A T E C A N C E R . DA Decker, * M Subramanian, and A Singhakowinta. Wayne S t a t e University, School of Medicine, Detroit, Michigan Lt8201. Ketoconazole, a broad s p e c t r u m oral a n t i f u n g a l agent, has been shown to inhibit sterol synthesis in fungi. Adrenalcortisol synthesis has also been shown to be t e m p o r a r i l y blocked by k e t o c o n a z o l e in healthy male adults. A f t e r measuring cortisol (C), t e s t o s t e r o n e (T), androstenedione (ANSD), dehydroepiandrosterone (DHEA), follicle s t i m u l a t i n g hormone (FSH), luteinizing hormone (LH) and prolactin (PRL) response to ACTH stimulation we a d m i n i s t e r e d k e t o c o n a z o l e 400rag bid for 5-7 days to ¢ p a t i e n t s with m e t a s t a t i c p r o s t a t e c a n c e r . Three of the p a t i e n t s had had prior o r c h i e c t o m y ; all ¢ r e c e i v e d d e x a m e t h a s o n e 2rag bid during the k e t o c o n a z o l e trial to p r o t e c t against hypocortisolism. R e p e a t A C T H stimulation t e s t s w e r e p e r f o r m e d on the last day of k e t o c o n a z o l e t r e a t m e n t . Mean baseline cortisol levels were suppressed by 96%, t e s t o s t e r o n e by 65%, ANSD by 80% and DHEA by 88%. Analysis of v a r i a n c e t e s t i n g on the m e a n s e r u m hormone levels a f t e r A C T H s t i m u l a tion showed s i g n i f i c a n t suppression of C (p=0.02) and DHEA (p=0.01) as well as suppression of T (p=0.05) and ANSD (p=0.07), which we a t t r i b u t e to synthetic inhibition by ketoconazole. Serum FSH, LH and P R L levels were not a f f e c t e d by k e t o conazole administration. T h e r a p e u t i c b e n e f i t could not be a s s e s s e d b e c a u s e of the short duration of this trial. We conclude t h a t k e t o c o n a z o l e can e l f e c t i v e l y suppress androgen production in p r o s t a t e c a n c e r p a t i e n t s and s u g g e s t that this a g e n t may be of clinical b e n e f i t if chronic androgen suppression by k e t o c o n a z o l e can be d o c u m e n t e d . Since endogenous e s t r o g e n s are derived f r o m t h e androgenic hormones (T and ANSD) suppression of t h e s e androgenic h o r m o n e s by k e t o c o n a z o l e may produce a t h e r a p e u t i c b e n e f i t in p o s t m e n o p a u s a l w o m e n with b r e a s t c a n c e r , Results of our a n t i c i p a t e d trial in b r e a s t c a n c e r will be reported,
52
PECTORAL NERVE PRES£RVING OPERATION FOR BREAST CANCER IN THE CONSERVATIVE RADICAL (PATEY'S) M A S T E C T O M Y - - I T S MORPHOLOGICAL AND FUNCTIONAL EFFECTS AGAINST MAJOR PECTORAL M U S C L E - - , * S N a k a t a n i , K Morimoto,T Ueda,M F u j i m o t o , K Sakai, 2nd Department of Surgery,Osaka City University Medical School, Osaka Japan 545 In recent y e a r s , c o n s e r v a t i v e radical m a s t e e t o m y , e s p e cially Patey's operation,has been frequentry performed in the early stage of breast cancer. But there were few reports on p o s t o p e r a t i v e shape and function of the preserved majio pectoral m u s c l e . T h e n we studied these two points in 40 patients w h o h a d undergone Patey's operation (postoperative period 34 months on average,20 months at shortest).It was found that the muscle had been deformed in 70% of them,and more deformity had showed more decrease in muscular strength of shoulder horizontal adduction. Each atrophy might be caused to the operative injury of the medial pectoral nerve, to which little interest had been paid in Patey's m a s t e c t o my. So,we studied the location and innervation of pectoral nerves in autopsied and m a s t e c t o m i z e d cases (46 cases).The three pectoral nerve branches w e r e identified according to the site where they could be detected,as follows:l) the nerve seen in the lateral of the minor pectoral muscle-NA, 2) the one running through that muscle-NB,3) the one seen in the medial of that m u s c l e - N C . T h e s e three nerve branches innervated the major pectoral muscle segmentaly,the more in m e d i o c r a n i a l , t h e more upper part they did.Accordingly we devised a pectoral nerve preserving operation in the Patey's masteetomy. Sixty cases operated on by new technique showed the f a v a r a b l e p o s t o p e r a t i v e findings:the major pectoral muscle was better preserved in terms of m o r p h o l o g y and muscular strength than after classical Patey's operation. Our pectoral nerve preserving technique well conforms to the purpose of conservative radical mastectomy.
316
~
Abstracts FINE NEEDLEASPIRATION (FNA) IN BREASTCANCERMANAGEMENT: SENSITIVITYAND ROLE. L.Fesbla~R.Arisio~,G.Betta*,M.Sussio**,M.P.Nane*KP.Sismondi**. *Serviz]o di Anatoa~ia Pato]og~ca e Ricerche Cllniche,Osp.Spec,Ost.Gir, ec. Sant'Anna;*~l Cliniea Ost.Ginec.dell'UniVeFsit~.iOI2B Torino,ltal V.
54
LOCAL/REGIONALLY RECURRENT CARCINOMA OF THE BREAST WITHOUT EVIDENCE OF SYSTEMIC DISEASE. RESULTS OF THERAPY IN 126 PATIENTS. Thomas M. Beck, M.D., Deborah A. Woodard, M.P.H., Nan E. Hart, B.S., Charles E. Smith, M.D., Mountain States Tumor Institute, Boise, Idaho. During the period from Jan. I, 1970 through April 30, 1983, 126 patients with a local or regional recurrence and no evidence of systemic disease were seen at our institution. These patients were evaluated as to initial stage of disease, time to recurrence, type of therapy applied & the influence of therapy upon survival. Initial Stage (S): SI 35 pts; SIT 63 pts; SIII 28 pts. Management consisted of surgical removal only (12 pts); removal followed by irradiation (XRT) 26 pts; biopsy (Bx) only followed by XRT (36 pts); hormonal therapy after Bx (35 pts); chemotherapy after Bx (17 pts). Median follow-up for all patients is 74.5 me. XRT produced more frequent and durable local control than did systemic therapy. Patients experiencing a complete response to therapy had significant improvement in overall survival at 5 yrs (p ~ 0.05). When the group of patients with local therapy after Bx was compared to those receiving systemic therapy after Bx those receiving systemic therapy experienced improvement in overall survival at 5 yrs (p ~ 0.051. Both overall and disease free survival are significantly affected by the extent of local recurrence. (p < 0.01) Important prognostic factors includeinitial stage of disease & time to first recurrence. Pts whose initial stage was I or IT experienced improved survival vs. SIII. A recurrence within 24 mos of primary surgical management indicated a poor overall prognosis. We conclude that pts experiencing a local or regional recurrence without evidence of systemic disease should be considered for both local (XRT) and systemic therapy.
56
LOCAL F~NT~)L AND I~FPLICATIONS IN PBIMARY R%DIATION TH;RHAFY OF [~A~d.Y B ~ A S r CANCg~. i~ I~ Greene*, H ~ Thompson, G H Creenber~, ~ C !Vexler, P J J{osemark, Department of ~{adiatiou Therapy, C~ars-I inai ~edio~l Center, Los %n~eles, ~ l ] f . ~ince IO76, i00 women ~ith 104 esr!y breast carcinomas have been treated at Cedars-Sinai Medical Center with excision and primary radiation therapy. Axillary staging was performed in 79/I05 ~ s e s . The radiation therapy consisted of 4500 to ~000 rad delivered to the breast and appropriate draining lymphatics. ~ NoV photon beam treatment was followed by an Ir-lg2 implant in 92/104 of the oases. Mean followup has been 26 months since the end of treatment. Of I05 breasts treated, there have been seven local recurrences. Two were associated with distant metastasis. Three are currently N~I following salvage mastectomy. Most complications were self limiting. F~jor complications included nericarditis (I), Radiation pneumonitis (q), and skin necrosis (2). Minor complications included rib fractures (~), breasb edema (2), arm edema (2), Lhremitte's syndrome (2), herpes zoster of the treated breast (3), minor shoulder stiffness (2), match-line fibrosis (2), and persistent breast discomfort (2). The cosmetic results were assessed by the physicians as good or excellent in 91%. The results demonstrate the good local control, acceptable morbidity, and good cosmeels with primary radiation therapy.
In a series of 1389 breast cancers (BC) submitted for frozen section diagnosis(FSD),434 were examined by FNA also;bother diagnoses were checked against the Final pathological report.ln 381 non minimal 8C(NMIC) the FNA results were as follow: 272(71.39%)cerrect(mallgnant)diagnosis(CO);2#(6.2~) false negatlve(FN);RO(10.Rg~)doubtful diagnosls(OO);45(I1.81%)inadeguate sample(NS).In 36 minimal invasiv~ cancers(MIC)(invasion ~I0% or meandiamet~ S O.gcm)the corresponding values were:15(Al.6B%) CO;13 (36.II%)FN;6(I~.6%) DD;2(5.55%)NS.In 27 d~etal and lobular in situ 8C(CIS) the results ~e~e: 2(7.40%) CD;]7(62.96%) FN;4(14.BI%)DD;4(14.B]%)NS. For FSD the results im NMIC were:378(Bg.21%) CD;2(0.52%) deferred diagnoses (DEF);I(O.26%)FN.In MIC:2B(80.55%)CD;3(8.33%)DEF;4(11.II%)FN.InCIS:2(7.~0~ CO;3(II.lI%)DEF;22(81.~B%)FN. Even i f in selected cases the cytological diagnosis of malignancy was certain and FSD could be bypassed,we did not ai~ed at this step for the fol]owing reasons:1)the small but probably inevitable False positive rate of FNA(O.5% in our series of benign ]esions);B)the need of fresh neoplastic tissue for hormonal receptor determination,the sampling of ~hlch is better performed by macroscopical or sometimes by submacroscopical examination in pathology lahoratory;3)the lower sensitivity of FNA compared to FSD in NMIC and in NIC(im CIS bother methods were nearly useless). Nonetbeless,FNA use is justified by several other advantages:1)diagnostictherapeutic usefulness in cystic lesions;2)avoldlng surgical treatment in no operable patlents;3)more effective psychological preoperative counseling 4)more efficient surgical operations planr, ing.
5 ~- -
LOCAL-REGIONAL FAILURE IN PATIENTS TREATED W I T H A D J U V A N T CHEMOTHERAPY FOR B R E A S T C A N C E R .
D S t e f a n i k * , R Goldberg,P J Byrne,F P Smith, W Ueno,L T H i l l , L Bachenheimer,C Beiser,L Smith, A D r i t s c h i l o , Vincent T. Lombardi Comphrensive Cancer Center, 3800 Reservoir Road, NW, Washington, D.C. 20007. Risk f a c t o r s for l o c a l - r e g i o n a l recurrence of b r e a s t cancer were analyzed in a r e t r o s p e c t i v e review of 151 p a t i e n t s t r e a t e d with adjuvant chemotherapy (~MF or CMFVP) following modified r a d i c a l mastectomy at the Vincent T. Lombardi Comprehensive Cancer Center. Thirty-one p a t i e n t s had documented l o c a l - r e g i o n a l recurrence for an incidence of 20.5%. The median follow-up was 52 months following masteetomy, and the median time to recurrence was 29 months. Risk of local f a i l u r e c o r r e l a t e d with s i z e of primary (29% for T3 tumors versus 11% for T1 tumors) and a x i l l a r y node s t a t u s (31% for 4 or more p o s i t i v e nodes versus 11% for 3 or fewer pos i t i v e nodes). Outer quadrant tumors with g r e a t e r than 4 p o s i t i v e nodes had a 32% local f a i l u r e r a t e whereas those with 3 or fewer nodes f a i l e d l o c a l l y only 5% of the time. Inner quadrant and c e n t r a l tumors had a local f a i l u r e r a t e of 25%. A drug dose response trend was observed. 11 of 27 (41%) of p a t i e n t s r e c e i v i n g a low dose CMF schedule relapsed l o c a l l y whereas 12 of 67 (18%) r e c e i v i n g high or standard dose CMF or C[VIFVP relapsed l o c a l l y . These f i n d i n g s suggest a role for the addition of p o s t - o p e r a t i v e r a d i a t i o n therapy in highrisk patients.
Abstracts
317
57
THE USE OF PREOPERATIVE IRRADIATION IN TREATMENT OF FEMALE BREAST CNNCER PATIENTS. *V J Fish and G R Ray, Palo Alto Medical Foundation, Palo Alto, California 94301 In 1963 prospective guidelines were established at the Palo Alto Medical Foundation to determine the usefulness of preoperative irradiation therapy for female patients with breast cancer. 206 patients are included in this study and are divided according to the clinical findings into 3 groups. 65 patients received preoperative radiation therapy followed by mastectomy 4-6 weeks later. 44 patients received postoperative radiotherapy 4 weeks following mastectomy. 97 patients had modified radical mastectomy as the definitive method of treatment. The selection of patients for each of the groups as well as therapy will be described. All histological material was reviewed by a single pathologist using Tornberg classification. All patients were treated with Telecobalt-60 unit. There were more patients with extensive disease in the preoperative group than in the surgery alone group. Survival curves are calculated from the date of diagnosis. In the preoperative group of patients we were able to evaluate the effect of radiation therapy on the tumor. 51% of the patients had no evidence of tumor in the surgical specimen. Local recurrence occurred in 8 of the 206 patients. Results and complications in all three groups are presented and discussed. Ten years survival for all patients and certain subgroups were calculated.
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WEIGHT IN BREAST CANCER PATIENTS RECEIVING ADJUVANT CHEM0THERAPY: REFOCUSING THE ISSUE. JL Ramstack,* RD Carter, Tulane Medical Center, Dept. of Surgery, New Orleans, La. 70112. Twenty six Stage II breast cancer patients receiving adjuvant+chemotherapy+(phenylalanine mustard + 5-fluorouracil, - tamoxifen, - adriamycin) were followed prospectively for changes in nutritional status, including weight changes, for 12 months. Complete nutritional assessments, including anthropometrics, biochemical assessment of blood and urine, and dietary histories were conducted at 3 month intervals for a total of 5 assessments on each patient. Initial weights post-mastectomy ranged from 100-175% of ideal body weight, with a mean of 30% over ideal body weight. A 5-6% weight change was noted overall at one year. Lean body mass/protein status was depleated initially, and improved with time. Part of the observed weight gain was considered to be recovery of loss of lean body mass from surgery and/or presence of tumor. Estrogen receptor (ER) negative patients showed a greater increase in weight than ER positive patients. Half of the ER negative patients became menopausal during the follow-up period. Obesity in breast cancer patients disguises initial protein malnutrition. Some weight gain can be explained by recouperation of lean body mass. Further weight gain may be a function of menopausal status. Patients began the treatment obese and malnourished and at one year were obese and well nourished. The focus on the weight issue in breast cancer patients needs to be changed from one of "weight gain" to one of obesity throughout.
59
FAMILIAL BREAST C A N C E R : IMPLICATIONS F O R THE SURGEON. C H O r g a n 3r ~ and WA Albano, Dept. of Surgery, University of O k l a h o m a Health Science C e n t e r , O k l a h o m a City, O k l a h o m a 73126. G e n e t i c s plays a s i g n i f i c a n t role in a f r a c t i o n of p a t i e n t s with b r e a s t c a n c e r (7.5%). At our I n s t i t u t e of F a m i l i a l C a n c e r M a n a g e m e n t and Control, in comparision with tile sporadic v a r i e t y , we h a v e observed the following c a r d i n a l f e a t u r e s in f a m i l i a l b r e a s t c a n c e r : an e a r l i e r a v e r a g e a g e of onset (49 yrs vs. 57 yrs), e x c e s s bllaterality, other t u m o r a s s o c i a t e d h e t e r o genity, an autonomous dominant mode of inheritance~and i m proved survival (67% vs. 45%). In a study of 33 h e r e d i t a r y b r e a s t c a n c e r kindreds who w e r e a s c e r t a i n e d by m o t h e r - d a u g h t e r proband pairs, with v e r i f i e d b r e a s t c a n c e r , the m e a n a g e a t b r e a s t c a n c e r diagnosis for t h e s e p a r e n t - o f f s p r i n g pairs was 57.1 y e a r s for t h e m o t h e r s and 44 y e a r s for t h e d a u g h t e r s , which c o n s t i t u t e s a highly s i g n i f i c a n t intrapair d i f f e r e n c e of 13 years. When only second p r i m a r y c a r c i n o m a s of t h e c o n t r a l a t e r a l b r e a s t w e r e considered, t h e 2 0 - y e a r risk was 37.1%. The responsibility of t h e surgeon is to identify those p a t i e n t s possibly a t risk by developing an extended nuclear pedigree. P a t i e n t s with a high index of suspicion (one or more of the c a r d i n a l f e a t u r e s ) a r e r e f e r r e d for g e n e t i c evaluation. The m a n a g e m e n t of the c o n t r a l a t e r a l b r e a s t and long t e r m follow-up guidelines must be r e v i e w e d with the a f f e c t e d r e l a t i v e (Proband). In t h e n o n a f f e c t e d but y e t high risk r e l a t i v e , s t r i c t p a t i e n t surveillance beginning in t h e early t w e n t i e s and f a m i l y counseling should be outlined. Extended p e d i g r e e analysis with t u m o r and genologic v e r i f i c a t i o n is an on-going d y n a m i c process. Before c o n s i d e r a t i o n can be g i v e n to the c o n t r a l a t e r a l b r e a s t , the initial c a n c e r must be under a d e q u a t e control.
60
UNUSUAL DISSEMINATION OF BREAST CANCER ON CHEST WALL FOLLOWING ELECTRON BEAM RADIOTHERAPY. L M Lev,* A Kuten and E Robinson, Institute of Technology, Rambam Medical Center, Haifa 35254, Israel. Local irradiation of the chest wall is commonly utilized both to treat and prevent local recurrence of breast cancer. We have observed a stimulatory effect of radiotherapy to the chest wall, resulting in a unique distribution of metastatic deposits from breast cancer. The patient is a fifty-nine year old lady who underwent a mastectomy due to breast cancer. She received no postoperative therapy. Six months after surgery the patient developed a local recurrence in the chest wall. She was then treated with combination chemotherapy (CMF) to a total of six courses. Subsequently radiotherapy was administered to the chest wall using a 15 X 20 6 MEV electron beam up to a dose of SO00 rads in 2S treatment sessions. Five months after completion of radiotherapy the patient developed a widespread dissemination of cancer in the chest wall which correlated closely with the margins of the radiotherapy field. This is the second case of dissemination on the chest wall correlating to the electron radiotherapy field that we have observed at our institute. To our knowledge this phenomenon has not been previously reported in conjunction with electron beam therapy of the chest wall. The possibility of immunological local effects contributing to this unusual metastatic spread should be considered.
318
Abstracts
1 DEHYDROEPIANDROSTERONE (DHEA) IN THE TREATMENT OF CANCER. W. Regelson, Medical College of Virginia/Virginia Cor~monwealth University, Richmond, Virginia 23298 Dehydroepiandrosterone (DHEA) is a native hormone that is decreased with age, at a time of increasing cancer incidence. DHEA production is decreased in women with breast cancer and has been found to block mammary tumor virus cancer induction in rodents, abort benzpyrene induced lung cancers and block methyl hydrazine induced bowel cancer (Schwartz et al., 1983). DHEA aborts methylcholanthrene, phorbol ester skin tumor production (Schwartz, 1983), and on direct intraperitoneal injection, has inhibited ascites tumor growth in mouse models. DHEA has anti-diabetic activity (Coleman, et a1.,1982) and anti-obesity activity in inbred strains of mice and rats and can abort thymic involution to stress (Riley, 198~ One mechanism of DHEA action may be its inhibition of glucose-6-phosphate dehydrogenase, an enzyme vital to the pentose shunt which effects purine synthesis and ribosylation of DNA and RNA. We will report on DHEA effects on syngeneic transplanted mouse tumors and spontaneous tumors in dogs. DHEA is ready for clinical trial in man for the treatment of breast cancer and other advanced solid tumors for cancer prevention and anti-diabetic action. (Supported by the National Foundation for Cancer Research)
63
NON-AGGRESSIVE SIMULTANEOUS POLYCHE~OTHERAPY (hASP) F O R T H E P A L L I A T I V E T R E A T M E N T OF A D V A N C E D B R E A S T CANCER. O s c a r M i r 6 - Q u e s a d a , Jr. C e n t r o M 4 d i c o , C l l n i c a W S a n F e l i p e " , L i m a ll, P e r d (South America). W i t h the o v e r w h e l m i n g e x p e r i m e n t a l e v i d e n c e bac king the c o n c e p t of C e l l K i n e t i c s , it was p a s s ~ b l e to d e s i g n a n e w c h e m o t h e r a p e u t i c approach f o r the p a l l i a t i v e t r e a t m e n t of d i s s e m i n a t e d B r e a s ~ Cancer, a v o i d i n g in g r s a t m e a s u r e the u ~ d e s i r a b l e s e c o n d a r y t o x i c e f f e c t s of C y t c t c x i c agents. T h i s p e r m i t t e d a r e a s o n a b l e n e o p l a s t i c c e l l - k i l l at the o n s e t of t h e r a p y , a l l o w i n g the r e c r u i % m e n t of c l o n o g e n i c m a l i g n a n t c e l l s sens i t i v e to c o n v e n t i o n a l p r o t o c o l s . T h e f o l l o w i n g r e g i m e n h a s b e e n a d o p t e d s i n c e 1976. F o r m u l a 1 A (F - 1 A ) : M ~ C 2mg., C T X 2 0 0 mg., 5- F U 5 0 0 m g . , M T X 25 mg., V C R 1 mg., D e x a m e t h a s o n e (DXM) 8 mg. Pyridoxin (PDX~ 900 mg., d i s o l v e d in D e x t r o s e 5% w a t e r (D 5% W) 2 0 0 ml., i.v., D1 ~ d D5. ~ o r m u l a - 4 8 B (F - 48B): B L ~ 15 rag., ~ M C 2 rag. V C R 1 rag. a r a - C 5 0 rag., DX~ 16 rag., P D X 1 , 2 0 0 mg., d i s o l v e d in D 5% W 2 0 0 ml. i.v. D12, a r a C 25 mg. s.c. D13, D14, D15, D16. C M F P D32. T h i s p r o t o c o l is r e p e a t e d q. 4 to 6 wk. x lO. This regimen produced 80% palliative response rate i n 55 p a t i e n t s , i r r e s p e c t i v e of m e n o p a u s a l status, as c o m p a r e d to 1 5 0 h i s t o r i c a l c o n t r o l s %rea%ed with conventional protocols.
62
64
PROGNOSTIC FACTORS IN METASTATIC BREAST CARCINOMA. Basel fanes, M.D., Miami Valley Hospital, Dayton, Ohio 45409. 80 patients with metastatic breast carcinoma seen and followed by the author were studied. 18 of them (22%) survived more than 5 yrs while 51 survived less than that. Of these, 33 patients died within 2 years, ii are still alive less than 5 years from the diagnosis of their disease. The clinical parameters that determined the survival of these patients were assessed. These included age, menopausal state, race, carcinoembryonic antigens (CEA) level, estrogen receptors, hormonal response, chemotherapy response, disease free interval and sites of metastases. When the 18 patients surviving more than 5 years were compared with those dying within 2 years, the factors thst influenced the survival most were hormonal response and sites of metastases. 16/18 of the long term survivors responded to hormonal manipulation compared to 6/33 of the short term survivors. 17/18 of the first groups had metastases in one "organ" only, compared to 18/33 in the second group. These sites are shown as follows: 5 yrs. -Q2 yrs. Soft tissue alone 10/18 3/33 Lung alone 4/18 4/33 Bone alone 2/18 8/33 Liver alone 0/18 3/33 Metastatic breast carcinoma is a heterogeneous disease. About one fifth of the patients will survive more than 5 years. They can be determined by the presence of metastases in a single "organ", most often in the soft tissue and the response to hormonal manipulation. Supported by MVH Cancer Research Fund.
COMBINATION CHEMOTHERAPYFOR PRIMARY TREATMENT OF ADVANCED BREAST CANCER. MF Chen, FF Chou, CS Wang, YY Jan, Chang Gung Memorial H o s p i t a l , LinKou Medico1 Center, T a i p e i , Taiwan Between Dec. 1977 and Dec. 1982, eighteen p a t i e n t s wlth advanced breast cancer were Rrlmary t r e a t e d w i t h a combination of adriamycin (20mg/m 2, I . V . on day 1,8), methothraxate (20mg/m 2, I . V . on day 1,8), 5-Fu (300mg/m 2, I . V . on day 1,8), and cyclophosphamlde (200mg/m 2, o r a l l y from day 1 to day 14). Course were repeated a t 28 day i n t e r v a l s . The mean age of pat i e n t s was 58 (range, 36-74) and e i g h t were postmenopausal. F i f t e e n of them had d i s t a n t metastasis, the other 3 was advanced i o c a l i z e d l e s i o n . None of the p a t i e n t s had received p r i o r t r e a t m e n t . Of the 17 evaluabie p a t i e n t , 7 had complete remission (C.R.) and 4 had p a r t i a l remission ( P . R . ) , while 3 had s t a b l e disease ( S . D . ) . The t o t a l response r a t e in t h i s study was 64% (C.R.+P.R.) or 82% (C.R.+P.R.+S.D.). Operat i o n was c a r r i e d on in two of the 18 p a t i e n t s a f t e r each had 3 and 5 courses of chemotherapy. The median remission duration was estimated to be 18 months. T o x i c i t y was acceptable and included mild nausea, vomiting, alopecia and parestheslas. Only two i n stances of mild i n f e c t i o n and no instance of bleeding were observed. The combination chemotherapy with adriamycin, methotraxate, 5 Fu and cyclophosphamide is a c t i v e in the prlmary treatment of advanced breast cancer.
Abstracts 85SENSITIVITY OF HUMAN CELL LINES TO TAMOXIFEN AND EFFECTS ON CELL CYCLE KINETIC PARAMETERS, Reddel, R.R., Hall, R.E., Taylor, I.W., and *Sutherland, R.L. Ludwig I n s t i t u t e f o r Cancer Research (Sydney Branch), University of Sydney, N.S.W. A u s t r a l i a , 2006. Recent studies from this laboratory have demonstrated that tamoxifen (Tam) is a cell cycle phase specific growth i n h i b i t o r y and c y t o t o x i c agent in MCF 7 cells in v i t r o . Following treatment c e l l s accumulate in the Go/G1 phase of the cell cycle due mainly to an increase in the proportion of c e l l s with slow GI t r a n s i t times, i . e t½ h 30 hr. The s e n s i t i v i t y to Tam in terms of i n h i b i t i o n of cell cycle progression and c y t o t o x i c i t y was r e s t r i c t e d to a 2-4 hr period in mid-G 1, Tam effects in MCF 7 cells were compared to those in a range of human cell lines including 4 estrogen receptor (ER) +re breast carcinoma lines (T47D, ZR75-1, MOA MB 361, BT 474), 2 ER-ve breast carcinoma lines (MDA MB 231 & 330), and 3 ER-ve lines from other sources ( l a c t a t i n g breast-HBL 100, malignant melanoma - RPMI 7932, and leukemic T-lymphoblast-CCRF CEM). All lines were grown in RPMI 1640 medium/5% f e t a l c a l f serum, and treated with 0.115~M Tam. Cells were harvested and counted a f t e r 4 control population doublings. Samples were stained f o r DNA with ethidium bromide/mithramycin, and cell cycle analysis carried out a f t e r flow cytometry. A 10% decrease in doubling rate occurred at < 0.1 - 0.5 ~M Tam in MCF 7 cells and the 4 other ER+ve l i n e s , and 2.5-5uM f o r the r e s t , thus ER+ve cells were 5- to >50-fold more sensitive. Cytot o x i c i t y occurred at 5-I0~M Tam in ER+ve lines and 7.5-12.5 ~M in the others. Tam-induced accumulation of c e l l s in Go/G1 phase of the cell cycle occurred only in ER+ve lines. I t was concluded that in these cell l i n e s , the cell cycle phase-specific c y t o s t a t i c low-dose Tam e f f e c t was seen only in ER+ve breast carcinoma c e l l s , whereas cytot o x i c i t y was seen at higher doses in all lines.
We have previously reported that colony-formation of human breast tumors can be improved by factors required for the growth in semisolid cultures of established human breast carcinoma cell lines (V. Hug, et a l : AACR abstract #138, 1983). We subsequently found that the major growth stimulatory e f f e c t was confered by hormone supplementation, p a r t i c u l a r l y of 17-~-estradiol. We therefore determined the c o r r e l a t i o n s of in v i t r o growth of estrogen positive breast tumors and the c l i n i c a l response to anti-estrogens, and found that the in v i t r o tumor growth could s i g n i f i c a n t l y improve the value of the estrogen receptor to predict for hormone response: IN VITRO TUMOR GROWTH AND HORMONERESPONSE No. of Patients
ResponseRate
> 50
11
82%
a
< 50
7
29%
a
asignificance of d i f f e r e n c e :
DOS£-RELATED EFFECT OF 17B-ESTRADIOL DETERMINED BY GROWTH CURVES AND FLOW CYTOMETRIC DNA ANALYSIS OF A HUMAN BREAST CARCINOMA (T61) G R O W N IN N U D E M I C E . N. B r [ n n e r , M. S p a n g - T h o m s e n , L. V i n d e l @ v , A. N i e l s e n , S v . A a . E n g e l h o l m and B,.'Svenstrup. The University I n s t i t u t e of P a t h o l o g i c a l Anatomy, ii F r e d e r i k V ' s V e j , D K - 2 1 O O ~ C o p e n h a g e n , Denmark. By f l o w c y t o m e t 9 ~ c DNA analysis (FCM) i n f o r m a t i o n c a n be o b t a i n e d on t r e a t m e n t - i n d u c e d perturbations in t h e c e l l c y c l e ' d i s t r i b u t i o n , which m a y be of m o r e i m p o r t a n c e for t h e u n d e r s t a n d i n g of t h e t h e r a p e u t i c response than information on c e l l k i n e t i c s p e r se, d u r i n g u n p e r t u r b e d growth. In t h e p r e s e n t s t u d y , an e s t r o g e n a n d p r o g e s t e rone receptor-positive human breast carcinoma (T61) g r o w n in n u d e m i c e w a s e x p o s e d to 4 l o g d o ses 1 7 ~ - e s t r a d i o l . T h e e f f e c t of t h e t r e a t m e n t was evaluated by g r o w t h c u r v e s a n d b y F C M On t u m o r t i s s u e o b t a i n e d by f i n e - n e e d l e aspirations with intervals following the treatment. The treatment induced a dose-dependent growth delay, whereas t h e r a t e of t u m o r r e g r e s s i o n was independent of t h e d o s e a p p l i e d . On t h e c e l l c y c l e d i s t r i b u tion the treatment induced dose-re~ated perturbations comprizing accumulation of c e l l s in t h e S p h a s e of t h e c e l l c y c l e a c c o m p a n i e ~ by p o l y p l o i dization. S i n c e g r o w t h d e l a y is an ~ c c e p t e d p a r a m e t e r of c e l l k i l l , t h e r e s u l t s s u g g e s t t h a t estradiol induce a dose-dependent cell killing e f f e c t on t h e T 6 1 h u m a n b r e a s t c a r c i n o m a . The corr e l a t i o n b e t w e e n t h e c e l l k i l l i n g e f f e c t of e s t r a diol and the effect on the cell cycle distribution s u g g e s t s t h a t F C M m a y be u s e d to e s t i m a t e t h e e f f e c t o{ e s t r a d i o l on h u m a n b r e a s t c a n c e r .
68
87PREDICTIVE VALUE OF IN VITRO GROWTH FOR RESPONSETO HORMONES OF PATIENTS WITH ESTROGEN RECEPTOR POSITIVE BREAST TUMORS. V. Hug, G. Spitzer, G.R. Blumenschein, B. Drewinko, and E.J Freireich. M.D. Anderson Hospital and Tumor I n s t i t u t e , Houston, Texas 77030.
Colonies/5xlO 5 Cells Seeded
88
p = 0.039 by Fischer's exact test
We conclude that colony-formation in 17-~-estradiol enriched medium can be used to d i f f e r e n t i a t e between tumors that form i n e f f e c t i v e ER-estradiol-complexes from those whose ER-estradiol-complexes translate into cell d i v i s i o n , and that patients with these l a t t e r tumors are those more l i k e l y to respond to anti-hormonal agents.
319
RESPONSE TO TAMOXIFEN OR MEGESTROL ACETATE IN ADVANCED BREAST CANCER PREDICTED BY QUANTITATIVE PROGESTERONE RECEPTOR LEVELS.P A Johnson,P D Bonomi,L D Bacon,J N Wolter, K M Anderson,S E Economou. Rush Presbyterian St. Luke's Medical Center,Chicago,Illinois 60612 In a retrospective analysis,the records of 98 patients with advanced breast cancer,and with known estrogen and receptor levels,were reviewed for response to megestrol acetate (49 cases) or to tamoxifen (49 cases). As part of a multiple regression nodel including four possible indicators of response to hormonal manipulation (age,diseasefree interval,quantitative progesterone receptor level) the progesterone receptor level was the only significant predictor of response for the patients treated with megesterol acetate,the patients treated with tamoxifen, and the group taken as a whole. Adding the estrogen receptor, age,or disease-free interval did not improve upon the predictive accuracy of the progesterone receptor level (p < 0.0001). A linear discriminant analysis using only the progesterone receptor level as a predictor of response, with a progesterone receptor level of 40.6 fm/ng considered "positive",correctly classified 83% of the patients as objective responders (complete or partial response) or nonresponders (stable disease or progression). Response rates to tamoxifen and megestrol acetate were very similar when groups of similar receptor levels were compared. We conclude that since the progesterone receptor level predicts as well for response to tamoxifen as to megestroi acetate, there is not a unique relationship between the progesterone receptor level and response to progestational agents. Further,the quantitative progesterone receptor level should be determined whenever possible on all breast cancer specimens,since it is superior to the other possible indicators of hormone response.
320
Abstracts
9
AGGRESSIVE COMBINED MODALITY THERAPY FOR ADVANCED LOCALREGIONAL BREAST CARCINOMA. C. Loprinzi,* P. Carbone, D. Tormey, R. Rosenbaum, W. Caldwell (deceased), J. Kline, R. Steeves and G. Ramirez, Wisconsin Clinical Cancer Center, University of Wisconsin, Madison, WI. 53792. In 1976 we initiated a prospective pilot study to evaluate the benefits and toxicity (TOX) of an aggressive combined program utilizing surgery, local regional (LR) radiation (XRT), and ehemohormonal therapy (CT) in 32 women with advanced (ADV) LR breast carcinoma. Eligible patients (PTS) did not have distant metastases but had either: primary tumors >7.5 cm. (3), a 3.5 cm. axillary lymph node (I), breast edema (3), satellite ipsllateral breast nodules (3), fixed axillary lymph nodes (7), supraclavicular or internal mammary lymph node involvement (3), skin ulceration (2), chest wall invasion (I), or pathologically diagnosed inflammatory breast carcinoma(9). Following surgical debulking, the PTS were scheduled to have 2 courses of eyelophosphamide, methotrexate, 5-fluorouracil, ± prednlsone, ± tamoxlfen [CMF(P)(T)] followed by LR cobalt XRT (5,000 rad whole chest + 1500-2000 tad tumor bed boost) and then CT with CMF(P)(T) alternating with adriamycln (ADR), vlncrlstine, ~ tamoxifen for one year. The current actuarial 3 year survival is 65% with a median time to progression (TTP) of 29.5 months. The median TTP was shorter (p=.Ol) in the PTS with surgically unresectable gross disease. Cardiac (CARD) TOX was seen in g PTS, 7 of whom had left (L) breast tumors (p<.05). Total ADR doses were 105,106,250,282,364,375,414 and 420 mg/m 2 and the TOX consisted of congestive heart failure (4), assymptomatic cardiac hypertrophy (3), or palpatations (I). To date no patient has died as a result of ADR CARD TOX. Aggressive combined modality treatment appears beneficial in women with ADV LR breast carcinoma but significant ADR CARD TOX can occur following ADR and L chest cobalt XRT+
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CHANGES IN NUCLEAR PROTEIN AND HORMONALDEPENDENCY IN GR MOUSE MAMMARYTUMORS. D T Kiang* and H-J Zhang, Section of Medical Oncology, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455. Evolution from hormonal dependency (HD) to independency (HI) frequently occurs in human and rodent breast cancers. Since non-histone chromosomal protein (NHCP) plays an important role on gene regulation, i t s changes were studied in GR mouse mammary tumors during t h e i r a l t e r a t i o n of hormonal dependency through serial transplantations. Estrogen receptors (ER) were measured by the sucrose gradient method. GR mouse mammary tumors from the "early" transplant generations (TG I - 3 ) were HD, containing ER ranging from 20-40 fmol/mg. Tumors of " l a t e " generations (TG 6-9) were HI and contained less ER (10-15 fmol/mg). The nuclear chromosomal proteins were extracted by 0.35 M NaCI (according to the method of H. Busch) and analyzed by the two-dimensional gel electrophorectic technique. 12 HD tumors in the early TG and 14 HI tumors in the late TG were studied. A 31,000 dalton nuclear protein near pH 6 (which was l a t e r i d e n t i f i e d to be NHCP in p u r i f i e d chromatin) was c o n s i s t e n t l y present in 11 of 12 HD tumors, while i t is markedly diminished in 5, and not observed in g HI tumors. I t appears that this 31 K nuclear protein may play a role in the regulation of hormonal dependency even though the ER was present in both HD and HI tumors. (Supported by NIH Grant CA-30350 and Minnesota Medical Foundation, Inc.)
OE EARLY O RISK BREAST CANCER
AND LATE CARDIOTOXICITY IN DOXORUB!CIN-THEATED PATIENTS. A. Buzdar, T. Smith, C. Marcus, G. Blumenschein. M.D. Anderson Hospital, Houston, Tx. 77030. Five hundred and ninety-six patients (pts.) with breast cancer (stage II, III or isolated recurrences) following regional therapy were treated with a combination of fluorouracil, doxorubicin, and cyclophosphamide (FAC). Total dose of doxorubicin was limited to 300 mg/m 2 in pts. with stage II or III disease (group i), and to 450 mg/m 2 for pts. with isolated recurrence (group 2). The incidence of early and late cardiotoxicity was evaluated in both subgroups. In group 1 eight pts. (1.7%) and in g r o u p 2 eight pts. (6%) showed cardiac abnormalities. The types of abnonm93/ti~g were: Total dox./m 2 Total CH[F Arrhythmia M.I. Other 300 460 pts. 3 pts. 2 pts. 3 pts. 450 136 pts. 5 pts. 1 pts. 1 pts. i pts. In group 1 three pts. died of congestive heart failure (CHF), and 4 pts. were alive and asymptomatic at a median of 40+ months (20+ -- 72+ mos.) from onset of symptoms. In group 2 one pt. died of CHF, and 4 pts. were alive at median of 38+ mos. (16+--65+ mos.) from onset of symptoms. One pt. in group i, and 3 in group 2 died of metastatic disease. The median time from last dose of doxorubicin to onset of cardiac abnormalities for group 1 was 7 mos., and for group 2 was 1 ms. Two pts. showed evidence of CHE more than 1 year from the last dose of doxorubicin. One pt. had acute M.I. at 27 mos. and subsequently had CHF and the other pt. had a history of alcohol abuse and developed CHE at 33 mos. The data illustrate that incidence of early cardiotoxicity is <1% in pts. receiving doxorubicin up to 300 mg/m 2 and 3.6% in pts. treated up to 450 mg/m 2. There has been no clinical evidence of late-onset cardiac toxicity among 345 pts. followed >3 yrs. or 130 pts. followed >5 yrs. It is concluded that the risk of late-onset cardiac toxicity is neglible in pts. treated with FAC regimen.
72
EXPOSED IAMININ RECEPqDRS IN INVASIVE BREAST CARCINOMA. Sanford H Barsky,* C Nageswara Rao, and Lance A Liotta, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205 H~rmn breast carcinoa~s contain exposed high affinity plasma membrane receptors for the basement membrane glycoprotein laminin. These receptors can be measured in plasrea membrane fractions prepared from sanloles of htm~n breast carcinctna obtained at surgery. Scatchard analysis indicates a single class of receptors with an estimated kd of 2 nm and 50,000-100,000 receptors per cell. The receptor can be solubilized with 0.1% Triton X i00 or NP40 detergent extracts of breast carcinoma plasma membrane and purified by laminin affinity chromatography. The isolated receptor has a molecular weight of approximately 70,000. Sections of htmmun breast carcinoma stained with antibodies to laminin with the immunoperoxidase method reveal that the c a r c i n c ~ cells lose their extracellular basement membrane during the process of invasion and contain absent extracellular immunoreaetivity; in contrast, benign ducts and ducts containing in-situ carcinoma demonstrate ocntinuous basement membranes. Pre-incubation of these sections with laminin or a laminin fragment containing the receptor binding site results in cell surface staining of the invasive cells. These data indicate that whereas normal, benign, and pre-invasive rag/rn~ry epithelilml rest on a laminin-containing basement membrane and thereby have saturated l~minin receptors, invasive breast carcinoma cells exhibit exposed laminin receptors. Laminin receptors have been shown to mediate attac~nent of BL6 melanclra cells to blood vessel basement membranes during the metastatic process in C57 mice. similarly laminin receptors may be involved in the metastases of human breast carcinoma.
Abstracts
73
EFFECTS OF VARIOUS TREATMENTS ON PRIMARYAND METASTATIC TUMOR GROWTH IN VIVO AND TUMOR CELL GROIqTH IN VITRO. MP Moyer,* D Escobar, J Kraus, A Armstrong, RC Moyer, OG Morrison and JB Aust,The U n i v e r s i t y of Texas Health Science Center at San Antonio and T r i n i t y U n i v e r s i t y , San Antonio, Texas 78284;Baylor College of Medicine,Houston,Texas 78284. This research was done to assess the effects of r e t i noids, ascorbic acid, amiloride, c o r t i c o s t e r o i d , a s i l i c a d e r i v a t i v e , or mode of drug d e l i v e r y on primary and metast a t i c tumor growth in vivo and/or tumor cell growth in v i tro. Breast carcinomas and several other types of animal and human tumors, including g a s t r o i n t e s t i n a l cancers, sarcomas, leukemias, and lymphomas were studied. For most tumors, therapy resulted in at least p a r t i a l responses ( e . g . , tumor regression, increased lifespan) which were s t a t i s t i cally significant. Of p a r t i c u l a r i n t e r e s t was that combination therapy with r e t i n o i d and ascorbic acid decreased tumor metastases. Growth of some primary tumors was reduced to almost zero by amiloride alone, or by combination r e t i n o i d , ascorbate, c o r t i c o s t e r o i d treatment. However, no single therapeutic regimen proved e f f e c t i v e , and there were marked differences in the responsiveness of various tumors. The s i l i c a d e r i v a t i v e , Percoll, enhanced primary tumor growth and/or metastases. Delivery of drugs in crossl~nked albumin beads often decreased primary tumor growth r a t e , but more metastatic lesions were present. Both posit i v e and negative correlations were observed when tumor responses in vivo were compared to the effects of the agents on cell growth and phenotypic properties in v i t r o . These studies suggest that combinations of retinoids and ascorbic acid alone, or in concert with other agents, may be useful adjunct therapy and emphasize the importance of using met a s t a t i c models for developing appropriate modalities for cancer treatment.
71::~ HEAT SENSITIVITIES
OF PRIMARY TUMOR AND CONCURRENT METASTASES M.S. levarthy, H,N. Keer, J.D. Travis J. D, Khandekar, E.F. Scanlon. Evanston Hospital/Northwestern University Medical School, Evanston, IL 60201
Local hyperthermia (HT) to TA3Ha mammary adenocarcinoma implanted subcutaneously in the tails of Strain A mice reduced the frequency of renal lymph node (RLN) metastasis by 50% without affecting that of lumbar lymph node (LLN) metastasis, This suggested that cells metastasizing RLN and LLN may have different heat sensitivities. Therefore, we inveso o " tigated the effect of HT (43 C-I hr,) to the 1 tumor,RLN and LLN cells on their ability to form tumors in mice and to form colonies in soft agar. Results are given below: RLN LLN 1 O Tumor Latent period 37°C 15!4---~25)~ 15!4-~26) T3+~(15) (day. S.D.) 43°C 28±4(14) 22±4(15) 22±5(15) Survival period (day. S.D.)
37°C 43°C
% colony inhibition
45±8(5) 66!3(4) +
38±2(5) 48±12(5)
35±9(5) 53±9(5)
61
8
28
* Number of mice; + did not produce tumor in 1/5 mice. RLN tumors implanted in the tails of mice and locally treated by HT, were significantly smaller (p<0.05) after 2 treatments than the controls. LLN tumors, however, required 3 treatments to show such a difference. These results demonstrate that the biological properties of tumor cells that determine metastatic pattern and growth in different organs, are associated with differential heat sensitivities. Supported by the Peter Garard Memorial Fund, Butz Foundation, and Dee & Moody Funds.
321
74
SERUM COLD AGGLUTININ AND IgM LEVELS IN BREAST CARCINOMA (BCa) VE Dube,*M Haid, B Anderson, from Evanston Hospital/ Northwestern U n i v e r s i t y , 2650 N. Ridge, Evanston,It 60201. Supported by NCl Grant # CA 26268. Serum cold hemagglutinins were determined in 170 pat i e n t s with BCa, 97 women with benign breast disease, and 37 age matched controls. The results were expressed as an a n t i - I score. IgM was measured by radial immunodiffusion . The BCa patients were divided into groups by pathologic stage (PS) and histology. Contingency table analysis showed an increase of a n t i - I scores in PS I l l (p< 0.01) and a decrease in PS IV (p< 0.05) compared to controls (median: control=16;PS I = 18; PS I I = 16; PS I l l = 31; PS IV = 11; benign = 18). The IgM concentrations were not d i f f e r e n t from the controls (median: control = 139; P S I = 151; PS I I = 158; PS I l l = 168; PS IV = 118; benign = 136 mg/dl). The a n t i - I scores were increased in mucinous BCa ( median = 37, p< 0.001) and apocrine BCa (median = 28, p< 0.006) compared to controls. The findings suggest that the a l t e r a t i o n s in a n t i - I scores may represent a more specific host response than changes in IgM concentrations, probably resulting from the production of I antigen or I a n t i g e n - l i k e substances by BCa c e l l s . H i s t o r i c a l l y BCa has been dealt with conceptually as i f i t represented one disease. However, our finding of increased a n t i - I scores in mucinous and apocrine BCa's suggests an antigenic difference from other h i s t o l o gic types. Whether the natural course of BCa is influenced by the a n t i - I score remains to be seen and is the subject of ongoing study at our i n s t i t u t i o n . I f such a r e l a t i o n s h i p e x i s t s , then measurement of the a n t i - I score might prove useful as a prognostic tool in addition to providing i n sight into the immune modulation of BCa.
76
PROLIFERATIVE POTENTIAL AND BIOCHEMICAL PROPERTIES OF CLONED HUMAN MALIGNANT MAMMARY EPITHELIAL CELLS. R Schmidt-Ullrich, '~ PS I-in, and RB Mikkelsen, Radiobiology Division, Tufts-New England Medical Center, Boston, Massachusetts 0211 I. We have examined the clonal heterogeneity of human malignant mammary epithelial cells (HMMEC) that were isolated in vitro from 8 human mammary carcinomas (HMC). The HMC tissue was digested with collagenase/hyaluronidase to yield single cells and small cell clumps. The primary cultures of HMMEC were established in conditioned media on lethally irradiated human W138 fibroblasts. The mammary epithelial nature of the cells was monitored by immune peroxidase stainingi for carcinoembryonic antigen and alpha-lactalbumin. Cloning was performed during the first subpassage when actively growing HMMEC colonies of more than I00 ceils were released and dispersed into single cells with trypsin and grown in 94-well microtiter plates that were preseeded with WI3g ceils. From the number of HMMEC that were released/gin HMC tissue and that underwent active proliferation in vitro we could quantitate the colony formation efficiency (CEF) of freshly isolated HMMEC. Cells isolated from histologically well-differentiated and poorly-differentiated (pd) HMCs differed significantly with CEFs of
7%, respectively. Of 3 pd HMCs we examined the proliferative potential of at least five clones each on days 2, 5, and I0 after seeding and cell attachment. The average cell cycle times of clones from a given HMC varied between 30 and 75 hrs. The different growth rates ~orrelated positively with lactate production of ~200 nmole/10 ceils for rapidly proliferating and <50 nmole/10 cells for slowly growing ceils. The prote~3~sbiosythesis and ph~phorylation, monitored by incorporation of S-methionine and P-phosphate, was examined by bidimensional isoelectric focussing/dodecylsulfate polyacrylamide gel electrophoresis. Proteins with M s between 60 000 and I00 000 and isoelectric points (pl) betweenr pl 4.0 and pl 5..5 varied with the proliferative rates of HMMEC.
322 77
Abstracts PRESERVATION OF THE INTERCOSTOBRACHIAL NERVE IN TBE STANDDARD AXILLARY DISSECTION. WJ Temple*and AS Ketcham, Univ. of Miami School of Medicine, Miami, Florida. In the standard axillary resection for early stage breast cancer, the intercostobrachial nerve (ICBN) is routinely resected despite the preservation of the medial and lateral pectoralis and latissimus dorsi nerves. This may result in dysesthesia, anesthesia or an occasional neuroma. The ICBN is easily saved. The nerve and its tributaries are identified leaving the second and third intercostal space. If free of gross nodal disease, it is then dissected free to the medial arm. 50 out of 85 available patients (with ICBN saved) were examined for sensory changes and local recurrence. Minimal change was defined as hypesthesia to light touch or pin prick, and2marked as a large area of hypesthesia greater than 25 cm or anesthesia. Mean follow-up was 29 months with a range of 6-60 months. No axillary recurrence or residual dysesthesia was noted in these patients. This contrasted to 15 patients with ICBN resection, 50% who had marked sensory changes and 33% had dysesthesia in the postoperative phase.
78
RESULTS: # OF PATIENTS SENSORY CHANGE NONE
MEDIAL ARM 43
POSTERIOR ARM 42
AXILLA 39
POSTERIOR AXILLARY FOLD 34
MINIMAL
7
8
i0
15
MARKED
0
0
1
i
REAL-TIME TRANSILLUMINATION L I G H T S C A N N I N G OF THE BREAST. C R B Merritt, M A Sullivan ,A Segaloff and W P McKinnon. Ochsner Medical Institutions~ N e w O r l e a n s , LA 70121. Recently the d e v e l o p m e n t of v i d e o - a n d c o m p u ter-based s y s t e m s has s t i m u l a t e d new interest in t r a n s i l l u m i n a t i o n as a m e t h o d of b r e a s t evaluation. We have u s e d a c o m m e r c i a l l y available transillumination s y s t e m to e x a m i n e over i000 p a t i e n t s referred for b r e a s t evaluation. Results have been correlated with mammographic f i n d i n g s and w i t h b i o p s y in o v e r 200 p a t i e n t s . Transilluminatiou examinations were performed and i n t e r p r e t e d w i t h o u t k n o w l e d g e of m a m m o g r a phic findings. Final diagnosis was established by o p e n b i o p s y in a l l p a t i e n t s . Mammography and t r a n s i l l u m i n e t i o n had s e n s i t i v i t e s of 0.75 and 0.77 a n d s p e c i f i c i t i e s of 0.81 a n d 0.85 respectively. Positive predictive values for mammography and transillumination were 0.54 and 0.58 and negative predictive values were 0.92 for m a m m o g r a p h y a n d 0.93 for t r a n s i l l u m i nation. Our e x p e r i e n c e with real-time transillumination of the b r e a s t indicates promise for this modality and we view transillumin a t i o n as a v a l u a b l e adjunct to p h y s i c a l e x a mination and m a m m o g r a p h y . Used together, mammography and transillumination were highly effective in d e t e c t i o n of b o t h s y m p t o m a t i c and clinically occult breast carcinoma.
In conclusion, ICBN preservation is a practical, safe, and functionally superior modification to the routine axillary dissection where clinically positive nodes are not in proximity of the nerve.
79
ALL BREAST CANCER IS NOT SYSTEMIC: THE IMPORTANCE OF ADEQUATE LOCAL THERAPY. Hiram S. Cody, 111, M.D., Edward H. Laughlin, M.D., and Jerome A. Urban, M.D. - Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. Using a selective surgical approach, without systemic adjuvant therapy, in 496 patients with infiltrating breast carcinoma (treated between 1965 and 1970) i0 year NED survivals for radical mastectomy, extended radical mastectomy, and modified radical mastectomy were 63%, 60%, and 86%, respectively. Fifty per cent of all axillary node positive patients were disease free at 10 years, 6% of all patients developed local recurrence, and in only 3% was local recurrence the initial sign of treatment failure. For patients treated since 1970, comparable survivals were obtained: even when stratified by extent of nodal involvement (i to 3 versus 4 or more) and menopausal status, 5 year NED survivals equal or exceed those reported from trials of postoperative adjuvant chemo therapy conducted concurrently at other institutions. Until the benefits of systemic adjuvant therapy are clarified by long term follow up (particularly with reference to patterns of local or distant relapse, and the incidence of second malignancies), adequate local therapy must remain the essential first step toward the cure of operable breast cancer.
80
BREAST ASPIRATION BIOPSY WITH A MULTIHOLE NEEDLE FOR HISTOLOGY AND CYTOLOGY. * H Vorherr and R Klein, The University of New Mexico, School of Medicine, Albuquerque, New Mexico 87131. Aspiration biopsy is widely applied for breast cancer detection (accuracy: 50 to 90%). A disadvantage of the conventionally used single-hole fine needle is the small amount of material (a few drops) obtained for cytologic examinatidn. We designed a needle with the objectives: (i) to aspirate sufficient amounts of tissues not only for cytology but also for histology, thereby increasing the diagnostic accuracy and reducing the need for surgical biopsy and (2) to more efficiently follow-up patients treated for benign and malignant breast disease. Cormnercially available 16-, 17-, and 18-gauge hypodermic needles (40 to 75 mm in length) are prepared with three sharp-edged, ovoid holes (0.8 to 1.2 mm by 2 to 4 mm in diameter) using a 1.7 man wide grinding wheel. These holes are located within 12 to 15 mm of the tip of the needle. After disinfection ( H i b i c i e n s ~ ) and local anesthesia (1% lidocaine), the sterile needle attached to a 20 ml disposable syringe is inserted into the mass or suspicious area to be sampled. Under negative pressure approximately i0 needle passages back and forth are performed. Thereby tissues sucked onto or into the needle's holes are cut off by the sharp edges and can be aspirated for histology and cytology; the volume of aspirate is 1 to 3 ml. go far, 64 patients have been studied. In only one out of 12 patients with breast cancer, multihole needle biopsy failed to discover malignant cells. We conclude that multihole needle biopsy represents an improvement over the single-hole needle used currently.
Abstracts 81
ADJUVANT THERAPY OF BREAST CANCER WITH MEGESTROL ACETATE *R W Talley, Henry Ford Hospital, Detroit, Michigan 48202, A Segaloff, Ochsner Clinic, New Orleans, Louisiana 70121, E J Gregory, Jr., San Antonio, Texas 78229, and J B Weeth, Gundersen Clinic, Lacrosse, Wisconsin 54601. Megestrol acetate (MA) was studied as adjuvant therapy in a non-randomized group of 126 patients (pts) with one or more axillary nodes after a radical or modified radical mastectomy for carcinoma of the breast. All pts had pretreatment bone surveys, liver scans, chest X-rays; repeated at 6-month intervals for at least 4 years after onset of therapy. M A w a s administered orally at 160 mg daily for 24 months. All pts have been followed at least 4 years or until death. 88 pts were postmenopausal, 38 were premenopausal. 62 pts had 1-3 positive nodes and 64 had 4 or more positive nodes. Estrogen receptor (ER) analysis was not required but was performed on 92 pts and was positive in 62 pts (67.3%). The results were compared with a group of 182 untreated pts from San Antonio (SA) and were found to be comparable in relationship to time of data collection, age and disease distribution. Statistical analysis of these two groups were significant for the MA patients compared to controls only in patients with 3 or more positive nodes, as presented below: Treatment N Recurrence Death MA 63 30 22 None (SA) 69 36 30 p (X 2) : 0.0008 0.0039 Results in only postmenopausal pts were slightly better with p - 0.0005 for recurrence and 0.0035 for deaths. MA is effective, easily administered, non-toxic adjuvant therapy for postmenopausal pts with 4 or more axillary nodes. MA pts had superior survival statistics for the entire group. Data will be presented in all pt categories as well as comparison with other studies.
82 MEGESTROL SAL WOMEN
323
ACETATE (M) VERSUS TihMOXIFEN (T) IN POSTMENOPAUWITH ADVANCED BREAST CANCER: A PROSPECTIVE RANDOMIZED TRIAL OF THE PIEDMONT ONCOLOGY ASSOCIATION (POA). HB Muss*, DV Jackson, FC Richards, CL Spurr, MR Cooper, DR White, J Hopkins, JJ Stuart, D Case, RL Capizzi and Participating Investigators, The Bo~man Gray School of Medicine of Wake Forest University, Winston-Salem, N. C. 27103. Since January 1981, 83 patients (pts) have been randomized to M-40 mg po q.i.d, or T-10 mg po b.i.d. Eligibility required that estrogen receptor (BR) or progesterone receptor (PR) he positive or both unkno~n (not performed), that patients have either measurable or evaluable disease and that they be 5 years postmenopause. Ten pts. are too early to evaluate and 1 has been excluded (BR-/PR-). Prior chemotherapy was given to 32% of pts. receiving T and M while other hormonal therapy was given to 16 and 15% respectively. Pretreatment characteristics including age, disease-free interval, performance status, and sites of disease were similar. ER+ or PR+ patients comprised 66% receiving M and 65% receiving T, the remainder not having steroid receptor analysis. Response rates are as follows (IUCC criteria) after a median follow-up of 9.4 months. M ~NO. (%)) T (NO. (%)) NO. PTS (%) 38 (I00) 34 (I00) COMPLETE + PARTIAL (PR) 2 + 9 (29) 1 + 6 (21) STABLE 12 (32) 8 (24) PROGRESSION 11 (29) 16 (47) DATA PENDING 4 (Ii) 3 (9) Time to progression and survival are similar for both groups. Thirteen pts. failing M have been crossed-over to T with 1 PR; ii failing T to M with no responses. Preliminary data indicate no advantage for either regimen. Toxicity has been minimal for both groups. The trial continues to accrue pts.
