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Introduction: There is continuing debate whether efficacy of ET is different in non-visceral metastases (nVM) than VM. Recently fulvestrant 500mg, has been reported to have greater efficacy than an aromatase inhibitor (AI), anastrozole, particularly in nVM – implying efficacy may be both site and agent dependent. Absence of significant overall survival (OS) difference in PALOMA 1 & 3 has increased interest in site of disease, especially given the OS advantage for fulvestrant 500mg monotherapy. Patients & Methods: Individual patient level data was obtained from 7 randomised controlled trials (RCTs) involving SERM, AI & SERD used as 1st Line ET in known HR+ BC were used in this meta-analysis (MA). Five were Phase 3 double-blind, placebo controlled RCTs. Details of the studies, type of ET and patient numbers are shown in Table. All were rigorously assessed for clinical benefit rate (CBR), progression free survival (PFS), duration of clinical benefit (DoCB) and OS.: Details of the studies, types of ET and patient numbers are shown in the Table. Aa two stage MA IPD meta-analysis was used to analyse these outcomesCBR, PFS, OS & DoCB. Peto method for pooled odds ratios was used to calculate p values and CI for CBR, yYusef pPeto method was used to calculate p-values and CI for PFS, OS, and DoCB. Random effect for trial was included when Tarone's test for heterogeneity was significant, otherwise fixed effect models were generated. Results: Outcome data is present for each study and then summarised under SERM, AI, SERD and 'all Ets combined'. Odds Ratios (Ors) & Hazard Ratios (HRs) for VM versus nVM by endocrine agent are shown in the Table ETStudyNo. of Pats.HR+ Pats.CBRPFSOSDoCBSERM(n)(n)OR (95%CIs)HR (95%CIs)HR (95%CIs)HR (95%CIs)TamEORTC1891781.410.850.770.95Tam00273281441.330.981.051.26Tam00301821622.800.590.440.79Tam00252742091.100.780.730.78subtotal9736931.53** (1.11-2.10)0.79** (0.67-0.94)0.70* (0.52-0.94)0.92 (0.72-1.18)AIExeEORTC1821680.841.110.731.02Ana00273401543.850.550.361.06Ana00301711510.970.881.140.82AnaFALCON2322321.070.980.831.05AnaFIRST1031030.970.540.510.53Subtotal10288081.28 (0.73-2.22)0.80 (0.60-1.06)0.66* (0.45-0.95)0.92 (0.74-1.14)SERDFul 500CONFIRM1621622.940.630.561.15Ful 500FALCON2302302.710.410.450.61Ful 500FIRST1021024.110.580.440.55Subtotal4944943.06*** (2.00-4.06)0.56*** (0.45-0.70)0.50*** (0.39-0.65)0.71* (0.53-0.91)Total249519981.66*** (1.37-2.02)0.73*** (0.62-0.86)0.61*** (0.53-0.71)0.87* (0.75-1.00)CBR-Clinical Benefit Rate (n)= number of patients, pvalues p Conclusions: This is the largest reported individual patient MA for nVM versus VM in patients with known HR+ advanced BC and clinical outcomes (CBR, DoCB, PFS & OS) approved to regulatory standards. 1) nVM had significantly better clinical outcomes compared to VM when treated by anti-estrogen receptor blocking agents (SERM & SERD) but not when treated by Ais, which have a fundamentally different mechanism of action. 2) SERD (Fulvestrant 500mg) significantly increased all four clinical outcomes. For nVM compared to VM, fulvestrant put more patients into CB, kept them in remission (DoCB) for longer, resulting in 44% reduction in disease progression and a 50% reduction in death. 3) Site of metastases (ie nVM or VM) is one of the factors to consider when selecting patients for endocrine mono or combination ET (plus CDK4/6i) in the 1st Line setting. Citation Format: Robertson JFR, Paridaens R, Bogaerts J, Lichfield J, Bradbury I, Campbell C. Meta-analyses of visceral versus non-visceral metastases treated by SERM, AI & SERD agents as 1st line endocrine therapy (ET) for HR+ breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-11.

Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ER beta 1 and ER beta 2 expression in primary tumours in order to determine benefit in the two treatment arms. Primary tumour samples were available for 1256 patients (27% IES population). ER beta 1 and ER beta 2 expression was dichotomised at the median IHC score (high if ER beta 1 a parts per thousand yen 191, ER beta 2 a parts per thousand yen 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs. Neither ER beta 1 nor ER beta 2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ER beta 1 expression compared with low was associated with better DFS [HR = 0.38:95% confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95% CI 0.22-0.70) was found in the low ER beta 1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ER beta 2 expression in either DFS or OS. In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ER beta 1 expression but not in those with high ER beta 1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted.

The EORTC Breast Cancer Cooperative Group carried out a randomized trial to compare doxorubicin with epirubicin as second-line chemotherapy in patients with metastatic breast cancer. Two hundred and fifty-nine patients with at least one site of metastatic disease entered this trial, of whom 232 patients were eligible. Treatment consisted of doxorubicin 75 mg m(-2) or epirubicin 90 mg m(-2) i.v. every 3 weeks. The overall response rates for doxorubicin and epirubicin were 36% and 28% respectively (P = 0.173). The median time to progression was 23 weeks for doxorubicin and 19 weeks for epirubicin (P = 0.063) and the median duration of response was 40 weeks for doxorubicin and 32 weeks for epirubicin (P = 0.059). The median survival was 47 weeks for doxorubicin and 44 weeks for epirubicin (P = 0.196). Leucocyte count on retreatment day (P = 0.011) and platelet nadir (P = 0.031) were significantly lower in the doxorubicin-treated group. Also mucositis (P < 0.001), diarrhoea (P = 0.005) and haemorrhage (P = 0.048) were significantly worse in the doxorubicin arm. Nine patients on doxorubicin and two patients on epirubicin experienced congestive heart failure (CHF). At the dose levels used in this study, no statistical differences in response rate and survival were found between the two treatment arms. Treatment with doxorubicin tended to result in a slightly longer duration of response and time to progression but doxorubicin was more toxic than epirubicin.

We investigated whether estrogenic recruitment could enhance the antitumor effect of chemotherapy in 165 patients with advanced breast cancer, presumably sensitive to hormonal treatments (ER + and/or PgR + lesions). The therapeutic regimen consisted of: (a) estrogenic suppression by aminoglutethimide 1 g/day + hydrocortisone 40 mg/day; surgical castration in premenopausal patients only; (b) FAC (5FU 500 mg/m2; ADM 50 mg/m2; CPA 500 mg/m2) for 3 weeks; (c) following randomization, exactly 24h prior to chemotherapy, patients had to take 1 tablet of either placebo (PL) or 50 μg ethinylestradiol (EE2). Tolerance, responses, time to progression and median survival were identical in both groups. Thus, EE2 before chemotherapy did not contribute to the efficacy of this particular therapeutic regimen, which yielded an overall response rate of 64%. We conclude that the validity of the hormonal recruitment concept has not yet been established in clinical practice, so that this approach remains experimental.

Almost all patients that undergo hormonal manipulation for metastatic prostate cancer will ultimately progress because of hormone resistance. Therefore we assessed the effect of early addition of intravenous Mitomycin C to orchiectomy in patients with newly diagnosed metastatic prostate cancer.178 patients with histologically proven and previously untreated metastatic prostate cancer were included in a prospective, randomized multicenter trial. Randomization was done centrally between orchiectomy alone and orchiectomy with Mitomycin C. 148 patients were evaluable.At the final analysis 139 patients have deceased. The remaining 9 patients are still alive, but all present progression. There was no statistically significant difference in the real time to progression, or in the estimated cancer related and overall survival between both groups. Mean time to progression was 29 months in group 1 (orchiectomy alone), and 26 months in group 2 (orchiectomy and Mitomycin C) (p = 0.64). Mean time to cancer related death was 32 months and mean overall survival was 31 months in both groups.Mitomycin C has no beneficial effect when used in conjunction to orchiectomy in patients with newly diagnosed metastatic prostate cancer.

Psychosocial correlates of hormone receptor status in primary breast cancers were investigated in 93 consecutive patients. Life event, coping style, and psychological adjustment self-report scales were completed. The 75 patients with receptor-positive (oestrogen and/or progesterone) tumours were better adjusted psychologically than the 18 patients with receptor-negative lesions. These findings may explain the relations that have been found between psychosocial variables and survival.

The anthracyclines are among the most active agents in the treatment of breast cancer. In recent years, the taxoids have produced promising results as single agents in breast cancer. Average overall response rates of 43% in previously untreated and 29% in pretreated metastatic breast cancer have been reported in phase II trials with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Based on the known activity of doxorubicin and the single-agent phase II results of paclitaxel, two phase III randomized trials comparing these drugs as monotherapy in first-line, with crossover on progression, were conducted by the European Organization for Research and Treatment of Cancer and the Intergroup. The preliminary results of these studies were presented at international congresses and will be discussed here.

Vorozole (Rivizor) is a potent and stereospecific inhibitor of aromatase having shown promising endocrine effects in phase I studies. In the present trial, 27 postmenopausal patients with advanced breast cancer, measurable lesions, presumably hormone responsive (ER or PR+, or ER? with disease-free survival longer than 1 year, or prior documented response to tamoxifen), were treated with vorozole one tablet 2.5 mg daily. All had been previously treated with tamoxifen as adjuvant (two patients) or for advanced disease (24 patients), or both (one patient). Objective remissions were observed in eight patients (30%) with two complete responses (CR) and six partial responses (PR) lasting for a median of 14.3 months (range 6.8-40.6); nine stabilizations were also recorded (median 7.9 months; range 3.7-40.1). Median time to progression for the 27 patients was 5.9 months. Sites of response were skin (three patients), lymph nodes (two patients), lung (two patients) and chest wall plus lymph nodes (one patient). Treatment was very well tolerated: mild hot flushes (four patients), gastrointestinal complaints (four patients) and no significant toxicity (common toxicity criteria grade above 2) or drug-related severe adverse event. It is concluded that vorozole is an active second-line endocrine treatment, deserving consideration for randomized comparison with other agents such as aminoglutethimide, megestrol acetate or medroxyprogesterone acetate.

As long as advanced prostate cancer remains androgen-dependent, it can be treated by castration in combination with anti-androgens. When despite maximal androgen blockade (MAB), progression occurs, the anti-androgen withdrawal can result in partial remission. Otherwise corticosteroids can be used in low doses in order to suppress the androgens originating from the adrenal gland: total androgen suppression (TAS). The minimal side effects and the low cost price of this treatment are important advantages, given the fact that only few efficient cytostatic agents are actually available for hormone-escaped prostate cancer. About 30% of the patients with advanced prostate cancer that became androgen independent will show a secondary remission under low doses hydrocortisone or prednisone.

This retrospective study was undertaken to characterise the natural history of women achieving complete response (CR) following standard dose combination chemotherapy for metastatic breast cancer (MBC), and to analyse the significance of various patient, disease and treatment characteristics in determining survival and time to disease progression. 75 patients achieving a CR following standard dose combination chemotherapy or combined chemoendocrine therapy for MBC have been studied. At a median follow-up of 6 years, 28% of patients are still alive, with 18 of 21 patients showing no evidence of disease. 15 (20%) patients, with median follow-up of 61 months from start of chemotherapy, have never experienced relapse. Median overall survival is 32.5 months. Multivariate analysis for survival identified inclusion of anthracyclines and WHO performance status as significant predictors of good long-term outcome. Concomitant hormonotherapy almost reached statistical significance in our multivariate analysis. Neither dominant site of disease nor disease-free interval were significant determinants of complete remission. With conventional dose combination chemotherapy, approximately 20% of women with MBC who have achieved a clinical CR have been shown to be expected to remain alive and free of disease at 5 years. Inclusion of an anthracycline appears to be an important determinant of durability of CR and patient survival.

The activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in advanced breast cancer patients who have failed doxorubicin treatment is well established, but the optimal sequence between these two important agents remains to be determined. The European Organization for Research and Treatment of Cancer therefore designed a prospective randomized clinical trial in which patients not exposed to anthracyclines in the adjuvant setting received either first-line paclitaxel, given as a 3-hour infusion at a dose of 200 mg/m2 followed at the time of disease progression by second-line doxorubicin, given as a bolus injection at a dose of 75 mg/m2 or the reverse sequence. The target accrual is 330 patients. Interim results on 207 evaluable patients of 289 randomized are presented.

Forty patients with intermediate stage (T23 cm-T3, N0-N1) operable breast cancer received neoadjuvant chemotherapy by MCF (mitoxantrone, cyclophosphamide, 5-fluorouracil). Four cycles were administered at 3-week intervals. The obvious hematological toxicity (64% of grade III for the leucocytes and up to 34% of grade IV for the granulocytes) was rapidly reversible and did not hinder completion of the treatment. Ten patients showed a complete remission and a tumor volume regression of more than 50% was observed in 12 other patients. Tumor shrinkage allowed breast-saving surgery in 50% of the cases. A complete sterilisation of the surgical specimen was found in only two of the 40 patients and a few persisting neoplastic cells were found in ten other cases. A positive response at the level of the axillary lymph nodes was also obtained in more than 50% of the cases. In 25 of the 36 cases examined, the primary chemotherapy induced cellular lesions (fibrosis, necrosis) at the tumor level. A feasibility study was undertaken in order to determine quantitatively several biochemical parameters (steroid hormone receptors, cathepsin D, c-erbB-2 oncoprotein) in very small tumor samples obtained by Tru-Cut before any treatment and in surgical specimens. In the future, these micromethods will be used systematically with the aim of estimating the value of these potential prognostic factors for therapeutic follow-up of the patients.

A 33-year-old woman, who at 29 underwent mastectomy for a localised breast cancer (TINOMO), presented a relapse shown by a rapid rise in seric level of CEA. The classical complete work-up was negative. The location of the relapse was demonstrated by anti-CEA immunoscintigraphy. Radiotherapy, hormonotherapy and chemotherapy allowed to achieve a complete remission with normalization of CEA level and of immunoscintigraphy.

Five years ago, a 44 year-old woman presented with an apparently localized cancer of the right breast, initially treated by surgery, adjuvant chemotherapy and radiotherapy. After a 4 year disease-free interval, she developed bi-temporal hemianopsy, due to a suprasellar tumor causing compression of the optic chiasma. The tumor was resected by the transsphenoidal route and histological examination revealed neuroendocrine characteristics described as "argyrophilic breast carcinoma". The exceptional association of this peculiar histology for breast cancer with a rare pattern of recurrence (single pituitary metastasis) is worthwhile reporting.

This study investigates the efficacy and safety of Taxol (T) (200 mg/m 2 over 3 h, 3-weekly) or Doxorubicin (D) (75 mg/m 2 , 3-weekly) given as first-line chemotherapy (CT) for ABC, with a crossover upon progression. Until now, a total of 185 pts (T:91, D:94) have been randomized and data have been received for 106. Pretreatment characteristics were well balanced between the two groups. The following table summaries the toxicities according to the CTC Toxicity Scale encountered in both arms before crossover. Taxol (n = 51) Doxorubicin (n = 55) Neutropenia gr 4 35% 78% Febrile Neutropenia 4% 13% Vomiting gr 3–4 4% 18% Stomatitis gr 3–4 0% 13% Sensory Neurotoxicity gr 2–3 22% 0% Delays in Drug Administration (% of cycles) 5% 19% Possible hypersensitivity reactions (Weiss R.B. JCO Vol. 8: 1263–68) were seen in 2 of 236 Taxol cycles. This analysis shows that Taxol 200 mg/m 2 over 3-hours is well tolerated in comparison to Doxorubicin 75 mg/m 2 for the same population of patients. Accrual is planned to be completed by May 1995 (total of 240 pts). At the time of the meeting, further toxicity data will be presented.

Five hundred and twenty-one patients with ABC were randomized to receive PTX over 3-hr or 24-hr q 3 wks at an initial dose of 175 mg/m2 (with escalation when possible). The pre-randomization strata were defined according to prior chemotherapy (CT): none, adjuvant CT only, CT for ABC. Two-thirds of the patients had prior anthracycline exposure; 24% of these were anthracycline resistant, i.e. progressing on or relapsing within 6 months of an anthracycline regimen. The response rate was 29% in the 3-hr vs 32% in the 24-hr (P = 0.629). It was 28% in both arms among anthracycline pretreated patients. Among all patients, treatment over 24-hr resulted in a longer time to progression (TTP) (median 3.8 mos vs 4.6 mos: P = 0.021) and survival time (median 9.8 mosvs 13.4 mos; P = 0.021). This difference was not apparent after adjustment for prognostic factors, TTP: P = 0.081, survival: P = 0.099. Treatment was well tolerated as documented by the # of crs administered (median 6 (1–22+) vs 7 (1–21); P

An extensive experimental investigation of buckling of conical shells that are supported only along their lower edge and that are loaded by the weight of a liquid leads to diagrams and formulas which can be used directly in the design of such shells. The margin of safety to be applied, the influence of welding stresses and the limitations on the validity of the formulas for structures with different boundary conditions are discussed.

Using an in vitro tritiated thymidine (3H-dThd) nuclear labeling followed by autoradiography, the effects of 17-beta-estradiol (E2) or progesterone (Pg) on cell proliferation were studied in 22 human benign breast tumors, i.e. 7 fibroadenomas 8 fibrocystic dysplasias 4 gynecomastias and 3 phyllodas. Small tumor fragments were incubated in a chemically-defined medium without serum and were hormonally stimulated in vitro. The procedure used allowed discrimination between weak labeling, suggestive of DNA repair mechanism, and strong labelling, suggesting a true DNA synthesis (S phase). Taking this into account, our results have shown that both estradiol and progesterone can induce in vitro cell replication of both ER+PgR+ and ER-PgR- human breast fibroadenoma, without affecting those of fibrocystic dysplasia, gynecomastia and phylloda. Progesterone, but not estradiol, might significantly decrease DNA repair mechanism in fibrocystic dysplasia, according to the Pg-induced decrease of nuclear incorporation of small amounts of 3H-dThd. We have thus characterized a dynamic test of hormone dependence which permits in vitro study of the hormonal sensitivity of human benign breast tumors, as well as that of any other human neoplasm. This test could be of great value to help clinicians to diagnose and treat hormone-dependent neoplasms properly. Its clinical relevance is now under study.

Estrogens stimulate growth of MCF-7 breast cancer cells in monolayer culture. Possible interference of serum factors leading to an estrogen-insensitive cell growth was analyzed in various experiments carried out on serum batches producing no estradiol stimulation. Out of five estrogen conjugates, only 3-glucurono-estradiol partly suppressed the inhibition of hydroxytamoxifen; the conjugate also reduced the estrogen receptor content of the cells, probably by a down regulation process ("processing"). Moreover, prolonged subcultures in dextran-coated charcoal-treated serum attempting to remove possible intracellular estrogens produced no growth stimulation. Interference by hormone carriers of the serum was ruled out by the fact that two strong synthetic estrogens, moxestrol and diethylstilbestrol with weak binding affinity for these carriers, were unstimulatory. Reduction of the carrier concentration also failed to confer any estrogen sensitivity. This lack of effect of most estrogen conjugates and serum carriers seems to contradict the hypothesis of their interference leading to an estrogen-insensitive growth. Presence in the serum of potential inhibitors towards estrogen action was also examined. Dilution of sera inducing an estrogenic stimulated growth failed to show any growth increase, either in the absence or presence of estradiol, thus excluding the possibility of a major influence of an antagonism on growth control. Moreover, clonogenic assays in soft agar eliminated the hypothesis that a difference between "active" (stimulatory with estradiol) and "inactive" serum batches may result from distinct adherence properties rather than from real growth stimulation. All of these data are consistent with the concept that serum factors which are not of estrogenic nature mediate the trophic effect of estradiol; their absence in some serum batches may lead to an estrogen-insensitive cell growth.

A pilot study analyzed the relationship between several morphonuclear parameters and the Bloom-Richardson score for 37 invasive, not-otherwise-specified (NOS) ductal breast carcinomas. The SAM-BA 200 cell image processor and its software were used to measure the nuclear features on Feulgen-stained imprint smears. Two parameters representing the numbers of large and dense chromatin clots and two parameters describing the heterogeneity of the chromatin among nuclei in a specimen evolved in a continuous manner parallel with the Bloom-Richardson score from stages NOS-4 to NOS-8. The systematic measurement of these four parameters on a large series of breast cancers may be able to define an objective and reproducible "scale" of differentiation that could be a helpful tool for pathologists and clinicians.

The MXT tumor is an experimental mammary tumor, maintained by transplantation in B6D2F1 mice, which contains significant amounts of estrogen and progesterone receptors. The aim of the present work was to study the effect of estradiol (E2) administration on the cell kinetic parameters (thymidine labeling index: TLI, S phase duration: TS, cell cycle duration: Tc, growth fraction: GF, potential doubling time: T, cell loss factor: luminal diameter) of an MXT anaplastic carcinoma strain. These parameters were analyzed using single-, double- or repetitive-tritiated thymidine (3H-TdR) labeling techniques. Uteri were used as controls for the methodology. Our data clearly demonstrate that E2 exerted a marked stimulatory effect on the tumor cell proliferation. This effect is the net result of a shortening of the mean cell cycle duration (Tc) and of a 3-fold increase of the number of cells produced per time unit in 89% of the total cancer cell population. Beside this stimulatory effect, E2 produces a marked increase of the tumoral cell loss. This loss seems to affect a cell fraction which has reached the quiescent state (Q) for a short time.

The predictive value of the estrogen receptor (ER) assay with regard to the response to hormonal treatment was analyzed in women with advanced breast carcinoma. The significance of ten clinical variables of putative prognostic value was also investigated. A total of 49 courses of endocrine therapy were available for study. The respective merits of using the receptor information as a qualitative or a quantitative variable were compared. Linear logistic regression analysis showed that the quantitative information was significantly related to the therapeutic response (P0.0001) and proved to be superior to the qualitative information. Compared with the clinical variables tested with the logistic model, receptor concentration was by far the most important single predictor of response. Nevertheless, introduction of two of these clinical variables (i.e., age and menopausal status) into the model in addition to receptor concentration improved its predictive value. Presented in graphic form, the improved model provides a simple means to estimate the probability that a given patient will respond to endocrine therapy. Successive ER assays were available in a series of patients who had received no systemic treatment. In ER+ cases, there was a significant correlation between receptor concentrations in the consecutive assays. There was no influence of the time interval between tissue samplings. Data were also consistent in ER- patients. These results give support to the practice of routine receptor determination in the primary tumor at the time of mastectomy. It is concluded that the distinction between hormone-responsive and hormone-resistant tumors appears artificial. The therapeutic implications of a continuous gradient of hormone-dependency among breast cancers are discussed.

Forty-one Feulgen-stained cervical imprint smears were analyzed by means of the SAMBA 200 cell image processor in order to quantitatively score human papillomavirus (HPV) 16-18-induced morphonuclear modifications as assessed by morphometric, densitometric, and textural parameters. Molecular hybridization technology using 16 and 18 type specific genetic probes made it possible to divide our series into three groups: Group 1, containing noninfected smears; Group 2, containing "suspicious", i.e., borderline positive, smears; and Group 3, those related to infected patients. Our results show that nuclei from infected smears are much more hyperchromatic and bigger than those arising from noninfected smears. This quantitative description of HPV 16-18-induced chromatin modifications enabled us to create preliminary data banks which could lead to an objective and reproducible grading of unknown cases. This approach is now being prospectively assessed on a large series of cases because the value of the current study is limited until the data bank is tested against unknown specimens with a broader spectrum of HPV infection.

Estrogen receptors (ERs) were assayed in 23 breast carcinomas by: (1) the conventional biochemical assay with dextran-coated charcoal (DCC); (2) the immunoenzymatic assay using a monoclonal antibody (MAb), ER-EIA (Abbott); and (3) an original cytochemical method using another MAb, ER-ICA (Abbott). The first two techniques were performed on biopsy samples, whereas the last was carried out on fine needle aspiration (FNA) samples. The ER contents in aspirates were evaluated by: (1) scaled proportions of colored neoplastic cells; (2) scaled coloration intensity; (3) total grading (= proportion plus intensity); (4) product grading (= proportion times intensity); and (5) a new index (NI) described in this paper. The ER-EIA assay correlated best, with a high statistical significance, with the NI (P less than .001); NI was also the only index that significantly correlated (P less than .05) with the DCC results. The results show that the ER-ICA assay offers the great advantages of being applicable to FNA specimens and of producing rapidly available results. This new technique enriches the panel of MAbs for the diagnosis of adenocarcinomas and offers a new tool for the therapeutic follow-up of breast cancer patients. Our preliminary results suggest that the anti-ER MAbs might be helpful for measuring the hormone dependence of small lesions not assayable by DCC, even under endocrine therapy, thus avoiding false-negative assays.

The aim of the present work was to study the effects of estradiol (E2) on cell proliferation in well-differentiated mammary MXT tumors borne either by intact (INT), or by castrated (OVX), or by hypophysectomized (HX), or by castrated and hypophysectomized mice) OV-X-HX). Ovariectomy and hypophysectomy were performed, respectively, 6 days and 5 days before the sacrifice of animals bearing tumors during a 28 day period. Cell proliferation was measured by using an in vivo nuclear labeling with tritiated thymidine (3H-TdR) followed by autoradiography. Uteri were used as controls for the methodology. Our data demonstrate that E2 exerts a significant and transient stimulatory effect on cell proliferation in the uterine luminal and glandular epithelia of OVX or OVX-HX adult mice. This mitogenic enhancement is significantly higher in OVX-HX mice than in the other experimental groups. In MXT tumors, a significant increase of cell proliferation is induced by E2 in INT or OVX mice; however, no enhancement occurs after HX performed either in intact or in castrated mice. In the latter situation (HX), a dramatic increase of basal cell proliferation rates is consistently observed in tumors, as compared to those levels observed in INT or in OVX animals. The paradoxical increase in basal proliferation rates of MXT mammary tumors in HX animals was not suppressed by administration of ovine prolactin. This suggests that other hypothalamo-hypophysial factors might be endowed with direct inhibitory influence on growth of the MXT tumors.

Ninety postmenopausal women with advanced breast cancer were randomly assigned to be treated with HD-MPA administered either by oral route (daily dose 900 mg) or by intramuscular injections (1 g IM daily X 5 q w during 4 consecutive weeks followed by maintenance with 1 g twice weekly). Among 78 evaluable cases, most heavily pretreated, remissions, lasting for a median duration of 11 months, were more frequent on oral (8/37 = 22%) than on IM therapy (5/41 = 12%). In both arms, high estrogen receptor levels and various clinical factors were associated with higher response rates i.e., age greater than 60, Karnofsky greater than 70, light prior systemic treatment. Side-effects, consisting mainly of weight gain, hypertension and tremor occurred with equal frequency on oral or IM treatment. Five patients complained of pain at the sites of IM injections. Thus, we recommended that, whenever possible, the oral route should be preferred. During the same study, in 20 patients (11 on oral and 9 on IM therapy), blood was drawn at 0, 30, and 60 days of treatment for the assessment of MPA and hormone levels. In both arms, at 60 days, comparable levels of circulating MPA were obtained, with a very significant drop of cortisol, androstenedione, and estrone. These endocrine results, together with our clinical data, indicate that HD-MPA therapy is active on estrogen-dependent tumors with the same specificity as that of other modalities aiming to suppress the adrenal function. Its antineoplastic action in humans could be ascribed at least in part to its suppressive action on the adrenals, resulting in a severe estrogenic deprivation in postmenopausal women.

We have previously reported the characterization of an intraperitoneally (IP) transplantable bone-forming MXT tumor. However, the question was unresolved as whether the bone-forming cells originated from either the host animal or from the neoplasm itself. The present work attempts to answer this question by studying the influences of inoculation sites (subcutaneously, SC; intraperitoneally, IP; in the brain, IB; intracranially, ICR) on both the cartilage- and bone-forming tumor phenotypes. Furthermore the influence of cell culture procedures (two- and three- dimensional cultures) on these phenotypes was investigated. SC administered MXT cancer cells never produce bone-forming tumors, suggesting the existence in the dermis of substance(s) inhibitory to the formation of cartilage or bone. On the contrary, our data clearly demonstrate that bone-forming tumors can be obtained by either IP route, in a way which mimics endochondral ossification, or in the brain (IB), a region usually devoid of connective tissue. This observation substantiates the hypothesis according to which the tumor itself is able to produce osseous tissue. Another main finding is the increasing occurrence of skeletal tissues produced by cells proceeding from three-dimensional culture. Finally, ICR and IB tumors exerted a bone-lytic action against the host skull suggesting that tumor cells either produce osteolytic substances (prostaglandins, enzymes) and/or that they contain various cell types exhibiting different properties toward osteogenesis. This model offers new perspectives for studying the mechanisms of both normal and pathologic osteogenesis.

SummarySeven patients with far advanced breast cancer, heavily pretreated, were treated with a combination of vindesine (3 mg/m2 d 1, 8, 15) and cisplatin (100 mg/m2 d 1) administered every 4 weeks. Among 4 evaluable cases, 2 had partial remission in liver (2) and soft tissue metastases (1). These results are encouraging and further exploration of dose scheduling is ongoing in order to reduce drug-induced myelosuppression.

THIS review will briefly summarize the subjects addressed during the workshop and poster session on advanced disease and present the conclusions drawn on the basis of data from the literature and the data presented at the conference. The following three major topics were discussed; (1) neoadjuvant approach for operable breast cancer, (2) locally advanced breast cancer and (3) metastatic disease.

The sensitivity of MXT mouse mammary tumors to ovarian hormones was assessed by the following parameters: growth in vivo; presence or absence of estrogen receptors and progesterone receptors; and histological differentiation. A spontaneous evolution from hormone sensitivity (HS) to hormone independence (HI) was observed when the tumors underwent monthly transplantation onto intact recipient mice, with the tumors fulfilling the criteria of HI tumors after the 12th transplantation. In contrast, the tumors recovered most of the criteria of hormone sensitivity when pituitary isografts were placed under the kidney capsules of HI tumor-bearing animals or when these animals received daily administrations of prolactin over several months. Sensitivity to 17 beta-estradiol, progesterone, or prolactin was further assessed by actinomycin binding on the nucleus and thymidine labeling index, both measured by autoradiography. These technical approaches revealed that 17 beta-estradiol and prolactin stimulated the thymidine labeling index of both HI (despite the lack of detectable estrogen receptors) and HS MXT tumors whereas progesterone influenced only that of HS cancers. The three hormones significantly stimulated [3H]actinomycin D binding within HS tumors but not within HI ones. However, such "HI" tumors were characterized by increased actinomycin binding and thymidine labeling index in comparison with HS neoplasms. Thus, all the data presently reported strongly suggest that prolactin is able to restore the hormone-sensitive phenotype within so-called MXT hormone-independent tumors.