Receptor 2-negative Metastatic Breast Cancer Research Articles

A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000-1,500mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50mg/day and 2.5mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease>6months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA+ldCM); median age was 55 (35-80); nearly all had visceral involvement. Despite dose escalation in 90% of patients, only 17 (57%) patients ever achieved MPA trough concentrations>50ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7%) had stable disease for>6months. Skin Nm23 expression increased after 4weeks of MPA+ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation.

PCN10 - Relationship Between Progression-Free Survival (Pfs) and Overall Survival (OS) in Hormone Receptor-Negative Metastatic Breast Cancer (Mbc): A Comparative Effectiveness Analysis Using Linked Claims, Emr, and Mortality Records

PCN10 RelatioNshiP BetweeN PRogRessioN-FRee suRvival (PFs) aNd oveRall suRvival (os) iN hoRmoNe ReCePtoR-Negative metastatiC BReast CaNCeR (mBC): a ComPaRative eFFeCtiveNess aNalysis usiNg liNked Claims, emR, aNd moRtality ReCoRds Schabert V.F.1, Chen Y.J.1, Sun K.2, Wang Y.2 1IMS Health, Alexandria, VA, USA, 2IMS Health, Plymouth Meeting, PA, USA Objectives: FDA accelerated approvals for some chemotherapies used PFS as an OS surrogate. However, one mBC approval was revoked after OS gains were not observed post-approval. We compared PFS with OS by first-line (1L) chemotherapy using real world evidence from US mBC patients. MethOds: IMS Health Comprehensive Disease Records for Breast Cancer link IMS PharMetrics Plus, oncology EMRs, and Social Security Death Index. Female breast cancer patients (ICD-9-CM 174.x, 233.0) were selected with index metastasis (ICD-9-CM 196.x-198.x or EMR Stage IV) 7/1/2006-3/31/2012, age ≥ 18, no HR overexpression, 1L chemotherapy (anthracyclines or txanes [AT] or new cytotoxic agents [NCA]), enrollment 180 days pre-index and ≥ 30 days post-index, and no other malignancies. PFS proxy was 1L duration; OS was measured until death or censoring (end of enrollment). Log-rank analysis compared PFS by 1L treatment. A Cox proportional hazards model assessed post-1L OS by 1L chemotherapy and duration, propensity for NCA vs. AT, HER2 status, and patient characteristics. Results: Of 845 mBC patients, 334 met study criteria (mean [SD] age= 51.7 [8.7] years, 20.4% HER2+). Propensity for NCA (n= 70) vs. AT (n= 264) increased with diabetes history (OR= 2.79, 95% CI 1.12-6.90) and higher pre-index health care expenditures (OR= 1.27, 95% CI 1.05-1.54). 1L NCAs were administered a mean (median) 195.2 (73.0) days (anthracyclines 53.5 [44.0], taxanes 122.2 [47.5], -2Log LR 54.3, 2 df, p< .0001). Cox regression estimated that 30 additional days of 1L chemotherapy predicted slightly shorter post-1L OS (HR= 1.03, 95% CI 1.00-1.06); NCA (vs. AT) predicted stronger decreases in post-1L OS (HR= 2.32, 95% CI 1.11-4.86) despite propensity adjustment. cOnclusiOns: Duration of 1L chemotherapy, as a proxy for PFS, predicted slightly shorter post-1L OS. Choice of 1L chemotherapy was a stronger predictor of post-1L OS, adjusted for selection bias. Real world data suggests that PFS is a poor OS surrogate in mBC.

A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007

Phase II Trial of Bicalutamide in Patients with Androgen Receptor–Positive, Estrogen Receptor–Negative Metastatic Breast Cancer

Patients with hormone receptor-negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer. Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer. Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%-39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11-22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed. AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer.

Transient receptor potential melastatin 7 is involved in oestrogen receptor-negative metastatic breast cancer cells migration through its kinase domain

Oestrogen receptor negative (ER−) invasive ductal carcinoma (IDC) represents a significant clinical challenge and therefore prompts the discovery of novel biomarkers. Transient receptor potential melastatin 7 (TRPM7), a channel protein that also contains a regulatory kinase domain, is overexpressed in IDC and regulates migration. However, the molecular mechanism remains poorly defined. Here, we examined whether TRPM7 regulates migration by its channel function or by its kinase domain. A Magnesium Inhibited Cation current was recorded in two ER− highly metastatic breast cancer cell lines. Down-regulation of TRPM7 neither affected Ca2+-, nor Mg2+-homoeostasis but significantly reduced cell migration via a Ca2+-independent pathway. Notably, the overexpression of the truncated kinase domain form of TRPM7 decreased cell migration, while the overexpression of the wild-type form strongly increased it. Concomitantly, TRPM7 silencing reduced the myosin IIA heavy chain phosphorylation. Furthermore, we found higher TRPM7 expression in ER− IDC tissues and lymph nodes than in the non-invasive tumoural samples. In conclusion, TRPM7 plays a critical role in breast cancer cell migration through its kinase domain, and our data support the consideration of using TRPM7 as a novel biomarker and a potential therapeutic target in the treatment of human ER− IDC.

Cost-Effectiveness Analysis of Bevacizumab in Combined Chemotherapy for Human epidermal growth factor receptor 2-negative Metastatic Breast Cancer in Japan

Cost-Effectiveness Analysis of Bevacizumab in Combined Chemotherapy for Human epidermal growth factor receptor 2-negative Metastatic Breast Cancer in Japan

Phase II Trial of Bicalutamide in Patients with Androgen Receptor-Positive, Estrogen Receptor-Negative Metastatic Breast Cancer

Phase II Trial of Bicalutamide in Patients with Androgen Receptor-Positive, Estrogen Receptor-Negative Metastatic Breast Cancer

Abstract P5-15-05: Budget impact analysis of everolimus for estrogen receptor positive, human epidermal growth factor receptor-2 negative metastatic breast cancer patients in the United States

Abstract BACKGROUND: A phase III randomized clinical trial demonstrated significantly longer progression-free survival of everolimus and exemestane combination therapy compared to exemestane alone in postmenopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor-2 negative (HER2−) metastatic breast cancer (MBC) who failed letrozole or anastrozole. This study estimates the budget impact of adding everolimus as the first or second treatment after failure of letrozole or anastrozole for post-menopausal, ER+ HER2− MBC patients from a third-party payer perspective in the United States. METHODS: Pharmacy and medical budget impacts were estimated over the first year of everolimus use in this indication. Published epidemiology data were used to estimate target population size. Market share was assumed to be divided between exemestane, fulvestrant and tamoxifen before everolimus entry based on market research data on file. Market share of combination therapy of everolimus and exemestane was assumed to increase linearly during the one-year period and replace 10% of overall market share by the end of the year, proportional to the pre-entry market share distribution of the other three treatments. Pharmacy budget inputs (wholesale acquisition cost of the therapies, daily dose, treatment duration, dispensing fee and copayment) were obtained from published and unpublished sources. Patients were assumed to be on treatment until progression or death. Medical costs were estimated as the average costs before and after progression, weighted by time in each state and adjusted for survival. Pre- and post-progression costs, time to progression and survival rates were derived from published literature. Compliance was assumed to be 100% until progression and adverse events were not considered. All costs were reported in 2011 US dollars. RESULTS: In a hypothetical health plan with 1 million members, there would be 72 patients expected to use one of the study drugs (exemestane, tamoxifen, fulvestrant or everolimus+exemestane) as the first treatment option immediately after letrozole or anastrozole failure, and 159 expected to use one of the study drugs as the second treatment option after letrozole or anastrozole failure. For the first treatment option after letrozole or anastrozole failure, total budget impact was $0.013 per member per month (PMPM), including a $0.017 PMPM increase to the pharmacy budget and $0.004 PMPM decrease to the medical budget one year after everolimus entry. For the second treatment option after letrozole or anastrozole failure, total budget impact was $0.029 PMPM, including a $0.037 PMPM increase to the pharmacy budget and $0.009 PMPM decrease to the medical budget one year after everolimus entry. Total budget impact was $0.042 PMPM, including a $0.055 PMPM increase to the pharmacy budget and $0.013 PMPM decrease to the medical budget one year after everolimus entry. CONCLUSION: Use of everolimus for ER+, HER2− MBC is expected to reduce the medical budget due to improved efficacy but increase the pharmacy budget due to higher drug cost. The total budget impact is relatively small. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-15-05.

The use of bevacizumab among women with metastatic breast cancer: A survey on clinical practice and the ongoing controversy

The US Food and Drug Administration's (FDA's) recent decision to remove the indication of bevacizumab for metastatic breast cancer (MBC) has fueled a debate in the breast cancer community. We conducted a survey to assess the perception of health care workers involved in the management of women with MBC on the FDA's decision to ascertain how it will affect practice and to determine how bevacizumab is commonly used in the community for MBC. E-mails were sent out between September and November 2010 using a database of 3000 addresses maintained by the United Arab Emirates Cancer Congress. Individuals working for Roche or Genentech were excluded. The survey consisted of 22 questions that were divided into 3 parts addressing each participant's demographic profile, their opinion of the FDA's decision, and the typical use of bevacizumab in the community in the setting of MBC. A total of 564 participants were included in the final analysis, contributing to an 18.8% response rate. Of these participants, 14.6% were from the United States, 7.8% were from Canada, 31.1% were from Europe, 2.0% were from the United Arab Emirates, 11.1% were from Asia, and 33.3% were from other countries. The majority of participants believed progression-free survival to be a surrogate for overall survival, that cost played a role in the FDA's decision, and that the decision would adversely affect the future of newer drugs currently being investigated for MBC. The majority of participants indicated that they would use bevacizumab for triple receptor-negative MBC (46.5%), would use it in a first-line setting (44.7%), and would use it in combination with paclitaxel (51.9%). Our survey results highlight the discord between the opinion of community oncologists and the FDA's recent decision to withdraw the indication of bevacizumab for MBC.

Phase II Trial of Saracatinib (AZD0530), an Oral SRC-inhibitor for the Treatment of Patients with Hormone Receptor-negative Metastatic Breast Cancer

Background SRC activation is associated with cell migration, proliferation, and metastasis. Saracatinib is an oral tyrosine kinase inhibitor (TKI) selective for SRC. We performed this trial to evaluate the efficacy and safety of saracatinib monotherapy in patients with estrogen receptor (ER) – and progesterone receptor (PR) – metastatic breast cancer (MBC). Patients and Methods Patients who had undergone ≤ 1 previous chemotherapy regimen for measurable ER – and PR – MBC received saracatinib 175 mg orally daily. The primary endpoint was disease control defined as complete response (CR) + partial response (PR) + stable disease (SD) > 6 months. Secondary endpoints included toxicity and progression-free survival (PFS). Levels of circulating tumor cells (CTCs) in response to therapy were measured over time. Results Nine patients were treated on study. After a median of 2 cycles (range 1-3), no patient had achieved CR, PR, or SD >6 months. The median time to treatment failure was 82 days (12-109 days).The majority (89%) of patients discontinued saracatinib because of disease progression. One patient acquired potentially treatment-related grade 4 hypoxia with interstitial infiltrates and was removed from the study. Common adverse events included fatigue, elevated liver enzymes, nausea, hyponatremia, dyspnea, cough, and adrenal insufficiency. Conclusions These efficacy results were not sufficiently promising to justify continued accrual to this study. Based on this series, saracatinib does not appear to have significant single-agent activity for the treatment of patients with ER −/PR − MBC.

Chemotherapy Treatment and Survival in Older Women with Estrogen Receptor–Negative Metastatic Breast Cancer: A Population‐Based Analysis

To investigate the survival benefit associated with chemotherapy receipt in older women with estrogen receptor-negative (ER-) Stage IV breast cancer. Observational, retrospective cohort study using Cox proportional hazards regression to determine effect of chemotherapy on hazard of all-cause mortality. The two samples were an overall sample (n=1,519) and a propensity score-matched sample (n=580) to control for selection to treatment receipt. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained for regression models. U.S. women within the National Cancer Institute Surveillance, Epidemiology and End Results cancer registries (SEER) linked to Medicare enrollment and claims database. Female Medicare beneficiaries aged 66 and older with Stage IV ER- breast cancer diagnosed between 1999 and 2005. Outcome measure was all-cause death during the follow-up period. Survival was measured as time from breast cancer diagnosis until death or last follow-up date. Information on receipt of chemotherapy, defined as chemotherapy received within 6 months after diagnosis, was obtained from linked Medicare claims. One thousand five hundred nineteen ER- women diagnosed with metastatic breast cancer were identified; 494 (33%) received chemotherapy. Chemotherapy was associated with a statistically significant survival benefit (HR=0.61, 95% CI=0.54-0.70). Age did not modify the survival benefit of chemotherapy. Chemotherapy received within 6 months after diagnosis was associated with a 39% lower hazard of death within the time period for the study. These findings reflect chemotherapy use outside of the clinical trial setting and have important clinical and policy implications for the study of treatments in older women with advanced ER- breast cancer.

Chemotherapy Treatment and Survival in Estrogen Receptor Negative Metastatic Breast Cancer: A Population-Based Analysis.

Abstract Introduction: Although controlled clinical trials have demonstrated a beneficial effect of various chemotherapy regimens on survival in breast cancer (BC), little is known about treatment patterns and survival benefit in the “real world” population of elderly women with metastatic BC. Methods: We identified female Medicare beneficiaries aged ≥66 years with metastatic BC diagnosed from 1999 to 2005 in the Surveillance, Epidemiology and End Results cancer registries (SEER). Patients with a prior history of any cancer were excluded. Treatment-related data were abstracted from linked Medicare claims. Since Medicare claims have incomplete information on oral selective estrogen receptor modulators, we limited our study cohort to estrogen receptor negative (ER-) women. Chemotherapy was defined as the receipt of any chemotherapeutic regimen within 6 months after diagnosis. Initial regimens were characterized based on drugs given during the first 30 days of chemotherapy. We used a continuous-time interval-censored survival analysis to determine the effect of chemotherapy on hazard of any-cause death, controlling for sociodemographic and clinical factors, including proxy measures for performance status. Results: We identified 1518 ER(-) women diagnosed with metastatic BC in SEER. Mean age was 77.6 (SD 7.6) years, 84% were white race and 27% were married at the time of diagnosis. Of the 1518 metastatic ER(-) BC patients, 493 (32%) received chemotherapy. As compared to women who did not receive chemotherapy, women who received chemotherapy were more likely to be younger, married, have lower pre-cancer comorbidity as measured by the Charlson comorbidity index, have seen an oncology specialist and have cancer-directed surgery or radiation prior to chemotherapy. Initial regimens comprised predominantly one (31%) or two (46%) drug classes. The most common regimens were taxanes only (18%), anthracycline+alkylating agents (17%) and antimetabolite+alkylating agent (9%). Overall median followup time was 7 months; 1223 women (81%) died during followup. Median survival time was 5 months among women who did not receive chemotherapy and 15 months among women who received chemotherapy. Chemotherapy was associated with a statistically significant survival benefit (adjusted Hazard Ratio 0.61, 95% confidence interval 0.54, 0.70). Conclusion: In this population-based study of older women, there was a variety of chemotherapy regimens used for metastatic ER(-) BC. Chemotherapy received within 6 months after diagnosis was associated with a 39% reduction in hazard of death. These findings reflect chemotherapy use outside of the clinical trial setting and have important clinical and policy implications for the study of treatments among older women with advanced BC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2064.

Gemcitabine-oxaliplatin combination (SEGEMOX) in anthracycline (A) and taxanes (T) pretreated metastatic breast cancer (MBC): Results from the GERCOR-SEGEMOX phase II trial

1108 Objectives: To evaluate efficacy and safety of SEGEMOX regimen for previously A and T pre-treated MBC patients. Methods: Forty-five women with MBC not eligible for A and/or T chemotherapy were enrolled on SEGEMOX study. SEGEMOX was delivered as follows: Gemcitabine was given at 1000 mg/m2/100min on day 1, followed by oxaliplatin at 100 mg/m2/120min iv on day 2 every 2 weeks. Efficacy results were analyzed and are presented in an intention to treat analysis and toxicity according to the total number of cycles regimen. Results: Forty-four of the 45 patients received at least 1 cycle of SEGEMOX. Fifty-eight perccent of the patients have received previous adjuvant chemo, 36% 1st line and 42% 2nd line for MBC before the protocol inclusion. Visceral metastases were dominant site of disease (44% liver; 36% lung; 44% bone). Median age of the population was 55.8 years (36–73). After a median of 7.7 cycles (3.5 months of treatment); the overall response rate (ORR) is 38% [95%CI; 23%-51%] [1 CR (2.2%) and 16 PR (35.6%)]; 33% of stable disease [95%CI; 17%-43%], 24.4% progressive disease with a clinical benefit (CB) of 71% [95%CI; 57%-85%]. The median progression free survival (PFS) is 7.1 months for responders and 4.8 months for patients with stable disease. The all population median overall survival (OS) is 21.4 months with 22.7 months MOS for responders. Concerning toxicity analysis: 339 cycles of gemcitabine and 312 of oxaliplatinum were delivered. Respectively, grade 3–4 neutropenia occurred in 43% of patients (febrile neutropenia in 7%), grade 3–4 thrombocytopenia in 41%, and anemia in 2.3%. The most frequent non hematologic toxicities were represented by grade 3 peripheral neuropathy (Levi Scale) in 11.4% of the patients and grade 2 alopecia in 11.4%. For the subgroup of hormone receptor negative MBC (n = 12) the ORR is 33% [95%CI; 2%-64%], CB 50% [95%CI; 16%-73%], PFS of 2.8 months and MOS of 12 months. Conclusions: The SEGEMOX combination has relevant activity in A and T not eligible MBC patients, with a manageable toxicity profile. In the limited number of patients with HRN MBC even if the response rate is close to the overall population the prognosis seems still worse. No significant financial relationships to disclose.

Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells.

Disruption of apoptosis may allow metastatic cell survival and confer resistance to chemotherapeutic drugs. We have analysed the molecular pathways that activate these survival genes in specific sites of metastasis. Estrogen receptor-negative breast cancer cell line MDA-MB435 and two metastatic sublines derived from lung (435L) and brain (435B) were analysed for the expression of members of the Bcl-2 family of apoptosis regulators. The levels of Bcl-2 were higher in the metastatic sublines than in parental cells, which correlated with the activation of Stat3, but not with the expression and/or activation of known bcl-2 transcription factors (CREB and WT1). In the brain subline, both expression of Bcl-2 and Stat3 activation were induced by epidermal growth factor and abrogated after treatment with kinase inhibitors specific for epidermal growth factor receptor or Jak2. Furthermore, transfection of 435B with a dominant-negative Stat3 markedly reduced the expression of Bcl-2 protein, whereas transient expression of a constitutively active Stat3 increased Bcl-2 in parental 435 cells. In addition, blockade of Stat3 activation by treatment with epidermal growth factor receptor and Jak2 kinase inhibitors or transfection with a dominant negative Stat3, sensitizes 435B cells to chemotherapy-induced apoptosis. Our data suggest that an increased activation of the Stat3-Bcl-2 pathway in estrogen receptor-negative metastatic breast cancer cell lines confer a survival advantage to these cells and contribute to their chemoresistance.

Activation of estrogen receptor transfected into a receptor-negative breast cancer cell line decreases the metastatic and invasive potential of the cells.

Breast cancers containing estrogen receptors are responsive to antiestrogen treatment and have a better prognosis than estrogen receptor-negative tumors. The loss of estrogen and progesterone receptors appears to be associated with a progression to less-differentiated tumors. We transfected the human estrogen receptor into the estrogen receptor-negative metastatic breast cancer cell line MDA-MB-231 in an attempt to restore their sensitivity to antiestrogens. Two stable sublines of MDA-MB-231 cells (HC1 and HE5) expressing functional estrogen receptors were studied for their ability to grow and invade in vitro and to metastasize in athymic nude mice. The number and size of lung metastases developed by these two sublines in ovariectomized nude mice was not markedly altered by tamoxifen but was inhibited 3-fold by estradiol. Estradiol also significantly inhibited in vitro cell proliferation of these sublines and their invasiveness in Matrigel, a reconstituted basement membrane, whereas the antiestrogens 4-hydroxytamoxifen and ICI 164,384 reversed these effects. These results show that estradiol inhibits the metastatic ability of estrogen receptor-negative breast cancer cells following transfection with the estrogen receptor, whereas estrogen receptor-positive breast cancers are stimulated by estrogen, indicating that factors other than the estrogen receptor are involved in progression toward hormone independence. Reactivation or transfer of the estrogen receptor gene can therefore be considered as therapeutic approaches to hormone-independent cancers.

Mitoxantrone, cyclophosphamide, and fluorouracil in metastatic breast cancer unresponsive to hormonal therapy.

Fifty-two patients with hormonally unresponsive or estrogen receptor negative metastatic breast cancer who had not received prior chemotherapy received mitoxantrone 10 mg/m2, cyclophosphamide 500 mg/m2, and 5-fluorouracil 1000 mg/m2 (MCF) by short intravenous infusion every 21 days. Disease that was resistant or stable to this regimen was treated with doxorubicin 25 mg/m2/day for two days and vinblastine 1.4 mg/m2/day for four days (DV). Both drugs were given by continuous infusion. Thirty-one partial remissions and four complete remissions occurred after treatment with MCF. Only thirty-four evaluable patients crossed to the DV phase with partial remission (11 patients), stable (five patients), or resistant (18 patients) disease. Eleven patients' responses were upgraded. The median overall time to progression (TTP), defined as the sum of the TTP on MCF and TTP on DV, was 12 months. The median survival of all patients was 19 months. Granulocytopenia was the dose limiting toxicity for MCF, but cumulative thrombocytopenia was noted. Nausea and vomiting occurred in most patients but was mild. Severe alopecia occurred in half the patients. One patient developed congestive heart failure after receiving a cumulative dose of 206 mg/m2 of mitoxantrone. The incidence of infectious complications was 35% on each regimen; 50% of these were mild. MCF is an effective combination that was well tolerated. Objective responses, durations of response, and survival were similar, but not superior, to standard doxorubicin-based combinations. Toxicity was somewhat less.

Sinophobic growth in oestrogen receptor-negative metastatic breast cancer.

The mode of growth of tumour cells from primary breast carcinoma in the axillary nodes is shown to be related to the oestrogen receptor (ER) status of the primary tumour. ER-positive primaries are described as tending to show sinophilic growth, the tumour cells spreading along the nodal sinuses; while the ER-negative are sinophobic, spreading more diffusely in the lymphoid tissue.