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Background. Data regarding the effects of estrogen replacement therapy (ERT) and its withdrawal in patients with breast cancer are limited. Methods. Four cases were observed involving estrogen replacement therapy withdrawal as management of metastatic breast cancer. Results. Three patients with a history of primary breast cancer developed metastatic disease while on ERT. A fourth patient presented with metastatic breast cancer while on ERT. Withdrawal of this 'physiologic' ERT alone as the only therapeutic intervention resulted in regression of metastatic disease in all four patients. Conclusions. In patients receiving ERT who develop metastatic breast cancer, withdrawal of ERT alone is a therapeutic option. Awareness of this phenomenon may be of value in management of these patients. The role of ERT and value of ERT withdrawal in patients with breast cancer deserve further study.

Background. This study was designed to evaluate the prognostic importance of c-erbB2 overexpression in a standardized cohort of patients with axillary lymph node positive breast cancer. Methods. Paraffin embedded primary breast cancers from 354 patients with axillary lymph node positive breast cancer, treated on a North Central Cancer Treatment Group adjuvant protocol, were studied immunohistochemically. c-erbB2 staining was classified as negative, weak (1+), moderate (2+), or strong (3+) and was assessed for effectiveness as a predictor of outcome in univariate and Cox model multivariate analyses. Results. Twenty percent of specimens exhibited moderate or strong c-erbB2 staining. The median disease free survival period of the strong staining group was 2.9 years, compared with 7.1 years for all other patients (P = 0.01). The median overall survival for the strong staining group was 5 years, compared with 12 years for all other patients (P = 0.03). A definite correlation was noted between degree of nodal involvement and the likelihood of strong cerbB2 staining (P = 0.001). There was also a significant correlation between c-erbB2 staining and higher nuclear grade and estrogen receptor negativity. In a multivariate analysis, c-erbB2 staining was not a significant predictor of either disease free survival or overall survival. Conclusion. According to this analysis, the strong correlation between c-erbB2 expression and degree of nodal involvement, higher grade disease, and estrogen receptor negativity suggests expression of this protooncogene product in a biologically more aggressive form of breast cancer. In a multivariate analysis, c-erbB2 expression was not an independent prognostic factor. Thus, cerbB2 assessment did not appear to add significantly to the information provided by currently available standard disease parameters. Cancer 1994; 74:2956-63.

Background. Previous cell kinetic studies have shown that the percentage of cells in S-phase (%S) of the tumor may be an important prognostic factor for relapse-free survival (RFS) and overall survival (OS) in patients with resected lymph node negative breast cancer. Methods. This study examined DNA ploidy and %S from the paraffin embedded primary tumors of 265 patients who had surgery between 1975 and 1981, had lymph node negative cancer, and had no adjuvant therapy. The %S and %G2M values were calculated using a debris and aggregate subtraction model. Results, The results of the DNA ploidy analysis revealed 130 (49%) DNA diploid tumors and 135 (51%) DNA nondiploid tumors. Ploidy was not significant for either RFS (P = 0.20) or OS (P = 0.13). The total %S (using a cutoff of 8%) was a statistically significant prognostic factor for RFS (P = 0.003) and borderline for OS (P = 0.08). The proliferation fraction (%S + %G2M), using a cutoff of 12.5, was a statistically significant prognostic factor for RFS (P = 0.01) and for OS (P = 0.01). In a Cox multivariate analysis for RFS, the total %S remained significant (P = 0.05) along with tumor size. In the analysis of OS, the proliferation fraction remained significant (P = 0.03) along with tumor size and age. DNA ploidy was not significant in any multivariate analysis. Conclusions. This study suggests that tumor size and cell proliferation parameters are independent prognostic factors for patients with resected lymph node negative breast cancer. However, the clinical usefulness of the cell kinetic parameters appears limited. Cancer 1994; 74:1752-61.

Background. Doxorubicin generally is considered to be the most effective single chemotherapeutic agent for the treatment of breast cancer. The major cumulative dose-limiting toxicity is cardiac toxicity, which may be related to the formation of free radicals with subsequent lipid peroxidation, leading to membrane damage. The anthrapyrazoles, of which piroxantrone is a member, were synthesized in an attempt to eliminate this toxicity. Methods. A Phase II clinical trial was conducted in 30 women with metastatic breast cancer in whom piroxantrone was administered at a dose of 160 mg/[m.sup.2] by 1-hour infusion. The planned cycle length for retreatment was 3 weeks. Measurable metastatic disease and failure on one prior chemotherapy regimen, but no prior anthracycline exposure, were required for response evaluation. Results. Twenty-nine patients were evaluable for response, and 6 (21% and 95% confidence intervals: 10-43%) achieved an objective response (1 complete, 5 partial responses), with a median response duration of 244 days. The median time-to-disease progression for all patients was 124 days. Eight patients received cumulative doses of piroxantrone approaching or exceeding 1000 mg/[m.sup.2], and all had reductions in the resting left ventricular ejection fraction (LVEF). The estimated median decrease in LVEF at 1000 mg/[m.sup.2] was 16%, with a range of 10-28%. Clinical findings of congestive heart failure developed in two patients. Conclusions. Piroxantrone had definite antitumor activity in women who had metastatic breast cancer and failure on prior chemotherapy that did not include an anthracycline. The 95% confidence interval for response probability was broad, but the level of activity observed was relatively low. The clear association with cardiac toxicity combined with the relatively low efficacy led to the conclusion that piroxantrone cannot be recommended for further development as therapy for women with breast cancer. Further study of other anthrapyrazoles is necessary to determine if the promise of this new class of agents can be fulfilled. Cancer 1994; 74:1733-8.