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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.

Background. The fraction of breast cancer cells undergoing DNA synthesis at any one time is relatively low, which is problematic because most chemotherapeutic agents are most effective against dividing cells. Estrogens administered in vitro and in vivo can increase breast cancer cell proliferation. A randomized clinical trial was performed to determine if estrogenic recruitment could increase the effectiveness of combination chemotherapy. Methods. One hundred sixty-five women were randomized, with two excluded from these analyses, to either an intravenous cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) regimen alone (cyclophosphamide, 600 mg/[m.sup.2]; methotrexate, 40 mg/[m.sup.2]; 5-fluorouracil, 600 mg/[m.sup.2]) or CMF preceded by 3 days of diethylstilbestrol (DES) at a dose of 1 mg orally per day. The planned cycle length was 3 weeks. Results. Objective responses were seen in 20 of 80 patients (25%) treated with CMF and 32 of 83 patients (39%) treated with DES-CMF, and this difference almost achieved statistical significance (chi-square, two-sided P = 0.06). However, duration of response, time to disease progression, and survival time were similar for the two regimens. Conclusions. Estrogenic recruitment with DES as used in this study does not substantially increase the efficacy of a CMF regimen administered intravenously every 3 weeks. Cancer 1994; 73:2337-43.

Background. This analysis was conducted to evaluate the impact of selected clinical, histopathologic, and flow cytometric factors on sites of initial tumor relapse after postmastectomy adjuvant systemic therapy. Methods. Five hundred sixty-four patients with axillary node-positive breast cancer were entered in two prospectively randomized trials and received cyclophosphamide, 5-fluorouracil and prednisone with or without tamoxifen as sole adjuvant therapy. These patients were studied to assess the risk of locoregional recurrence and to identify factors that might predict tumor relapse site. Results. With a median follow-up of 9.3 years, the 8-year cumulative incidences of initial locoregional or distant relapse were 20% and 35%, respectively. Pathologic tumor stage, estrogen receptor content, and number of involved axillary nodes were independent predictive factors for an increased risk of locoregional recurrence. With the exception of tumor stage, these factors also were associated with an increased risk of distant relapse so that tumor stage (T3a) remained the sole factor predictive of increased relative risk for initial locoregional (versus distant) recurrence in patients with tumor progression. Clinical and flow cytometric factors were not predictive of initial locoregional or distant relapse. Conclusions. Exploratory data analysis of two prospective trials of postmastectomy adjuvant systemic therapy has demonstrated a significant risk for initial isolated locoregional recurrence in certain patients with node-positive breast cancer. The benefit of improved locoregional tumor control in appropriately selected patients with axillary node-positive breast cancer who receive adjuvant systemic therapy requires additional investigation.

Treatment of breast cancer in women is predicated upon menopausal status. For postmenopausal women with advanced breast cancer, the most appropriate starting therapy is hormonal therapy, most commonly the anti-estrogen drug tamoxifen. This treatment is not appropriate for all postmenopausal patients, of course, and would be inappropriate for women whose cancers do not express estrogen receptors. Many studies have attempted to improve on the success rate of tamoxifen by combining it with other agents, but only one study indicated that some improvement had been achieved in this way. A study was undertaken, therefore, to investigate whether the addition of the steroid hormone prednisolone improves the results achieved with tamoxifen in the treatment of advanced breast cancer. A total of 320 postmenopausal patients were treated; 159 were randomly assigned to receive tamoxifen (plus a placebo, which has no physiological effect) and 161 received both tamoxifen and prednisolone. Of the 320 patients, only 256 had tumors which could be objectively assessed. Of these, a complete response was seen in 48 patients (38 percent) treated with only tamoxifen and in 61 patients (47 percent) treated with both drugs. This difference was not statistically significant. When the survival data were tabulated, the median survival time was 35 months for the tamoxifen-only group and 32 months for the group treated with tamoxifen and prednisolone. The three-year survival was just over 40 percent for both groups. Incidental to the outcome of the study was the finding of better survival for the patients with greater amounts of estrogen receptors on their tumor cells. The patients who received prednisolone in addition to the tamoxifen experienced greater weight gain and edema (fluid retention) as side effects. There seems to be no justification for the inclusion of prednisolone in the treatment of postmenopausal women with advanced breast cancer. (Consumer Summary produced by Reliance Medical Information, Inc.)

Postmenopausal women with breast cancer often benefit from the inclusion of an anti-estrogen agent in their treatment program. The drug tamoxifen has long been considered to be the hormonal agent of choice, but some preliminary results have indicated that the drug fluoxymesterone may provide some advantages. In a previous study, tamoxifen plus fluoxymesterone was demonstrated to provide some advantage over tamoxifen alone, but the advantage was not considered large enough to warrant recommending the inclusion of fluoxymesterone in the standard treatment protocol. Further research has now shown that the combination of drugs may be particularly useful in the treatment of postmenopausal women with higher levels of estrogen receptors on their cancer cells. A total of 238 women with metastatic breast cancer were treated with tamoxifen alone or in combination with fluoxymesterone. Forty-two percent of the tamoxifen-only patients achieved an objective response while 54 percent of the patients receiving the combination treatment did so, a difference which was not quite statistically significant. Twenty-three percent of the tamoxifen group and 17 percent of the combination group achieved disease-free survival for more than five years. Some of the patients, but not all, were tested for the levels of estrogen receptors. The majority of these patients were found to have estrogen receptor concentrations on their cancer cells greater than 10 femtomoles per milligram (a femtomole is one quadrillionth of a mole, about 600 million molecules). When only these patients were compared in a post hoc statistical analysis, patients treated with the combination of tamoxifen and fluoxymesterone had what the authors call a substantial survival advantage. (Consumer Summary produced by Reliance Medical Information, Inc.)

In 1994, the Eastern Cooperative Oncology Group (ECOG) initiated for the Breast Intergroup a randomized clinical trial (E3193) in premenopausal patients with early‐stage breast carcinoma (lymph node‐negative and receptor‐positive, with tumors measuring ≤ 3 cm) comparing tamoxifen as adjuvant systemic therapy with tamoxifen and ovarian ablation by one of three different methods. Ovarian ablation could be accomplished either via radiotherapy (RT) (20 Gray [Gy]/10 fractions to a modified pelvic volume), surgical oophorectomy, or goserelin/leuprolide injections as per patient/physician choice. In the current study, we report the efficacy of pelvic RT with this dose‐fractionation scheme in the induction of ovarian ablation.Twenty‐two of 174 patients (13%) who were randomized to treatment with tamoxifen and ovarian ablation received RT for ovarian ablation. RT quality assurance was performed. Of the 22 patients, 19 were treated per protocol, 1 patient had a minor violation (20 elapsed days for 10 RT fractions), and 2 patients had major violations (1 patient who was treated with RT as per protocol but who was treated at a non‐Intergroup center, and 1 patient who was treated at a dose of 15 Gy/5 fractions).No acute Grade 3 or 4 (according to the Common Toxicity Criteria of the National Cancer Institute) toxicities were reported during RT. Of the 22 patients receiving RT, evaluable follow‐up data were available for 20 patients. Based on postmenopausal levels of estradiol or follicle‐stimulating hormone at varying intervals after the completion of RT, 15 of 20 patients (75%) achieved successful ovarian ablation with RT. At a median follow‐up of 54 months (range, 21–66 months), no Grade 3 or 4 complications from RT were observed.Ovarian ablation by RT as performed in the current trial (given at a dose of 20 Gy in 10 fractions to a modified pelvic treatment volume) was found to be effective for ovarian ablation in the majority of patients, but may take some months to be complete. Consequently, patients should be evaluated to ascertain that ablation has been accomplished. Cancer 2004. © 2004 American Cancer Society.