We conducted a randomized, double-blind, placebo-controlled trial of postoperative therapy with tamoxifen (10 mg twice a day) in 2644 patients with breast cancer, histologically negative axillary nodes, and estrogen-receptor-positive (greater than or equal to 10 fmol) tumors. No survival advantage was observed during four years of follow-up (92 percent for placebo vs. 93 percent for tamoxifen; P = 0.3). There was a significant prolongation of disease-free survival among women treated with tamoxifen, as compared with those receiving placebo (83 percent vs. 77 percent; P less than 0.00001). This advantage was observed in both the patients less than or equal to 49 years old (P = 0.0005) and those greater than or equal to 50 (P = 0.0008), particularly in the former, among whom the rate of treatment failure was reduced by 44 percent. Multivariate analysis indicated that all subgroups of patients benefited. Tamoxifen significantly reduced the rate of treatment failure at local and distant sites, tumors in the opposite breast, and the incidence of tumor recurrence after lumpectomy and breast irradiation. The benefit was attained with a low incidence of clinically appreciable toxic effects. The magnitude of the improvement obtained does not preclude the need for future trials in which patients given tamoxifen could serve as the control group in an evaluation of potentially better therapies. Tamoxifen treatment is justified in patients who meet the eligibility criteria of the present study and who refuse to participate in those trials. Since patients with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not eligible for this study, no information is available to indicate that such patients should receive tamoxifen.

Background: Pathologic complete response (pCR) is a proposed surrogate endpoint for predicting long-term clinical benefit on endpoints such as disease-free survival (DFS), event-free survival (EFS), or overall survival (OS). A meta-analysis is needed to establish the magnitude of pCR improvement on a trial level that results in improved DFS, EFS, or OS. Methods: We identified 12 neoadjuvant randomized trials (N = 13,125) with pCR clearly defined and long-term follow-up available for EFS and OS. Trials included AGO 1 (n = 668), ECTO (n = 1355), EORTC 10994/BIG 1–00 (n = 1856), GeparDuo (n = 907), GeparQuattro (n = 1495), GeparTrio (n = 2072), GeparTrio-Pilot (n = 285), NOAH (n = 234), NSABP B18 (n = 760), and NSABP B27 (n = 2411), PREPARE (n = 733), and TECHNO (n = 217). Key objectives of the meta-analysis were to determine: (1) the relationship of pCR to EFS and OS, (2) the definition of pCR that correlates best with long-term outcome, (3) the breast cancer subtypes in which pCR is best correlated with long-term outcome and (4) the magnitude of pCR effect needed to improve EFS and OS. We compared three pCR definitions: absence of invasive cancer and in situ cancer in the breast and axillary nodes (ypT0ypN0), absence of invasive cancer in the breast and axillary nodes with DCIS allowed (ypT0/isypN0), and absence of invasive cancer in the breast with DCIS allowed irrespective of nodal involvement (ypT0/is). Results: Overall 13%, 18% and 22% of patients achieved a pCR defined as ypT0ypN0, ypT0/isypN0, and ypT0/is, respectively. Eradication of tumor from both the breast and lymph nodes (ypT0ypN0 or ypT0/isypN0) was better associated with improved EFS and OS compared to eradication of tumor from the breast alone (ypT0/is). Patients who achieved a pCR (ypT0/isypN0) had an improved EFS (HR = 0.48) and OS (HR = 0.36) compared to those who did not. pCR was uncommon in patients with low-grade hormone receptor-positive (HR+) tumors (7%) and more common in the following tumor subtypes: high-grade HR+ (16%), triple negative (34%), HR+/HER2+ (30%), and hormone receptor-negative (HR−)/HER2+ (50%). Patients with more aggressive tumor subtypes who achieved pCR had greater EFS compared to patients who did not achieve pCR as follows: HR+ high grade (HR = 0.27), HR+/HER2+ (HR = 0.58), HR−/HER2+ (HR = 0.25), and triple negative (HR = 0.24). A trial level analysis on the relationship between pCR effect size and EFS did not show a correlation. Conclusions: Individual patients who attain a pCR, defined as either ypT0ypN0 or ypT0/isypN0, have a more favorable long-term outcome. The data show comparable EFS or OS regardless of the presence or absence of DCIS. For consistency, a standard pCR definition (ypT0ypN0 or ypT0/isypN0) should be used in future trials. Impact of pCR effect is limited to patients with HR+/grade 3, HR−/HER2−, and HER2+ tumors. This meta-analysis did not establish the magnitude of increase in pCR rate needed to predict the superiority of one regimen over another in terms of EFS or OS. This may be due to low pCR rates and the heterogeneity of the patient population included in this meta-analysis. The absolute magnitude of improvement in pCR rate needed to impact long-term outcome may be greater than the observed difference in these trials and may vary according to breast cancer subtype. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-11.

Background: The risk of invasive breast cancer associated with benign breast disease (BBD) other than atypical hyperplasia and in situ breast cancer, especially with nonproliferative diagnosis, has not been explored extensively. This report evaluates the risk of breast cancer associated with this lower-category BBD (LC-BBD). Methods: 11 307 women without prior history of atypical hyperplasia or in situ breast cancer at randomization (1992-1997) were identified from the cohort of the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial. Pathologic findings from breast biopsy reports through August 2002 were reviewed, and Cox proportional hazards models were used to determine the relative risks (RRs) of breast cancer with 95% confidence intervals (CIs). The relative risks of breast cancer for LC-BBD were adjusted for treatment and for breast cancer risk as determined by the modified Gail model. Results: Of the 11 307 women, 1376 had LC-BBD, of whom 47 developed breast cancer, and of the 9931 women without LC-BBD, 291 developed breast cancer. The RR of breast cancer for women with LC-BBD relative to women without LC-BBD was 1.60 (95% CI ‫؍‬ 1.17 to 2.19). Among women 50 years of age and older, the RR of breast cancer for those with LC-BBD was 1.95 (95% CI ‫؍‬ 1.29 to 2.93). After adjustment for treatment and breast cancer risk, the RR of breast cancer for women with LC-BBD was 1.41 (95% CI ‫؍‬ 1.03 to 1.94). Conclusions: Women with LC-BBD had a statistically significant increased risk of breast cancer. The elevation of breast cancer risk was especially evident in women 50 years of age and older. Furthermore, this risk was independent of that associated with key epidemiologic breast cancer risk factors