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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.

Background: In 1998 the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated that tamoxifen treatment reduced the incidence of both invasive and noninvasive breast cancer in women at high risk for the disease. We examined the effect of tamoxifen treatment on the incidence of benign breast disease and the number of breast biopsies in the same group of women., Methods: We examined the medical records of 13 203 women with follow-up who participated in the NSABP Breast Cancer Prevention Trial. Included in this analysis were women who had undergone a breast biopsy and who had histologic diagnoses of adenosis, cyst, duct ectasia, fibrocystic disease, fibroadenoma, fibrosis, hyperplasia, or metaplasia. The relative risk (RR) for each histologic diagnosis was estimated for women who received tamoxifen and for women who received placebo. We also tallied the number of biopsies that women in the placebo and tamoxifen groups underwent., Results: Overall, tamoxifen treatment reduced the risk of benign breast disease by 28% (RR = 0.72, 95% confidence interval [CI] = 0.65 to 0.79). Tamoxifen therapy resulted in statistically significant reductions in the risk of adenosis (RR = 0.59, 95% CI = 0.47 to 0.73), cyst (RR = 0.66, 95% CI = 0.58 to 0.75), duct ectasia (RR = 0.72, 95% CI = 0.53 to 0.97), fibrocystic disease (RR = 0.67, 95% CI = 0.58 to 0.77), hyperplasia (RR = 0.60, 95% CI = 0.50 to 0.71), and metaplasia (RR = 0.51, 95% CI = 0.41 to 0.62). Tamoxifen therapy also reduced the risk for fibroadenoma (RR = 0.77, 95% CI = 0.56 to 1.04) and fibrosis (RR = 0.86, 95% CI = 0.72 to 1.03). Compared with the placebo group, the tamoxifen group had 29% (95% CI = 23% to 34%) fewer biopsies (1048 versus 1469) and 19% fewer women who underwent a biopsy (811 versus 1019). This resulted in a 29% reduction in the risk of biopsy in women treated with tamoxifen (RR = 0.71, 95% CI = 0.66 to 0.77). This risk reduction occurred predominantly in women younger than 50 years., Conclusion: Women in this study who received tamoxifen, especially younger women (i.e., <50 years), had a reduced incidence of clinically detected benign breast disease and underwent fewer breast biopsies.

Trastuzumab (Herceptin) provides clinical benefits for patients diagnosed with advanced breast cancers that have overexpressed the HER2 protein or have amplified the HER2 gene. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-31 is designed to test the advantage of adding Herceptin to the adjuvant chemotherapeutic regimen of doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) in the treatment of stage II breast cancer with HER2 overexpression or gene amplification. Eligibility is based on HER2 assay results submitted by the accruing institutions. We conducted a central review of the first 104 cases entered in this trial on the basis of immunohistochemistry (IHC) results. We found that 18% of the community-based assays, which were used to establish the eligibility of patients to participate in the B-31 study, could not be confirmed by HercepTest IHC or fluorescence in situ hybridization (FISH) by a central testing facility. This report provides a snapshot of the quality of HER2 assays performed in laboratories nationwide.

Background: Uncertainty about prognosis and treatment of axillary lymph node-negative patients with estrogen receptor (ER)-negative or ER-positive invasive breast tumors of 1 cm or less prompted the analysis of data from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials., Methods: Two hundred thirty-five patients with ER-negative tumors and 1024 patients with ER-positive tumors were identified in these trials. Patients with ER-negative tumors received surgery alone or surgery and chemotherapy. Patients with ER-positive tumors received surgery alone; surgery and tamoxifen; or surgery, tamoxifen, and chemotherapy. End points were relapse-free survival (RFS), event-free survival, and overall survival. A result was considered to be statistically significant with a P value of.05 or less; all statistical tests were two-sided., Results: The 8-year RFS of women with ER-negative tumors who received surgery alone or with chemotherapy was 81% and 90%, respectively (P = .06). Survival was similar in both groups (93% and 91%; P = .65). The 8-year RFS of women with ER-positive tumors was 86% after surgery alone, 93% when tamoxifen was added (P = .01), and 95% after the addition of tamoxifen and chemotherapy (P = .07 compared with tamoxifen). Survival in the three groups was 90%, 92% (P = .41), and 97%, respectively. The difference between the latter two groups was significant (P = .01). Regardless of ER status or treatment, overall mortality was 8%; one half of the deaths were related to breast cancer. Several covariates affected the risk of recurrence in ER-negative and ER-positive patients. Risk was greater in women with tumors of 1 cm than in those with tumors of less than 1 cm, in women aged 49 years or younger than in those aged 50 years or older, and in women with infiltrating ductal or lobular carcinoma than in those with other histologic tumor types., Conclusions: Chemotherapy and/or tamoxifen should be considered for the treatment of women with ER-negative or ER-positive tumors of 1 cm or less and negative axillary lymph nodes.

Background: The overall effect of prophylactic tamoxifen in women depends on the balance between the effects of the drug, which include preventing breast cancer and altering cardiovascular risk. In a recent clinical trial, postmenopausal estrogen-progestin therapy was shown to increase the risk of early cardiovascular events among women with a history of coronary heart disease (CHD). The cardiovascular effects of tamoxifen in women with and without CHD are not known. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT) is the only clinical trial that provides data to assess the cardiovascular effects of tamoxifen in women with and without CHD., Methods: A total of 13 388 women at increased risk for breast cancer were randomly assigned in the BCPT to receive either tamoxifen (20 mg/day) or placebo. Cardiovascular follow-up was available for 13 194 women, 1048 of whom had prior clinical CHD. Fatal and nonfatal myocardial infarction, unstable angina, and severe angina were tabulated (mean follow-up: 49 months). All statistical tests were two-sided., Results: Cardiovascular event rates were not statistically significantly different between women assigned to receive tamoxifen and those assigned to receive placebo, independent of pre-existing CHD. Among women without CHD (6074 on tamoxifen versus 6072 on placebo), risk ratios (95% confidence intervals [CIs]) for tamoxifen users were 1.75 (0.44 to 8.13) for fatal myocardial infarction, 1.11 (0.55 to 2.28) for nonfatal myocardial infarction, 0.69 (0.29 to 1.57) for unstable angina, and 0.83 (0.32 to 2.10) for severe angina. In women with CHD (516 on tamoxifen versus 532 on placebo), risk ratios (95% CIs) for tamoxifen users were 0.00 (0 to 1.58) for fatal myocardial infarction, 1.25 (0.32 to 5.18) for nonfatal myocardial infarction, 2.26 (0.87 to 6.55) for unstable angina, and 1.39 (0.23 to 9.47) for severe angina. There was no evidence that the lack of association between tamoxifen and cardiovascular events was related to an early increase in risk that may have been offset by a late decrease in risk., Conclusion: When used for breast cancer prevention in women with or without heart disease, tamoxifen is not associated with beneficial or adverse cardiovascular effects.

Background: Recent retrospective analyses have suggested that breast cancer patients whose tumors overexpress HER2 derive preferential benefit from treatment with anthracyclines such as doxorubicin. This has led some clinicians to propose that HER2 should be used as a predictive marker in choosing between anthracycline-based regimens and combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). We evaluated this recommendation in a retrospective study of National Surgical Adjuvant Breast and Bowel Project Protocol B-15, in which patients received a combination of doxorubicin and cyclophosphamide (AC), CMF, or AC followed by CMF. We hypothesized that AC would be superior to CMF only in the HER2-positive patients., Methods: Immunohistochemical detection of HER2 was performed on tumor sections from 2034 of 2295 eligible patients. We used statistical analysis to evaluate the interaction between the efficacy of the assigned treatments and HER2 overexpression. All statistical tests were two-sided., Results: Tumor sections from 599 patients (29%) stained positive for HER2. AC was superior to CMF in HER2-positive patients only, although differences in outcomes did not reach statistical significance. In the HER2-positive cohort, relative risks of failure (i.e., after AC treatment as compared with CMF treatment) were 0.84 for disease-free survival (DFS) (95% confidence interval [CI] = 0.65--1.07; P =.15), 0.82 for survival (95% CI = 0.63--1.06; P =.14), and 0.80 for recurrence-free survival (RFS) (95% CI = 0.62--1.04; P =.10). Tests for interaction between treatment and HER2 status were suggestive but not statistically significant (P =.19 for DFS, P =.11 for survival, and P =.08 for RFS)., Conclusions: These results, together with overview results indicating minor overall superiority for anthracycline-based regimens relative to CMF, indicate a preference for the AC regimen in patients with HER2-positive tumors. Both AC and CMF regimens may be considered for patients with HER2-negative tumors.

Background: Overexpression of the erbB-2 protein by breast cancer cells has been suggested to be a predictor of response to doxorubicin. A retrospective study was designed to test this hypothesis., Methods: In National Surgical Adjuvant Breast and Bowel Project protocol B-11, patients with axillary lymph node-positive, hormone receptor-negative breast cancer were randomly assigned to receive either L-phenylalanine mustard plus 5-fluorouracil (PF) or a combination of L-phenylalanine mustard, 5-fluorouracil, and doxorubicin (PAF). Tumor cell expression of erbB-2 was determined by immunohistochemistry for 638 of 682 eligible patients. Statistical analyses were performed to test for interaction between treatment and erbB-2 status (positive versus negative) with respect to disease-free survival (DFS), survival, recurrence-free survival (RFS), and distant disease-free survival (DDFS). Reported P values are two-sided., Results: Overexpression of erbB-2 (i.e., positive immunohistochemical staining) was observed in 239 (37.5%) of the 638 tumors studied. Overexpression was associated with tumor size (P=.02), lack of estrogen receptors (P=.008), and the number of positive lymph nodes (P=.0001). After a mean time on study of 13.5 years, the clinical benefit from doxorubicin (PAF versus PF) was statistically significant for patients with erbB-2-positive tumors--DFS: relative risk of failure (RR)=0.60 (95% confidence interval [CI]=0.44-0.83), P=.001; survival: RR=0.66 (95% CI=0.47-0.92), P =.01; RFS: RR=0.58 (95% CI=0.42-0.82), P=.002; DDFS: RR=0.61 (95% CI=0.44-0.85), P=.003. However, it was not significant for patients with erbB-2-negative tumors-DFS: RR=0.96 (95% CI=0.75-1.23), P=.74; survival: RR =0.90 (95% CI=0.69-1.19), P=.47; RFS: RR=0.88 (95% CI=0.67-1.16), P=.37; DDFS: RR=1.03 (95% CI=0.79-1.35), P=.84. Interaction between doxorubicin treatment and erbB-2 overexpression was statistically significant for DFS (P=.02) and DDFS (P=.02) but not for survival (P= .15) or RFS (P=.06)., Conclusions: These data support the hypothesis of a preferential benefit from doxorubicin in patients with erbB-2-positive breast cancer.

Background: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992., Methods: Women (N=13388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time., Results: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35-4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older., Conclusions: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease.