Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

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 = 13 388) 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. [J Natl Cancer Inst 1998;90:1371‐88]

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Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

Background In 1976, we initiated a randomized trial to determine whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer. Methods A total of 1851 women for whom follow-up data were available and nodal status was known underwent randomly assigned treatment consisting of total mastectomy, lumpectomy alone, or lumpectomy and breast irradiation. Kaplan–Meier and cumulative-incidence estimates of the outcome were obtained. Results The cumulative incidence of recurrent tumor in the ipsilateral breast was 14.3 percent in the women who underwent lumpectomy and breast irradiation, as compared with 39.2 percent in the women who underwent lumpectomy without irradiation (P<0.001). No significant differences were observed among the three groups of women with respect to disease-free survival, distant-disease–free survival, or overall survival. The hazard ratio for death among the women who underwent lumpectomy alone, as compared with those wh...

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Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.

https://www.chpso.org/sites/main/files/file-attachments/chest-2008-geerts-381s-453s.pdf

Prevention of Venous Thromboembolism* American College of Chest Physicians Evidence- Based Clinical Practice Guidelines (8th Edition)

Purpose To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers. Methods The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance. Results Up to 20% of current IHC determinations of ER and PgR testing worldwide may be inaccurate (false negative or false positive). Most of the issues with testing have occurred because of variation in preanalytic variables, thresholds for positivity, and interpretation criteria. Recommendations The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, reproducible assay performance is proposed. Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be considered positive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.

/pdf/american-society-of-clinical-oncology-college-of-american-33ect3oz8r.pdf

American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer

Breast cancer trials on trial: a case of conflicting ethical interests.

1524 Background: The double-blind, prospective, BCPT demonstrated a 50% reduction in the risk of breast cancer (bc) for tamoxifen (T) v placebo (P), yet many women at risk of bc do not adhere to the full 5-year course. The goal of this first report of the rich BCPT drug adherence data is to identify groups susceptible to poor adherence, based on their obesity, cigarette smoking, alcohol use, and leisure-time physical activity. Methods: 13,338 women at high risk of bc were randomly assigned 6/92-9/97 to 20 mg/day T v P; we analyzed the 11,064 enrolled more than 3 years (yrs) before the trial unblinding 5/98. Endpoints are drug adherence (taken 100% of assigned pills per staff-administered questionnaires, excluding protocol-required discontinuation) at 1 and 36 months (mos). Protocol-specified multivariable logistic regression tested lifestyle factors, controlling for anticipated demographic and medical predictors. Odds ratios (OR) are given with 95% bracketed confidence intervals. Results: At baseline, 60%...

Cigarette smoking, fitness, and obesity as predictors of chemoprevention adherence among women in the National Surgical Adjuvant Breast and Bowel Program (NSABP) Breast Cancer Prevention Trial (BCPT).

The chapter deals with multicenter clinical trials, which are defined as studies involving two or more field sites conducted according to a common protocol that uses a single data coordinating center to receive, process, and analyze study data. Several examples are provided. Organizational, structural, and analytic aspects of trials, and guidelines for the conduct of such studies are discussed.


Keywords:

multicenter trials;
clinical trials

Multicenter Trials: Rationale and Examples †

Purpose: This is the initial report from the healthrelated quality of life (HRQL) component of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. This report provides an overview of HRQL findings, comparing tamoxifen and placebo groups, and advice to clinicians counseling women about the use of tamoxifen in a prevention setting. Patients and Methods: This report covers the baseline and the first 36 months of follow-up data on 11,064 women recruited over the first 24 months of the study. Findings are presented from the Center for Epidemiological Studies‐Depression Scale (CES-D), the Medical Outcomes Study 36-Item Short Form Health Status Survey (MOS SF-36) and sexual functioning scale, and a symptom checklist. Results: No differences were found between placebo and tamoxifen groups for the proportion of participants scoring above a clinically significant level on the CES-D. No differences were found between groups for the MOS SF-36 summary physical and mental scores. The mean number of symptoms reported was consistently higher in the tamoxifen group and was associated with vasomotor and gynecologic symptoms. Significant increases were found in the proportion of women on tamoxifen reporting problems of sexual functioning at a definite or serious level, although overall rates of sexual activity remained similar. Conclusion: Women need to be informed of the increased frequency of vasomotor and gynecologic symptoms and problems of sexual functioning associated with tamoxifen use. Weight gain and depression, two clinical problems anecdotally associated with tamoxifen treatment, were not increased in frequency in this trial in healthy women, which is good news that also needs to be communicated. J Clin Oncol 17:2659-2669. r 1999 by American Society of Clinical Oncology.

Health-Related Q uality o f L ife a nd T amoxifen i n B reast Cancer P revention: A R eport F rom t he N ational S urgical Adjuvant B reast a nd B owel P roject P -1 S tudy

Walter M. Cronin

Papers

Breast cancer trials on trial: a case of conflicting ethical interests.

Cigarette smoking, fitness, and obesity as predictors of chemoprevention adherence among women in the National Surgical Adjuvant Breast and Bowel Program (NSABP) Breast Cancer Prevention Trial (BCPT).

Multicenter Trials: Rationale and Examples †

Health-Related Q uality o f L ife a nd T amoxifen i n B reast Cancer P revention: A R eport F rom t he N ational S urgical Adjuvant B reast a nd B owel P roject P -1 S tudy