Reena S. Cecchini

Update of the national surgical adjuvant breast and bowel project Study of Tamoxifen and Raloxifene (STAR) P-2 trial: Preventing breast cancer

The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)–approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05–1.47) and for noninvasive disease, 1.22 (95% CI, 0.95–1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36–0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12–0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60–0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer. Cancer Prev Res; 3(6); 696–706. ©2010 AACR.

Menstrual History and Quality-of-Life Outcomes in Women With Node-Positive Breast Cancer Treated With Adjuvant Therapy on the NSABP B-30 Trial

PURPOSE Premenopausal women with breast cancer receiving adjuvant chemotherapy are at risk for amenorrhea. The National Surgical Adjuvant Breast and Bowel Project B-30 trial included menstrual history (MH) and quality-of-life (QOL) studies to compare treatments on these outcomes. PATIENTS AND METHODS Patients were randomly assigned to sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T; AC→T), concurrent TAC, or AT, which varied in duration (24, 12, 12 weeks, respectively), and use of C. Endocrine therapy was prescribed for women with hormone receptor-positive tumors. MH and QOL were assessed with standardized questionnaires at baseline; cycle 4, day 1; and every 6 months through 24 months. Prespecified analyses examined rates of amenorrhea by treatment arm, the relationship between amenorrhea and QOL, and QOL by treatment arm. RESULTS Amenorrhea 12 months after random assignment was significantly different between treatment groups: 69.8% for AC→T, 57.7% for TAC, and 37.9% for AT (P < .001). The AT group without tamoxifen had the lowest rate of amenorrhea. QOL was poorer for patients receiving AC→T at 6 months but similar to others by 12 months. Post-treatment symptoms were increased above baseline for all treatments. Multivariable repeated measures modeling demonstrated that treatment arm, time point, age, and tamoxifen use were significantly associated with symptom severity (all P values < .002). CONCLUSION Amenorrhea rates differed significantly by treatment arm, with the AT arm having the lowest rate. Patients treated with longer duration therapy (AC→T) had greater symptom severity and poorer QOL at 6 months, but did not differ from shorter duration treatments at 12 months.

Body Mass Index and the Risk for Developing Invasive Breast Cancer among High-Risk Women in NSABP P-1 and STAR Breast Cancer Prevention Trials

High body mass index (BMI) has been associated with an increased risk for breast cancer among postmenopausal women. However, the relationship between BMI and breast cancer risk in premenopausal women has remained unclear. Data from two large prevention trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) were used to explore the relationship between baseline BMI and breast cancer risk. The analyses included 12,243 participants with 253 invasive breast cancer events from the Breast Cancer Prevention Trial (P-1) and 19,488 participants with 557 events from the Study of Tamoxifen and Raloxifene (STAR). Both studies enrolled high-risk women (Gail score ≥ 1.66) with no breast cancer history. Women in P-1 were pre- and postmenopausal, whereas women in STAR (P-2) were all postmenopausal at entry. Using Cox proportional hazards regression, we found slight but nonsignificant increased risks of invasive breast cancer among overweight and obese postmenopausal participants in STAR and P-1. Among premenopausal participants, an increased risk of invasive breast cancer was significantly associated with higher BMI (P = 0.01). Compared with BMI less than 25, adjusted HRs for premenopausal women were 1.59 for BMI 25 to 29.9 and 1.70 for BMI 30 or more. Our investigation among annually screened, high-risk participants in randomized, breast cancer chemoprevention trials showed that higher levels of BMI were significantly associated with increased breast cancer risk in premenopausal women older than 35 years, but not postmenopausal women. Cancer Prev Res; 5(4); 583–92. ©2012 AACR.

Quality of Life in Operable Colon Cancer Patients Receiving Oral Compared With Intravenous Chemotherapy: Results From National Surgical Adjuvant Breast and Bowel Project Trial C-06

PURPOSE We compared health-related quality of life (HRQL), symptoms, and convenience of care (COC) in patients with stage II/III carcinoma of the colon who received either oral uracil/ftorafur (UFT) plus leucovorin (LV) or standard intravenous (IV) fluorouracil (FU) plus LV as adjuvant chemotherapy. PATIENTS AND METHODS We measured HRQL with the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire, Short Form-36 Vitality Scale (SF-36), and a Quality of Life Rating Scale (QLRS) at baseline, once during chemotherapy, and at 1 year. We used the Symptom Distress Scale (SDS) and treatment-specific Symptom Checklist (SCL) to assess symptoms and a modified Burden of Care form to assess COC at baseline, on day 1 of each treatment cycle, and at 1 year. Repeated measures analyses controlling for demographic variables and baseline scores were used for statistical comparisons. RESULTS The study accrued 1,608 patients, 803 to the FU arm and 805 to the UFT arm. There were no differences between the arms in overall FACT-C scores, FACT-C scores within the subscales of colon-specific, physical, emotional, social, and functional health, or QLRS scores. Patients taking UFT reported substantially higher COC. Statistically significant but small differences were observed for SF-36, favoring FU, and for SDS and SCL, both favoring UFT. CONCLUSION Patients perceive adjuvant treatment with UFT + LV as more convenient than standard IV treatment with FU + LV. Both regimens are well tolerated and do not differ in their impact on HRQL.

Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial

BACKGROUND Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy. METHODS The double-blind, randomised, phase 3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial was done in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation were enrolled and randomly assigned (1:1) to receive either oral tamoxifen 20 mg per day (with matching placebo in place of anastrozole) or oral anastrozole 1 mg per day (with matching placebo in place of tamoxifen) for 5 years. Randomisation was stratified by age (<60 vs ≥60 years) and patients and investigators were masked to treatment allocation. The primary outcome was breast cancer-free interval, defined as time from randomisation to any breast cancer event (local, regional, or distant recurrence, or contralateral breast cancer, invasive disease, or ductal carcinoma in situ), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00053898, and is complete. FINDINGS Between Jan 1, 2003, and June 15, 2006, 3104 eligible patients were enrolled and randomly assigned to the two treatment groups (1552 to tamoxifen and 1552 to anastrozole). As of Feb 28, 2015, follow-up information was available for 3083 patients for overall survival and 3077 for all other disease-free endpoints, with median follow-up of 9·0 years (IQR 8·2-10·0). In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0·73 [95% CI 0·56-0·96], p=0·0234). A significant time-by-treatment interaction (p=0·0410) became evident later in the study. There was also a significant interaction between treatment and age group (p=0·0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism--a known side-effect of tamoxifen-for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group. INTERPRETATION Compared with tamoxifen, anastrozole treatment provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age. This finding means that women will benefit from having a choice of effective agents for ductal carcinoma in situ. FUNDING US National Cancer Institute and AstraZeneca Pharmaceuticals LP.

The use of tamoxifen and raloxifene for the prevention of breast cancer.

The NSABP Study of Tamoxifen and Raloxifene (STAR), launched in 1999, compared tamoxifen with raloxifene in a population of healthy postmenopausal women at increased risk for breast cancer to determine the relative effects on the risk of invasive breast cancer. To be eligible for participation, a woman had to be healthy with at least a 5-year predicted breast cancer risk of 1.66% based on the Gail model or a history of lobular carcinoma in situ (LCIS) treated by local excision alone. All participants were at least 35 years of age and postmenopausal. Between July 1999 and November 2004, 19,747 participants were randomized to receive either tamoxifen (20 mg, plus placebo) or raloxifene (60 mg, plus placebo) daily for a 5-year period. The mean age of the participants was 58.5 years; 93% were white and 51.6% had a hysterectomy prior to entering the study. Of the women, 71% had one or more first degree female relatives (mother, sister, daughter) with a history of breast cancer and 9.2% of the women had a personal history of LCIS. A history of atypical hyperplasia of the breast was noted in 22.7% of the participants. The mean predicted 5-year risk of developing breast cancer among the study population was 4.03% (SD, 2.17%) with a lifetime predicted risk of 16%. The mean time of follow-up is 3.9 years (SD, 1.6 years). There was no difference between the effect oftamoxifen and the effect of raloxifene on the incidence of invasive breast cancer; there were 163 cases of invasive breast cancer in the tamoxifen-treated group and 168 cases in those women assigned to raloxifene (incidence 4.30 per 1,000 vs 4.41 per 1,000; RR 1.02; 95% CI, 082-1.28). There were fewer cases of noninvasive breast cancer (LCIS and ductal carcinoma in situ [DCIS]) in the tamoxifen group (57 cases) than in the raloxifene group (80 cases), although the difference is not yet statistically significant (incidence 1.51 vs 2.11 per 1,000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 cases with raloxifene (RR, 0.63; 95% CI, 0.35-1.08).

Gynecologic conditions in participants in the NSABP breast cancer prevention study of tamoxifen and raloxifene (STAR)

OBJECTIVE This study reports the gynecologic conditions in postmenopausal women (intact uterus on enrollment) in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study of tamoxifen and raloxifene (STAR)/P-2 trial. STUDY DESIGN This study, with a median follow-up period of 81 months, evaluated the incidence rates/risks of gynecologic conditions among women who were treated with tamoxifen and raloxifene. RESULTS Compared with women who received tamoxifen therapy, women who received raloxifene therapy had a lower incidence of uterine cancer (relative risk, 0.55)/endometrial hyperplasia (relative risk, 0.19), leiomyomas (relative risk, 0.55), ovarian cysts (relative risk, 0.60), and endometrial polyps (relative risk, 0.30) and had fewer procedures performed. Women receiving tamoxifen therapy had more hot flashes (P < .0001), vaginal discharge (P < .0001), and vaginal bleeding (P < .0001). CONCLUSION Our results suggest that tamoxifen has more of an estrogenic effect on the gynecologic reproductive organs. These effects should be considered in counseling women on options for breast cancer prevention.

Patient-reported outcomes with anastrozole versus tamoxifen for postmenopausal patients with ductal carcinoma in situ treated with lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial

BACKGROUND The NSABP B-35 trial compared 5 years of treatment with anastrozole versus tamoxifen for reducing subsequent occurrence of breast cancer in postmenopausal patients with ductal carcinoma in situ. This report assesses the effect of these drugs on quality of life and symptoms. METHODS The study was done at 333 hospitals in North America. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole breast irradiation were randomly assigned to receive either tamoxifen (20 mg/day) or anastrazole (1 mg/day) for 5 years, stratified by age (<60 years vs ≥60 years). Patients and investigators were masked to treatment allocation. Patients completed questionnaires at baseline and every 6 months thereafter for 6 years. The primary outcomes were SF-12 physical and mental health component scale scores, and vasomotor symptoms (as per the BCPT symptom scale). Secondary outcomes were vaginal symptoms and sexual functioning. Exploratory outcomes were musculoskeletal pain, bladder symptoms, gynaecological symptoms, cognitive symptoms, weight problems, vitality, and depression. We did the analyses by intention to treat, including patients who completed questionnaires at baseline and at least once during follow-up. This study is registered with ClinicalTrials.gov, NCT00053898. FINDINGS Between Jan 6, 2003, and June 15, 2006, 3104 patients were enrolled in the study, of whom 1193 were included in the quality-of-life substudy: 601 assigned to tamoxifen and 592 assigned to anastrozole. We detected no significant difference between treatment groups for: physical health scores (mean severity score 46·72 for tamoxifen vs 45·85 for anastrozole; p=0·20), mental health scores (52·38 vs 51·48; p=0·38), energy and fatigue (58·34 vs 57·54; p=0·86), or symptoms of depression (6·19 vs 6·39; p=0·46) over 5 years. Vasomotor symptoms (1·33 vs 1·17; p=0·011), difficulty with bladder control (0·96 vs 0·80; p=0·0002), and gynaecological symptoms (0·29 vs 0·18; p<0·0001) were significantly more severe in the tamoxifen group than in the anastrozole group. Musculoskeletal pain (1·50 vs 1·72; p=0·0006) and vaginal symptoms (0·76 vs 0·86; p=0·035) were significantly worse in the anastrozole group than in the tamoxifen group. Sexual functioning did not differ significantly between the two treatments (43·65 vs 45·29; p=0·56). Younger age was significantly associated with more severe vasomotor symptoms (mean severity score 1·45 for age <60 years vs 0·65 for age ≥60 years; p=0·0006), vaginal symptoms (0·98 vs 0·65; p<0·0001), weight problems (1·32 vs 1·02; p<0·0001), and gynaecological symptoms (0·26 vs 0·22; p=0·014). INTERPRETATION Given the similar efficacy of tamoxifen and anastrozole for women older than age 60 years, decisions about treatment should be informed by the risk for serious adverse health effects and the symptoms associated with each drug. For women younger than 60 years old, treatment decisions might be driven by efficacy (favouring anastrozole); however, if the side-effects of anastrozole are intolerable, then switching to tamoxifen is a good alternative. FUNDING US National Cancer Institute, AstraZeneca Pharmaceuticals.

Baseline mammographic breast density and the risk of invasive breast cancer in postmenopausal women participating in the NSABP Study of Tamoxifen and Raloxifene (STAR)

Mammographic breast density is an established risk factor for breast cancer. However, results are inconclusive regarding its use in risk prediction models. The current study evaluated 13,409 postmenopausal participants in the NSABP Study of Tamoxifen and Raloxifene. A measure of breast density as reported on the entry mammogram report was extracted and categorized according to The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) classifications. An increased risk of invasive breast cancer was associated with higher mammographic breast density (P < 0.001). The association remained significant after adjusting for age, treatment, and smoking history [HR 1.35, 95% confidence interval (CI): 1.16–1.58], as well as when added to a model including the Gail score (HR 1.33, 95% CI: 1.14–1.55). At five years after random assignment, time-dependent area under the curve (AUC) improved from 0.63 for a model with Gail score alone to 0.64 when considering breast density and Gail score. Breast density was also significant when added to an abbreviated model tailored for estrogen receptor-positive breast cancers (P = 0.02). In this study, high BI-RADS breast density was significantly associated with increased breast cancer risk when considered in conjunction with Gail score but provided only slight improvement to the Gail score for predicting the incidence of invasive breast cancer. The BI-RADS breast composition classification system is a quick and readily available method for assessing breast density for risk prediction evaluations; however, its addition to the Gail model does not seem to provide substantial predictability improvements in this population of postmenopausal healthy women at increased risk for breast cancer. Cancer Prev Res; 5(11); 1321–9. ©2012 AACR.

An association between postoperative radiotherapy for primary breast cancer in 11 National Surgical Adjuvant Breast and Bowel Project (NSABP) studies and the subsequent appearance of pleural mesothelioma.

Objectives:Among the minority of patients with pleural mesothelioma and no known exposure to asbestos, there have been case reports suggesting a possible association with previous radiotherapy. The association between radiotherapy for primary breast cancer and the subsequent occurrence of mesothelioma was investigated in women entered into 11 National Surgical Adjuvant Breast and Bowel Project (NSABP) prospective clinical trials for breast cancer. Methods:Follow-up information was obtained on 22,140 patients entered into 11 NSABP clinical trials for treatment of primary breast cancer between 1971 and 1994. Postoperative radiotherapy was administered to 9342 patients, mainly after lumpectomy. Postlumpectomy patients were treated with radiotherapy just to the ipsilateral breast and without regional nodal irradiation. There were 12,798 patients who did not have postoperative radiotherapy, and almost all had mastectomy. Results:Three pleural mesotheliomas were identified, and all occurred in the ipsilateral thorax of the irradiated patients (P = 0.009). All had received postlumpectomy breast irradiation for ductal carcinoma in situ. None had a known previous exposure to asbestos. Conclusions:There appears to be a small but statistically significant increased risk of developing mesothelioma following radiotherapy administered for primary breast cancer. However, in absolute numbers, the risk is too small to be considered a contraindication to administering radiotherapy when indicated.