The Breast Cancer Weight Loss trial (Alliance A011401): A description and evidence for the lifestyle intervention.

The Breast Cancer Weight Loss (BWEL) trial is a randomized controlled trial designed to determine whether weight loss after a breast cancer diagnosis can reduce the risk of cancer recurrence in women with overweight or obesity. The BWEL trial will compare the efficacy of a telephone-based weight-loss intervention plus health education materials versus health education materials alone on invasive disease-free survival in 3,181 women with stage II or III breast cancer and BMI > 27 kg/m2 . This report provides a detailed description of the goals and methods of the lifestyle intervention and the evidence supporting the intervention used in the BWEL trial. The intervention's primary goal for participants is to achieve and maintain a weight loss ≥ 10% of baseline weight through increased physical activity and caloric restriction. The evidence supporting the diet, physical activity, and behavioral components of this telephone-based weight-loss intervention, as well as strategies to promote participant engagement and retention, is described. The intervention is provided through 42 sessions delivered by trained health coaches over a 2-year period. If the BWEL lifestyle intervention is successful in improving cancer outcomes, then weight loss will be incorporated into the care of thousands of breast cancer patients.

Randomized phase III trial evaluating the role of weight loss in adjuvant treatment of overweight and obese women with early breast cancer (Alliance A011401): study design.

Excess body weight is a poor prognostic factor in women with early breast cancer, but the effect of weight loss on the risk of breast cancer recurrence and mortality in women who are overweight or obese at the time of breast cancer diagnosis has not been evaluated. The Alliance for Clinical Trials in Oncology Breast Cancer Weight Loss trial, also known as A011401, is testing the impact of a telephone-based weight loss program on invasive disease-free survival in 3136 women with a body mass index ≥27 kg/m2 who have recently been diagnosed with stage II-III, HER-2 negative breast cancer. Secondary outcomes of the trial include the impact of the weight loss intervention on overall survival, body weight, physical activity, dietary intakes, incidence of comorbidities, serum biomarkers and patient reported outcomes. Participants are randomized 1:1 to a 2-year, telephone-based weight loss intervention or to an education control group. The intervention is delivered through 42 telephone calls, delivered by health coaches based at the Dana-Farber Cancer Institute. Calls are supplemented by an intervention workbook, as well as a number of tools to help facilitate weight loss. Intervention goals include loss of 10% of baseline body weight, achieved through caloric restriction and increased physical activity. This large-scale study testing the impact of purposeful weight loss after cancer diagnosis on the risk of breast cancer recurrence and mortality has the potential to make weight loss programs a standard part of breast cancer treatment.

Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32.

BACKGROUND: Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples. METHODS: VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables. RESULTS: 237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15µmol/L). At 6 months, one patient (metformin) had MMA >0.4µmol/L and 3 (2 metformin, 1 placebo) had HC > 15µmol/L. CONCLUSIONS: There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.

Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32.

BACKGROUND: Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples. METHODS: Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo)adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80°C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided. RESULTS: Mean age was 52.1±9.5 years in the metformin group and 52.6 ± 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo)adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin. CONCLUSIONS: Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin.

Should women younger than 40 years of age with invasive breast cancer have a mastectomy? 15-year outcomes in a population-based cohort.

PURPOSE: Optimal local management for young women with early-stage breast cancer remains controversial. This study examined 15-year outcomes among women younger than 40 years treated with breast-conserving surgery plus whole-breast radiation therapy (BCT) compared with those treated with modified radical mastectomy (MRM). METHODS AND MATERIALS: Women aged 20 to 39 years with early-stage breast cancer diagnosed between 1989 and 2003 were identified in a population-based database. Primary outcomes of breast cancer-specific survival (BCSS), overall survival (OS) and secondary outcomes of local relapse-free survival (LRFS), locoregional relapse-free survival (LRRFS), and distant relapse-free survival (DRFS) were calculated using Kaplan-Meier methods and compared between BCT and MRM cohorts using log-rank tests. A planned subgroup analysis was performed on patients considered "ideal" for BCT (ie, T1N0, negative margins and no extensive ductal carcinoma in situ) and in whom local therapy may have the largest impact on survival because of low systemic risk. RESULTS: 965 patients were identified; 616 had BCT and 349 had MRM. The median follow-up time was 14.4 years (range, 8.4-23.3 years). Overall, 15-year rates of BCSS (76.0% vs 74.1%, P=.62), OS (74.2% vs 73.0%, P=.75), LRFS (85.4% vs 86.5%, P=.95), LRRFS (82.2% vs 81.6%, P=.61), and DRFS (74.4% vs 71.6%, P=.40) were similar between the BCT and MRM cohorts. In the "ideal" for BCT subgroup, there were 219 BCT and 67 MRM patients with a median follow-up time of 15.5 years. The 15-year BCSS (86.1% vs 82.9%, P=.57), OS (82.6% vs 82.9%, P=.89), LRFS (86.2% vs 84.2%, P=.50), LRRFS (83.1% vs 78.3%, P=.24), and DRFS (84.8% vs 79.1%, P=.17) were similar in the BCT and MRM cohorts. CONCLUSIONS: This population-based analysis with long-term follow-up confirmed that women younger than 40 years treated with BCT had similar 15-year outcomes compared with MRM. Young age alone is not a contraindication to BCT.

Is mastectomy superior to breast-conserving treatment for young women?

PURPOSE: To examine whether modified radical mastectomy (MRM) improves outcomes compared with breast-conserving treatment (BCT) in young women. METHODS AND MATERIALS: Women aged 20-49 years, diagnosed with early breast cancer between 1989 and 1998, were identified. Management with BCT or MRM was compared for local (L), locoregional (LR), and distant relapse-free survival (DRFS) and breast cancer-specific survival (BCSS) by age group (20-39 years, 40-49 years). The analysis was repeated for patients considered "ideal" candidates for BCT: tumor size < or =2 cm, pathologically negative axillary nodes, negative margins, and no reported ductal carcinoma in situ. RESULTS: A total of 1,597 women received BCT, and 801 had MRM. After a median follow-up of 9.0 years, the outcomes (L, LR, BCSS) were worse for the younger age group; however, the outcomes were not statistically different by type of local treatment. For women aged 20-39 years considered "ideal" for BCT, those treated with BCT had slightly lower LRFS compared with those treated with MRM (p = 0.3), but DRFS and BCSS were similar. CONCLUSIONS: A difference in LRFS at 10 years potentially favored MRM among women aged 20-39 years considered "ideal" BCT candidates but was not statistically significant and did not translate into a noticeable difference in DRFS or BCSS. Our data suggest that young age alone is not a contraindication to BCT.

Radiotherapy omission after breast-conserving surgery is associated with reduced breast cancer-specific survival in elderly women with breast cancer.

PURPOSE: To evaluate the effect of radiotherapy (RT) omission on survival in older breast cancer patients treated with breast-conserving surgery. METHODS: Data were analyzed for 4836 women aged 50 to 89 with T1-T2, N0-N1, M0 breast cancer. Tumor and treatment factors, relapse rates, and overall survival (OS) and breast cancer-specific survival (BCSS) were compared between women treated with and without RT in 3 age categories: 50 to 64 (n = 2398), 65 to 74 (n = 1665), and > or = 75 years (n = 773). RESULTS: Median follow-up was 7.5 years. Rates of RT omission significantly increased with advancing age (7%, 9%, and 26% in age 50-64, 65-74, and > or = 75 years respectively, P < .0001). RT omission was associated with significantly reduced local control, BCSS, and OS. Despite similar tumor characteristics and higher rates of systemic therapy use, women aged > or = 75 years were observed to have lower 5-year OS and BCSS when RT was omitted. CONCLUSION: These findings support the hypothesis that inadequate local therapy is associated with reduced survival in elderly women treated with breast-conserving therapy.

The value of FDG positron emission tomography in the management of patients with breast cancer.

Increasing experience with positron emission tomography (PET) scanning in breast cancer patients is revealing a significant role for this imaging modality. This report summarizes the experience of 2-[F18]fluoro-2-deoxy-D-glucose (FDG) PET scanning in 165 breast cancer patients from the BC Cancer Agency, British Columbia, Canada, and reviews the literature on this topic. Using the database at PETSCAN Vancouver, we identified imaged patients with a diagnosis of breast cancer. We then conducted a retrospective review of these patients' BC Cancer Agency charts to extract demographic and follow-up information. Between November 2000 and March 2003 we identified 165 patients with histologically confirmed breast cancer who had undergone PET scanning, were registered at the BC Cancer Agency, and had follow-up information. The median patient age was 52 years. The sensitivity of PET in detecting axillary metastases was 28%, and the specificity was 86%. At diagnosis, 5% of patients were diagnosed with distant metastases. In patients undergoing PET scanning because of suspected recurrence, the sensitivity and specificity for detecting recurrence were 89% and 88%, respectively. Distant metastases were demonstrated in 30% of patients who were thought only to have local-regional recurrence. The results suggest that there are two clinical situations in which PET appears to be particularly valuable. The first is in the evaluation of patients who are suspected of having a tumor recurrence. The other is in identifying patients with multifocal or distant sites of malignancy who otherwise appear to have an isolated, potentially curable, local-regional recurrence.

Adjuvant radiation therapy after breast-conserving surgery in elderly women with early-stage breast cancer: controversy or consensus?

Breast-conservation therapy (BCT), which consists of breast-conserving surgery (BCS) and postoperative radiation therapy (RT), provides similar levels of local control and survival compared with mastectomy. Although the incidence of breast cancer increases with age and the proportion of elderly women in the population continues to increase, clinical trials of BCT have included few women aged > or = 65 years, limiting the ability to establish clear consensus regarding optimal therapy in this population. This article examines the literature on BCT in elderly women with early-stage breast cancer. A systematic search of the Medline and CancerLit databases was conducted to identify articles specifically addressing BCT in elderly women. The outcomes evaluated were local control, disease-free survival, overall survival, and treatment-related toxicities. The lack of consensus in breast-conservation management in elderly patients is highlighted by a paucity of prospective data and numerous retrospective series reporting diverse treatment approaches with conflicting results. The available evidence from BCT trials with and without age subgroup analyses support BCS with postoperative RT as the standard approach associated with the most favorable local control outcomes. A low-risk subset of patients in whom RT may be omitted without compromising local control remains to be defined. Despite these findings, the use of standard therapy significantly decreases with advancing patient age. Although data specifically addressing BCT in elderly patients are limited, age should not preclude consideration of standard treatment strategies to optimize local disease control. Modern clinical trials with representative samples of elderly patients evaluating cancer recurrence and survival as well as functional and quality-of-life outcomes are needed to define optimal breast-conservation management for this important patient population.

Age-related variations in the use of axillary dissection: a survival analysis of 8038 women with T1-ST2 breast cancer.

PURPOSE: The use of axillary dissection (AD) in women with invasive breast cancer is increasingly questioned. This study analyzes the survival in women with T1-2 breast cancer according to age and AD use. METHODS AND MATERIALS: Data from the Breast Cancer Outcomes Unit Database were analyzed for 8038 women aged 50-89 years referred to the British Columbia Cancer Agency between 1989 and 1998 with invasive T1-2,M0 breast cancer. Tumor and treatment characteristics were compared between women treated with and without AD (AD+ vs. AD-) according to three age groups: 50-64, 65-74 and 75+ years. Regional relapse and actuarial 5-year overall and breast cancer-specific survival were compared between AD+ and AD- women. Multivariate analysis of age, tumor and treatment factors, and adjusted hazard ratios with AD omission were performed. RESULTS: AD was omitted more frequently with advancing age (4% vs. 8% vs. 22% in women aged 50-64, 65-74, and 75+ years, respectively, p <0.0001). Tumor characteristics were more favorable in AD- women, with fewer having Grade III disease, T2 tumors, or lymphovascular invasion (all p <0.0001). Women treated without AD were also less likely to undergo radiotherapy after lumpectomy or mastectomy (both p <0.0001). Systemic therapy use and regional relapse rates were comparable between AD- and AD+ women in each age-specific cohort. Multivariate analysis identified age, tumor size, grade, lymphovascular invasion, estrogen receptor status, clinical nodal palpability, type of surgery, and radiotherapy use as independent variables affecting survival. Hazard ratios adjusted for these variables showed AD omission to be associated with lower overall survival in the entire cohort (hazard ratio 1.52, p <0.0001) and lower breast cancer-specific survival in women aged 65-74 years (hazard ratio 1.99, p = 0.02). CONCLUSION: AD was more frequently omitted with advancing age. The lack of differences in systemic therapy use, regional relapse, and breast cancer-specific survival among AD- compared with AD+ women aged 75+ years suggests that AD use may be selectively omitted in this elderly cohort. However, the lower survival associated with AD omission among women aged 65-74 years, and the lack of a survival advantage among AD- women aged 50-64 years despite more favorable tumor characteristics and comparable systemic therapy use support the hypothesis that definitive locoregional therapy has an impact on survival.