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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. [ABSTRACT FROM AUTHOR]

Background: Favorable progression‐free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth receptor 2 (HER2)‐positive metastatic breast cancer (MBC), treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first‐ and second‐line setting, with a median follow‐up of 33 months. Here, we report updated PFS and OS results with more than 2 years of additional follow‐up. Materials and Methods: In this phase II study, adult patients with HER2‐positive MBC who received no or one prior therapy received intravenous paclitaxel (80 mg/m2 weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21‐day cycles. Primary endpoint was 6‐month PFS, and secondary endpoints included median PFS and OS. Results: From January 2011 to December 2013, 69 patients were enrolled: 51 (74%) and 18 (26%) were treated in first‐ and second‐line metastatic settings, respectively. As of August 21, 2017, the median follow‐up was 59 months (range, 20–75 months; 67 [97%] patients were evaluable for efficacy). The 6‐month PFS was 86% (95% confidence interval [CI] 0.76–0.93). The median PFS was 24.2 months (95% CI 17–35) for the overall population; it was 25.7 months (95% CI 17.0 to not reached) and 20.1 months (95% CI 8.5–33.0) for patients with no and one prior treatment, respectively. The median OS was not reached for the overall group; it was not reached and 39.7 months (95% CI 32.9–66.7) for patients with no and one prior treatment, respectively. Treatment was well tolerated with no additional safety concerns. Conclusion: With a longer follow‐up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and a median OS not reached. Implications for Practice: The combination of weekly paclitaxel, trastuzumab, and pertuzumab has been endorsed by the National Comprehensive Cancer Network as one of the first‐line treatment options in patients with human epidermal growth receptor 2 (HER2)‐positive metastatic breast cancer (MBC). However, the long‐term safety and efficacy are still unknown. Findings from this phase II study provide favorable preliminary data on the safety and efficacy of trastuzumab and pertuzumab in combination with weekly paclitaxel at 5‐year follow‐up, and it remains an effective first‐line treatment option for patients with HER2‐positive MBC. The development of HER2‐targeted therapy has dramatically changed the outcomes of patients with HER2‐positive breast cancer. This article reports 5‐year outcome and toxicity data for patients originally enrolled in a phase II study evaluating the combination of weekly paclitaxel, trastuzumab, and pertuzumab for HER2‐positive metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Background: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer.Methods: In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy.Results: Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2-4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8-55).Conclusion: The RP2D of ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer.Trial Registration: ClinicalTrials.gov NCT02060253 . Registered 30 January 2014. [ABSTRACT FROM AUTHOR]

PURPOSE In breast cancer, preclinical models suggest that antiangiogenic therapy in combination with antiestrogens may prevent or overcome resistance to endocrine therapy. This review aims to discuss feasibility and phase II studies that have led to ongoing randomized trials of combination treatment with antiangiogenic agents and endocrine therapy. METHODS A systematic search of PubMed and conference databases was performed to identify reports of phase I-III clinical trials investigating combination endocrine therapy with antiangiogenic agents in breast cancer. In addition, results of our feasibility trial of letrozole plus bevacizumab were updated. RESULTS We identified 11 trials that reported data for or are currently evaluating the combination of antiangiogenic agents with endocrine therapy: seven trials evaluated endocrine therapy plus bevacizumab, and four trials evaluated endocrine therapy plus tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor receptor (VEGFR). Side effects that have emerged from this combination include hypertension (HTN), proteinuria, and ''off-target'' TKI side effects including skin rash and diarrhea. Early efficacy data suggests activity for this combination. CONCLUSION Clinical trials have demonstrated the feasibility of endocrine therapy in combination with antiangiogenic agents. Phase III proof-of-efficacy trials of endocrine plus anti-VEGF therapy are ongoing (CALGB 40503, GEICAM 2006-11/GBG 51). [ABSTRACT FROM AUTHOR]

Abstract: Adjuvant chemotherapy for breast cancer reduces the risks of recurrence and death in many subsets of patients. The quest for better regimens, defined as both more effective and less toxic has led to numerous clinical trials testing the taxanes in the adjuvant setting. These trials are generally positive but do not clearly identify a single best or ideal regimen for all patients. This paper reviews the available data in this area of clinical research. [Copyright &y& Elsevier]

Background: Preclinical and observational studies suggest a relationship between dietary fat intake and breast cancer, but the association remains controversial. We carried out a randomized, prospective, multicenter clinical trial to test the effect of a dietary intervention designed to reduce fat intake in women with resected, early-stage breast cancer receiving conventional cancer management. Methods: A total of 2437 women were randomly assigned between February 1994 and January 2001 in a ratio of 40 : 60 to dietary intervention (n = 975) or control (n = 1462) groups. An interim analysis was performed after a median follow-up of 60 months when funding for the intervention ceased. Mean differences between dietary intervention and control groups in nutrient intakes and anthropometric variables were compared with (tests. Relapse-free survival was examined using Kaplan-Meier analysis, stratified log-rank tests, and Cox proportional hazards models. Statistical tests were two-sided. Results: Dietary fat intake was lower in the intervention than in the control group (fat grams/day at 12 months, 33.3 [95% confidence interval {CI} = 32.2 to 34.5] versus 51.3 [95% CI = 50.0 to 52.7], respectively; P<.001), corresponding to a statistically significant (P = .005), 6-pound lower mean body weight in the intervention group. A total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) have been reported in 96 of 975 (9.8%) women in the dietary group and 181 of 1462 (12.4%) women in the control group. The hazard ratio of relapse events in the intervention group compared with the control group was 0.76 (95% CI = 0.60 to 0.98, p = .077 for stratified log rank and P = .034 for adjusted Cox model analysis). Exploratory analyses suggested a differential effect of the dietary intervention based on hormonal receptor status. Conclusions: A lifestyle intervention reducing dietary fat intake, with modest influence on body weight, may improve relapse-free survival of breast cancer patients receiving conventional cancer management. Longer, ongoing nonintervention follow-up will address original protocol design plans, which called for 3 years of follow-up after completion of recruitment. [ABSTRACT FROM AUTHOR]

The article presents a medical report concerning estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. The article suggests the much progress has been made in the treatment of early stage breast cancer, and that in patients with hormone-sensitive tumors, tamoxifen reduces the risk of recurrence and death by more than 30%. Additionally, treatment with aromatase inhibitors further reduces the risk of recurrence in post-menopausal women with estrogen-receptor positive tumors.

Summary: Modern chemotherapy has diminished the risks of distant relapse and death in many subgroups of patients with early stage breast cancer. Although the initial trials relied on empirically designed regimens, studies are increasingly based on preclinical science and reflect the growing understanding of the molecular basis of cancer. Empiric clinical trials proved the worth of combination chemotherapy, the limited value of very long courses of treatment, and the benefits of adding first anthracyclines and then later taxanes. More recent trials have demonstrated the limits on empiric dose escalation and the benefits of optimized scheduling. Many trials are currently focused on novel targeted agents. Based on several decades of studies in thousands of women it is reasonable to consider a combination of chemotherapy agents for patients with hormone unresponsive or otherwise high-risk tumors. Anthracyclines and taxanes should be incorporated into the treatment plans of patients in the higher risk subsets and the specific regimens should be taken from the several randomized studies. When available, eligible patients should be enrolled on prospective clinical trials. [Copyright &y& Elsevier]

This article focuses on adjuvant breast cancer therapy. Increased early detection and improved treatment have made clinical cure possible for more patients with breast cancer than ever before. The medical oncologist contributes to this outcome through participation in the multidisciplinary care of patients with early stage disease and by providing systemic adjuvant therapy designed to treat undetectable metastatic foci of disease. The article reviews the metaanalyses performed every fifth year at Oxford University to provide a foundation for clinical practice, and clinical trials.

Big data represents a new opportunity to increase our understanding of cancer care as it is practiced globally and to improve it through the refinement of clinic guidelines and the identification of knowledge gaps. Here we review the historical approach to evidence development (randomized clinical trials), some of their limitations, and the complementary role that big data analytics may play. [ABSTRACT FROM AUTHOR]

Summary: Background: The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. Methods: The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. Findings: There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0·006; hazard ratio [HR] 2·64, 95% CI 1·33–5·27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0·97; HR 1·02, 0·54–1·93), but an improvement in disease-free survival for those with a high recurrence score (score ≥31; log-rank p=0·033; HR 0·59, 0·35–1·01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0·029), with no additional prediction beyond 5 years (p=0·58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. Interpretation: The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. Funding: National Cancer Institute and Genomic Health. [Copyright &y& Elsevier]

Summary: The neoadjuvant setting provides a unique opportunity to study the effect of systemic treatments on breast cancer biology and to identify clinically useful prognostic and predictive biomarkers. Discrepancies and inconsistencies in the use of definitions and endpoint assessments in this setting confound the analysis and interpretation of results across clinical trials and hinder research progress. This Review represents a joint effort of the Breast International Group and the National Cancer Institute-sponsored North American Breast Cancer Group to provide clinicians and researchers with a series of standardised definitions and endpoints that could be implemented in future neoadjuvant clinical trials. Definitions of the setting of interest and of survival endpoints are recommended, together with proposals for standard assessment of the response to treatment, use of functional and molecular imaging endpoints, and characterisation and selection of the population to treat. We expect that implementation of these recommendations will improve the conduct, reporting, and effectiveness of clinical trials and fully exploit the clinical and scientific potential of the neoadjuvant setting in breast cancer. [ABSTRACT FROM AUTHOR]