Background: BCIRG-006 was study designed to assess the relative efficacy and safety of two trastuzumab-based regimens compared to a standard (non-trastuzumab) regimen in the adjuvant treatment of early HER2+ breast cancer. We present the final, protocol-specified analysis of the long-term results from this trial that was initially developed to determine how to maximize adjuvant treatment efficacy and safety in these patients. Material & Methods: Between April, 2001 and March, 2004, we randomized 3,222 HER2+ operable breast cancer patients with axillary lymph node-positive or high risk node-negative disease, to either standard AC (60/600mg/m2 q3wk x 4) followed by T (100mg/m2 q3wk x 4) (AC-T) or two trastuzumab-based regimens. The trastuzumab-based regimens were AC followed by T (100mg/m2 q3wk x 4) and trastuzumab (H) x 1 year (AC-TH), or TCarbo (75mg/m2/AUC6 q3wk x 6) and H x 1 year (TCH). Patients were prospectively stratified by number of positive nodes (0, 1-3 vs ≥4) and hormone receptor status and those with ER and/or PR positive disease received hormone-directed therapy for 5yrs post chemotherapy. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety, with extensive cardiac evaluation (symptomatic events and asymptomatic, sustained LVEF declines). Results: Baseline characteristics of the study population were well balanced in the three study arms. At a median follow-up of 10.3 years, a persistent significant DFS benefit is seen in both trastuzumab-containing arms compared to AC-T with only 10 DFS events separating the two trastuzumab-based regimens: AC-TH (HR=0.70, 95%CI [0.60, 0.83]; p<0.001)) and TCH (HR=0.76, 95% CI [0.65, 0.90]; p<0.001). At this final analysis, the DFS HRs for AC-TH and TCH are closer than those observed in any prior protocol-directed study analyses (at 5 years follow-up the HRs were 0.64 and 0.75 for AC-TH and TCH respectively). Also, an OS benefit was observed in both AC-TH (HR=0.64, 95% CI [0.52, 0.79]; p<0.001)) and TCH (HR=0.76, 95% CI [0.62, 0.93]; p=0.0081). Importantly, TCH has significantly lower symptomatic CHF events by five-fold compared to AC-TH; 21 (2.0%) for AC-TH vs. 4 (0.4%) for TCH; p=0.0005. The AC-T control arm had 8 (0.8%) symptomatic CHF events. The incidence of patients with a relative LVEF decline >10% is doubled in the AC-TH compared to TCH regimens (206 vs 97; p<0.0001). Discussion: The long-term 10 years final results of the BCIRG 006 trial confirm the significant benefit of trastuzumab in the adjuvant treatment of HER2+ breast cancers, no significant efficacy difference between AC-TH and TCH as well as a significant symptomatic and asymptomatic cardiac safety benefit in the non-anthracycline, TCH trastuzumab-based regimen. Citation Format: Slamon DJ, Eiermann W, Robert NJ, Giermek J, Martin M, Jasiowka M, Mackey JR, Chan A, Liu M-C, Pinter T, Valero V, Falkson C, Fornander T, Shiftan TA, Bensfia S, Hitier S, Xu N, Bée-Munteanu V, Drevot P, Press MF, Crown J, On Behalf of the BCIRG-006 Investigators. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-04.

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Metabolic demand and altered supply of essential nutrients is poorly characterised in patients with advanced cancer. A possible imbalance or deficiency of essential fatty acids is suggested by reported beneficial effects of fish oil supplementation. To assess fatty acid status (composition of plasma and neutrophil phospholipids) in advanced cancer patients before and after 14 days of supplementation (12±1 g day −1 ) with fish (eicosapentaenoic acid, and docosahexaenoic acid) or placebo (olive) oil. Blood was drawn from cancer patients experiencing weight loss of >5% body weight ( n =23). Fatty acid composition of plasma phospholipids and the major phospholipid classes of isolated neutrophils were determined using gas liquid chromatography. At baseline, patients with advanced cancer exhibited low levels (<30% of normal values) of plasma phospholipids and constituent fatty acids and elevated 20 : 4 n -6 content in neutrophil phospholipids. High n -6/ n -3 fatty acid ratios in neutrophil and plasma phospholipids were inversely related to body mass index. Fish oil supplementation raised eicosapentaenoic acid and docosahexaenoic acid content in plasma but not neutrophil phospholipids. 20 : 4 n -6 content was reduced in neutrophil PI following supplementation with fish oil. Change in body weight during the supplementation period related directly to increases in eicosapentaenoic acid in plasma. Advanced cancer patients have alterations in lipid metabolism potentially due to nutritional status and/or chemotherapy. Potential obstacles in fatty acid utilisation must be addressed in future trials aiming to improve outcomes using nutritional intervention with fish oils. British Journal of Cancer (2002) 87 , 1370–1378. doi: 10.1038/sj.bjc.6600659 www.bjcancer.com © 2002 Cancer Research UK

Background The humanized monoclonal antibody (mAb) trastuzumab (H) + chemotherapy (chemo) prolongs disease-free survival (DFS) in patients (pts) with HER2-positive breast cancer (BC) in the adjuvant setting. Vascular endothelial growth factor (VEGF-A), one central regulator of angiogenesis, is a downstream target of HER2. Tumors overexpressing HER2 also overexpress VEGF-A and exhibit increased angiogenic potential. Combining H with the anti-VEGF-A mAb bevacizumab (B) significantly decreased tumor volume vs B or H alone in HER2-positive xenograft models and demonstrated efficacy in phase 2 studies. In the phase 3 AVEREL study in pts with HER2-positive metastatic BC, adding B to H + docetaxel (T) led to a non-significant increase in a duration of PFS and objective response rates. Chemo plus H±B is now explored in this large phase 3 trial to assess the impact of VEGF-A blockade on residual or micrometastatic disease in the adjuvant setting. Methods BETH (NCT00625898) is a randomized, phase 3, open-label study evaluating the addition of B to 2 different H-chemo regimens. Pts had centrally-confirmed HER2-positive BC (FISH+ and/or IHC 3+), ECOG PS 0-1, unilateral invasive breast adenocarcinoma, total mastectomy or lumpectomy, and LVEF ≥55%. Prior therapy with anthracyclines, taxanes, carboplatin (C), H or B for any malignancy or radiotherapy, chemo, and/or targeted therapy for the currently diagnosed BC were not permitted. Pts were stratified by center, hormone receptor status (ER and/or PR-positive, ER/PR-negative), and axillary lymph node status (0, 1-3, 4+) before inclusion into 1 of 2 chemo cohorts, and then randomized. All pts were recruited by investigators from the Translational Research in Oncology (TRIO/CIRG), the National Surgical Adjuvant Breast and Bowel Project (NSABP) or a group of independent sites. Cohort 1 (3231 pts) included pts receiving 6 cycles of TCH±B followed by H±B for 1 yr after the first dose. Cohort 2 (278 pts) included pts from some independent sites electing to use anthracycline-based therapy and these pts received 3 cycles of TH±B followed by 3 cycles of 5-fluorouracil, epirubicin, cyclophosphamide followed by H±B to complete 1 yr of treatment. T was given at 8 mg/kg IV loading dose, 6 mg/kg IV q3w thereafter; B was given at 15 mg/kg IV q3w. The primary endpoint is invasive DFS (IDFS) for B-containing vs. non-B-containing regimens. Secondary endpoints are IDFS within chemo cohorts, DFS, overall survival, recurrence-free interval (RFI), distant RFI, safety including specific cardiac assessments, and the identification of predictive biomarkers for B. The sample size was determined to test the hypothesis of interest, both in the faster accruing cohort and overall. With 3509 pts enrolled, the trial will have 85% power to detect a HR of 0.70 favoring the addition of B overall, irrespective of chemo regimen. With ∼3000 pts in the faster-accruing cohort, the study will have 80% power to detect a hazard ratio (HR) of 0.70 at a 2-sided alpha of 0.05. Median duration of follow-up will be 36 months in Jun 13, cut-off date of the primary analysis. Initial efficacy, safety, and plasma marker analyses will be reported. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-03.