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Background: Recent trials have provided evidence that obesity and a low level of physical activity are not only associated with a higher risk of developing breast cancer, but also with an increased risk for recurrence and reduced survival in breast cancer patients (pts). The SUCCESS C study is the first randomized Phase III trial to evaluate the effect of an intensive lifestyle intervention program, focusing on both physical activity and healthy diet following adjuvant chemotherapy on disease-free survival in women with early breast cancer. Methods: SUCCESS C is a German multicenter, 2×2 factorial design, randomized phase III study comparing disease-free survival (DFS) in pts with HER2-negative early breast cancer treated with either 3 cycles of epirubicine, fluorouracil, cyclophosphamide chemotherapy followed by 3 cycles of docetaxel (FEC-D) or 6 cycles of docetaxel-cyclophosphamide (DC). The second randomization compares DFS in pts with a body mass index (BMI) of 24—40 kg/m2 receiving either a telephone-based individualized lifestyle intervention (LI) program aiming at moderate weight loss for 2 years (LI arm) or general recommendations for a healthy lifestyle alone (non-LI arm). DFS according to lifestyle intervention was analyzed using both univariable cox regressions and multivariable cox regressions adjusted for age (years, continuous), BMI (kg/m2, continuous), menopausal status (premenopausal, postmenopausal), tumor size (pT1, pT2, pT3/pT4), nodal stage (pN0, pN1, pN2, pN3), hormone receptor status (positive, negative), grading (G1, G2, G3), histological type (ductal, lobular, other) and chemotherapy randomization (FEC-D, DC). Median follow-up was 64.2 months. Results: Overall, 2292 of the 3643 pts recruited for the SUCCESS C study were randomized for the lifestyle intervention program (1146 pts in both the non-LI arm and the LI arm). The Intention-to-treat analysis revealed no difference in DFS between the two treatment arms (LI vs. non-LI) in univariable analysis (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.76 — 1.28, p = 0.922) and in adjusted multivariable cox regression (HR 0.91, 95% CI 0.70 — 1.18, p = 0.48). At the 2-year follow up, pts in the LI arm lost on average 1.0 kg weight compared to the start of the LI program, while pts in the non-LI arm gained on average 0.95 kg (p < 0.001). Overall, 1477 pts completed the 2-year LI program (non-LI arm: 80.7%, 925 of 1146 pts; LI arm: 48.2%, 552 of 1146 pts; p < 0.001). Pts that completed the 2-year LI program had a significant better DFS than non-completers (HR 0.35, 95% CI 0.27 — 0.45, p < 0.001). Among completers, pts in the LI arm had a significantly better DFS than pts in the non-LI arm both in univariable analysis (HR 0.53, 95% CI 0.35 — 0.82, p = 0.004) and in adjusted multivariable cox regression (HR 0.51, 95% CI 0.33 — 0.78, p = 0.002). Conclusions: This explorative and non-planned interim analysis indicates that the completion of a systematic telephone life style intervention program may positively impact patient outcome in early breast cancer. Citation Format: Janni W, Rack BK, Friedl TW, Müller V, Lorenz R, Rezai M, Tesch H, Heinrich G, Andergassen U, Harbeck N, Schochter F, De Gregorio A, Tzschaschel M, Huober J, Hepp P, Fehm TN, Schneeweiss A, Lichtenegger W, Blohmer J, Hauner D, Beckmann MW, Häberle L, Fasching PA, Hauner H. Lifestyle Intervention and Effect on Disease-free Survival in Early Breast Cancer Pts: Interim Analysis from the Randomized SUCCESS C Study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS5-03.

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Patients with documented metastatic breast cancer and therapy 1462 Patients with available germline DNA from time of study entry and successful genotyping 112 patients without metastatic breast cancer 42 patients with no germline DNA available 20 BRCA1 43 BRCA2 35 CHEK2 11 PALB2 9 ATM 3 RAD51D 3 BARD1 2 MSH6 123 patients (8.4%) with mutation in a moderate or high risk gene 1339 patients without mutation in a moderate to high risk gene Data collection Clinical data were collected by trained and dedicated staff at the sites participating in the prospective PRAEGNANT study. These data are monitored using automated plausibility checks and through random on-site field monitoring. Blood Samples and Genotyping Germline DNA was extracted from EDTA-Blood samples, which were obtained at the time of study entry. DNA libraries for coding sequences and intron/exon boundaries of coding exons from 37 cancer risk genes, including BRCA1 and BRCA2, were generated using a QIAseq multiplex PCR-base panel. Libraries were pooled in batches of 768 and sequenced on a HiSeq4000 to 400× mean coverage of target regions. After demultiplexing, trimming of adapters, and alignment of sequences to the human genome, variants were called using GATK Haplotype Caller and Vardict. Likely pathogenic mutations were validated using Sanger sequencing. Copy number variants were identified using PatternCNV. Statistical Analysis Continuous characteristics are presented as means and standard deviations (SD), categorical characteristics are presented as frequencies and percentages. The influence of ALL genes, BRCA1/2, CHEK2, and PALB2 on overall survival was analyzed using the Kaplan-Meier product limit method and Cox regression models. Kaplan-Meier curves and hazard ratios (HR) with 95% confidence interval (CI) adjusted for age at study entry, body mass index, hormone receptor status, HER2 status, grading, and therapy line are shown.

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Background: A recent meta-analysis has reported benefits of adjuvant bisphosphonate treatment in early breast cancer patients with improved breast cancer survival and reduced rate of breast cancer recurrences in the bone, especially in postmenopausal patients. However, a comparison between bisphosphonate treatments duration is lacking. Therefore, we examined 2 and 5 years of zoledronate treatment following adjuvant chemotherapy in the SUCCESS A trial. Methods: The SUCCESS A trial is a randomized, open-label, 2x2 factorial design Phase III study in high-risk early breast cancer patients that were randomized to adjuvant chemotherapy treatment with 3 cycles of FEC followed by either 3 cycles of docetaxel or 3 cycles of gemcitabine-docetaxel. After chemotherapy, patients were subject to a second randomization of 5 years of zoledronate treatment (4 mg i.v. every 3 months for 2 years, followed by 4 mg i.v. every 6 months for 3 years) vs. 2 years of zoledronate treatment (4 mg i.v. every 3 months for 2 years). Outcome was analyzed using adapted disease-free survival (DFS) and adapted overall survival (OS), with survival times measured as of 2 years after the start of zoledronate treatment. Maximal observation time was set to 4 years. Median observation time was 2.95 years for DFS and 3 years for OS. Results: Overall, 3421 of the 3754 patients randomized in the SUCCESS A study received at least one zoledronate dose. 434 patients had a DFS event or were lost to follow up in the first two years after the start of zoledronate treatment; thus, 2987 patients were available for analysis (1540 and 1447 patients in the 5-year and 2-year zoledronate treatment arm, respectively). Both adapted DFS and adapted OS did not differ between the two treatment arms (5 vs. 2 years) as shown by multivariate cox regressions adjusted for patient and tumor characteristics as well as chemotherapy (DFS: hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.75 – 1.25, p = 0.81; OS: HR 0.98, 95% CI 0.67 – 1.42, p = 0.90). In addition, subgroup analyses according to menopausal status revealed no difference in DFS or OS between the two treatment arms in premenopausal women (DFS: HR 1.21, 95% CI 0.81 – 1.81, p = 0.35; OS: HR 0.93, 95% CI 0.57 – 1.53, p = 0.78) or postmenopausal women (DFS: HR 0.85, 95% CI 0.62 – 1.16, p = 0.30; OS: HR 0.96, 95% CI 0.67 – 1.39, p = 0.84). Conclusions: Our study showed no difference in DFS or OS between 5-years and 2-years of adjuvant zoledronate treatment in early breast cancer patients, irrespectively of menopausal status. Thus, our results indicate that extended treatment with zoledronate does not improve DFS or OS in high-risk early breast cancer patients. Citation Format: Janni W, Friedl TWP, Fehm T, Müller V, Lichtenegger W, Blohmer J, Lorenz R, Forstbauer H, Bauer E, Fink V, Bekes I, Jückstock J, Schneeweiss A, Tesch H, Mahner S, Brucker SY, Heinrich G, Beckmann MW, Coleman R, Rack B. Extended adjuvant bisphosphonate treatment over five years in early breast cancer does not improve disease-free and overall survival compared to two years of treatment: Phase III data from the SUCCESS A study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-06.