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Purpose To estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families and to determine predictive risk factors. Patients and Methods A retrospective, multicenter, cohort study was performed from 1996 until 2008 and comprised 2,020 women with unilateral breast cancer (index patients, n = 978; relatives, n = 1.42) from 978 families who had a BRCA1 or BRCA2 mutation. Cox regression analysis was applied to assess the association of age at first breast cancer with time from first to contralateral breast cancer, stratified by the affected BRCA gene. Results The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 47.4% (95% CI, 38.8% to 56.0%) for patients from families with BRCA1 or BRCA2 mutations. Members of families with BRCA1 mutations had a 1.6-fold (95% CI, 1.2-fold to 2.3-fold) higher risk of contralateral breast cancer than members of families with BRCA2 mutations. Younger age at first breast cancer was associated with a significantly higher risk of contralateral breast cancer in patients with BRCA1 mutation, and a trend was observed in patients with BRCA2 mutation. After 25 years, 62.9% (95% CI, 50.4% to 75.4%) of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer developed contralateral breast cancer, compared with only 19.6% (95% CI, 5.3% to 33.9%) of those who were older than 50 years of age at first breast cancer. Conclusion Contralateral breast cancer risk depends on age at first breast cancer and on the affected BRCA gene, and this risk should be considered in treatment planning.

5546 Background: BRCA associated cancers show a distinct pattern of genomic gains and losses that is associated with impaired repair of DNA double-strand breaks via homologous recombination (HR). We investigated whether BRCA1- and BRCA2-like classifiers could predict BRCA1 and BRCA2 mutation status in ovarian cancer. In addition, we explored whether promoter hypermethylation or mutations in other genes involved in DNA repair associate with a BRCA-like profile in ovarian cancer. Methods: The AGO-TR1 cohort study (NCT02222883 ) enrolled 525 consecutive patients with primary (PR) and platinum sensitive relapsed (RE) ovarian cancer to perform paired mutational analysis of germline and tumor tissue. We performed mutation panel sequencing, BRCA1 promoter hypermethylation and low-coverage whole genome sequencing to classify samples as BRCA1-like or BRCA2-like in 298 ovarian cancer samples (PR: n = 159, RE: n = 139). Results: A BRCA-like profile was observed in 58.1% of the samples without germline or somatic mutation in BRCA1/2 (n = 179; BRCA1-like: n = 26, BRCA2-like: n = 23, BRCA1- and 2-like: n = 55). There was no significant difference between PR- and RE-cases (54.5% vs 61.3%). 64 of 70 BRCA1 germline mutation carriers could be identified by the BRCA1-like classifier (sensitivity: 0.91). The BRCA2-like classifier identified BRCA2 germline mutation carrier with a sensitivity of 0.71 (17 of 24). The complementary use of both classifiers led to the detection of 22 of 25 somatic mutations in BRCA1 (16/16) or - 2 (6/9). Remarkably, 12 of 13 tumor samples from germline RAD51C mutation carriers were recognized by the BRCA1-like classifier (sensitivity: 0.92). No correlation of PALB2 mutation status (n = 7) with BRCA-like profile was observed. Of 28 tumor samples with a BRCA1 promoter hypermethylation 26 had a BRCA1-like profile (sensitivity: 0.93). Conclusions: A high number of ovarian cancer cases display a BRCA-like profile. Mutations (germline and somatic) in BRCA1, BRCA2, RAD51C as well as BRCA1 hypermethylation strongly associate with a BRCA-like profile and can explain 146 of 212 cases. Future studies will investigate whether the classifiers identify patients who benefit from HR-deficiency directed approaches beyond the BRCA mutation status. Clinical trial information: NCT02222883.

1512 Background: Breast and ovarian cancer (BC/OC) predisposition has been associated with several high-, moderate-, and low-penetrance susceptibility genes. Despite comprehensive testing by next-g...

TPS1137 Background: Intense dose-dense (idd) chemotherapy (CT) significantly improves overall survival in breast cancer patients. Two preceding trials explored iddETC vs a dd combination of EC-TX (GAIN) and dtEC-dtD vs conventional dosed FEC-D (Panther). Nab-paclitaxel (nP) provides a better toxicity profile and higher efficacy compared to solvent based taxanes and might be preferred in an idd regimen. Methods: This is a multicenter, prospective, randomized, open-label phase III trial comparing iddEnPC or dtEC-dtD as adjuvant CT. Pts with uni- or bilateral primary high risk node-positive (N+) breast cancer (BC) and centrally confirmed ER/PR/HER2 and Ki-67 status can be included. Luminal A pts are only recruited with N+ ≥4. Randomization to iddEnPC or dtEC-dtD will be stratified by biological subtype defined by hormone receptor, HER2 and Ki-67. The iddEnPC arm will receive epirubicin (150mg/m2) q2w x3 followed by nP (260-330mg/m2, dose to be determined in run-in phase) q2w x3, followed by cyclophosphamide (2g/m2) q2w x3. The dtEC-dtD arm will receive EC (38-120/450-1200 mg/m2) q2w x4 followed after 1 wk rest by docetaxel (60-100mg/m2) q2w x4. GAIN-2 will compare toxicity and efficacy of an idd regimen (EnPC) vs a dd regimen with modification of single doses depending on individual hematological and non-hematological toxicities. Primary objective is invasive disease-free survival (IDFS). Secondary objectives are survival by other definitions, compliance, safety, side effects of taxanes and subgroup analyses (by 0-3, 4-9 or 10+ involved nodes and Ki-67). Efficacy analyses are planned 60 mths after end of accrual, safety interim analyses after 200 and 900 pts have completed CT. It was assumed that dtEC-dtD will achieve a 5-yr IDFS of 75% and ddEnPC will improve IDFS to 79% (HR 0.819) with a power of 80% (α=0.05, ß= 0.2).GAIN-2 is registered under NCT01690702 Results: 75pts were recruited since 1stOct 2012. Recruitment (in total 2886 pts) is planned for 36 mths in 80-100 sites in Germany. Run-in safety data to be presented. Conclusion: GAIN-2 will compare the efficacy of adjuvant iddEnPC and dtEC-dtD in pts with early N+ BC. Clinical trial information: NCT01690702.

1013 Background: A high incidence of contralateral breast cancer has been reported in patients with BRCA1or BRCA2 mutations while the risk in patients with familial non-BRCA-associated breast cancer remains unclear. This study was undertaken to estimate the risk for contralateral breast cancer in patients of BRCA1- and BRCA2-negative high risk families and to determine predictive risk factors. Methods: A retrospective, multicenter, cohort study was performed from 1996 until 2010 and comprised 3,580 women with unilateral breast cancer from 2,793 high-risk families who were tested negative for BRCA1 or BRCA2 mutations. Kaplan-Meier analysis was used to estimate age-dependent contralateral breast cancer risks. Cox regression analysis was applied to assess the impact of age at first breast cancer on contralateral breast cancer risk. Results: The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 19% (95%CI 16% to 22%) for patients from families with non-BRCA-associated brea...