Abstract P2-03-06: Genomic characterization of 992 primary breast cancers
Authors: S Lauttia, G Gundem, R Huovinen, P Auvinen, S Loi, P Campbell, H Joensuu
Journal: Cancer Research (2017)

Abstract Background: We studied the associations between cancer gene alterations with clinical parameters in primary breast cancer (BC) samples of patients treated in either the FinHer or the FinXX adjuvant trial. These randomized trials accrued patients using similar inclusion criteria (node-positive, or node-negative with size &amp;gt;20 mm and PgR-) from the same centers, and had a similar control arm (3 cycles of docetaxel (T) followed by 3 cycles of CEF; T+CEF). Methods: Mutations of 371 cancer-associated genes and copy number alterations (CNAs) of 86 genes or chromosomal regions were analyzed using next generation sequencing from the DNA extracted from formalin-fixed BCs. In FinHer, the comparator arm to T+CEF consisted of 3 cycles wkly vinorelbine (V) followed by 3 cycles of CEF (V+CEF), and in FinXX of docetaxel plus capecitabine (TX) followed by 3 cycles of cyclophosphamide, epirubicin and capecitabine (CEX; TX+CEX). Adjuvant trastuzumab was administered to patients with HER2+ BC in FinHer based on random allocation for 9 weeks with either T or V, and in FinXX to all patients after May 2005, usually for 1 yr. Results: 1,014 BCs were analyzed for mutations and CNA alterations; 992 and 915 analyses were successful, respectively. 73.7% of the BCs were ER and/or PgR+ (cut-off 10%), 11.9% ER/PgR-/HER2+, and 14.7% triple-negative. 32 genes were mutated in ≥10 cancers, most commonly TP53 (38%), PIK3CA (33%) and GATA3 (10%); ErbB2 was mutated in 2.0% and ErbB3 in 1.3%. Mutations of genes associated with hereditary BC were frequent, CHEK2 4.8%, BRCA2 3.1%, PALB2 2.3%, BRCA1 1.7%. All 101 GATA3 mutations were found in ER/PgR+ BCs, whereas BRCA1, ErbB3, PREX2 and PIK3R1 mutations showed the strongest associations with ER/PgR- BC. TP53 and ErbB3 mutations were associated with HER2-positivity, whereas no AKT1, BRCA1 or SF3B1 mutations were detected in HER2+ BC. RB1, BRCA1, PALB2 and TP53 mutations were associated with high Ki-67%; MAP3K1, CDH1 and CBFB mutations with low Ki-67%. 70% of lobular cancers harbored mutated CDH1, whereas TP53 mutations were rare (4.5%). Presence of RAD50, PALB2, CHEK2 and TP53 were significantly associated with poor recurrence-free survival (RFS) with a hazard ratio (HR) of 4.11, 2.34, 2.22 and 1.56, respectively, whereas PIK3CA and GATA3 mutations with favorable RFS (HR 0.68 and 0.55). Lobular cancers with or without CDH1 mutation had similar RFS. The most frequently amplified genes were ErbB2 (26%), CCND1 (17%), RAD21 (14%) and c-MYC (14%). HER2+ BCs (defined by CISH or immunohistochemistry) frequently harbored amplified ErbB2 (88%), but also amplifications of ErbB3, MYB, WT1, FOXA1 and PIK3CA were associated with HER2+ BC. Amplifications of several genes significantly correlated with a negative ER/PgRstatus, the ductal histological type or high Ki-67%. In the FinXX trial subset patients with mutated TP53 had unfavorable outcome when treated with T+CEF but not when treated with TX+CEX, whereas patients with mutation in one of the 11 genes involved in DNA repair had poor outcome when treated with TX-CEX, but not when treated with T-CEF. Conclusions: Cancer gene aberrations show varying associations with the clinical and histopathological features of BC. Such molecular variations may explain in part the variations found in the efficacy of cancer drugs between clinical trials. Citation Format: Lauttia S, Gundem G, Huovinen R, Auvinen P, Loi S, Campbell P, Joensuu H. Genomic characterization of 992 primary breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-06.