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Author: Fox, Stephen × Author: Mileshkin, Linda × End date: 2019 × Start date: 2010 × Type: Journal Article ×

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    Survival difference according to mutation status in a prospective cohort study of Australian patients with metastatic non-small-cell lung carcinoma
    Tan, L ; Alexander, M ; Officer, A ; MacManus, M ; Mileshkin, L ; Jennens, R ; Herath, D ; de Boer, R ; Fox, SB ; Ball, D ; Solomon, B (WILEY, 2018-01)
    BACKGROUND: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease comprising not only different histological subtypes but also different molecular subtypes. AIM: To describe the frequency of oncogenic drivers in patients with metastatic NSCLC, the proportion of patients tested and survival difference according to mutation status in a single-institution study. METHODS: Metastatic NSCLC patients enrolled in a prospective Thoracic Malignancies Cohort Study between July 2012 and August 2016 were selected. Patients underwent molecular testing for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) gene rearrangements, Kirsten rat sarcoma (KRAS), B-Raf proto-oncogene (BRAF) mutations and ROS1 gene rearrangements. Survival was calculated using the Kaplan-Meier method for groups of interest, and comparisons were made using the log-rank test. RESULTS: A total of 392 patients were included, 43% of whom were female with median age of 64 years (28-92). Of 296 patients tested, 172 patients (58%) were positive for an oncogenic driver: 81 patients (27%) were EGFR positive, 25 patients (9%) were ALK positive, 57 patients (19%) had KRAS mutation and 9 patients (3%) were ROS1 or BRAF positive. Patients with an actionable mutation (EGFR/ALK) had a survival advantage when compared with patients who were mutation negative (hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.33-0.71; P < 0.01). Survival difference between mutation negative and mutation status unknown was not statistically significant when adjusted for confounding factors in a multivariate analysis (HR 1.29; 95% CI 0.97-1.78, P = 0.08). CONCLUSION: In this prospective cohort, the presence of an actionable mutation was the strongest predictor of overall survival. These results confirm the importance of molecular testing and suggest likely survival benefit of identification and treatment of actionable oncogenes.
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    RAD51B in Familial Breast Cancer
    Pelttari, LM ; Khan, S ; Vuorela, M ; Kiiski, JI ; Vilske, S ; Nevanlinna, V ; Ranta, S ; Schleutker, J ; Winqvist, R ; Kallioniemi, A ; Doerk, T ; Bogdanova, NV ; Figueroa, J ; Pharoah, PDP ; Schmidt, MK ; Dunning, AM ; Garcia-Closas, M ; Bolla, MK ; Dennis, J ; Michailidou, K ; Wang, Q ; Hopper, JL ; Southey, MC ; Rosenberg, EH ; Fasching, PA ; Beckmann, MW ; Peto, J ; dos-Santos-Silva, I ; Sawyer, EJ ; Tomlinson, I ; Burwinkel, B ; Surowy, H ; Guenel, P ; Truong, T ; Bojesen, SE ; Nordestgaard, BG ; Benitez, J ; Gonzalez-Neira, A ; Neuhausen, SL ; Anton-Culver, H ; Brenner, H ; Arndt, V ; Meindl, A ; Schmutzler, RK ; Brauch, H ; Bruening, T ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Hartikainen, JM ; Chenevix-Trench, G ; Van Dyck, L ; Janssen, H ; Chang-Claude, J ; Rudolph, A ; Radice, P ; Peterlongo, P ; Hallberg, E ; Olson, JE ; Giles, GG ; Milne, RL ; Haiman, CA ; Schumacher, F ; Simard, J ; Dumont, M ; Kristensen, V ; Borresen-Dale, A-L ; Zheng, W ; Beeghly-Fadiel, A ; Grip, M ; Andrulis, IL ; Glendon, G ; Devilee, P ; Seynaeve, C ; Hooning, MJ ; Collee, M ; Cox, A ; Cross, SS ; Shah, M ; Luben, RN ; Hamann, U ; Torres, D ; Jakubowska, A ; Lubinski, J ; Couch, FJ ; Yannoukakos, D ; Orr, N ; Swerdlow, A ; Darabi, H ; Li, J ; Czene, K ; Hall, P ; Easton, DF ; Mattson, J ; Blomqvist, C ; Aittomaki, K ; Nevanlinna, H ; Brusgaard, K (PUBLIC LIBRARY SCIENCE, 2016-05-05)
    Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.