Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival
Authors: Morra Anna , Schreurs Maartje A. C. , Andrulis Irene L. , Anton-Culver Hoda , Augustinsson Annelie , Beckmann Matthias W. , Behrens Sabine , Bojesen Stig E. , Bolla Manjeet K. , Brauch Hiltrud , Broeks Annegien , Buys Saundra S. , Camp Nicola J. , Castelao Jose E. , Cessna Melissa H. , Chang-Claude Jenny , Chung Wendy K. , Collaborators NBCS , Colonna Sarah V. , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Daly Mary B. , Dennis Joe , Devilee Peter , Dörk Thilo , Dunning Alison M. , Dwek Miriam , Easton Douglas F. , Eccles Diana M. , Eriksson Mikael , Evans D. Gareth , Fasching Peter A. , Fehm Tanja N. , Figueroa Jonine D. , Flyger Henrik , Gabrielson Marike , Gago-Dominguez Manuela , García-Closas Montserrat , García-Sáenz José A. , Genkinger Jeanine , Grassmann Felix , Gündert Melanie , Hahnen Eric , Haiman Christopher A. , Hamann Ute , Harrington Patricia A. , Hartikainen Jaana M. , Hoppe Reiner , Hopper John L. , Houlston Richard S. , Howell Anthony , Investigators ABCTB , Investigators kConFab , Jakubowska Anna , Janni Wolfgang , Jernström Helena , John Esther M. , Johnson Nichola , Jones Michael E. , Kristensen Vessela N. , Kurian Allison W. , Lambrechts Diether , Marchand Loic Le , Lindblom Annika , Lubiński Jan , Lux Michael P. , Mannermaa Arto , Mavroudis Dimitrios , Mulligan Anna Marie , Muranen Taru A. , Nevanlinna Heli , Nevelsteen Ines , Neven Patrick , Newman William G. , Obi Nadia , Offit Kenneth , Olshan Andrew F. , Park-Simon Tjoung-Won , Patel Alpa V. , Peterlongo Paolo , Phillips Kelly-Anne , Plaseska-Karanfilska Dijana , Polley Eric C. , Presneau Nadege , Pylkäs Katri , Rack Brigitte , Radice Paolo , Rashid Muhammad U. , Rhenius Valerie , Robson Mark , Romero Atocha , Saloustros Emmanouil , Sawyer Elinor J. , Schmutzler Rita K. , Schuetze Sabine , Scott Christopher , Shah Mitul , Smichkoska Snezhana , Southey Melissa C. , Tapper William J. , Teras Lauren R. , Tollenaar Rob A.E.M. , Tomczyk Katarzyna , Tomlinson Ian , Troester Melissa A. , Vachon Celine M. , Veen Elke M. van , Wang Qin , Wendt Camilla , Wildiers Hans , Winqvist Robert , Ziogas Argyrios , Hall Per , Pharoah Paul D.P. , Adank Muriel A. , Hollestelle Antoinette , Schmidt Marjanka K. , Hooning Maartje J. 
Published: February 2023

Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09–1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words)