Sensitivity to systemic therapy for metastatic breast cancer in CHEK2 1100delC mutation carriers.

Mieke Kriege,Judith R Kroep,Marion E Meijer-Van Gelder,J Margriet Collée,Caroline Seynaeve,Jannet Blom,Ans Van Den Ouweland,John W M Martens,Agnes Jager,Antoinette Hollestelle,Maartje J Hooning,Anieta M Sieuwerts,Els M J J Berns

doi:10.1007/s00432-015-1981-7

Abstract

PurposeThe role of CHEK2 in DNA repair by homologous recombination suggests that CHEK2-associated breast cancer (BC) patients might be more sensitive to chemotherapy inducing double-strand DNA breaks, but results hereon are lacking. We compared the sensitivity to first-line chemotherapy and endocrine therapy between CHEK2 1100delC and non-CHEK2 metastatic breast cancer (MBC) patients.MethodsSixty-two CHEK2 1100delC MBC patients were selected from three cohorts genotyped for CHEK2 1100delC (one non-BRCA1/2 cohort and two sporadic cohorts). Controls were 62 non-CHEK2 MBC patients, matched for age at and year of primary BC diagnosis, and year of metastatic disease. Objective response rate (complete and partial response) to, and progression-free survival (PFS) and overall survival (OS) after start of first-line chemotherapy and endocrine therapy were compared between CHEK2 and non-CHEK2 patients.ResultsMedian age at BC diagnosis was 46 and 51 years at MBC diagnosis. First-line chemotherapy consisted of anthracycline-based chemotherapy (n = 73), taxanes (n = 16), CMF(-like) chemotherapy (n = 33) and taxane/anthracycline regimens (n = 2). CHEK2 and non-CHEK2 patients had a comparable objective response rate (44 vs. 52 %). Also, PFS and OS after start of chemotherapy were comparable between both patient groups (hazard ratio 0.91; 95 % confidence interval 0.63–1.30 and 1.03; 95 % CI 0.71–1.49, respectively). Thirty-six CHEK2 and 32 non-CHEK2 patients received first-line endocrine therapy (mainly tamoxifen) for MBC. No significant differences were observed in objective response rate to, and PFS and OS after start of endocrine therapy.ConclusionNo differential efficacy of chemotherapy and endocrine therapy given for MBC was observed in CHEK2 versus non-CHEK2 patients.

Highlights

CHEK2 is a tumor suppressor gene associated with a moderately increased cumulative lifetime breast cancer (BC) risk (1.4- to 3-fold; Cybulski et al 2011; MeijersHeijboer et al 2002; Weischer et al 2008)
Only a few biomarkers are used for therapy stratification in BC patients (e.g., estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2)), whereas biomarkers predictive of treatment response will contribute to further tailoring and improving BC treatment, i.e., avoiding toxic therapy for those not benefiting of it
Mutations in BC risk genes might be valuable markers for therapy response prediction, which already has been reported for BRCA1- and BRCA2-associated BC, suggesting higher sensitivity to anthracyclines, platinum and potentially other agents (Bayraktar and Gluck 2012; Kriege et al 2009; Tutt et al 2010)

Summary

Introduction

CHEK2 is a tumor suppressor gene associated with a moderately increased cumulative lifetime breast cancer (BC) risk (1.4- to 3-fold; Cybulski et al 2011; MeijersHeijboer et al 2002; Weischer et al 2008). A worse distant disease-free survival and overall survival (OS) for CHEK2 1100delC BC patients have been reported (de Bock et al 2004; Kriege et al 2014; Schmidt et al 2007; Weischer et al 2012). The function of the CHEK2 protein kinase in the repair of double-strand DNA breaks suggests that BC patients carrying a CHEK2 mutation might have an increased sensitivity to chemotherapeutic agents causing double-strand DNA breaks, such as platinum, alkylating agents and/or anthracyclines (Nevanlinna and Bartek 2006). In a previous study of our group regarding distant disease-free survival and breast cancer-specific survival of primary BC, no differential effect of adjuvant chemotherapy or endocrine therapy was observed in CHEK2 1100delC compared with non-CHEK2 breast cancer patients (Kriege et al 2014)

Methods

Results

Conclusion