Abstract
BackgroundPersonalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment.MethodsWe assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p < 0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed.Resultsrs878156 in PARP2 showed a differential effect by chemotherapy (p = 0.093) and was replicated in BCAC studies (p = 0.009; combined analysis p = 0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency = 0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR) = 0.75, 95 % 0.53–1.07) and poorer survival when not treated with chemotherapy (HR = 1.42, 95 % 1.08–1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR = 0.73, 95 % CI 0.40–1.32). None of the SNPs showed significant differential effects by radiotherapy.ConclusionsOur data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1957-7) contains supplementary material, which is available to authorized users.
Highlights
Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival
Our data suggest for the first time that a single nucleotide polymorphism (SNP) in poly polymerase 2 (PARP2), rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy
In the MARIE study, we identified 14 SNPs in five genes (OGG1, PARP2, POLB, SMUG1, XRCC1) with differential effects by any type of chemotherapy (p
Summary
Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Breast cancer ranks among the most important causes of cancer death in women worldwide, but data from recent years reveal that mortality rates are steadily decreasing in Northern European and American countries [1, 2] This increase in survival can be attributed to both progress in early detection and improved treatment protocols using classical cytostatics and new targeted drugs for estrogen receptor positive tumours and HER2 positive tumours [3, 4]. Two major components of past and current breast cancer treatment protocols are chemotherapeutics such as anthracyclines like epirubicin or doxorubicin and ionizing radiation. Their efficiency is based on their strong potential to induce cellular DNA damage. The base excision repair (BER) system with its DNA glycosylases specific for various types of oxidative DNA damage is one of the crucial determinants of tumour chemotherapy [10, 11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
