Abstract LB-118: High APOBEC3B mRNA levels in estrogen receptor-positive primary tumors predict short time to progression for hormone-naive breast cancer patients treated with 1st line tamoxifen

Abstract

Abstract Introduction: Recent evidence has implicated APOBEC3B as a source of mutations in cervical, bladder, lung, head and neck, and breast cancers. The innate immune enzyme APOBEC3B contributes to mutagenesis and is a biomarker for poor prognosis in estrogen receptor positive (ER+) breast cancer1. APOBEC enzymes normally function in the innate immune system and in the protection against viral pathogens, but these enzymes can also generate C to T and DNA rearrangements in the host genome2-4. The role of this enzyme as a predictive biomarker for the response to first-line tamoxifen, a common therapy for ER+ breast cancer patients, is unknown. Here, we evaluated the predictive potential of APOBEC3B mRNA expression measured in the primary tumor using 2 independent Dutch retrospective ER+ cohorts of a total of 285 hormone-naive recurrent breast cancer patients treated with first-line tamoxifen. Materials and methods: APOBEC3B mRNA levels were measured by reverse transcriptase quantitative PCR (RT-qPCR) as described1 and the length of progression-free survival (PFS) was used as the primary endpoint. Cox univariate and multivariate regression analysis for PFS were used to assess the predictive potential of APOBEC3B mRNA expression. Results: In both cohorts individually, high levels of APOBEC3B were associated with an unfavorable response to 1st line tamoxifen (Dutch cohort-1, 225 patients: HR = 1.58, P = 0.0009; Dutch cohort-2, 60 patients: HR = 2.12, P = 0.009). Stratified for study cohort, high APOBEC3B mRNA levels were also significantly associated with an unfavorable PFS in multivariate analysis that included the traditional predictive factors: age, dominant relapse site, disease-free interval, ER and progesterone receptor (PGR), and adjuvant chemotherapy (HR = 1.67, P = 0.0001). Conclusion: Altogether, our data show that high APOBEC3B mRNA expression is an independent and validated predictor of not only poor prognosis but also of poor PFS after 1st line tamoxifen in recurrent breast cancer, which supports the notion that APOBEC3B is a promising therapeutic target to prevent metastasis and tamoxifen failure in ER± disease. 1 Sieuwerts, A. M. et al. Elevated APOBEC3B correlates with poor outcomes for estrogen-receptor-positive breast cancers. Hormones & cancer 5, 405-413, doi:10.1007/s12672-014-0196-8 (2014). 2 Stephens, P. J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005-1010, doi:10.1038/nature08645 (2009). 3 Burns, M. B. et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494, 366-370, doi:10.1038/nature11881 (2013). 4 Nik-Zainal, S. et al. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer. Nature genetics 46, 487-491, doi:10.1038/ng.2955 (2014). Citation Format: Anieta M. Sieuwerts, Marion E. Meijer-van Gelder, Fred C.G.J. Sweep, Paul N. Span, John A. Foekens, John W.M. Martens. High APOBEC3B mRNA levels in estrogen receptor-positive primary tumors predict short time to progression for hormone-naive breast cancer patients treated with 1st line tamoxifen. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-118. doi:10.1158/1538-7445.AM2015-LB-118