Abstract
Locally advanced breast cancer (LABC) cases have a varying five-year survival rate, mainly influenced by the tumor response to chemotherapy. Paclitaxel activity (response rate) varies across populations from 21.5% to 84%. There are some reports on genetic traits and paclitaxel; however, there is still considerable residual unexplained variability. In this study, we aimed to test the association between eleven novel markers and tumor response to paclitaxel and to explore if any of them influenced tumor protein expression. We studied a cohort of 140 women with LABC. At baseline, we collected a blood sample (for genotyping), fine needle aspirates (for Western blot), and tumor measurements by imaging. After follow-up, we ascertained the response to paclitaxel monotherapy by comparing the percent change in the pre-, post- tumor measurements after treatment. To allocate exposure, we genotyped eleven SNPs with TaqMan probes on RT-PCR and regressed them to tumor response using linear modeling. In addition, we compared protein expression, between breast tumors and healthy controls, of those genes whose genetic markers were significantly associated with tumor response. After adjusting for multiple clinical covariates, SNPs on the LPHN2, ROBO1, SNTG1, and GRIK1 genes were significant independent predictors of poor tumor response (tumor growth) despite paclitaxel treatment. Moreover, proteins encoded by those genes are significantly downregulated in breast tumor samples.
Highlights
Breast cancer is the second most common cancer worldwide and the most prevalent cancerous disease among women [1]
Studies have only assessed the contribution of some genetic traits on either disease phenotype or tumor response based on drug metabolism, but there remains a substantial knowledge gap on the variability in response to neoadjuvant chemotherapy, paclitaxel and genetic markers [5]
To test if any genetic marker had a significant differential tumor response based on genotypes after paclitaxel, we modeled the relative change in tumor diameter as a function of each single nucleotide polymorphism (Supplementary Table 4)
Summary
Breast cancer is the second most common cancer worldwide and the most prevalent cancerous disease among women [1]. Regardless of race and ethnicity, the five-year survival of women with intermediate or locally advanced breast cancer (stages TNM IIB to IIIC) ranges from 50% to 74% [2]. This varying response is common across populations and might be largely influenced by the tumor molecular subtype and the patients’ intrinsic response to chemotherapy [2]. Across studies, the range of response rate to taxanes, to paclitaxel, varies significantly from 21.5% to 84% [5, 6] Part of this variability is explained by genetic traits and might contribute to the differences observed in the five-year survival [5]. Studies have only assessed the contribution of some genetic traits on either disease phenotype (i.e. molecular subtypes) or tumor response based on drug metabolism (pharmacokinetics or pharmacodynamics), but there remains a substantial knowledge gap on the variability in response to neoadjuvant chemotherapy, paclitaxel and genetic markers [5]
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