Genetic variants of kinases suppressors of ras (KSR1) to predict survival in patients with ER-alpha positive metastatic breast cancer

Background In addition to its activating role of MAPK pathway, the protein kinase suppressor of ras 1 (KSR1) has been identified as a novel modulator of estrogen receptor alpha (ERa), as silencing of KSR1 in ERa+ breast cancer (BC) cells lines resulted in dowregulation of ERa transcriptional activity in the presence of oestradiol. Our previously data revealed the existence of single nucleotide polymorphisms (SNPs) in EGFR and ERa pathway genes that may predict clinical outcome in ERa positive metastatic BC (mBC) patients. With respect to those findings we aimed to evaluate the clinical implication of KSR1 SNPs on survival in patients with primary ERa+ mBC treated with tamoxifen. Methods Tumoral DNA was obtained from 222 patients treated with tamoxifen withERa+ invasive BC who had undergone surgery between 1981 and 2003 (median age 56 [28-90]). Three relevant KSR1 SNPs were selected based on public literature resources and databases, including 2 SNPs localised in the regulating 3’untranslated region (rs224190, rs 1075952) and 1 non-synonymous SNP localised in the coding exon 7 region (rs2293180). All SNP were analysed using DNA sequencing with OS and DFS as primary endpoint. Results The overall median follow-up was 6.4 years.In univariate analysis the rs2241906 SNP was significantly associated with DFS and OS and patients with the TT genotypedemonstrated shorter DFS (2.1 vs. 7.1 months, p=0.005) and OS ( 2.6 vs. 8.4 months p=0.002) than patients with the x/C genotypes. The associations remained significant in the multivariate analysis adjusting age, lymph node status and HER2 status (HR (95%CI): 4.81 (2.00-11.59) and 5.74 (2.29-14.43), for DFS and OS, respectively). The same significant correlation was retrieved with the SNP rs1075952 in linkage disequilibrium with rs2241906 that was used as a control. No relationship was shown between rs2293180 and survival. Conclusions Our findings demonstrated that KSR1 polymorphisms could arise as a potential marker to predict survival in patients with mBC treated with tamoxifen. The putative role of KSR1 as a modulator of ERa activity could functionally explain our results yielding insight for further studies.