Abstract 4258: Genetic profiling of breast cancer confirms a pivotal Role of EGFR pathway in the development of acquired resistance to Tamoxifen in locally recurrent and metastatic breast cancer patients

Abstract

Background: Acquisition of resistance to Tamoxifen is a major drawback in the treatment of estrogen receptor (ER)-positive breast cancer (BC) patients. The role of CYP2D6 in predicting response to Tamoxifen is debatable. We assessed the involvement of aberrant EGFR pathway genes expressions and CYP2D6 polymorphism in predicting response to Tamoxifen in a cohort of BC patients from Egypt.

Patients and methods: This prospective study included 157 females with hormone receptor positive, locally recurrent inoperable and/or metastatic BC patients treated in the National Cancer Institute, Cairo. Patients were categorized according to their response to Tamoxifen into: responders and refractory groups. RNA and DNA were extracted from tumour and normal tissue samples obtained from all patients. The expression of 92 genes in the EGFR pathway was evaluated using the SABioscience array (Qiagen) with four house-keeping genes and CYP2D6 polymorphism was assessed by PCR.

Results: We found that 58.6% of the patients were ER/PR positive, 32.48% were ER positive and 8.91% were PR positive. Response to Tamoxifen correlated significantly with the site of the disease (patients with bone only disease demonstrated better and maintained response compared to those with visceral involvement; p. = 0.005) and CYP2D6 polymorphism (p. = 0.034). CYP2D6 *3, *4 were significantly prevalent in the refractory group (86.6%), whereas variants *10/*10 and *10/*3 were more common in the in the responders (85.5%) (p. = 0.027). RNA profiling of the EGFR pathway showed that 56 genes were differentially over-expressed in the refractory group compared to the responders, of which only JAK1, COL1A1, GAB1, FN1, MKNK1, AKT1, EGFR, NFKB1 and HGDC showed a significant difference between the groups (p<0.05).. Thirty four genes were differentially reduced, of which only STAT5A, RHOA, MAPK9, MAPK10, CCND1 showed significant difference between groups (p<0.05)..

Conclusion: The EGFR pathway contributes significantly to patients’ response to Tamoxifen in locally advanced/ metastatic breast cancer. A panel of 13 genes (JAK1, COL1A1, GAB1, FN1, MKNK1, EGFR, NFKB1, HGDC, STAT5A, RHOA, MAPK9, MAPK10, CCND1) in this pathway together with CYP2D6 polymorphisms can predict response to Tamoxifen though this has to be verified in a larger study.

Citation Format: Abdel-Rahman N. Zekri, Abeer Bahnassy, Ibrahim Malash, Mohammad Mansour,Sabry Shaarawy, Hoda Abdel-Raouf, Rabab Gaafar. Genetic profiling of breast cancer confirms a pivotal Role of EGFR pathway in the development of acquired resistance to Tamoxifen in locally recurrent and metastatic breast cancer patients. [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 4258. doi:10.1158/1538-7445.AM2015-4258