Abstract 2397: Correlation between biomarker status and response to EGFR inhibition in triple-negative breast cancer (TNBC): findings from a Phase II trial.
Authors: Yardley Denise , Yardley Denise , Ma Zeqiang , Ward Patrick , Hendricks Carolyn , Daniel Brooke , Harwin William , Kannarkat George J. , Shastry Mythili , Peacock Nancy , Liang Shile 
Published: August 2014

Background: Epidermal growth factor receptor (EGFR) inhibition in TNBC has shown promising response in some studies, however, these studies have not investigated the correlation between response to EGFR inhibition and EGFR-related biomarker status. In this study, EGFR-related biomarkers in TNBC including p53 expression, EGFR gene amplification, and signalling pathways including RAS and PI3K were investigated to explore potential biomarkers that may correlate with response to EGFR inhibition.

Methods: A total of 71 locally advanced or metastatic TNBC patients with no prior EGFR inhibitor treatment and 0 - 1 prior chemotherapy regimens for metastatic breast cancer were evaluated. All patients received gemcitabine 1500mg/m2 IV, carboplatin AUC = 2.5 IV, and panitumumab 6 mg/kg IV every 2 weeks. Archival tumor tissue was obtained from 68 patients for central biomarker analyses. Protein expression of PTEN and p53 in tumor samples was assessed by Immunohistochemistry (IHC). Fluorescence-in-situ-hybridization (FISH) was used to detect EGFR gene amplification. KRAS (codons 12 and 13 in exon 2) and PI3KCA (exons 9 and 20) mutations were analyzed by direct DNA sequencing using capillary gel electrophoresis and fluorescence detection. Bioinformatics analyses were performed to correlate the status of these biomarkers with objective response rate (ORR), progression free survival (PFS) and overall survival (OS).

Results: 27 patients had partial response (PR), median PFS was 4.30 months and median OS was 12.58 months. 12/68 (18%) tumors had EGFR amplification. No KRAS mutations were detected in the 62 samples tested (6 patients not evaluable). 18% of tumors demonstrated PI3KCA mutations (12/67). 5/67 (7%) samples had PTEN loss. 50% of the tumors exhibited p53 loss (34/68). 13/68 (19%) tumors had more than one biomarker alteration. PTEN loss and PI3KCA mutation were mutually exclusive in the 67 tumors evaluated. In univariate analyses, none of these biomarkers significantly correlated with ORR, PFS or OS (all, P&gt;0.05). There was a marginal trend to shorter PFS (P=0.08) with PTEN loss and a marginal trend to longer PFS (P=0.106) with p53 loss. In multivariate analyses, none of the four biomarkers (EGFR, PI3KCA, PTEN and p53) showed prognostic significance on OS (all, P&gt;0.05).

Conclusions: We hypothesize that constitutive activation of the PI3K pathway due to PTEN loss and activation of EGFR by p53 loss may be potential mechanisms for the observed responses to panitumumab. This single arm study suggests that EGFR gene amplification may not be a predictor for response to panitumumab in TNBC. Further investigation in a randomized trial with a more homogenous patient population is warranted to confirm these findings.

Citation Format: Denise Yardley, Denise Yardley, Zeqiang Ma, Patrick Ward, Carolyn Hendricks, Brooke Daniel, William Harwin, George J. Kannarkat, Mythili Shastry, Nancy Peacock, Shile Liang. Correlation between biomarker status and response to EGFR inhibition in triple-negative breast cancer (TNBC): findings from a Phase II trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2013-2397