Abstract P3-04-01: Molecular determinants of post-mastectomy breast cancer recurrence

Introduction The management of breast cancer (BC) patients who undergo mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated the molecular aberrations associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to controls in an effort to identify molecular predictors associated with recurrence. Methods/Materials We identified 115 HER2 negative, therapy naive, T 1-3 and N 0-1 BC patients treated with mastectomy and no post mastectomy radiation therapy from 1997 to present with available FFPE tissue blocks. The cohort included 32 patients with LRR, 34 with DM, and 49 controls (without recurrence) who were matched for stage, grade, hormone receptor status, age ≤ or u003e 50, chemotherapy receipt, and margin status. Matched primary and recurrent LRR samples were available for 3 patients. Hybrid capture next generation sequencing (NGS) of 142 cancer related genes and RNAseq were performed to identify DNA/RNA alterations associated with LRR or DM. The frequency of common alterations on NGS was compared with Fisher9s exact test. Expression of each gene from mRNA-Seq was treated as an explanatory variable. Immunohistochemistry (IHC) was performed for PTEN, Ki-67 and cleaved caspase 3 (CC3). PTEN loss and percentage of Ki-67 and CC3 positive cells were compared between groups with Fisher9s exact test and nonparametric methods, respectively. Results RNAseq was performed on 115 patients; there was no difference in RNA expression levels between the groups. DNA analysis was performed on 57 patients (17 LRR, 15 DM and 25 controls), NF1 mutation rate was significantly elevated in both the LRR (24%) and DM (27%) samples compared to controls 0%; (p=0.0070). The mitogen activated protein kinase (MAPK) pathway was significantly mutated in both LRR (47%) and DM (40%) samples compared to the controls 0%; (p Conclusions In this matched cohort analysis, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in this pathway are associated with a more aggressive tumor phenotype. However, there were no molecular features that discriminated between those likely to recur locally alone versus distantly. Further study is needed to validate these findings, and to determine whether targeting alterations in this pathway could decrease the risk of recurrence. Citation Format: Keene KS, King T, Hwang ES, Peng B, McGuire K, Tapia C, Zhang H, Bae S, Nakhlis F, Klauber-Demore N, Meszoely I, Sabel MS, Willey SC, Eterovic KA, Hudis C, Wolff A, De Los Santos J, Thompson A, Mills GB, Meric-Bernstam F. Molecular determinants of post-mastectomy breast cancer recurrence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-01.