Abstract 538: A role for mutated hydrophobic amino acids in patients with triple-negative breast cancer
Authors: Kotoula Vassiliki , Lakis Sotiris , Papadopoulou Kyriaki , Vlachos Ioannis , Giannoulatou Eleni , Alexopoulou Zoi , Timotheadou Eleni , Efstratiou Ioannis , Zagouri Flora , Pentheroudakis George , Gogas Helen , Miliaras Spyros , Sotiropoulou Maria , Zografos George , Pectasides Dimitrios , Fountzilas George 
Published: July 2016

Abstract
Background - Aim: Nodal status and stromal tumor infiltrating lymphocyte (TILs) density are independently associated with patient outcome in triple-negative breast cancer (TNBC). Herein we examined whether the nature of tumoral mutated amino acids, in association with TILs and nodal status, interferes with the outcome of patients with operable TNBC treated with adjuvant chemotherapy.Methods: Two independent cohorts of TNBC patients and tumors were examined: (a) 133 patients treated upon clinical service (training set; TS), and (b) 190 patients treated in the context of phase III adjuvant trials (validation set; VS). All 323 patients had received adjuvant anthracycline-taxanes chemotherapy. All 323 tumors yielded informative data upon massively parallel sequencing for breast cancer related targets in 47 genes. Amino acid changing variants were considered as mutations (MUT) for minor allele frequencies 50% TILs) and nonLP. Disease-free survival (DFS) was the clinical endpoint.Results: The 2 cohorts did not differ regarding MUT tumor incidence (TS, 71%; VS, 67%); TILs (10% LP in each set); nodal status (TS, 0-3 positive nodes in 68%; VS, 64%); and, MUT a.a. classes (TS, charged 11%, polar 25%, hydrophobic 13%, mixed 15%; VS, 12%, 17%, 9%, and 13%, respectively). No statistically significant difference was obtained in the rates of MUT tumors or MUT a.a. classes with respect to TILs and nodal status. In the TS, patients with tumors bearing hydrophobic MUT a.a. fared worse than those with other MUT types (HR 2.43, 95%CI 1.17-5.03, p = 0.017) or than those without MUT (HR 5.13, 95%CI 1.95-13.52, p&lt;0.001). Similar trends were observed in VS. When classifying tumors for nodal status, TILs and the presence of hydrophobic MUT a.a., the latter independently conferred worse DFS in patients with &gt;3 positive nodes and non-LP tumors (TS, HR 3.03, 95%CI 1.11-8.29, p = 0.031; VS, HR 2.90, 95%CI 0.97-8.70, p = 0.057). Patients with &gt;3 positive nodes, non-LP tumors with hydrophobic MUT a.a. were revealed as the only subset with significantly worse DFS when compared to patients with LP tumors in both TS (p = 0.003) and VS (p = 0.015). Charged and polar MUT a.a., as well as the presence of MUT in the most frequently affected genes (TP53 and PIK3CA) did not have any impact on DFS in either TS or VS.Conclusions: In the adjuvant setting, the presence of hydrophobic MUT a.a. seems to be associated with worst prognosis in nonLP TNBC patients with high nodal burden. The finding was obtained in 2 independent patient series, which makes it worthy validating in further studies for this most difficult to treat breast cancer patient subset.
Citation Format: Vassiliki Kotoula, Sotiris Lakis, Kyriaki Papadopoulou, Ioannis Vlachos, Eleni Giannoulatou, Zoi Alexopoulou, Eleni Timotheadou, Ioannis Efstratiou, Flora Zagouri, George Pentheroudakis, Helen Gogas, Spyros Miliaras, Maria Sotiropoulou, George Zografos, Dimitrios Pectasides, George Fountzilas. A role for mutated hydrophobic amino acids in patients with triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 538.