Genomic Alterations and Radioresistance in Breast Cancer: An Analysis of the Profiler Protocol

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Vallard, A. | Bernichon, E. | Q., Wang | Attignon, Valéry | Pissaloux, Daniel | Bachelot, Thomas | Heudel, P.E. | Ray-Coquard, Isabelle | Fouchardière, A. de La | Faure, C. | Chopin, N. | Beurrier, F. | Racadot, S. | Sunyach, M.P. | Langrand-Escure, J. | Rancoule, C. | Perol, David | Blay, J.Y. | Magné, N. | Trédan, Olivier

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International audience. Purpose/Objective(s)Breast cancer (BC) patients with comparable prognostic features have heterogeneous outcomes, partly because of radiotherapy resistance leading to loco-regional recurrences (LRR). The ProfiLER (Profilage LYric et Région, NCT01774409) clinical trial aims at establishing a simple genetic profile of metastatic cancers in order to offer patients personalized molecular targeted therapies. In the breast cancer area, the genomic profiling of a population who ultimately became metastatic, and its correlation with the patient outcome years after LRR, provided an opportunity to identify post hoc biomarkers of the initial radiation resistance. The aim of the present study was to determine if specific tumor genetic alterations were associated with radiation resistance, defined as a LRR despite optimal surgery, radiotherapy, and systemic adjuvant therapies, in a ProfiLER series.Materials/MethodsGenetic profile of 162 BC patients’ tumors included in ProfiLER between 2013 and 2016 were analyzed using Next-Generation-Sequencing and Comparative-Genomic-Hybridization tests. Patients and tumor characteristics were analyzed for association with genomic rearrangements (mutations, amplification, homozygous deletions). Only gene alterations observed in >3% of the tumors, or included in well-known molecular pathways (PI3 Kinases pathway, MAP Kinases pathway, Tyrosine Kinase receptors family) were selected. The Cox multivariate analysis was based on (P<0.2)-factors in univariate analysis.ResultsTwo hundred eighteen genomic rearrangements were identified, and 18 were observed in >3% of tumors. PIK3CA and ROS1 mutations were statistically correlated to the risk of LRR. A median loco-regional progression free survival (LRPFS) of 19.8 years was reported for PIK3CA mutation carriers (n = 34, 21%) versus 9.1 years for wild-type patients (HR = 0.29, 95% CI = 0.13-0.64, P = 0.002 in univariate analysis). PIK3CA mutation was identified as an independent protective factor of LRR using multivariate analysis (HR = 0.27, 95% CI = 0.09-0.82), P = 0.02). ROS1 mutated cancer patients (n = 8, 4.9%) had a median LRPFS of 4 years versus 16.1 years for wild-type patients (HR = 2.5, 95% CI = 1.74-7.05, P = 0.08 in univariate analysis), but was not identified as an independent LRR risk factor (HR = 2.45 95% CI = 0.83-7.26, P = 0.11 in multivariate analysis). Other mutations and amplifications were not associated with LRR. Among relapsing patients, the median time to LRR was nearly significantly different regarding status of the PIK3CA mutations, with 8.6 years for mutated patients versus4.7 years for non-mutated patients (P = 0.09).ConclusionPIK3CA mutation was associated with a lower risk of LRR in this BC population. ROS1 mutation was marginally associated with a higher risk of LRR, possibly because of a limited population. Results suggest PIK3CA and ROS1to be possible biomarkers of radio-sensitivity.

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