Abstract 3807: ATM protein loss and clinical outcomes with platinum chemotherapy in patients with advanced solid tumors
Authors: Sundar Raghav , Miranda Susana , Carreira Suzanne , Chénard-Poirier Maxime , Rodrigues Daniel Nava , Figueiredo Ines , Bertan Claudia , Yuan Wei , Perez Desamparados Roda , Ferreira Ana , Tunariu Nina , Mateo Joaquin , Bono Johann de 
Published: July 2017

Abstract
Background Loss of ataxia telangiectasia mutated (ATM), a key protein regulating DNA damage repair signaling, appears to sensitize tumors to platinum chemotherapy in preclinical studies. In this study, the incidence of ATM loss in patients with advanced solid tumors and clinical outcomes with platinum chemotherapy was analyzed.
Methods Archival tumor and biopsy samples of primary or metastatic sites of patients treated in a phase I trial unit were retrieved and ATM immunohistochemistry (IHC), as well as targeted next generation sequencing (NGS) was performed. Analytic validation and assay optimization of rabbit monoclonal antibody [Y170] to ATM (Abcam ab32420) was undertaken using known positive (VCaP xenograft material and GM14680 cell pellet) and negative (GM01526 cell pellet) controls. IHC slides were assessed by a trained pathologist for nuclear staining intensity of ATM and semi-quantitatively scored. ATM loss was defined as a nuclear H score of ≤10. Clinical data were collected retrospectively from case records. Duration on platinum therapy was defined as time from start of first platinum therapy to time to subsequent therapy (adjuvant platinum excluded).
Results Overall, 679 samples of 587 patients were tested for ATM IHC, of which 517 samples had NGS performed; 5% of patients (n = 31) had ATM IHC loss, and 5% (n = 27) had somatic ATM mutations detected by NGS (Table 1). In 70 matched primary/metastatic or different metastatic sites, concordance of ATM IHC loss occurred in 99% (n = 69; 7 with ATM IHC loss) of samples. Of the colorectal cancer cohort (n = 223), duration on platinum therapy was significantly longer for the ATM loss group (11 vs 8 months, HR: 0.57, 95% CI: 0.35 to 0.93, p = 0.04).
Discussion Loss of ATM expression was detected among 5% of this cohort of advanced solid cancers, primarily in breast and gastrointestinal tumors. Sensitivity to platinum therapy is significantly higher in ATM loss colorectal cancer. Further prospective studies with larger cohorts are required to validate these findings.
ATM IHC and ATM mutation by NGS by tumor groupTumor typesTotalATM IHC loss (%)ATM mutation (%)Concomitant ATM loss and ATM mutationConcomitant TP53 mutation with ATM IHC loss or mutationTotalMisense nFrameshift nTruncating n(as % of those with ATM IHC loss)(as % of those with ATM IHC loss/mutation)Colorectal22316(7)9(4)544 (25)10 (48)Gynaecological1051(1)7(7)4125 (63)Thoracic801(1)3(4)211 (100)2 (67)Breast448(18)4(9)223 (38)4 (44)Upper GI372(5)1(3)12 (67)Hepatobiliary221(5)1(5)11 (50)Others762(3)2(3)21 (50)Total58731(5)27(5)14 (52)3 (11)10 (37)9 (29)24 (49)
Citation Format: Raghav Sundar, Susana Miranda, Suzanne Carreira, Maxime Chénard-Poirier, Daniel Nava Rodrigues, Ines Figueiredo, Claudia Bertan, Wei Yuan, Desamparados Roda Perez, Ana Ferreira, Nina Tunariu, Joaquin Mateo, Johann de Bono. ATM protein loss and clinical outcomes with platinum chemotherapy in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3807. doi:10.1158/1538-7445.AM2017-3807