Abstract 5360: Mutational profile and genomic instability according to response to therapy in rectal carcinomas
Authors: Canto Luisa Matos do , Larsen Simon J. , Kupper Bruna E. Catin , Begnami Maria D. Ferreira de Souza , Neto Cristovam Scapulatempo , Baumbach Jan , Petersen Annabeth Høgh , Jørgensen Mads Malik Aagaard , Aguiar Samuel , Rogatto Silvia R. 
Published: August 2018

Abstract
Rectal cancer (ReCa) patients with locally advanced disease present a high risk of locoregional recurrence and death by the disease. Preoperative neoadjuvant chemoradiotherapy (nCRT) and total mesorectal surgery have been used to reduce these events. However, nCRT has resulted in significant morbidity and up to 30% of patients present pathologic incomplete response (pIR) and ~20% develop distant metastasis or minimal regression to stable disease. These findings reinforce the relevance of identifying predictive markers of response to therapy. Genomic instability (GI) is one of the cancer hallmarks. Patterns of genomic alterations (gains, losses, and cnLOH) and the mutational profile have resulted in prognostic and predictive signatures in several cancer types. Targeted next-generation sequencing (105 cancer-related genes panel, including 13 genes involved in the homologous recombination-HR and, 5 in the mismatch repair-MMR pathways) was performed in 31/33 pretreatment ReCa biopsies. 33 samples were evaluated by SNP array to identify the GI index and the HR deficiency (HRD) scores (LST: large-scale transitions, tAI: telomeric allele imbalance, HRD-LOH: loss of heterozygosity). The GI index represents the fraction of the altered genome and the HRD scores (LST, tAI, HRD-LOH) are reported as markers of deficiency in DNA repair by HR pathway. We found 161 mutations in 51 genes; TP53 (84%), APC (81%) and KRAS (45%) were more frequently mutated. No survival differences were observed among the subgroups studied according to the presence of two APC mutations, KRAS, and TP53 mutations or lacking APC mutations. Overall, a high burden of genomic alterations was observed in ReCa samples. The median GI index was 0.358, much higher than those observed in breast cancer. Patients with complete pathologic response (pCR) presented higher GI index (0.475) compared to pIR (0.294). A significant difference was observed grouping responders (TRG 0+1) and nonresponders (TRG 2+3) (p = 0.043). The GI index of chromosome 12 was higher in pCR (p=0.019). Deficient mismatch repair indicates ineffectiveness of 5-FU used in the nCRT. Three tumors presented mutations in MLH3 or MSH6. An additional analysis performed in HR pathway genes revealed that 7/31 cases presented mutations. Three of these seven ReCa showed high tAI scores, indicating sensitivity to platinum-based therapy. HR-defective tumors have been associated with better platinum response rates. In addition, five cases presented PTEN loss; five, PIK3CA mutations; and one case, BRAF mutation. These alterations have been reported as promising predictors for treatment response in colorectal cancer. The involvement of HR pathway or other driver mutations in the response to therapy in rectal cancers remains unclear. Comprehensive studies in a large set of cases are required to confirm the predictive value of these alterations in rectal cancer.
Citation Format: Luisa Matos do Canto, Simon J. Larsen, Bruna E. Catin Kupper, Maria D. Ferreira de Souza Begnami, Cristovam Scapulatempo Neto, Jan Baumbach, Annabeth Høgh Petersen, Mads Malik Aagaard Jørgensen, Samuel Aguiar, Silvia R. Rogatto. Mutational profile and genomic instability according to response to therapy in rectal carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5360.