Dados do Resumo

Título

Assessing the impact of structural genomic variation in rectal cancer heterogeneity and response to neoadjuvant treatment

Introdução

Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer (LARC), aimed at reducing tumor size and facilitating surgical resection. Organ preservation is an emerging strategy, but clinical features poorly predict response. Intratumoral genetic heterogeneity (ITGH) has emerged as a biomarker for tumor response. However, the effects of copy number alterations (CNAs) and structural variations (SVs) on LARC outcomes and ITGH remain underexplored.

Objetivo

This study aims to investigate the genomic profile of LARC by assessing the impact of CNAs and SVs on ITGH. We also evaluated the ITGH, measured by the MATH score, as a potential biomarker for predicting clinical outcomes in response to nCRT.

Métodos

In this retrospective study, we evaluated 71 patients with LARC, with pre-treatment tumor biopsy collected and subjected to whole exome sequencing. All patients received long-course nCRT with either 5FU-based chemotherapy or Capecitabine. Patients were categorized into three groups based on clinical outcomes: nCRT-Responders (n=16), nCRT-Not Responders (n=38), and nCRT-Not Responders Metastatic (n=17). We used (SNVs/Indels) data to measure ITGH using the MATH score. SV events, including translocations, duplications, deletions, and insertions, were identified using MANTA, while CNAs (gains and losses) were detected with the GATK pipeline. We further explored whether CNAs could influence the MATH score's association with clinical outcomes by recalculating the MATH score separately for SNVs within and outside CNA regions. By the end, we applied a ROC curve, and multivariate regression analyses to evaluate the MATH score as a potential biomarker in non-metastatic clinical outcomes.

Resultados

The ITGH measured by the MATH score shows a significant association between low MATH scores and nCRT response (p ≤ 0.05, Wilcoxon test), especially when comparing nCRT-Responders to non-metastatic nCRT-Not Responders. Investigation about SV and CNA events showed no correlation with clinical outcomes (p > 0.05, Wilcoxon test). We further recalculated the MATH score using SNVs within and outside CNA regions individually and found no change in its association with clinical outcomes. Finally, we analyzed patients with non-metastatic clinical outcomes (n=53). Using ROC curve analysis, we determined the best MATH score threshold (34.04), with a sensitivity of 89% and specificity of 53% (AUC=0.67). Multivariate analysis with the clinical-radiological features shows that MATH-low is significantly associated with nCRT-R (OR:11.66; p=0.01).

Conclusões

Our results show no correlation between CNAs and SV events with clinical outcomes, that CNAs events do not impact ITGH, and suggest that the MATH score may help select patients for preoperative treatment, potentially achieving a complete response and enabling organ preservation.

Financiador do resumo

FAPESP 2022/03631-0; FAPESP 2018/15582-9

Palavras Chave

LARC; Neoadjuvant Chemoradiotherapy; Intratumoral Heterogeneity