Response to DNA-damaging agents and PARP inhibitors in ATM mutated metastatic colorectal cancer: case series.

Abstract

Background: The ataxia-telangiectasia mutated (ATM) gene is central to homologous recombination (HR) repair and cell-cycle checkpoint control. Pathogenic ATM mutations are increasingly recognized in metastatic colorectal cancer (mCRC) and are associated with improved prognosis, with survival nearly twice that of ATM wild-type disease. DNA-damaging chemotherapy combined with poly (ADP-ribose) polymerase (PARP) inhibition is effective in other HR-deficient cancers, but data in mCRC are limited.

Case description: We describe four patients with mCRC harboring germline or somatic ATM mutations with high variant allele frequency (VAF). All demonstrated clinical and radiographic benefit from DNA-damaging chemotherapy, including platinum- and topoisomerase-based regimens, exceeding historical controls. In two patients, the addition of PARP inhibitors (PARPi) therapy was associated with sustained disease control. These cases illustrate the potential therapeutic relevance of targeting HR deficiency in ATM-mutated colorectal cancer (CRC).

Conclusions: This series underscores the sensitivity of ATM-mutated mCRC to DNA-damaging chemotherapy and highlights the potential role of PARPi. The therapeutic benefit of PARPi in these patients cannot be fully separated from concurrent chemotherapy, and the observed responses are likely to reflect combined effects. Nonetheless, these findings suggest potential synergy and warrant further investigation of PARP inhibition, alone or in combination, in biomarker-selected mCRC populations.