| Summary: | A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient’s immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients’ immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The <i>IL15RA</i> rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, <i>p</i> = 0.0327, Bootstrap <i>p</i>-value = 0.0280) and replication (HR: 1.71, <i>p</i> = 0.0411) cohorts. Conversely, <i>SMAD3</i> rs7179840-C allele was associated with better OS in both discovery (HR: 0.65, <i>p</i> = 0.0202, Bootstrap <i>p</i>-value = 0.0203) and replication (HR: 0.61, <i>p</i> = 0.0216) cohorts. A genetic prognostic score was generated integrating <i>IL15RA</i>-rs7910212 and <i>SMAD3</i>-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [<i>NR1I2</i>]-rs1054190, <i>VDR</i>-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (<i>p</i> < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as <i>IL15RA</i> and <i>SMAD3</i> markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI.
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