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. 2021 Apr 3;13(7):1705.
doi: 10.3390/cancers13071705.

IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm

Elena De Mattia  1 , Jerry Polesel  2 , Rossana Roncato  1 , Adrien Labriet  3 , Alessia Bignucolo  1 , Sara Gagno  1 , Angela Buonadonna  4 , Mario D'Andrea  5 , Eric Lévesque  6 , Derek Jonker  7 , Félix Couture  6 , Chantal Guillemette  3 , Erika Cecchin  1 , Giuseppe Toffoli  1
Affiliations

IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm

Elena De Mattia et al. Cancers (Basel). .

Abstract

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 IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR: 1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR: 0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR: 0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI.

Keywords: FOLFIRI; IL15RA; SMAD3; colorectal cancer; genetic score; immune system; polymorphisms; survival.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
Kaplan-Meier estimates of overall survival according to the selected IL15RA-rs7910212 and SMAD3-rs7179840 polymorphisms in the combined discovery and replication cohorts (pooled population, n = 335).
Figure 3
Figure 3
Kaplan-Meier estimates of progression-free survival according to the selected IL15RA-rs7910212 and SMAD3-rs7179840 polymorphisms in the combined discovery and replication cohorts (pooled population, n = 335).
Figure 4
Figure 4
Kaplan-Meier estimates of overall survival according to the genetic score in the combined case series (n = 320).
See this image and copyright information in PMC

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