Y. Shimada1, Y. Tajima1, M. Nagahashi1, H. Ichikawa1, M. Nakano1, H. Kameyama1, J. Sakata1, T. Kobayashi1, Y. Takii2, S. Okuda3, K. Takabe4,5, T. Wakai1 1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata, , Japan 2Niigata Cancer Center Hospital,Department Of Surgery,Niigata, , Japan 3Niigata University Graduate School Of Medical And Dental Sciences,Division Of Bioinformatics,Niigata, , Japan 4Roswell Park Cancer Institute,Breast Surgery,Buffalo, NY, USA 5University At Buffalo Jacobs School Of Medicine And Biomedical Sciences,Department Of Surgery,Buffalo, NY, USA
Introduction: Right-sided colorectal cancer (RCRC), which is derived from midgut, has different molecular and biological characteristics compared with left-sided colorectal cancer (LCRC) which is derived from hindgut. Recently, several unplanned retrospective analyses revealed the differences between RCRC and LCRC in prognosis and response to targeted therapy. We hypothesized that primary tumor sidedness is a surrogate for non-random distribution of genetic alterations, and is a simple and useful biomarker in patients with Stage IV CRC. To teste this hypothesis, we investigated the genetic alterations using comprehensive genomic sequencing (CGS), and analyzed the clinical impact of primary tumor sidedness in patients with Stage IV CRC.
Methods: One-hundred-eleven Stage IV CRC patients with either RCRC or LCRC were analyzed. We investigated genetic alterations using 415-gene panel, which includes the genetic alterations associated with resistance to anti-EGFR therapy. The differences of clinicopathological characteristics and genetic alterations were analyzed between RCRC and LCRC using Fisher’s exact test. The differences in response to targeted therapies, and clinical significance of residual tumor status were analyzed between RCRC and LCRC using log-rank test.
Results: Thirty-four patients (31%) and 77 patients (69%) had RCRC and LCRC, respectively. Histopathological grade 3 was significantly associated with RCRC (P = 0.042). Pulmonary metastasis was significantly associated with LCRC (P = 0.012), and peritoneal metastasis was significantly associated with RCRC (P = 0.002). Regarding residual tumor status, R0 resection of both primary and metastatic lesions showed significantly better overall survival compared with R2 resection in both RCRC and LCRC (P = 0.026 and 0.002, respectively). Regarding genetic alterations, RCRC has more genetic alterations associated with resistance to anti-EGFR therapy (BRAF, ERBB2, FGFR1, KRAS, PIK3CA, PTEN) compared with LCRC (P = 0.040). In 73 patients with anti-VEGF therapy, there was no significant difference on progression-free survival (PFS) between RCRC and LCRC (P = 0.866). Conversely, in 47 patients with anti-EGFR therapy, RCRC showed significantly worse PFS than LCRC (P = 0.019).
Conclusion: RCRC is more likely to have the genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC, and shows resistance to anti-EGFR therapy. Primary tumor sidedness is a surrogate for non-random distribution of molecular subtypes in CRC.
