PI3K Pathway Alterations in Peritoneal Metastases are Associated with Earlier Recurrence in Patients with Colorectal Cancer Undergoing Optimal Cytoreductive Surgery.

Background: Colorectal cancer with peritoneal metastasis (CRC-PM) represents a biologically heterogeneous disease; yet little is known regarding the impact of tumor biology on survival outcomes following optimal cytoreductive surgery (CRS). We analyzed the frequency of alterations in cancer signaling pathways in patients with CRC-PM and their impact on recurrence-free survival (RFS) following optimal CRS.

Methods: Thirty-five consecutive CRC-PM patients who underwent optimal CRS/HIPEC and next generation sequencing of peritoneal metastases were included in the study. Alterations in eight cancer-related signaling pathways were analyzed: Wnt/APC, p53, RTK-RAS, PI3K, TGF-B, Notch, Myc, and cell cycle. The association of pathway alterations with RFS and OS following optimal cytoreduction was estimated using Cox proportional hazard modeling.

Results: The most frequently altered pathways were Wnt/APC (63%), p53 (63%), RTK-RAS (60%), and PI3K (23%). Among optimally cytoreduced patients with CRC-PM, PI3K pathway alterations were an independent predictor of worse RFS (hazard ratio 3.2, 95% confidence interval CI 1.3-8.3, p = 0.01) with a clinically meaningful impact on median months to recurrence (5 vs. 13 months, p = 0.02). Alterations in p53, Wnt, and RTK-RAS pathways were not significantly associated with a difference in RFS following CRS. Alterations in the four pathways were not associated with differences in OS following CRS (median OS was 50 (interquartile range 23-80) months).

Conclusions: In patients with CRC-PM, PI3K pathway alterations are associated with earlier recurrence following optimal CRS, which may represent a distinct molecular subtype. This novel finding can tailor clinical trials by using PIK3CA-directed interventions to reduce risk of recurrence after optimal CRS.