Aspirin use and PI3K mutations in metastatic colorectal cancer (mCRC).

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189 Background: Aspirin use is established as adjuvant therapy for PIK3CA mutant (mt) stage II-III colorectal cancer, but its role in mCRC remains unclear, with conflicting findings after resection of liver metastases. We evaluated overall survival (OS) in mCRC patients by PI3K status and aspirin use. Methods: Institutional datasets were used to acquire the data. PI3K alterations were classified as PIK3CA mt or other ( PTEN and PIK3R1 ). Aspirin use was defined as ≥30 days of use at any time after diagnosis. To mitigate immortal time bias, a landmark analysis at 12 months was performed for patients who initiated aspirin within 335 days of diagnosis. OS was assessed using Kaplan–Meier and Cox regression adjusted for age, ECOG, primary tumor location, number of metastatic sites, aspirin use, PIK3CA , and RAS/ BRAF . The interaction between PI3K/ PIK3CA and aspirin use were evaluated with the Wald test. Results: Of 1,529 patients (137 aspirin users, 1392 non-users; median age 55 years; 60% male), 484 (32%) had PIK3CA mt (exon 9, 44%; exon 20, 16%; other, 31%), and 103 (7%) other PI3K mutations. Among aspirin users, OS was similar for PI3Kmt vs wildtype (wt) (39.2 vs 38.9 months; HR 0.79; 95% CI 0.46-1.40; p = 0.403) and for PIK3CA mt vs wt (38.1 vs 39.2 months; HR 0.97; 95% CI 0.55-1.70; p = 0.914). In patients not using aspirin, OS was worse for PI3Kmt vs wt (47.3 vs 58.5 months; HR 1.20; 95% CI 1.00-1.40; p = 0.022) and for PIK3CA mt vs wt (45.7 vs 59.1 months; HR 1.30; 95% CI 1.10-1.50; p = 0.001). In the multivariable analysis, age ≥55 years, poor ECOG PS, multiple metastatic sites, and RAS mutations remained significant adverse prognostic factors, while PIK3CA mt and aspirin use were prognostic only in the univariable model (Table). No significant interaction was observed between aspirin use and PI3K ( p = 0.199) or PIK3CA ( p = 0.498). Conclusions: PIK3CA and PI3K pathway mutations are associated with worse prognosis in mCRC, particularly among patients not receiving aspirin. This effect was not observed in aspirin users with no significant interaction detected. These findings are hypothesis-generating, and further investigation is needed to clarify the role of aspirin in PI3K/ PIK3CA mt mCRC. Variables Univariable HR(95% CI) p Multivariable HR(95% CI) p Age (≥55 vs <55) 1.40 (1.20–1.60) <0.001 1.31 (1.13–1.50) <0.001 ECOG (1 vs 0) 1.40 (1.20–1.60) <0.001 1.29 (1.10–1.50) 0.001 ECOG (≥2 vs 0) 2.10 (1.70–2.60) <0.001 1.93 (1.54–2.40) <0.001 Primary location (Right vs Left) 1.37 (1.18–1.60) <0.001 1.16 (0.98–1.50) 0.008 Number of metastasis (≥2 vs 1) 1.40 (1.19-1.70) <0.001 1.35 (1.14–1.60) <0.001 Aspirin use (Yes vs No) 1.30 (1.00-1.60) 0.032 1.27 (1.00–1.60) 0.054 PIK3CA ( mt vs wt) 1.20 (1.10–1.40) 0.003 1.08 (0.93–1.30) 0.331 RAS (mt vs RAS/ BRAF wt) 1.30 (1.15–1.50) <0.001 1.24 (1.06–1.40) 0.006 BRA

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