Superior Overall Survival in Patients with Colorectal Cancer, Regular Aspirin Use, and Combined Wild-Type PIK3CA and KRAS-Mutated Tumors

Abstract

The impact of aspirin use after the diagnosis of colorectal cancer is unknown. Among others, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutational status was proposed as a molecular biomarker for the response to adjuvant aspirin therapy. However, prognostic data on aspirin use after a colorectal cancer diagnosis in relation to KRAS mutational status is limited. In a single-center retrospective study, we obtained KRAS and PIK3CA mutational status in a cohort of 153 patients with a first diagnosis of colorectal cancer receiving tumor surgery with curative intent. PIK3CA mutational status was determined by pyrosequencing, and KRAS mutational status was determined by next-generation sequencing. Clinicopathological data and survival data were assessed using patient records and reporting registers. We observed a significant 10-year overall survival benefit in patients with aspirin use and combined wild-type PIK3CA and mutated-KRAS tumors (HR = 0.38; 95% CI = 0.17–0.87; p = 0.02), but not in patients without aspirin use. Our data indicate a benefit of aspirin usage particularly for patients with combined wild-type PIK3CA and mutated-KRAS tumor characteristics.

Aspirin and Cancer Survival: An Analysis of Molecular Mechanisms

“…The first group includes primary genes controlled directly by aspirin, i.e., PTGS2 and PTGES2 . The second group consists of genes involved in cell signaling and cell proliferation like cMyc , EGFR , BCL2 , WNT , KRAS , WNT6 , BRAF , MUC1 , PIK3CA , PARP1 , PARP2 , STAT3 , MAPK , JAK/STAT , and BAX [ 6 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]; the third group includes genes for cytokines or their receptors (e.g., IFNγ , IL1β , IL2 , IL4 , IL5 , IL6 , IL7 , IL8 , IL10 , IL12 (p70) , IL13 , IL17 , CXCR1 , CXCR2 , PTGS2 , PTGES2 , NFKB1 , and TNFα ) [ 30 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]; and the fourth group consists of tumor suppressor genes including P53 , BRCA1 [ 43 ], hMLH1 , hMSH2 , hMSH6 , and hPMS2 [ 44 , 45 ] ( Table 1 ).…”

“…It has also been observed that the benefit appears in all cancers and is not limited to any cancer in particular. For example, aspirin use has been associated with improved survival for colorectal cancer (HR = 0.38; 95% CI = 0.17–0.87; p = 0.02) [ 6 ], biliary tract cancer [ 7 , 8 ], breast cancer (adjusted HR = 0.69, 95% CI 0.47–0.98) [ 9 ], prostate cancer (adjusted hazard ratio, 0.43; 95% CI, 0.21 to 0.87; p = 0.02) [ 10 ], and Endometrial cancer (hazard ratio 0.46, 95% CI 0.25–0.86, p = 0.014) [ 11 ].…”

Aspirin and cancer survival-related pathways: a review and analysis of molecular mechanisms

“…The rst group includes primary genes controlled directly by aspirin, i.e., PTGS2 and PTGES2. The second group consists of genes involved in cell signaling and cell proliferation like cMyc, EGFR, BCL2, WNT, KRAS, WNT6, BRAF, MUC1, PIK3CA, PARP1, PARP2, STAT3, MAPK, JAK/STAT, BAX 6,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] ; the third group, genes for cytokines or their receptors (e.g., IFNγ, IL1β, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12 (p70), IL13, IL17, CXCR1, CXCR2, PTGS2, PTGES2, NFKB1, and TNFα); 30,[33][34][35][36][37][38][39][40][41][42] and the fourth group, tumor suppressor genes including P53, BRCA1, 43 hMLH1, hMSH2, hMSH6, hPMS2 44,45 (Table 1).…”

“…It has also been observed that the bene t appears in all cancers and is not limited to any cancer in particular. For example, aspirin use has been associated with improved survival for colorectal cancer (HR = 0.38; 95% CI = 0.17-0.87; p = 0.02), 6 biliary tract cancer 7,8 , breast (adjusted HR=0.69, 95% CI 0.47-0.98), 9 prostate (adjusted hazard ratio, 0.43; 95% CI, 0.21 to 0.87; P = .02) 10 and Endometrial cancer (hazard ratio 0.46, 95% CI 0.25-0.86, P=.014). 11 Various mechanisms have been proposed to explain the protective role of aspirin in cancer.…”

Survival Analysis of 1140 Patients with Biliary Cancer and Benefit from Concurrent Renin-Angiotensin Antagonists, Statins, or Aspirin with Systemic Therapy

“… 85-88 We did not include tumor and/or pharmacogenomic alteration data in our analyses, but this should be a future consideration, exemplified by patients with wild-type PIK3CA, Lynch syndrome and KRAS-mutated colorectal cancers experiencing survival benefit from aspirin. 54 , 89 , 90 …”