Background/Objective: Studies have shown an association between colorectal cancer (CRC) sidedness and gene mutations that may affect CRC clinical behavior. This study examined the association between specific KRAS, NRAS, and BRAF hot-spot mutations and primary CRC sidedness. Methods: We performed a retrospective cohort analysis of 722 patients diagnosed with primary CRC and tested for KRAS, NRAS, and BRAF hot-spot mutations at the University of Texas Medical Branch (UTMB) from January 2016 through July 2023. Multivariable logistic regressions analyses were conducted. Results:KRAS, NRAS, and BRAF hot-spot mutations rates were 37.8%, 4.6%, and 6.1%, respectively. Right-sided primary CRC had the highest prevalence of mutated tumors (64%). KRAS and BRAF hot-spot mutations were significantly different according to tumor sidedness. KRAS p.Gly12Asp, p.Gly12Val, and p.Gly13Asp showed a significantly increased likelihood of right-sided primary CRC compared to KRAS wildtype, 128%, 134%, and 221% higher, respectively. Conversely, KRAS p.Gly12Val and p.Gly13Asp mutations were associated with decreased likelihood of rectal cancer (53% lower) and left-sided tumors (56% lower), respectively. BRAF p.Val600Glu mutation, as opposed to BRAF wildtype, was associated with a 278% higher likelihood of right-sided CRC. No significant associations were observed between NRAS mutations and primary CRC sidedness. Conclusions: In primary CRC, specific mutations in KRAS (p.Gly12Asp, p.Gly12Val, and p.Gly13Asp) and BRAF p.Val600Glu were associated with increased likelihood of right-sided tumors. KRAS p.Gly12Val and p.Gly13Asp mutations were associated with decreased likelihood of rectal cancer and left-sided tumors, respectively. These findings suggest that tumorigenesis and mutational processes differ based on tumor sidedness. Further studies are needed to substantiate these findings.

Background/Objective: The prognostic value of specific hot-spot mutations within KRAS, NRAS, and BRAF genes in metastatic colorectal cancer (mCRC) genes remains debatable. This study explores whether certain KRAS, NRAS, and BRAF mutations are associated with the risk of all-cause mortality in mCRC. Methods: We retrospectively analyzed records of 494 patients with mCRC treated at the University of Texas Medical Branch between January 2016 and July 2023. Data on genetic mutations and clinicopathological features were collected for this analysis. We estimated survival probabilities and conducted multivariable Cox proportional hazards regression to evaluate the impact of specific mutations on all-cause mortality risk. Results: KRAS c.35G>T (p.Gly12Val) and c.34G>T (p.Gly12Cys) mutations were significantly associated with an increased risk of all-cause mortality in the overall mCRC population and the treated mCRC subgroup. KRAS c.38G>A (p.Gly13Asp) was significantly associated with an increased risk of all-cause mortality in the treated mCRC subgroup but BRAF c.1799T>A (p.Val600Glu) was significantly associated with an increased risk of all-cause mortality in the overall mCRC population. No significant association was observed between NRAS mutations and mortality risk in mCRC, possibly due to their lower frequency or different biological effects compared to KRAS and BRAF mutations. Conclusions: These findings suggest that specific KRAS [c.35G>T (p.Gly12Val), c.34G>T (p.Gly12Cys), and c.38G>A (p.Gly13Asp)] and BRAF c.1799T>A (p.Val600Glu) mutations may have prognostic value in mCRC. However, given the single-center study design and lack of direct therapeutic implications, larger multicenter studies are needed to substantiate these results and better define the clinical relevance of these mutations.

Background/Objectives: The increasing prevalence of obesity has led to a growing interest in anti-obesity medications (AOMs). While these medications have shown promise in aiding weight loss, their potential impact on reducing obesity-related cancers (ORCs) incidence remains poorly understood, particularly among women over 65 years of age. This study examined the association between the use of AOMs and the risk of ORCs in this population. Methods: A retrospective cohort study was conducted using 2007–2015 SEER-Medicare data, including 10,830 women aged ≥65 years in a 1:2 propensity-score matching design. The primary exposure was AOM use, with additional analyses focused specifically on phentermine and liraglutide exposure. Conditional multivariable Cox proportional hazards models were conducted. Results: We found an inverse association between the use of AOMs and the risk of ORCs (aHR: 0.78; 95% CI: 0.73–0.84; p < 0.001). Similar findings were observed in cancer-specific sites analysis, advanced-stage ORCs (aHR: 0.76; 95% CI: 0.65–0.89; p < 0.001), breast (aHR: 0.84; 95% CI: 0.77–0.91; p < 0.001), colorectal (aHR: 0.82; 95% CI: 0.71–0.96; p = 0.010), and advanced-stage colorectal cancers (aHR: 0.71; 95% CI: 0.54–0.91; p < 0.001). In secondary analyses, phentermine was inversely associated with the risk of ORCs, breast, and endometrial cancers, but no associations with liraglutide were observed. Conclusions: The use of AOMs, including phentermine, was inversely associated with ORCs and some cancer-specific sites in a cohort of older women. Further prospective studies are warranted to validate these findings among women of different age groups and to identify the underlying biological mechanisms.

Background/Objectives: Metformin is one of the most frequently used concomitant medications among prostate cancer (PCa) patients. However, the effects of metformin on all-cause and PCa-specific mortality among men diagnosed with advanced/metastatic PCa treated with androgen-deprivation therapy (ADT) remain poorly understood, but they may be specifically explained by emulating a target trial. Methods: We emulated a target trial of metformin therapy and survival using observational data on 7361 patients diagnosed with advanced PCa, who were treated with ADT, from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2008–2019), with completed follow-up until 2020. We included patients with diabetes, and participants were assigned as either “initiator of metformin within 6 months after advanced PCa diagnosis” or “non-initiator of metformin.” We estimated mortality risks using Cox proportional hazards models with adjustment for risk factors via inverse probability weighting using both intention-to-treat and per-protocol analyses. Results: Over 13 years of follow-up, with a maximum 3 years of follow-up after PCa diagnosis, all-cause mortality occurred in 52 metformin initiators (47.7%) versus 3052 non-initiators (42.1%), while PCa-specific mortality occurred in 36 initiators (33.0%) versus 1919 non-initiators (26.5%). In the intention-to-treat analysis, metformin initiation was not associated with all-cause mortality (Hazard Ratio [HR] = 1.38, 95% CI: 0.98–1.95) or PCa-specific mortality (HR = 0.99, 95% CI: 0.63–1.55). Similarly, in per-protocol analysis, there was no evidence of risk reduction with all-cause (HR = 1.20, 95% CI = 0.80–1.81) or PCa-specific mortality (HR = 1.45, 95% CI = 0.88–2.38) after adjusting for time-varying covariates and allowing a 30-day gap for metformin discontinuation, adjusted for via inverse probability weighting. Conclusions: Our findings align with prior randomized trials showing no survival benefit of metformin in advanced PCa patients receiving ADT. Timing of metformin discontinuation also showed no significant effect. However, the small size of the metformin initiator group precluded subgroup analyses for hormone-sensitive (HSPC) and castrate-resistant prostate cancer (CRPC), limiting our ability to explore potential differential effects.

Background/Objectives: The associations of statins and testosterone replacement therapy (TTh) with the risk of obesity-related cancers (ORC, breast [BrCa], colorectal [CRC], ovarian, and endometrial cancers) in older women remain poorly understood. This study examined the associations between the use of statins and TTh with risk of ORC and its cancer-specific sites in women aged 65 years and older. Methods: A retrospective cohort study was conducted using 2007–2015 SEER-Medicare data, including 142,772 women aged ≥ 65 years. We identified 52,086 women with incident ORC (BrCa [n = 32,707], CRC [n = 11,070], ovarian [n = 2601], and endometrial [n = 5708] cancers). The primary exposures were use of statins and TTh. Weighted multivariable time-dependent Cox proportional hazards and models were conducted to estimate hazard ratios (HRs) of incident ORC. Results: We found an inverse association of statins with incident [HR, 0.76; 95% CI: 0.74, 0.78], high-grade [HR, 0.75; 95% CI: 0.72, 0.78], and advanced-stage [HR, 0.91; 95% CI: 0.88, 0.95] ORC. Concurrent use of statins and TTh was associated with a reduced incidence of ORC and high-grade ORC. Similar associations were observed with BrCa. Statins were inversely associated with high-grade ovarian cancer and endometrial cancer (incident, high-grade, and advanced-stage). Conclusions: Use of statins was inversely associated with ORC, BrCa, and endometrial cancer (high-grade and advanced-stage) and high-grade ovarian cancer in older women. Concurrent use of statins and TTh was inversely associated with ORC and BrCa and their high-grade disease. Future prospective studies are needed to substantiate these findings, especially with a focus to examine time– and dose–response associations and to identify underlying biological mechanisms through which statins and TTh influence incidence of ORC.