The KRAS p.G12C mutation, prevalent in non-small-cell lung cancer (NSCLC), has only recently become a viable target. Here we present results of the largest retrospective observational study analyzing KRAS p.G12C in patients with advanced NSCLC. Materials and Methods: Adults with advanced NSCLC (All Advanced NSCLC cohort) and subcohorts with different mutation profiles (KRAS p.G12C [G12C] and KRAS/EGFR/ALK wild type [Triple WT]) diagnosed January 2011 to March 2019 were selected from a US clinico-genomic database; treatment-related characteristics, molecular profiles, real-world overall (rwOS) and progression-free survival (rwPFS) were analyzed. Results: Demographics were similar across cohorts, with more smokers and nonsquamous cell carcinoma histology in the G12C cohort. KRAS p.G12C was nearly mutually exclusive (≤1.2 %) with known actionable driver mutations, but non-driver co-mutations were common (STK11, 21.5 %; KEAP1, 7.0 %; TP53, 48.0 %). Among G12C patients, 20 % had no documentation of receiving systemic therapy. Across treated G12C patients, 67 % received immune checkpoint inhibitors; first-line usage increased from 0% (2014) to 81 % (2019). Among G12C patients, median (95 % CI) rwOS was 12.0 (9.6-15.3), 9.5 (8.1-13.1), and 6.7 (5.9-10.7) months after first, second, and third line of therapy, respectively; median (95 % CI) rwPFS was 5.0 (4.4-5.8), 4.0 (2.8-5.3), and 3.1 (2.4-4.3) months. Outcomes for the G12C subcohort were similar to those for all patients (All Advanced NSCLC cohort). Mutations in STK11/KEAP1 were associated with poorer survival across all cohorts. Conclusion:The poor outcomes associated with KRAS p.G12C mutated advanced NSCLC indicate an unmet need for more effective novel treatments.Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; CGDB, clinico-genomic database; CGP, comprehensive genomic profiling; EGFR, epidermal growth factor receptor; EHR, electronic health records; FH-FMI, Flatiron Health-Foundation Medicine; G12C, patients with KRAS p.G12C mutated NSCLC included in study; KEAP1, Kelch-like ECH-associated protein 1 oncogene; KRAS, Kirsten rat sarcoma viral oncogene homolog; KRAS p.G12C, codon 12 glycine-tocysteine substitution of KRAS; MET, mesenchymal-epithelial transition; NGS, next-generation sequencing; NSCLC, non-small-cell lung cancer; NTRK1-3, neurotrophic tyrosine kinases 1-3 gene; PD-1, programmed death 1; PD-L1, programmed death ligand 1; RAS, rat sarcoma viral oncogene homolog; RECIST, Response Evaluation Criteria in Solid Tumors; RET, rearranged-during-transfection gene; ROS1, ROS proto-oncogene 1; rwOS, real-world overall survival; rwPFS, real-world progression-free survival; STK11/LKB1, serine/threonine kinase 11, liver kinase B1; TP53, tumor protein p53; Triple WT, KRAS/EGFR/ALK wild-type; VEGF, vascular endothelial growth factor.

BackgroundMSM are at higher risk for invasive anal cancer. Twelve human papillomaviruses (HPVs) cause cervical cancer in women (Group 1 high-risk HPVs (hrHPVs)) and 13 HPVs are probable/possible causes (Group 2 hrHPVs) of cervical malignancy. HPVs rarely associated with malignancy are classified as lower-risk HPVs (lrHPVs).Materials and MethodsDacron-swab anal-cytology specimens were collected from and data complete for 97% (1262/1296) of Multicenter AIDS Cohort Study (MACS) men tested for HPVs using the Linear Array assay. Multivariate Poisson regression analyses estimated adjusted prevalence ratios for Group 1/2 hrHPVs and lrHPVs, controlling for the effects of age, race, ethnicity, sexual partnerships, smoking; HIV-infection characteristics, treatment, and immune status among HIV-infected men.ResultsHIV-infected men showed 35–90% higher prevalence of Group 1/2 hrHPVs and lrHPVs than HIV-uninfected men, and higher prevalence of multi-Type, and multiple risk-group infections. CD4+ T-cell count was inversely associated with HPV Group 2 prevalence (p<0.0001). The number of receptive anal intercourse (RAI) partners reported in the 24 months preceding HPV testing predicted higher prevalence of Group 1/2 hrHPVs. Men reporting ≥30 lifetime male sex partners before their first MACS visit and men reporting ≥1 RAI partners during the 24 months before HPV testing showed 17–24% and 13–17% higher prevalence of lrHPVs (p-values ≤0.05). Men reporting smoking between MACS visit 1 and 24 months before HPV testing showed 1.2-fold higher prevalence of Group 2 hrHPVs (p = 0.03). Both complete adherence to CART (p = 0.02) and HIV load <50 copies/mL (p = 0.04) were protective for Group 1 hrHPVs among HIV-infected men.ConclusionsHIV-infected men more often show multi-type and multi-group HPV infections HIV-uninfected men. Long-term mutual monogamy and smoking cessation, generally, and CART-adherence that promotes (HIV) viremia control and prevents immunosuppression, specifically among HIV-infected MSM, are important prevention strategies for HPV infections that are relevant to anal cancer.

Background The KRAS p.G12C mutation has recently become an actionable drug target. To further understand KRAS p.G12C disease, we describe clinicopathologic characteristics, treatment patterns, overall survival (OS), and real-world progression-free survival (rwPFS) in patients with metastatic colorectal cancer (mCRC), KRAS p.G12C mutations (KRAS G12C), and other KRAS mutations (KRAS non-G12C) using a de-identified database. Patients and Methods Clinical and tumor characteristics, including treatments received, genomic profile, and clinical outcomes were assessed for patients from a US clinical genomic database with mCRC diagnosed between January 1, 2011, and March 31, 2020, with genomic sequencing data available. Results Of 6477 patients with mCRC (mCRC cohort), 238 (3.7%) had KRAS G12C and 2947 (45.5%) had KRAS non-G12C mutations. Treatment patterns were generally comparable across lines of therapy (LOT) in KRAS G12C versus KRAS non-G12C cohorts. Median (95% CI) OS after the first LOT was 16.1 (13.0-19.0) months for the KRAS G12C cohort versus 18.3 (17.2-19.3) months for the KRAS non-G12C cohort, and 19.2 (18.5-19.8) months for the mCRC overall cohort; median (95% CI) rwPFS was 7.4 (6.3-9.5), 9.0 (8.2-9.7), and 9.2 (8.6-9.7) months, respectively. The different KRAS non-G12C mutations examined did not affect clinical outcomes. Median OS and rwPFS for all cohorts declined with each subsequent LOT. Conclusions Patients with KRAS p.G12C-mutant mCRC have poor treatment outcomes, and outcomes appear numerically worse than for those without this mutation, indicating potential prognostic implications for KRAS p.G12C mutations and an unmet medical need in this population.

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Background An anal histological high‐grade squamous intraepithelial lesion (hHSIL) is an anal cancer precursor. Experts recommend Dacron swab anal cytology as a primary screen for anal hHSILs, especially among human immunodeficiency virus–infected and –uninfected men who have sex with men (MSM). Studies have shown that Dacron cytology inaccurately predicts anal hHSILs and results in unnecessary diagnostic procedures. Nylon‐flocked (NF) swabs have been shown to trap pathogens and cells well. Thus, this study compared test characteristics of anal cytology using NF and Dacron swab collection protocols to predict anal hHSILs. Methods A single‐visit, randomized clinical trial compared NF and Dacron swab anal cytology specimens to predict high‐resolution anoscopy and biopsy–diagnosed anal hHSILs. Data for 326 gay men, bisexual men, other MSM, and male‐to‐female transgender women contributed descriptive and tabular statistics with which unadjusted and fully adjusted logistic regression models were constructed. The models estimated the odds of hHSILs, test accuracy (area under the curve [AUC]) and sensitivity, and specificity as well as the positive and negative predictive values of abnormal NF and Dacron cytology for predicting hHSILs. Results In the fully adjusted model, the sensitivities for NF and Dacron cytology were nearly equal (48% vs 47%), but the specificity was higher with NF cytology (76% vs 69%). Comparisons of the areas under receiver operating characteristic curves showed that NF cytology alone predicted hHSILs better than the covariate model (AUC, 0.69 vs 0.63; P = .02), but NF and Dacron cytology comparisons showed no statistically significant differences (AUC, 0.69 vs 0.67; P = .3). Conclusions NF cytology and Dacron cytology provide modest sensitivity, but NF cytology has higher specificity and accuracy, and this is important for lowering the costs of population‐based screening.