Publications

IMPORTANCE

The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown.

OBJECTIVE

To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population.

DESIGN, SETTING, AND PARTICIPANTS

In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018.

MAIN OUTCOMES AND MEASURES

Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases.

RESULTS

Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks.

CONCLUSIONS AND RELEVANCE

The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance.

Increasing rates of sexually transmitted infections (STIs) in the United States among men who have sex with men (MSM) have raised concerns that pre-exposure prophylaxis (PrEP) has been associated with higher engagement in condomless anal intercourse (CAI). While partnership characteristics have previously been found to influence condom use, the extent to which PrEP use may modify their effect on CAI remains unknown. A secondary analysis of 535 sexual partnerships from a cross-sectional study in San Francisco was conducted to evaluate interactions between PrEP use and partnership characteristics on CAI. Bivariate and multivariate generalized estimating equation (GEE) logistic regression models were used to estimate relative measures of association, adjusted for confounding by seroconcordance and partnership type, as well as account for repeated partnerships per respondent. Partnerships where both partners used biomedical prevention had significantly greater odds of CAI [odds ratio (OR) = 5.19, 95% confidence interval (CI): 2.27-11.9] compared to those where only one partner used biomedical prevention, while those where neither partner used biomedical prevention had significantly lower odds of CAI (OR = 0.61, 95% CI: 0.40-0.93). There was no significant association between meeting place (online vs. offline) and sexual risk taking (OR = 1.03, p = 0.894). Having one partner disclose their HIV status (compared to neither partner having disclosed) was associated with significantly higher odds of CAI among partnerships of PrEP-using MSM [adjusted OR (aOR) = 5.28, 95% CI: 1.91-14.61], while the association was not significant among the partnerships of non-PrEP-using MSM (aOR = 1.29, 95% CI: 0.75-2.21). Differences in condom use among MSM using PrEP may not be well explained by differences in the effect of partnership characteristics. MSM using PrEP appear to commonly practice biomedical matching and high engagement in CAI with other biomedical prevention users, which could indicate relatively concentrated sexual networks and partly explain their disproportionate risk for STIs. Future studies should further investigate biomedical matching to develop interventions that further promote the sexual health of those using PrEP.

Importance

Randomized clinical trials have demonstrated that patients with asymptomatic carotid stenosis are eligible for carotid endarterectomy (CEA) if the 30-day surgical complication rate is less than 3% and the patient's life expectancy is at least 5 years.

Objective

To develop a risk prediction tool to improve patient selection for CEA among patients with asymptomatic carotid stenosis.

Design, Setting, and Participants

In this cohort study, veterans 65 years and older who received both carotid imaging and CEA in the Veterans Administration between January 1, 2005, and December 31, 2009 (n = 2325) were followed up for 5 years. Data were analyzed from January 2005 to December 2015. A risk prediction tool (the Carotid Mortality Index [CMI]) based on 23 candidate variables identified in the literature was developed using Veterans Administration and Medicare data. A simpler model based on the number of 4 key comorbidities that were prevalent and strongly associated with 5-year mortality was also developed (any cancer in the past 5 years, chronic obstructive pulmonary disease, congestive heart failure, and chronic kidney disease [the 4C model]). Model performance was assessed using measures of discrimination (eg, area under the curve [AUC]) and calibration. Internal validation was performed by correcting for optimism using 500 bootstrapped samples.

Main Outcome and Measure

Five-year mortality.

Results

Among 2325 veterans, the mean (SD) age was 73.74 (5.92) years. The cohort was predominantly male (98.8%) and of white race/ethnicity (94.4%). Overall, 29.5% (n = 687) of patients died within 5 years of CEA. On the basis of a backward selection algorithm, 9 patient characteristics were selected (age, chronic kidney disease, diabetes, chronic obstructive pulmonary disease, any cancer diagnosis in the past 5 years, congestive heart failure, atrial fibrillation, remote stroke or transient ischemic attack, and body mass index) for the final logistic model, which yielded an optimism-corrected AUC of 0.687 for the CMI. The 4C model had slightly worse discrimination (AUC, 0.657) compared with the CMI model; however, the calibration curve was similar to the full model in most of the range of predicted probabilities.

Conclusions and Relevance

According to results of this study, use of the CMI or the simpler 4C model may improve patient selection for CEA among patients with asymptomatic carotid stenosis.