Publications

BACKGROUND

Currently available biomarkers are imperfect in their ability to predict responses to the multiple first-line treatment options available for patients with advanced non-small cell lung cancer (NSCLC). Having an early pharmacodynamic marker of treatment resistance may help redirect patients onto more effective alternative therapies. We sought to determine if changes in circulating tumor DNA (ctDNA) levels after initiation of first-line pembrolizumab±chemotherapy in NSCLC would enable early prediction of response prior to radiological assessment.

METHODS

Plasma collected from patients with advanced NSCLC prior to and serially after starting first-line pembrolizumab±platinum doublet chemotherapy was analyzed by next-generation sequencing using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes. Early change in ctDNA allele fraction (AF) was correlated with radiographic responses and long-term clinical outcomes.

RESULTS

Among 62 patients who received first-line pembrolizumab±platinum/pemetrexed and underwent ctDNA assessment, 45 had detectable ctDNA alterations at baseline. The median change in AF at the first follow-up (at a median of 21 days after treatment initiation) was -90.1% (range -100% to +65%) among patients who subsequently had a radiologic response (n=18), -19.9% (range: -100% to +1884%) among stable disease cases (n=15), and +28.8% (range: -100% to +410%) among progressive disease cases (n=12); p=0.003. In addition, there was a significant correlation between the percent change in ctDNA at the first follow-up and the percent change in tumor target lesions from baseline (R=0.66, p<0.001). AF decrease between the pretreatment and first on-treatment blood draw was associated with significantly higher response rate (60.7% vs 5.8%, p=0.0003), and significantly longer median progression-free survival (8.3 vs 3.4 months, HR: 0.29 (95% CI: 0.14 to 0.60), p=0.0007) and median overall survival (26.2 vs 13.2 months, HR: 0.34 (95% CI: 0.15 to 0.75), p=0.008) compared with cases with an AF increase.

CONCLUSION

In patients with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.

Men who have sex with men (MSM) have a high prevalence of hazardous alcohol consumption. While network-level characteristics such as social network size have been indicated as upstream determinants of alcohol use in general population samples, no studies have examined factors associated with alcohol using network size (ANS), among MSM.This secondary analysis examined demographic, substance use, and sexual behavior correlates of ANS using data from a diverse sample of alcohol-using MSM in San Francisco ( = 252). Associations were calculated using multivariable negative binomial regression, adjusting for age, race, education, and employment.The median ANS was 10. Factors associated with larger ANS in multivariable analyses included identifying as Hispanic/Latino, having completed a college education or higher, having a higher Alcohol Use Disorders Identification Test (AUDIT) score, having a greater number of sexual partners, polysubstance use, and being unaware of one's own HIV status. Factors associated with smaller ANS included being between 18 and 24 years of age, reporting a low income, and having any lifetime history of injection drug use.For MSM, ANS was associated with increased likelihood of hazardous alcohol use, as well specific individual-level substance use and sexual risk behaviors. These results highlight the role of ANS in hazardous alcohol consumption and sexually transmitted infection transmission among MSM. These results also indicate ways that research and intervention programs aimed at reducing alcohol use among MSM might be improved through network-based recruitment or engagement. Finally, these results suggest the need for further research on HIV-unknown MSM.