Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.

Landscape and Saturation Analysis of Mutations Associated With Race in Cancer Genomes by Clinical Sequencing.

Differences in cancer genomes between racial groups may impact tumor biology and health disparities. However, the discovery of race-associated mutations is constrained by the limited representation and sample size of different racial groups in prior genomic studies. We evaluated the influence of race on the frequency of gene mutations using the Genomics, Evidence, Neoplasia, Information, Exchange database, a large genomic dataset aggregated from clinical sequencing. Matched cohort analyses were used to identify histology-specific race-associated mutations including increased TERT promoter mutations in Black and Asian patients with gliomas and bladder cancers, and a decreased frequency of mutations in DNA repair pathway genes and subunits of the SWI/SNF chromatin complex in Asian and Black patients across multiple cancer types. The distribution of actionable mutations in oncogenes was also race-specific, demonstrating how targeted therapies may have a disparate impact on racial groups. Down-sampling analyses indicate that larger sample sizes are likely to discover more race-associated mutations. These results provide a resource to understand differences in cancer genomes between racial groups which may inform the design of clinical studies and patient recruitment strategies in biomarker trials.

Treatment Beyond Progression After Anti-PD-1 Blockade in Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICI) can induce atypical tumor responses including pseudoprogression in a subset of patients who may benefit from treatment beyond progression. While ICIs have emerged as frontline treatments for hepatocellular carcinoma (HCC) and are associated with clinical benefit in a minority of patients, it is unclear whether treatment beyond progression has utility in this disease type. In a multicenter cohort analysis, treatment beyond progression was associated with no new safety signals, objective responses in 5.8% of patients, and disease control in 44% of patients. Progression-free survival and overall survival were comparable between patients treated beyond progression and patients treated with subsequent therapies, demonstrating that treatment beyond progression was not detrimental to survival outcomes. Rather, treatment beyond progression may benefit select patients with HCC and could represent a viable strategy for maximizing treatment benefit in these patients. SIGNIFICANCE: Treatment beyond progression with ICIs in patients with HCC is safe and may benefit a subset of patients due to later-onset tumor responses or disease stability. These findings may guide the design of trials testing ICIs in HCC and the use of treatment beyond progression in routine practice.

A randomized control trial of a combined community health worker and re-entry intervention for people with HIV recently released from jail who use substances.

INTRODUCTION: People with human immunodeficiency virus (HIV; PWH) who use substances are disproportionately involved in the criminal justice system. While HIV viral suppression typically improves during incarceration, these gains are frequently lost after release. We evaluated the impact of a combined intervention (formerly incarcerated community health workers [CHW] plus a re-entry organization; CHW+) on postrelease HIV- and substance use-related outcomes. METHODS: We conducted a pilot randomized controlled trial of a CHW+ for PWH who use substances, within 30 days of release from a large southern, urban jail. Between February 2019 and August 2021, participants were recruited, enrolled, and randomized to treatment as usual (TAU; passive referral to care) or CHW+. Follow up study visits occurred at 3, 6, and 12 months. The primary outcome was HIV VL at 6 months; secondary outcomes included 6-month urinary toxicology and high-risk substance use at 12 months. RESULTS: A total of 31 participants were enrolled who were primarily male (n = 24; 77 %), Black (n = 22; 71 %), unemployed (n = 23; 74.2 %), had unstable housing (n = 18; 58 %), had food insecurity (n = 14; 45 %), and reported their drug of choice was stimulants (n = 24; 77 %). The study identified no significant difference in HIV VL suppression at 6 months (20 % v. 37 %; [CHW+ v. TAU], p = 0.61). We observed improved substance use outcomes in CHW+ v. TAU, including fewer positive urinary toxicology screens for stimulants (40 % v. 100 %; p = 0.01) and a trend toward less high-risk substance use (30 % v. 43 %). The CHW+ group met more basic needs, such as food security [+32 % v. +11 %], housing security [+52 % v. -7 %] and full-time employment [+20 % v. +5 %] compared to TAU. CONCLUSIONS: PWH who use substances assigned to a combined intervention of CHW+ after jail release did not achieve higher rates of HIV VL suppression than TAU; however, they had improved substance use outcomes and met more basic subsistence needs. Results highlight the potential of culturally informed interventions to address the competing needs of PWH who use substances after release from jail and call for further development of innovative solutions to successfully bridge to HIV care in the community.

Surrogate and modified endpoints for immunotherapy in advanced hepatocellular carcinoma.

BACKGROUND AND AIMS: Immunotherapies have altered the treatment paradigm in HCC. Surrogate and modified endpoints are used to assess early success in clinical studies and guide clinical practice. We sought to determine whether surrogate endpoints and modifications to the conventional criteria for tumor response (RECIST), including modified RECIST (mRECIST) and immune-modified RECIST (imRECIST), are valid measures to predict overall survival (OS) in HCC treated with immunotherapies. APPROACH AND RESULTS: We performed an individual-level post hoc analysis of patients treated with atezolizumab and bevacizumab in the IMbrave150 trial (N = 279) and a cross-sectional analysis of a multicenter real-world patient cohort treated with immunotherapy (N = 328). Landmark analyses showed that objective response rates by RECIST were associated with greater OS including among Child-Pugh A and B patients and among patients treated with immunotherapies in the first- or second-line setting (IMbrave150: HR 0.24, 95% CI, 0.17-0.33; RW: HR 0.25, 95% CI, 0.15-0.43). Objective response rates by mRECIST or imRECIST were not associated with the greater predictive power of OS benefit (mRECIST: HR 0.30, 95% CI, 0.22-0.42; imRECIST: HR 0.36, 95% CI, 0.30-0.51). Progression-free survival determined by RECIST was only moderately correlated with OS, and this association was not improved using mRECIST or imRECIST. CONCLUSIONS: Our results clarify the utility of surrogate and modified endpoints in HCC treated with immunotherapies and support the use of RECIST objective response rates as an appropriate signal-finding measure for the evaluation of emerging treatments. Contrary to their intended purpose, mRECIST and imRECIST did not provide meaningful improvements in predicting OS benefits.

Abnormal Genetic Testing in Males With Concomitant Neurodevelopmental Disabilities and Genital Malformation.

BACKGROUND: Neurodevelopmental disorders (NDDs) affect 1:6 children in the United States and are often linked to genetic disorders. Because many genes are enriched in brain and testicular tissue, genital malformations identified early may be a predictor of genetic disorders in children with NDDs. However, few studies have evaluated the specific effects of genital malformations. This study assesses the association between genital malformations and abnormal genetic testing among male patients with NDD. METHODS: A retrospective chart review was performed of 447 male patients seen at Children's Health Dallas (2009 to 2019) with concomitant genital malformations and NDDs. We assessed the strength of factors associated with obtaining a genetic test and having abnormal results. RESULTS: We identified 447 patients with concomitant genital malformations and NDD. Fifty-six percent (251 of 447) received genetic testing, of which 68.5% (172 of 251) had abnormal results. Patients with mixed genitourinary malformations, global developmental delay (GDD), intellectual delay, or autism spectrum disorder were more likely to have a genetic test. Patients with bilateral testicular involvement, GDD, severe language delay, wheelchair dependence, or abnormal magnetic resonance imaging findings were more likely to have abnormal results. CONCLUSION: The diagnostic yield of 68.5% in our cohort of male patients with genital malformations was higher than previous reports of 5% to 35% in NDD populations. More severe phenotypic features may be associated with increased yield. Identification of genital malformations during infancy may guide clinical surveillance, and copresentations with NDDs may support genetic testing.

Clinical Efficiency and Safety Outcomes of Virtual Care for Oncology Patients During the COVID-19 Pandemic.

PURPOSE: Telehealth has been an integral response to the COVID-19 pandemic. However, no studies to date have examined the utility and safety of telehealth for oncology patients undergoing systemic treatments. Concerns of the adequacy of virtual patient assessments for oncology patients include the risk and high acuity of illness and complications while on treatment. METHODS: We assessed metrics related to clinical efficiency and treatment safety after propensity matching of newly referred patients starting systemic therapy where care was in large part replaced by telehealth between March and May 2020, and 206 newly referred patients from a similar time period in 2019 where all encounters were in-person visits. RESULTS: Patient-initiated telephone encounters that capture care or effort outside of visits, time to staging imaging, and time to therapy initiation were not significantly different between cohorts. Similarly, 3 month all-cause or cancer-specific emergency department presentations and hospitalizations, and treatment delays were not significantly different between cohorts. There were substantial savings in travel time with virtual care, with an average of 211.4 minutes saved per patient over a 3-month interval. CONCLUSION: Our results indicate that replacement of in-person care with virtual care in oncology does not lead to worse efficiency or outcomes. Given the increased barriers to patients seeking oncology care during the pandemic, our study indicates that telehealth efforts may be safely intensified. These findings also have implications for the continual use of virtual care in oncology beyond the pandemic.