PURPOSE Androgen receptor ( AR) gene alterations, including ligand-binding domain mutations and copy number (CN) gain, have yet to be fully established as predictive markers of resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). The goal of this study was to validate AR gene alterations detected in cell-free DNA (cfDNA) as markers of enzalutamide and abiraterone resistance in patients with mCRPC. METHODS Patients with mCRPC (N = 62) were prospectively enrolled between 2014 and 2018. Blood was collected before therapies—enzalutamide (n = 25), abiraterone (n = 35), or enzalutamide and abiraterone (n = 2) —and at disease progression. We used deep next-generation sequencing to analyze cfDNA for sequence variants and CN status in AR and 45 additional cancer-associated genes. Primary end points were prostate-specific antigen response, progression-free survival (PFS), and overall survival (OS). RESULTS Elevated tumor-specific cfDNA (circulating tumor DNA) was associated with a worse prostate-specific antigen response (hazard ratio [HR], 3.17; 95% CI, 1.11 to 9.05; P = .031), PFS (HR, 1.76; 95% CI, 1.03 to 3.01; P = .039), and OS (HR, 2.92; 95% CI, 1.40 to 6.11; P = .004). AR ligand-binding domain missense mutations (HR, 2.51; 95% CI, 1.15 to 5.72; P = .020) were associated with a shorter PFS in multivariable models. AR CN gain was associated with a shorter PFS; however, significance was lost in multivariable modeling. Genetic alterations in tumor protein p53 (HR, 2.70; 95% CI, 1.27 to 5.72; P = .009) and phosphoinositide 3-kinase pathway defects (HR, 2.62; 95% CI, 1.12 to 6.10; P = .026) were associated with a worse OS in multivariable models. CONCLUSION These findings support the conclusion that high circulating tumor DNA burden is associated with worse outcomes to enzalutamide and abiraterone in men with mCRPC. Tumor protein p53 loss and phosphoinositide 3-kinase pathway defects were associated with worse OS in men with mCRPC. AR status associations with outcomes were not robust, and additional validation is needed.

Somatic genetic alterations including copy number and point mutations in the androgen receptor (AR) are associated with resistance to therapies targeting the androgen/AR axis in patients with metastatic castration resistant prostate cancer (mCRPC). Due to limitations associated with biopsying metastatic lesions, plasma derived cell-free DNA (cfDNA) is increasingly being used as substrate for genetic testing. AR mutations detected by deep next generation sequencing (NGS) of cfDNA from patients with mCRPC have been reported at allelic fractions ranging from over 25% to below 1%. The lower bound threshold for accurate mutation detection by deep sequencing of cfDNA has not been comprehensively determined and may have locus specific variability. Herein, we used NGS for AR mutation discovery in plasma-derived cfDNA from patients with mCRPC and then used droplet digital polymerase chain reaction (ddPCR) for validation. Our findings show the AR (tTC>cTC) F877L hotspot was prone to false positive mutations during NGS. The rate of error at AR (tTC>cTC) F877L during amplification prior to ddPCR was variable among high fidelity polymerases. These results highlight the importance of validating low-abundant mutations detected by NGS and optimizing and controlling for amplification conditions prior to ddPCR.

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BackgroundSignificant disparities in morbidity and mortality from cancer in HIV-infected persons exist compared with those with cancer in the general population. This study sought to identify psychological, social and economic factors impacting or impeding cancer care in the HIV-infected population.MethodsA voluntary, anonymous one-time questionnaire was completed by patients diagnosed with cancer who are HIV-infected and HIV-uninfected at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC). Andersen’s Behavioral Model of Health Services Use served as the theoretical framework for assessing psychological, social, and economic barriers to care. We used the chi-square test to evaluate the association between HIV status and barriers to accessing cancer care.ResultsA total of 25 HIV-infected and 100 HIV-uninfected cases were included. More HIV-infected patients with cancer experienced self-esteem and fear barriers to a greater degree than their HIV-uninfected counterparts (28% vs. 15% for self-esteem, and 40% vs. 21%). A significant proportion of HIV-infected individuals reported experiencing insufficient social support (32% vs. 10% in the HIV-uninfected population, P = 0.01). HIV-infected individuals reported that they did not feel looked down upon in the cancer clinic. They also described that their cancer and HIV diagnoses were delivered in a similar manner by the provider.ConclusionGiven that HIV-infected persons are experiencing lower survival rates for most cancer subtypes when compared with their HIV-uninfected counterparts, there is a need to further investigate the feelings of fear, low self-esteem, and insufficient support reported in the HIV-infected sample. Cancer care may need to be tailored to reflect the differences in psychological barriers and enabling resources that continue to be disproportionately prevalent in HIV-infected patients. Disclosures All authors: No reported disclosures.