No abstract

BackgroundMismatch repair deficiency (MMRD) is a common pathway of malignant transformation accounting for approximately 15–20 % of human carcinogensis. It has been postulated that MMRD increases tumor antigenicity and highlights a role for immunotherapeutic approach MMR-deficient cancers. This strategy was pursued in a patient with upper tract urothelial carcinoma, and the results are reported here.Case PresentationMolecular profiling was performed using next generation DNA sequencing and (IHC) testing for MMR and PD-L1. A patient with sporadic, high grade urothelial carcinoma of the renal pelvis was found to have a hypermutator genotype with 73 mutations occurring amidst 62 known drivers of malignancy, and 340 VUS alterations. MMR deficiency phenotype was confirmed by the absence of MSH2 and MSH6 as well as deleterious mutations in these genes. IHC staining for programmed cell death ligand-1 [PD-L1] revealed 2+ staining in 80 % of cells. The patient gained access to combination immunotherapy trial utilizing MEDI4736 and MEDI0680 through a clinical trial. The patient achieved a prolonged, complete remission within two months and had no severe ill effects from the treatment.ConclusionGiven their ability to generate neo-antigens, MMR-deficient cancers may be uniquely susceptible to immune checkpoint inhibitor strategies, including urothelial tract cancers. Screening for MMR deficient cancers has the potential to become a routine strategy for evaluating the role of PD-L1 inhibitors for patient with advanced disease. (Trial registration: Clinicaltrials.gov NCT00938834. Registered 13 July 2009)

Objectives: As delivery of PrEP becomes an HIV prevention priority in the U.S., standard, pragmatic measures of PrEP use are needed to compare and evaluate prevention implementation programs. By using readily available electronic health record data (EHR), we describe and compare measures of persistence and retention. Design: Retrospective cohortMethods: Using EHR prescription data for patients at a large urban Federally Qualified Health Center from 2015 to 2019, we calculated measures of persistence and retention and compared them to pharmacy claims data, PrEP biomarkers, and HIV outcomes.Results: Total PrEP time was 19.8 months on average. During this period, average adherence by medication prescription ratio (MRxR) was 89%; 77% of patients had an MRxR ≥85% and 90% have an MRxR ≥57%. Over the first six months, average proportion of day covered (PDC) ≥85% was 53% and PDC ≥57% was 57%. Prescription fill rates, based on claims data from a pharmacy partner, ranged from 45% to 60%. Using tenofovir-diphosphate as the gold standard, PDC had high sensitivity (97%) but low specificity (≤13%). As a measure of retention, over the first six months, 59% of patients had quarterly HIV tests. Conclusion:Total PrEP time is useful measure of overall persistence, while PDC can assess persistence and adherence at a specific time point. Adherence by PDC is more conservative compared to MRxR; both will overestimate true adherence. Retention in care can be measured by quarterly HIV tests. Using consistent terminology and reporting timepoints and adherence thresholds will help reporting and comparing PrEP delivery programs.

Improvements in the treatment of solid tumors may increase the incidence of tumor lysis syndrome for tumors once believed to be marginally responsive. Oncologists should remain cognizant of this problem as more active regimens become available.

No. 11108)Background: The multidrug resistance (MDR) phenotype reduces the efficacy of various chemotherapies. MDR is linked to the overexpression of ATP-binding cassette (ABC) transporters in cancer cells, including P-glycoprotein (PGP/ABCB1), multidrug resistance protein (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2). We assessed protein expression patterns of the drug efflux pumps across all tumor types for insight on how to exploit MDR status to circumvent treatment dilemmas.Methods: 51,939 patients molecularly profiled with a commercial multiplatform approach (Caris Life Sciences) were evaluated. Protein expression by IHC was assessed. The Caris Registry was queried for patients in this analysis with available clinical outcomes.Results: Across all tumors profiled (n=51,939), MRP1 positivity (pos.) was highest at 81% (19935/24682), BCRP at 66% (8849/13409) and PGP the lowest at 23% (11969/51313). GI cancers exhibited the most abundant expression of all three drug pumps (80%, 90%, 53%), with highest average combined expression observed in liver cancers (81%). In contrast, brain, thymic and head and neck cancers exhibited the lowest average combined expression of all 3 drug pumps (39%, 40% and 42%, respectively). 6,002 patients were evaluable for coexpression with 29% (1728/6002) exhibiting pos. for all 3 drug pumps (ABC+) (highest frequencies in colon, pancreas, ovary, breast and lung), 42% (2494/6002) pos. for 2/3 drug pumps and 21% (1263/6002) pos. for 1/3 drug pumps. Only 9% (517/6002) exhibited negative status for all 3 drug pumps (ABC-) (highest frequencies in breast, lung, ovary, skin and endometrial). To determine the prognostic role of the drug pumps on patient survival, we assessed the differences in median survival between a cohort of ABC+ (n=30) and ABC -(n=27) patients with breast (n=6, 2), ovary (n=12, 6) and lung cancers (n=13,19). Median survival since specimen used for profiling was collected for ABC + was 596 days compared to 855 days for ABC -patients. Conclusions:Tumors show broad and overlapped expression patterns for drug efflux pumps. Further study is needed to determine how transporter expression may impact clinical outcomes (e.g. ABC -status is more favorable than ABC + status).