CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

633 TET2 SNPs AND RISK OF CANCER IN THE START, SMART, AND ESPRIT COHORTS Daniel D. Murray 1 , Cameron MacPherson 1 , Birgit Grund 2 , Christina Ekenberg 1 , Adrian G. Zucco 1 , Dahlene Fusco 3 , Julien Gras 4 , Jan Gerstoft 5 , Marie Helleberg 1 , Álvaro H. Borges 1 , Mark Polizzotto 6 , Jens D. Lundgren 1 , for the INSIGHT START, SMART and ESPRIT Study Groups 1 Centre of Excellence for Health, Immunity and Infections, Copenhagen, Denmark, 2 University of Minnesota, Minneapolis, MN, USA, 3 Tulane University, Metairie, LA, USA, 4 AP–HP, Paris, France, 5 Rigshospitalet, Copenhagen, Denmark, 6 Kirby Institute, Sydney, NSW, Australia Background: Previously we have identified two groups of SNPs in the TET2 gene associated with either higher or lower HIV Viral Load (VL). These results indicated that TET2 is involved in HIV replication and the identified SNPs alter TET2 in a way that impacts that function. As TET2 also plays a role in cancer development, as a tumor suppressor gene, we hypothesized that these SNPs would also impact that function. To test this, we performed a targeted association analysis between VL-associated SNPs and risk of cancer across INSIGHT network cohorts. Methods: We assessed associations between the 36 previously identified TET2 VL-associated SNPs with incidence of cancer (any type) in the START (NCT00867048), SMART (NCT00027352) and ESPRIT (NCT00004978) cohorts, using Cox regression models adjusting for age, gender, study arm and race (using the first 4 eigenvectors). Only SNPs with minor allele frequency (MAF) > 1%were included in the analyses. P-values are shown unadjusted and adjusted using the max(T) permutation test (10000 permutations), which accounts for correlations amongst the SNPs. Results: In SMART, 60 (2.6%) pts were diagnosed with cancer during follow-up. Two SNPs, rs6811468 (HR=2.79, CI=1.41-5.53, p=0.003, adjusted p (Ap)=0.03) and rs72955158 (HR=3.24, CI=1.29-8.11 p=0.012, Ap=0.09) were associated with risk of cancer; the number of cancer events in pts with 0, 1 and 2 risk alleles of rs6811468 was 52/2141 (2.4%), 6/125 (4.8%) and 2/4 (50%), respectively. All 6 cancers associated with rs72955158 in SMART occurred in pts who also had rs6811468. In START, 38 participants (pts) (1.5%) were diagnosed with cancer during follow-up. One SNP, rs6811468 (HR=4.50, CI=1.14-17.76, p=0.03, Ap=0.19), was associated with risk of cancer; the number of cancers in pts with 0, 1 and 2 risk alleles of rs6811468 was 35/2412 (1.5%), 3/109 (2.8%) and 0/2 (0%), respectively. In ESPRIT, a total of 110 pts had cancer. No SNPs were associated with cancer in ESPRIT. Rs72955158 in START and both rs6811468 and rs72955158 in ESPRIT had MAF <1% and were not assessed in these cohorts. Rs6811468 associated cancers were primarily solid tumors (10/11) seen in persons of black ethnicity, with lung (n=3) and prostate (n=4) the most common cancer sites. Conclusion: One SNP, rs6811468, was associated with consistent elevated risk of cancer in two independent HIV+ cohorts. This finding requires additional studies to confirm these results and determine whether the effect is independent of perturbed VL. 634 NEXT-GENERATION SEQUENCING TO PROFILE CANCER-RELATED GENES IN HIV+ PATIENTS Margherita Digaetano 1 , Antonino Maiorana 1 , Roberto Sabbatini 1 , Carlotta Rogati 1 , Andrea Cossarizza 1 , Cristina Mussini 1 1 University of Modena and Reggio Emilia, Modena, Italy Background: Check-point inhibitors and other antitumor drugs have become a cornerstone in cancer treatment. Now it is very important to profile cancer- related genes to understand which could be the most active drug in a specific tumor. Recently, a novel test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletion, copy number alterations and selected fusions became available. Aim of our study was to evaluate, for the first time in HIV positive patients with cancer, the use of FoundationOne CDx, a new next-generation sequencing based assay (NGS) that identifies genomic findings within hundreds of cancer-related genes. Methods: FoundationOne CDx, that analyzes genomic changes in 324 genes of relevant importance for tumor cells, was used on stored clinical samples that were formalin-fixed and paraffin-embedded. Results: We analyzed 10 samples: type of cancer, genomic signatures, gene alterations and possible treatments are described in Table 1. Only one patient showed an high microsatellite instability, that suggests the possible use of check-point inhibitors. Among the 4 patients with kidney renal papillary carcinoma, gene alteration profile was markedly different, so potentially the

(neuropathy and thyroiditis). No drug-related fatal AE occurred. Overall, 6 pts (21%, 95%CI: 8–50) discontinued ICPi: 4 for progression and 2 for SAE (epilepsy and meningoradiculitis) and 12 died (8 with lung cancer). The 8-month survival rate was 56.8% (27.5-78.1) for lung cancer and 81.3% (52.5-93.5) for the other cancers. During the follow-up, 118 HIV RNA VL/CD4/CD8 were measured with a median of 2 per patient (IQR: 1-6). All patients with HIV VL<50 copies/mL at baseline maintained VL<50 copies/mL throughout the follow-up, while those with HIV VL≥50 copies/mL reached a VL<50 copies/mL. CD4 and CD8 T cell count significantly increased over time, respectively, +8.9/µL per month, P=0.007 and +19.4/µL, P=0.028, while CD4/CD8 ratio remained stable (-0.001, P=0.739). Conclusion: In this ongoing French cohort of PLHIV with cancer receiving ICPi, no HIV VL rebound occurred during an 8-month follow up. An increase of CD4 and CD8 cells was observed, associated with a low frequency of serious events relative to that expected in this population. 632 T-CELL SUBPOPULATION PROFILES AND CANCER RISK FOR HIV+ AND HIV– VETERANS Keith M. Sigel 1 , Suman Kundu 2 , Lesley S. Park 3 , Kaku So-Armah 4 , Margaret F. Doyle 5 , Russell Tracy 5 , Janet Tate 6 , Amy C. Justice 7 , Matthew Freiberg 2 1 Icahn School of Medicine at Mt Sinai, New York, NY, USA, 2 Vanderbilt University, Nashville, TN, USA, 3 Stanford University, Stanford, CA, USA, 4 Boston University, Boston, MA, USA, 5 University of Vermont, Burlington, VT, USA, 6 VA Connecticut Healthcare System, West Haven, CT, USA, 7 Yale University, New Haven, CT, USA Background: Alterations in cell-mediated immunity have been associated with cancer risk for people living with HIV (PLWH). Circulating levels of T regulatory cells (Tregs), and activated and senescent T cells have been linked to cancer risk and outcomes in HIV uninfected persons but there has been limited study of T cell subset alterations and cancer development unique to PLWH. We therefore aimed to determine whether the proportions of these T cell phenotypes predicted the incidence of non-AIDS cancers that have been associated with responses to immunotherapy (lung, anus, kidney). Methods: We used longitudinal data from 1,429 PLWH and 765 uninfected persons from the Veterans Aging Cohort Study Biomarker Cohort linked to VA cancer registry data to identify 75 incident lung, anus, and kidney cancers (the most common cancers arising in the cohort with known immunotherapy link). Subjects were followed from enrollment (2005-2006) until cancer incidence, death or were censored on 9/31/2017 (10 years of median follow-up). We measured the proportion of seven subpopulations of T cells, including Tregs (CD4+CD25+FOXP3+), activated (CD4+CD38+ and CD8+CD38+) and senescent (CD4+CD28-, CD4+CD57+, and CD8+CD28-, CD8+CD57+) CD4 and CD8 phenotypes. We used Cox proportional hazard regression to model associations between these immune cells and the risk of cancer while adjusting for age, sex, race/ethnicity and smoking status. Results: The cohort was mostly male (95%) of median age 52 years. PLWH accounted for the majority (75%) of the cancer cases. Among PLWH, lower overall CD4 count was associated with greater proportions of Tregs, senescent CD4 and activated CD8 phenotypes. Of the included T cell subpopulations, greater proportions of circulating Tregs were significantly associated with increased incidence of the combined group of lung, anus and kidney cancers for the overall combined cohort and for PLWH only (see Table). Alterations in the proportion of subsets of CD4 and CD8 cells expressing markers of senescence or activation were not significantly associated with cancer risk during follow-up. Conclusion: Among PWH increased circulating Tregs as a proportion of CD4 cells were associated with increased risk of lung, anus and kidney cancers. Correlation of these findings with the precancerous tumor microenvironment may provide greater insight into the role of HIV infection as an increased risk for some cancers.

Poster Abstracts

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