The prevalence of sickle cell phenotype and its association with clinical outcomes in patients with solid malignancies.

Abstract

10563 Background: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States and is caused by a mutation of β-globin ( HBB-Mt). The risk of developing solid malignancies in this population remains controversial, with research showing increased rates of some solid tumors (colon, kidney, and thyroid) and decreased rates of others (breast and male genitourinary). We report the prevalence of HBB mutations across a cohort of solid tumors and clinical outcomes between HBB-Wild type (-Wt) v Mutant (-Mt) tumors. Methods: Non-small cell lung cancer (NSCLC, N = 3307), breast (BC, N = 1960), colorectal (CRC, N = 2161), prostate (N = 899), and gynecologic cancers (N = 2,805) in persons of African descentwere tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (whole exome) and RNA (whole transcriptome). Her2/Neu (+: ≥3+ and >10%) and HR (ER or PR+: ≥1+ and ≥1%) expression was tested by immunohistochemistry. Tumors were assessed for single nucleotide variations (SNVs) and insertions/deletions (indels) in HBB associated with a sickle cell phenotype. Mutation prevalence for all other genes was calculated for pathogenic SNVs/indels. Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Fisher’s Exact/χ2 tests were applied as appropriate with p-values adjusted for multiple comparisons ( p < .05). Real-world overall survival (OS) and ethnicity data was obtained from insurance claims and log-rank estimates were calculated for molecularly defined subpopulations. Results: Amongst persons of African descent, uterine sarcoma had the highest prevalence of HBB-Mt (17.1%, 43/251) followed by uterine serous carcinoma (9.1, 70/768) and endometrial carcinoma (7.8, 55/708). Tumors with the highest absolute number of HBB-Mt tumors were NSCLC (7.0, 230/3307), CRC (8.1, 176/2161) and BC (6.7, 131/1960). In CRC, there was no significant difference in the prevalence of right-sided tumors between HBB-Wt v Mt (42% v 51, p = .06), nor in the prevalence of HBB-Mt by consensus molecular subtype ( p = .34). No significant enrichment of HBB-Mt across BC subtypes was observed (HR- HER2-: 7.8%, HR-HER2+: 9.7, HR+/HER2-:5.8, HR+/HER2+: 8.1, p = .34). No difference in the prevalence of pathogenic alterations was observed between HBB-Mt vs -Wt across NSCLC, CRC, and BC ( p > .05). HBB-Mt NSCLC were significantly enriched (GSEA) for genes related interferon /, inflammatory response and IL6/JAK/STAT3. No significant difference in OS was observed in CRC (median survival HBB-Wt: 957 days v -Mt: 1034, p = .43), NSCLC (-Wt: 591 v -Mt: 648, p = .59) or BC (-Wt: 924 v -Mt: 922, p = .61). Conclusions: No significant differences in the genomic landscape nor in OS of HBB-Mt vs HBB-Wt NSCLC, CRC or BC were observed. NSCLC HBB-Mt was enriched with inflammatory response genes. Future work should focus on potential role HBB-Mt plays in NSCLC.