In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 2617-2617
Abstract:
2617 Background: Pappalysin 2 ( PAPPA2) mutation, most occurring in skin cutaneous melanoma (SKCM) and non-small cell lung cancer (NSCLC), is found to be related to anti-tumor immune response. However, the association between PAPPA2 and efficacy of immune checkpoint inhibitors (ICIs) therapy remains unknown. Methods: Forty-one NSCLC patients receiving anti-PD-(L)1 (China cohort, n = 41) and seven public cohorts with whole-exome sequencing (WES) data were included to analyze the performance of PAPPA2 mutation as an indicator stratifying patients benefit from ICIs, consolidating a discovery set (n = 34) and two validation sets (NSCLC validation set, n = 172 ; SKCM validation set, n = 210). The mechanism was analyzed in the Cancer Genome Atlas (TCGA) database (n = 1467). Results: In the discovery set, patients with PAPPA2 mutation exhibited a significantly predominant PFS (HR, 0.11 [95% CI, 0.01-0.83] ; P = 0.01), ORR (100.0% vs 21.4%; P 〈 0.001) and durable clinical benefit (DCB, 83.3% vs 32.1%; P = 0.012) compared to those with wide-type PAPPA2, consistent in NSCLC validation set (PFS, HR, 0.3 [95% CI: 0.16-0.56], P 〈 0.001; ORR, 70.8% vs. 20.9%, P 〈 0.001; DCB, 83.3% vs. 36.5%, P 〈 0.001) and SKCM validation set (OS, HR, 0.49 [95% CI: 0.31-0.78]; P = 0.002; ORR, 34.1% vs. 16.9%, P = 0.039; DCB, 50.0% vs. 30.7%; P = 0.036). Similar results were observed in multivariable models. In contrast, no association between PAPPA2 mutation and OS or PFS was observed in TCGA datasets, suggesting that PAPPA2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, we found that PAPPA2 mutation was significantly associated with higher activated CD4 memory T cells and lower Treg cells in tumor immune microenvironment, related with higher TMB ( P 〈 0.001) and neoantigen load ( P 〈 0.001). In addition, gene set enrichment analysis (GSEA) analysis revealed that PAPPA2 mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway. Conclusions: Our findings indicated that PAPPA2 mutation could serve as a novel indicator to stratify beneficiaries from ICIs therapy in NSCLC and SKCM, warranting further prospective studies.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2022.40.16_suppl.2617
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2022
detail.hit.zdb_id:
2005181-5
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