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Targeting G1/S phase cell-cycle genomic alterations and accompanying co-alterations with individualized CDK4/6 inhibitor-based regimens

JCI insight, 2021-01, Vol.6 (1) [Peer Reviewed Journal]

2021 Kato et al. 2021 Kato et al. ;ISSN: 2379-3708 ;EISSN: 2379-3708 ;DOI: 10.1172/jci.insight.142547 ;PMID: 33427211

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  • Title:
    Targeting G1/S phase cell-cycle genomic alterations and accompanying co-alterations with individualized CDK4/6 inhibitor-based regimens
  • Author: Kato, Shumei ; Okamura, Ryosuke ; Adashek, Jacob J ; Khalid, Noor ; Lee, Suzanna ; Nguyen, Van ; Sicklick, Jason K ; Kurzrock, Razelle
  • Subjects: Clinical Medicine ; Oncology
  • Is Part Of: JCI insight, 2021-01, Vol.6 (1)
  • Description: BACKGROUNDAlthough CDK4/6 inhibitors are an established treatment for hormone receptor-positive, HER2-negative metastatic breast cancers, their benefit in other malignancies remains limited.METHODSWe investigated factors associated with clinical outcomes from CDK4/6 inhibitor-based therapy among patients with G1/S phase cell-cycle alterations (CDK4/6 amplifications, CCND1/2/3 amplifications, or CDKN2A/B alterations).RESULTSOverall, 2457 patients with diverse solid tumors that underwent clinical-grade, next-generation sequencing (182-465 genes) and therapy outcome of (non-breast cancer) patients treated with matched CDK4/6 inhibitors were analyzed. G1/S phase cell-cycle alterations occurred in 20.6% (507 of 2457) of patients; 99% of those patients (n = 501) harbored ≥1 characterized co-alteration (median, 4; range, 0-24). In 40 patients with G1/S phase cell-cycle alterations given CDK4/6 inhibitors as part of their regimen, significantly longer median progression-free survival (PFS) was observed when CDK4/6 inhibitor-based therapies matched a larger proportion of tumor alterations, often because CDK4/6 inhibitors were administered together with other drugs that were matched to genomic co-alterations, hence achieving a high matching score (high vs. low [≥50% vs. <50%] matching score, PFS, 6.2 vs. 2.0 months, P < 0.001 [n = 40] [multivariate]) and higher rate of stable disease ≥6 months or an objective response (57% vs. 21%, P = 0.048).CONCLUSIONIn summary, in cell-cycle-altered cancers, matched CDK4/6 inhibitors, as part of an individualized regimen targeting a majority of genomic alterations, was independently associated with longer PFS.TRIAL REGISTRATIONClinicalTrials.gov NCT02478931.FUNDINGJoan and Irwin Jacobs Fund, National Cancer Institute (P30 CA023100, R01 CA226803), and the FDA (R01 FD006334).
  • Publisher: United States: American Society for Clinical Investigation
  • Language: English
  • Identifier: ISSN: 2379-3708
    EISSN: 2379-3708
    DOI: 10.1172/jci.insight.142547
    PMID: 33427211
  • Source: PubMed Central
    DOAJ Directory of Open Access Journals
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