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Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer.

ABSTRACT: Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or abemaciclib and antiestrogen therapy were identified. Patients were grouped into early (<6 months); intermediate (6-24 months for 0-1 lines; 6-9 months for ≥2 lines); or late progressors (>24 months for 0-1 lines; >9 months PFS for ≥2 lines). NGS and RNA sequencing data were analyzed in association with PFS, and survival analysis was stratified by prior lines of chemotherapy. A total of 795 patients with HR+ MBC treated with CDK 4/6i were identified. Of these, 144 (18%) patients had genomic data and 29 (3.6%) had RNA data. Among the 109 patients who received CDK4/6i as 1st- or 2nd-line therapy, 17 genes showed associations with PFS (p-value ≤ 0.15 and HR ≥ 1.5 or HR < 0.5). Whole transcriptome RNAseq was analyzed for 24/109 (22%) patients with 0-1 prior lines of therapy and 56 genes associated with PFS (HR ≥ 4 or HR ≤ 0.25 and FDR ≤ 0.15). In this retrospective analysis, genomic biomarkers including FGFR1 amplification, PTEN loss, and DNA repair pathway gene mutations showed significant associations with shorter PFS for patients receiving CDK4/6 inhibitor therapy.

SUBMITTER: Lee JS

PROVIDER: S-EPMC9264913 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer.

Lee Jin Sun JS Yost Susan E SE Li Sierra Min SM Cui Yujie Y Frankel Paul H PH Yuan Yate-Ching YC Schmolze Daniel D Egelston Colt A CA Guo Weihua W Murga Mireya M Chang Helen H Bosserman Linda L Yuan Yuan Y

Cancers 20220628 13

Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or abemaciclib and antiestrogen therapy were identified. Patients were grouped into early (<6 months); intermediate (6−24 months for 0−1 lines; 6−9 months for ≥2 lines); or la ...[more]

PMID: 35804935

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Project description:PurposeMultiple treatment options exist for patients with metastatic breast cancer (MBC). However, limited information is available on the impact of prior treatment duration and class on survival outcome for novel therapies, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ HER2-) MBC.MethodsThis study used a nationwide, de-identified electronic health record-derived database to identify women with HR+ HER2- MBC who received at least one CDK 4/6i between 2011 and 2020. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for the association between prior duration and class of cancer treatment (both early-stage and metastatic) and prior CDK 4/6i survival as well as for those with multiple CDK 4/6i.ResultsOf 5363 patients, the median survival from first CDK 4/6 inhibitor administration was 3.3 years. When compared to patients with no prior treatments, patients with < 1 year of prior treatment duration had a 30% increased hazard of death (HR, 1.30; 95% CI 1.15-1.46), those with 1 to < 3 years a 68% increased hazard of death (HR 1.68; 95% CI 1.49-1.88), and those with 3 or more years a 55% increased hazard of death (HR 1.55; 95% CI 1.36, 1.76). Patients who received prior therapy (endocrine or chemotherapy) before their CDK 4/6i had worse outcomes than those who received no prior therapy. Similar results were seen when comparing patients in the metastatic setting alone. Finally, patients who received a different CDK 4/6i after their first saw a lower hazard of death compared to patients who received subsequent endocrine or chemotherapy after their first CDK 4/6i.ConclusionPrior treatment duration and class are associated with a decreased overall survival after CDK 4/6 inhibitor administration. This highlights the importance for clinicians to consider prior treatment and duration in treatment decision-making and for trialists to stratify by these factors when randomizing patients or reporting results of future studies.

Project description:ImportanceEndocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) agents is the standard first-line treatment for patients with hormone receptor-positive, ERBB2 (formerly HER2 or HER2/neu)-negative metastatic breast cancer. However, optimal therapy after tumor progression to ET plus CDK4/6i remains unclear.ObjectiveTo evaluate progression-free survival (PFS) and overall survival (OS) in the clinical practice setting in patients with hormone receptor-positive, ERBB2-negative metastatic breast cancer following progression with ET plus CDK4/6i.Design, setting, and participantsThe multicenter retrospective cohort study included 506 patients diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer between April 22, 2015, and January 31, 2023, and who received ET-based or chemotherapy (CT)-based treatment following progression during ET plus CDK4/6i. Outcomes were analyzed based on treatment type, clinicopathologic features, and the duration of prior CDK4/6i therapy.Main outcomes and measuresThe primary end point was PFS in the clinical practice setting, defined as the time between the initiation of the first systemic treatment on tumor progression to ET plus CDK4/6i treatment and the detection of disease progression or patient death from any cause. The secondary end point was OS in the clinical practice setting, defined as the time interval between tumor progression during ET plus CDK4/6i treatment and patient death from any cause.ResultsIn 506 women (median age at diagnosis, 52.4 [IQR, 44.6-62.8] years) diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer progressing during ET plus CDK4/6i, independent factors associated with poorer PFS outcomes were visceral metastases (hazard ratio [HR], 1.45; 95% CI, 1.17-1.80; P = .008) and de novo metastatic disease (HR, 1.25; 95% CI, 1.01-1.54; P = .04). A longer duration of CDK4/6i therapy (OS HR, 0.55; 95% CI, 0.41-0.73; P < .001) and an older age (PFS HR, 0.99; 95% CI 0.98-1.00; P = .03) were associated with better outcomes. Compared with oral CT, both intravenous CT- and ET-based treatments were associated with shorter PFS (intravenous CT: hazard ratio [HR], 1.45; 95% CI, 1.11-1.89; P = .006; everolimus plus exemestane: HR, 1.38; 95% CI, 1.06-1.78; P = .02; ET only: HR, 1.38; 95% CI, 1.05-1.89; P = .02). A duration of CDK4/6i treatment exceeding 12 months was associated with longer OS (HR, 0.55; 95% CI, 0.41-0.73; P < .001). Among patients with visceral metastases, intravenous CT was associated with shorter OS compared with oral CT (HR, 1.52; 95% CI, 1.03-2.24; P = .04).Conclusions and relevanceIn this cohort study, the duration of tumor control achieved with CDK4/6i-based therapy and the presence of visceral metastases emerged as key factors that may affect treatment decision. Oral CT may offer potential benefits for specific patient subgroups.

Dataset Information

Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer.

Publications

Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer.

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