Prospective longitudinal multi-omics study of palbociclib resistance in hormone receptor+/HER2- metastatic breast cancer.
Authors: Park Yeon Hee , Im Seock-Ah , Park Kyunghee , Wen Ji , Min Ahrum , Bonato Vinicius , Park Seri , Ram Sripad , Lee Dae-Won , Kim Ji-Yeon , Lee Kyung-Hun , Lee Won-Chul , Lee Jisook , Kim Hyunseon(Ally) , Lee Won-Woo , Choi Yoon-La , Weinrich Scott , Ryu Han Suk , Park Woong-Yang , Kan Zhengyan ,   Palbociclib Biomarker Translational Research Group (Palbo-Bio-TRG)
Published: June 2021

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Background: The development of CDK4/6 inhibitors represents a significant advance in the treatment of metastatic breast cancer (MBC). To better understand the impact of treatment and drug resistance at the molecular level, we performed multi-omics profiling of matched pre-treatment, on-treatment, and post-progression tumor biopsies from patients treated with palbociclib combined with endocrine blockades (AIs and fulvestrant). The purpose of the study was to identify biomarkers of palbociclib resistance as well as to assess molecular changes during treatment, and those appearing at disease progression. Methods: Patients with Hormone Receptor positive (HR+)/HER2- MBC treated with palbociclib in combination with endocrine therapies were prospectively enrolled from July 2017 to June 2020. Of the 89 patients enrolled, we obtained tumor biopsies and matched blood samples, taken at pre-treatment, on-treatment (6 weeks or 12 weeks) and progressive disease (PD) from 71 patients (first line: 55, second line or later: 16 pts.) who had agreed to informed consent form. Tumor biopsies were profiled using whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-Seq). Results: Median follow-up duration was 20 (3-48) months and median age of the patients was 45 (range 30-71) years. The median progression free survival (PFS) of 71 patients was 15 (0.7-39.8) months. The Luminal B subtype is associated with shorter PFS compared to Luminal A (8.6 m vs 19.3 m, p=0.03, HR=1.96). The Luminal B subtype along with multiple cell cycle regulatory genes such as CCNE1 (8.3 m, p=0.015, HR=2.07), CCNE2 (8.5 m, p=8.5e-3, HR=2.2), CDK2 (8.45 m, p=0.05, HR=1.79) are associated with shorter PFS while estrogen response signatures (20.9 m, p=4.6e-3, HR=0.43) and PGR gene expression (20.2 m, p=6.2e-2, HR=0.56) are associated with more favorable prognosis. A Cox-regression multivariate model (p=5.17e-5, C-Index=0.72) was developed and revealed that PFS is independently associated with BRCA1/2 (HR=1.44; CI=[0.49, 4.29]), TP53 mutation statuses (HR=3.58; CI=[1.58, 8.13]), the HRD mutation signature (HR=1.40; CI=[1.09, 1.81]) and the proliferative index (HR=1.53; CI=[1.00, 2.34]), an expression signature of cell proliferation. Tumors classified as Luminal A at baseline frequently switched into Luminal B or Her2-enriched subtypes at PD, along with up-regulation of cell cycle markers and proliferation signatures. Further, tumor mutation burden (TMB) and HRD index, a DNA-based measure of genomic instability, significantly increased from baseline to PD in patients with TP53 and BRCA1/2 wild-type tumors. Conclusions: Our longitudinal multi-omics study identified prognostic biomarkers as well as post-treatment enrichment of HRD related genomic scars and frequent switching into molecular subtypes with aggressive and estrogen independence characteristics. Clinical trial information: NCT03401359 .