Abstract PS5-19: Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study
Authors: Park Kyunghee , Kim Gun Min , Jung Kyung Hae , Kang Seok Yun , Park In Hae , Kim Jee Hyun , Ahn Hee Kyung , Park Woong-Yang , Im Seock-Ah , Park Yeon Hee 
Published: February 2021

Background: Young-PEARL study showed median progression-free survival (PFS) of 20·1 months in the palbociclib plus endocrine therapy group versus 14·4 months in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], log-rank p=0·0235). We conducted exploratory biomarker analysis to predict the efficacy of the trial. Methods: This was a phase II trial that randomized 184 patients with HR+ MBC in premenopausal women to palbociclib plus exemestane with GNRH agonist (Arm A, n=79) versus capecitabine (Arm B, n=62). We performed targeted sequencing (CancerSCANTM) containing 375 cancer-related genes (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response in terms of PFS.

Result: By research-based PAM50 subtyping, 73% of patients classified as Luminal (Luminal A and Luminal B), and showed better prognosis in all patients and Arm A (p&lt;0.05) in compared to no survival difference in Arm B (p=0.284). PFS difference between LumA and LumB was not statistically significant in Arm A (p=0.196). PIK3CA mutation (41%), TP53 mutation (33%), GATA3 mutation (25%), CCDN1 CNV (29%), BRCA2 mutation (14%) were the most frequently detected in this population. High TMB, TP53 mutation, ClinVar pathogenic somatic BRCA2 mutation (3.5%) showed worse prognosis in Arm A (p&lt;0.05). Non-luminal patients with TP53 or BRCA2 mutations were poor prognosis in Arm A. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless PAM50 subtypes, and luminal patients showed longer PFS compared to non-luminal patients among patients without BRCA2 pathogenic mutations in Arm A. RB1 loss, known as a resistant biomarker of CDK4/6 inhibitor was found in 4% of Arm A, and was associated with shorter PFS (log2 HR=2.26, 95% CI 0.51 to 4.01, p=0.011). AURKA mutation/amplification and RAD51C amplification were significantly associated to the patients with PFS less than 6 month. ESR1 mutations were found in 3.5% of patients, which was less than PEARL (29.4%) and PALOMA-3 (25.1%) trials. ESR1 mutations and ESR1/2 expression were not associated with shorter PFS. Notch 2/3/4 pathway expression was lower in patients with longer PFS (PFS more than 20month). ETIMATE ImmuneScore was higher in non-luminal compared to luminal patients, and didn’t show survival difference in Arm A, but luminal patients with low ImmuneScore showed better prognosis. The relative proportion of 22 immune cell types was deconvoluted by CIBERSORT, and T cell CD4 memory resting, Macrophage M0 and M2 were abundant. NK cell activated was higher proportion in patients with longer PFS. Low TIL patients with low interferon and high T cell regulation expression showed worse prognosis. Germline BRCA mutation and integrated analyses of genomic and transcriptomic profiles will be reported.

Conclusions: The alteration of a few genes including Rb1 loss may be associated with resistance of palbociclib in HR-positive premenopausal population with MBC. Luminal type showed better prognosis, and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. ESR1 mutation was found in low population frequency because all patients didn’t received AI therapy. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy. Clinical trial information: NCT02592746.

Citation Format: Kyunghee Park, Gun Min Kim, Kyung Hae Jung, Seok Yun Kang, In Hae Park, Jee Hyun Kim, Hee Kyung Ahn, Woong-Yang Park, Seock-Ah Im, Yeon Hee Park. Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-19.