Exploratory analysis of biomarkers associated with clinical outcomes from the study of palbociclib plus endocrine therapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer

Abstract

Background: Palbociclib plus endocrine therapy (ET) demonstrated significant progression-free survival (PFS) benefit in Young Pearl, a randomized phase ll trial comparing palbociclib þ ET versus capecitabine in premenopausal women with hormone receptor positive, HER2 negative metastatic breast cancer (MBC). This exploratory analysis investigated potential biomarkers of palbociclib plus ET on PFS. Patients and methods: Of 178 patients randomized (92 palbociclib plus ET; 86 capecitabine), we performed targeted sequencing (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response on PFS. Hazard ratios (HRs) were estimated using unstratified Cox proportional hazards models. Results: PIK3CA (41%) and TP53 (33%) mutations and CCND1 copy number variation (29%) were found most frequently in targeted sequencing of 141 patients. ESR1 mutations were found only in 3.5% of patients of this population. Luminal type showed better prognosis in palbociclib þ ET arm but no impact on PFS difference in capecitabine arm. High TMB, TP53 mutation, PTEN loss of function mutation and RB1 pathway alteration showed worse prognosis in palbociclib plus ET arm. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless of PAM50 subtypes. AURKA mutation/amplification, BRIP1/ MYC/RAD51C amplification were significantly associated to the patients with short PFS <6 month. Conclusion: Of palbociclib plus ET, luminal type showed better prognosis and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy and resistance.

Comparison of PIK3CA Mutation Prevalence in Breast Cancer Across Predicted Ancestry Populations

“…Additionally, compared with patients of EUR ancestry, patients of EAS ancestry with HER2+ BC and TNBC, as well as patients of SAS ancestry with HER2+ BC, were more likely to have tumors that harbor PIK3CAmut (Figs 2A, 2C and 2E). The ancestry-specific tumor PIK3CAmut prevalences observed across BC subtypes is supported by the findings from studies that sampled substantially fewer participants in Africa, [36][37][38][39] Latin America, [40][41][42][43][44] China or Korea, [45][46][47][48][49][50][51][52] and South Asian countries. [53][54][55][56][57] Inconsistencies between PIK3CAmut prevalences identified in our study and those reported in the literature were observed when sample sizes were small and when differences existed in the clinical characteristics of the populations evaluated and/or assay methodologies.…”

Role of Intrinsic Subtype Analysis with PAM50 in Hormone Receptors Positive HER2 Negative Metastatic Breast Cancer: A Systematic Review

“…However, the authors pointed out that the analysis was only exploratory and other studies would be necessary to acquire more consistent data [17]. In a recent analysis of the YOUNG PEARL trial [30], which compared the efficacy of palbociclib + exemestane + LHRH analogue vs. capecitabine in pre-menopausal women with HR+/HER2-mBC not previously treated with aromatase inhibitors, Lee et al confirmed better PFS in luminal vs. non-luminal subtypes in pts receiving combined treatment, excluding those with a pathogenetic BRCA2 mutation, characterized by worse prognosis regardless of subtype. However, this finding was not confirmed by the analysis of pts treated in MONALEESA trials [23], in which the addition of ribociclib resulted in an increase in PFS in all subtypes excluding basal-like, and furthermore, HER2E appeared to be the subtype that benefited most from the addition of ribociclib, although it is known to have a worse prognosis and show greater endocrine resistance than the luminal subtypes [7,8] (differences in PFS between experimental and control groups divided by intrinsic subtype were as follows: HER2E 10.8 months, LumA 10.1 months, LumB 9.4 months, basal-like 0.2 months, normal-like 11.24 months).…”

A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 16

“…The genes FGFR2 , CCND1 and TOX3 are still not studied much in relation to the roles in breast cancer although genetic studies have suggested their involvement in cancer risk. FGFR2 has been suggested to be implicated in breast cancer as a target for therapeutic strategies [ 44 ], CCND1 is frequently mutated by copy number variation and suggested as a prognostic biomarker [ 45 ]. The role of TOX3 in relation to breast cancer is less clear.…”