In a randomized phase ll trial (Young Pearl) comparing palbociclib + endocrine therapy (ET) vs capecitabine in premenopausal women with hormone receptor positive, HER2 negative metastatic breast cancer, significant progression-free survival (PFS) benefit was shown to be conferred by palbociclib plus ET. Researchers undertook this exploratory analysis to determine potential biomarkers of palbociclib plus ET on PFS. Luminal type was identified to be the most crucial prognostic marker in palbociclib plus ET treated premenopausal patients.

• Randomized patients were 178 in total (92 palbociclib plus ET; 86 capecitabine); of those, 141 and 165 patients were used for conducting targeted sequencing and whole transcriptome sequencing respectively.

• In targeted sequencing of 141 patients, PIK3CA (41%) and TP53 (33%) mutations and CCND1 copy number variation (29%) were identified most frequently.

• Only 3.5% of patients had ESR1 mutations.

• In palbociclib plus ET arm, worse prognosis was demonstrated by high tumor mutational burden, TP53 mutation, PTEN loss of function mutation and RB1 pathway alteration.

• Of palbociclib plus ET, luminal type demonstrated better prognosis and BRCA2 pathogenic mutation demonstrated worse prognosis irrespective of luminal/non-luminal type.

• AURKA mutation/amplification, BRIP1/MYC/RAD51C amplification were found to be significantly linked with the patients with short PFS <6 month.