Background: CDK4/6 inhibitors (CDK4/6i) paired with endocrine therapy (ET) remain firstline (1L) therapy for patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2-) advanced breast cancer (aBC). A subset of pts will demonstrate primary resistance to CDK4/6i, as characterized by early progression, while other patients will remain on CDK4/6i for an extended duration prior to progression. We sought to examine clinical and genomic differences between a cohort of early progressors and exceptional responders.

Methods: Pts with HR+ HER2- aBC from a phase II trial of an alternative schedule of palbociclib (palbo alt dosing trial NCT 3007979) and from a retrospective CDK4/6i study were included in this analysis. Pts in the retrospective CDK4/6i study included pts receiving CDK4/6i as part of standard of care (SOC) first-line therapy for HR+ HER2- aBC at Washington University in Saint Louis from 2016 to 2024. Clinical information, including treatment start and stop dates, was collected from the electronic medical record. Progression-free survival (PFS) was estimated by the treatment duration on a specified treatment regimen. Early progression (EP) on CDK4/6i was defined as PFS < 6 months (mo) and late progression (LP) was defined as PFS > 48 mo. Overall survival (OS) was defined as time to death from the initiation of CDK4/6i. NGS testing was performed using the Guardant360 or Tempus platforms per SOC at time points per the treating physicians discretion in the retrospective CDK4/6i study patients and Whole Exome Sequencing (WES) of circulating tumor DNA was performed on the palbo alt dosing trial patients at baseline and progression.

Results: Of the 54 pts enrolled on the palbo alt dosing trial, 10 experienced EP and had WES available. The median age of EP pts with WES was 64 years at time of metastatic diagnosis and the majority (6/10) had recurrent [AD1] disease with visceral involvement (8/10). The median PFS of EP pts with WES was 3.1 mo and OS was 14.5 mo. Of retrospective study pts, 20 patients had EP on CDK4/6i, 10 of which had SOC NGS testing during at least one time point. The median age of EP pts with SOC NGS testing was 61 years at time of metastatic diagnosis and the majority (8/10) had recurrent [AD2] disease with visceral involvement (6/10). The majority of these pts received palbo (9/10) paired with letrozole (9/10) and did not have recurrence on adjuvant endocrine therapy (6/10). The median PFS of EP pts with SOC NGS was 3.9 mo and OS was 22.3 mo. Of the 38 pts on the retrospective study with LP on CDK4/6i[EP3], 17 were excluded as they were still receiving therapy. 10 pts with LP had NGS testing available. The median age these pts was 64 at time of metastatic diagnosis and the majority (7/10) of the LP pts had recurrent disease with bone only involvement (6/10). The majority of these pts received palbo (10/10) paired with letrozole (8/10) and did not have recurrence on adjuvant endocrine therapy (8/10). The median PFS was 65.7 mo and most patients (6/10) were alive at data analysis. When analyzing genomic differences between the EP and LP pts, there was no significant difference in rates of PIK3CA, ESR1, TP53, and ATM mutations. More patients in the EP cohort had amplification (amp) of AR or AR mutations of uncertain significance (4/14 samples), CCND1 amps (2/14) and GATA3 mutations (2/14) at any time point. More patients in the LP cohort had RB1 (3/15 samples), GNAS (3/15), KRAS (2/15), EGFR (2/15) mutations and FGFR1 amps (2/15) at any time point.Frequencies of ESR1 alterations were similar in WES baseline (5/10), SOC EP (5/11), and SOC LP (5/9) samples, but less frequent in WES progression samples (1/10).

Conclusions: Early progression on CDK4/6i is associated with a particularly poor prognosis; however, there are patients with exceptional response to CDK4/6i who may remain on therapy for an extended time. There were variations in the mutation profiles between the two cohorts, though this data set was limited in size. Additional analysis of genomic variants is needed to identify profiles of patients who may significantly benefit from CDK4/6i.

VIEW THE PUBLICATION