Abstract
Preclinical data identified the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib as synergistic with antiestrogens in inhibiting growth of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) human breast cancer models. This observation was validated clinically in the randomized, placebo-controlled, phase III PALOMA-2 study. To determine markers of sensitivity and resistance to palbociclib plus letrozole, we performed comprehensive biomarker analyses, investigating the correlation with progression-free survival (PFS), on baseline tumor tissues from PALOMA-2. Despite a broad biomarker search, palbociclib plus letrozole demonstrated consistent PFS gains versus placebo plus letrozole, with no single biomarker or cassette of markers associated with lack of benefit from combination treatment. Palbociclib plus letrozole confers efficacy on both luminal A and B patients. Higher CDK4 levels were associated with endocrine resistance which was mitigated by the addition of palbociclib, whereas lower PD-1 levels were associated with greater palbociclib plus letrozole benefit. Tumors with more active growth factor signaling, as exemplified by increased expression of FGFR2 and ERBB3 mRNA, appeared to be associated with greater PFS gain from the addition of palbociclib. These data underscore the importance of CDK4/6 signaling in HR+/HER2- breast cancer and suggest that the interplay between steroid hormone and peptide growth factor signaling could drive dependence on CDK4/6 signaling.See related commentary by Anurag et al., p. 3.
Highlights
The molecular heterogeneity of breast cancer is well established [1], but breast cancer is still approached clinically as three large therapeutic subgroups: hormone receptor-positive (HRþ), human epidermal growth factor receptor 2-amplified (HER2þ), and the so-called triple-negative breast cancer (TNBC), defined by the lack of hormone receptors and HER2 amplification/overexpression
Despite a broad biomarker search, palbociclib plus letrozole demonstrated consistent progression-free survival (PFS) gains versus placebo plus letrozole, with no single biomarker or cassette of markers associated with lack of benefit from combination treatment
Higher CDK4 levels were associated with endocrine resistance which was mitigated by the addition of palbociclib, whereas lower PD-1 levels were associated with greater palbociclib plus letrozole benefit
Summary
A total of 568 of 666 (85%) baseline tumor tissues from the 666 patients randomized were collected: 379 of 444 patients (85%) in the palbociclib plus letrozole arm and 189 of 222 patients (85%) in the placebo plus letrozole arm. We initially focused our approach on potential biomarkers within the cyclin D:CDK4/6:RB pathway, including CDK4, CDK6, cyclin D, cyclin E, p16, and RB Expression of these markers, as determined by IHC or mRNA levels, was not predictive of palbociclib benefit in combination with letrozole in this population, i.e., patients who had not received prior systemic therapy for ERþ/ HER2À ABC. From an unbiased panel-wide analysis, we demonstrated that more active growth factor signaling, including high levels of ERBB3 and FGFR2 expression, was associated with a larger PFS gain from the combination of palbociclib and letrozole These data provide evidence that the interplay between steroid hormone and peptide growth factor signaling in ERþ breast cancer could drive dependence on CDK4/6, which leads to the greater clinical benefit seen with CDK4/6 inhibition through the addition of palbociclib to letrozole. Large adjuvant studies of palbociclib in early stage breast cancer are ongoing (clinicaltrials. gov: NCT02513394, NCT03609047) and will provide additional tissues for biomarker correlates
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