Biomarker Analyses of Response to Cyclin-Dependent Kinase 4/6 Inhibition and Endocrine Therapy in Women with Treatment-Naïve Metastatic Breast Cancer

Abstract

Purpose: 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 (HRþ/HER2À) human breast cancer models. This observation was validated clinically in the randomized, placebo-controlled, phase III PALOMA-2 study. Experimental Design: 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. Results: 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. Conclusions: These data underscore the importance of CDK4/ 6 signaling in HRþ/HER2À 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

Treatment effect of palbociclib plus endocrine therapy by prognostic and intrinsic subtype and biomarker analysis in patients with bone-only disease: a joint analysis of PALOMA-2 and PALOMA-3 clinical trials

“…Previous findings have shown that patients with luminal subtype disease benefit from the combination of palbociclib plus letrozole, regardless of luminal A or luminal B subtype [27,31]. In patients with luminal A tumors, the median PFS was 30.4 months with palbociclib plus letrozole compared with 17.0 months with placebo plus letrozole (hazard ratio, 0.55; 95% CI 0.39-0.77; P = 0.000547) [27,31].…”

“…In PALOMA-3, women (n = 521) of any menopausal status with HR+/HER2− ABC whose disease had progressed after previous ET were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule) plus fulvestrant (500 mg on days 1 and 15 of cycle 1 and on day 1 of each subsequent cycle) or placebo plus fulvestrant [22]. Microarray data from the PALOMA-2 and PALOMA-3 studies were previously deposited in Gene Expression Omnibus (accession numbers GSE133394 and GSE128500, respectively); 568 baseline tumor tissues from either primary or metastatic biopsies were collected from patients in PALOMA-2 [27] and 462 tumor samples were collected, including 302 evaluable samples (53% archival primary samples and 47% metastatic biopsy samples), from PALOMA-3 [28].…”

“…Luminal subtypes were determined by gene expression profiles from FFPE tumor tissue [27,28,31]. The EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics; Tucson, AZ, USA) was used for gene expression profiling [27,28].…”

“…Luminal subtypes were determined by gene expression profiles from FFPE tumor tissue [27,28,31]. The EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics; Tucson, AZ, USA) was used for gene expression profiling [27,28]. The intrinsic molecular subtypes were determined using the absolute intrinsic molecular subtyping algorithm through a set of binary rules that compared expression measurements for pairs of genes from each individual patient [27,28,31,32].…”

“…To assess the effect of luminal subtype in metastatic disease, PFS by luminal subtype only among patients who provided metastatic disease tumor tissues was evaluated in PALOMA-3. Intrinsic subtype analysis using data from PALOMA-2 have been previously reported [27]. Hazard ratios and 95% confidence intervals (CIs) were computed using the Brookmeyer and Crowley method.…”