Abstract
Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 − 3.2] p = 1.87e−08 and HR = 2.62 [1.9− 3.5] p = 8.6e−11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted.
Highlights
Cell cycle related genes and proteins are frequently deregulated in breast cancer leading to uncontrolled cell proliferation, a hallmark of cancer [1]
To test our hypothesis that a signature of functional retinoblastoma susceptibility gene product (Rb) loss would be predictive of palbociclib resistance in breast cancer cell lines, we first developed a signature (RBsig) from the The Cancer Genome Atlas (TCGA) dataset [3]
One of the main functions of Rb on cell cycle is repression of E2F1- and E2F2- mediated transcription; the RBsig was developed by analyzing genes that correlated with E2F1 and E2F2 expression
Summary
Cell cycle related genes and proteins are frequently deregulated in breast cancer leading to uncontrolled cell proliferation, a hallmark of cancer [1]. PALOMA-1 and PALOMA-2 are phase II and phase III randomized trials, respectively, of palbociclib in combination with letrozole versus letrozole alone for previously untreated patients in the metastatic setting [8, 10]; PALOMA-3 is a phase III randomized trial of palbociclib and fulvestrant versus placebo and fulvestrant for the treatment of patients relapsed on or progressed to a previous line of hormonal therapy [7, 9]. These trials clearly demonstrated the superiority of the combination over hormonal treatment alone in both hormone therapy-untreated and -pretreated populations [710] Abemaciclib, another CDK4/6 inhibitor, has recently been granted FDA breakthrough therapy designation for patients with refractory HR+ metastatic breast cancer based on encouraging results from a phase I study in which single-agent abemaciclib demonstrated a clinical benefit rate of 61.1% in patients with heavily pre-treated metastatic breast cancer [11]. Understanding which subgroup of patients is not likely to benefit from CDK4/6 inhibitors is of critical importance
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