Abstract
Simple SummaryAdvanced stage breast cancer is incurable, and a leading cause of cancer-related death in women. Recently, novel treatment options have improved clinical outcomes of breast cancer patients. Combined CDK4/6 inhibitor and endocrine therapy have been shown to be highly effective, improving both progression-free and overall survival, but resistance inevitably develops and disease progression occurs. Identification of clinically useful biomarkers predicting therapeutic response/failure and resistance mechanisms are essential for optimal patient stratification and the development of novel therapeutic strategies for patients who have progressed on combined CDK4/6 inhibitor and endocrine therapy. However, finding a universal single predictive biomarker is unlikely mainly due to the heterogenicity of the cancers and the associated resistance mechanisms. Here, we review the current state of knowledge on resistance mechanisms to combined CDK4/6 inhibitor and endocrine therapy and associated predictive molecular biomarkers, including the use of liquid biopsy.The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therapy inevitably develops and represents a major clinical challenge in the management of ER+ ABC. Currently, elucidation of the resistance mechanisms, identification of predictive biomarkers, and development of novel effective combined targeted treatments to overcome the resistance are active areas of research. Given the heterogeneity of the resistance mechanisms towards combined CDK4/6i and ET, identification of a single universal predictive biomarker of resistance is unlikely. Novel approaches are being explored, including examination of multiple genetic alterations in circulating cell-free tumor DNA in liquid biopsies from ABC patients with disease progression on combined CDK4/6i and ET treatment. Here, we review the molecular basis of the main known resistance mechanisms towards combined CDK4/6i and ET and associated potential biomarkers. As inhibiting key molecules in the pathways driving resistance may play an important role in the selection of therapeutic strategies for patients who experience disease progression on combined CDK4/6i and ET, we also review preclinical and early phase clinical data on novel combination therapies for these patients.
Highlights
Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death worldwide
Further analysis of the PALOMA-3 trial assessing relative changes in circulating tumor DNA (ctDNA) levels at further time points (30day/baseline and at progression) showed a similar correlation [42]. These results demonstrated that early ctDNA dynamics of PIK3CA mutation is a prognostic factor of progression-free survival (PFS) that can be used to monitor the efficacy of palbociclib and fulvestrant in patients with ER+/HER2− advanced breast cancer (ABC)
We have shown that the combined protein levels of CDK6, phospho-CDK2, and cyclin E1 significantly correlated with shorter PFS on aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) treatment in ER+ ABC patients [24]
Summary
Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer death worldwide. An association between Rb loss of function and resistance to combined CDK4/6i and ET was observed in 3 patients with ER+/HER2− ABC who received CDK4/6i (palbociclib or ribociclib) and showed somatic mutations in Rb in circulating tumor DNA (ctDNA) upon disease progression [17]. The predictive value of Rb remains uncertain, as tumor analyses performed on two large randomized phase 3 clinical trials (PALOMA-2 and 3, examining palbociclib in combination with AI or fulvestrant versus AI or fulvestrant alone, respectively, in patients with ER+/HER2−ABC) failed to show a statistically significant correlation between Rb (at mRNA or protein level) and resistance to CDK4/6i [18,19]. The analysis of liquid biopsy components such as tumor exosomes and circulating cell-free RNA are still at an early stage [26], future evaluation of alterations of the cyclin E1-CDK2 axis in liquid biopsies of ER+/HER2− ABC patients is promising
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