Breast cancer, a mechanism to bypass anti-ER and anti-HER2 resistance

CDK4/6 inhibition with palbociclib, in combination with fulvestrant, trastuzumab and pertuzumab, triggers sustained senescence: new data from a Michelangelo Foundation study

A new research coordinated by Michelangelo Foundation, recently published on Clinical Cancer Research, has found a mechanism to bypass breast cancer resistance to drugs targeted to estrogen receptors and HER2: the new combination, which includes the CDK4/6 inhibitor palbociclib, is an effective chemotherapy-free regimen for ER+/HER2+ breast cancer.

In these breast cancer endocrine therapy has limited efficacy and addition of anti-HER2  drugs leads in general to modest therapeutic improvement, suggesting that the crosstalk between HER2 and estrogen receptor is bypassed by alternative escape pathways. New data, obtained in vitro on seven different cell lines and after assessing gene-expression dynamic and association with Ki67 down-regulation in 28 patients, shows that CDK4/6 inhibition voids the escape mechanisms induced by ER/HER2 crosstalk and triggers the transition from cell-quiescence to sustained senescence; findings on patients demonstrate a Ki67 down-regulation at week 2 associated to up-regulation of senescence-related genes. These findings are consistent with those observed in the NAPHER-2 trial, which enrolled ER+/HER2+ breast cancer patients treated with neoadjuvant chemo-free combination of drugs targeting estrogen receptors, HER2 and CDK4/6. Results of this new study provide a mechanistic interpretation of the increased  clinical activity observed with fulvestrant, trastuzumab e pertuzumab in combination with palbociclib and provide a support for further development of this therapeutic strategy and further research of biomarkers to predict sustained tumor senescence in individual patients.