Against the above discussed background there is a clear rationale to further collect real world data confirming that the use of endocrine based therapy in metastatic breast cancer is beneficial for the patient cohort with symptomatic visceral metastases and high tumor burden. Data recently presented, showed that Abemaciclib in combination with Letrozole leads to substantial reduction in tumor size after only two cycles of therapy. Since Abemaciclib is the only CDK4/6-inhibitor that can be given "steady state" without a "one-week-off"-period and since there has been beginning evidence that Abemaciclib is penetrating the blood brain barrier in patients with brain metastases, it seems reasonable to choose Abemaciclib in combination with endocrine therapy for an observational study whose objective will be to collect efficacy data within clinical routine on Abemaciclib in combination with endocrine therapy within a cohort of ERpos/HER2neg breast cancer patients with symptomatic visceral metastases or high tumor burden.
LDH-levels above 400 U/l as well as abnormal levels of breast cancer specific tumor markers CA 15-3 and CEA have been proven to correlate with disease extent in metastatic breast cancer and thus can be used to identify metastatic breast cancer patients with high tumor burden. Recently it could be shown that circulating tumor DNA (ctDNA) bares greater correlation with changes in tumor burden than CA 15-3 and can provide the earliest measure of treatment response in women with metastatic breast cancer. This warrants further research to evaluate ctDNA as a tool for measuring early tumor response in MBC patients.
Translational research part:
In the era of personalized cancer therapy, testing for genetic alterations has become an essential tool in clinical practice. It allows clinicians to identify patients who are most likely to benefit from molecularly targeted treatments. Currently, evaluation of response to targeted drugs is largely based on imaging (CT or MRT), an approach unable to reveal mechanistic details on individual treatment effects. Sequential biopsies of tumors and their molecular analysis could yield additional information, but repetitive sampling of tissue that is representative and adequate in quantity and quality is rarely feasible, especially in the metastatic disease setting.
Liquid biopsies (LBs) represent a minimally-invasive alternative of great potential in this setting. Although recent technical advances allow very sensitive detection of LB-based tumor biomarkers, only few LB assays have yet entered into clinical routine.
Blood plasma samples from patients treated with Abemaciclib will be analyzed to identify predictive cell-free (cf) DNA-based biomarkers as indicators for treatment efficacy and early detection of resistance. To this end, cfDNA will be screened for mutations using a targeted next-generation sequencing panel (AVENIO ctDNA Expanded Kit, Roche). This panel is covering a total of 192 kb and consists of 77 genes, including those currently in the US National Comprehensive Cancer Network guidelines as well as emerging biomarkers currently being investigated in clinical trials.
For each plasma sample, concentration of cfDNA as well as presence and allelic frequencies of tumor mutations will be measured. Additionally, associations with progression-free survival and overall survival will be evaluated using Cox regression models. Clinical variables will be used as covariates in multivariable regression models to evaluate the independence of the LB-based biomarkers.
As a result, the investigators hope to identify minimally invasive LB-based biomarkers for serial monitoring of metastatic breast cancer patients. These biomarkers could add to the prediction of therapy response as well as the early detection of therapy resistance towards endocrine therapy and Abemaciclib.
