Predicting Response to Combination Therapies for Breast Cancer Brain Metastases
Posted: Tuesday, May 4, 2021
Sheheryar Kabraji, BM BCh, of the Dana-Farber Cancer Institute, Boston, and colleagues conducted a study to pinpoint predictors of resistance and response to brain-penetrant, small-molecule targeted therapies for patients with HER2-positive breast cancer. During the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021, they noted that the tumor suppressor p16INK4A, or p16, was scarce in most cases of HER2-positive breast cancer brain metastases and proposed it may prove to be a useful biomarker (Abstract 337).
“These data establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2-positive breast cancer brain metastases,” the investigator concluded.
The protein p16INK4A is involved in the cell cycle, inhibiting cell division by slowing the progression of the cell cycle from the G1 phase to the S phase; therefore, it acts as a tumor suppressor. Brain metastases develop in nearly half of patients with metastatic HER2-positive breast cancer, and depletion of this protein may play a role.
Whole-exome sequencing, RNA sequencing, and quantitative immunohistochemistry analysis were performed on 21 HER2-positive breast cancer brain metastasis tissues from 21 patients. Patient-derived orthotopic HER2-positive breast cancer brain metastasis xenograft models with insufficient p16 were resistant to the HER2 inhibitor tucatinib and the CDK4/6 inhibitor abemaciclib, both of which can cross the blood-brain barrier. The deficiency of this tumor suppressor seemed to predict response when tucatinib and abemaciclib were combined, specifically in these orthotopic HER2-positive breast cancer brain metastasis xenograft models.
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.