T. Takeshita1, E. Katsuta1, L. Yan2, K. Takabe1 2Roswell Park Cancer Institute,Biostatistics & Bioinformatics,Buffalo, NY, USA 1Roswell Park Cancer Institute,Breast Surgery, Surgical Oncology,Buffalo, NY, USA
Introduction: Endocrine therapies are one of the essential treatments for estrogen receptor (ER)-positive breast cancer, particularly in combination with targeted therapies. It is now established that endocrine therapy with targeted therapies, such as, CDK4/6 inhibitors and mTOR inhibitors, is a mainstay of treatments for ER-positive metastatic breast cancer (MBC). ESR1 mutation is a resistance factor of endocrine therapy and it is a useful biomarker predicting an effect of the treatment, but it is not certain whether or not it has same utility when used with targeted therapies. RB1 mutation and amplification of cyclin E1 (CCNE1) are now known as resistance factors of CDK4/6 inhibitors. PI3K pathway is known to play an important role in ER positive breast cancer and its activity affects both endocrine therapy and molecular target therapy. Therefore, it is noteworthy whether coexistence of ESR1 mutation and these genetic abnormalities is a predictor of effect of these combination therapies. Here we studied the frequency of PI3K pathway alterations (PIK3CA mutation/amplification and PTEN loss), Rb1 mutation, and amplification of CCNE1 with ESR1 mutation in ER-positive breast cancer.
Methods: We analyzed gene abnormalities using an ER-positive primary breast cancer (PBC) cohort from TCGA data (n = 525) and a MBC cohort (n = 216).
Results: In the PBC cohort, PI3K pathway alterations were recognized at 40%, Rb1 mutation at 0.9%, amplification of CCNE1 at 10%, and ESR1 mutation at 0.9%. As expected, presence of ESR1 mutation was very low and it was difficult to verify the relationship with other factors. In the MBC cohort, the frequency of PI3K pathway alterations, Rb1 mutation, and amplification of CCNE1 was almost unchanged, but ESR1 mutation was found to be 20%. Some cases with genomic alterations coexisting with ESR1 mutation were found, suggesting the possibility of showing resistance to combination therapies.
Conclusion: We showed the clinically important frequency of genomic alterations coexisting with ESR1 mutation in ER positive breast cancer cohort.