Abstract PD4-05: Patterns of genomic alterations in ER-positive advanced breast cancer patients treated with CDK4/6 inhibitors
Authors: Cruz MR , Limentani K , Taxter T , Santa-Maria CA , Behdad A , Gradishar WJ , Nagy RJ , Cristofanilli M 
Published: February 2018

Background:Cyclin D kinase inhibitors (CDK-is) have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer (MBC) when combined with aromatase inhibition or estrogen receptor (ER) antagonism. Despite the benefit of this approach, clinical resistance develops sometimes early in the treatment without any response to endocrine therapy (primary endocrine resistance) or after initial response (secondary resistance) in all patients in the metastatic setting and the molecular basis for this resistance are still largely unknown. We evaluated the pattern of genomic alterations in circulating cell-free tumor DNA (ctDNA) analysis of metastatic breast cancer patients with ER-positive tumors treated with palbociclib combined with either letrozole or fulvestrant and progressing during therapy.

Methods: We conducted a retrospective study of patients with ER-positive MBC who had longitudinal assessment of their disease by ctDNA analysis. The plasma-based assay was performed utilizing Guardant360 (Guardant Health, CA), a digital NGS technology to sequence a panel of &gt; 50 cancer genes. After tabulating number of genomic alterations detected for every patient at baseline and after CDK-i therapy, analysis was performed to identify molecular profile changes in the entire population and in individuals with early progression of disease (&lt;6 months).

Results: We analyzed data of 15 ER-positive MBC patients: 8 patients received fulvestrant/palbociclib and 7 received letrozol/palpociclib. The most common mutations before CDK-i therapy were: PIK3CA (16%), TP53 (16%), ESR1 (13%), KIT (9%), EGFR (3%), APC (3%), ERBB2 (3%), MYC (3%), PTEN (3%), RB1 (3%). After therapy with CDK-i the pattern of mutations showed stable and persistent incidence of PIK3CA, TP53 and ESR1. However, new mutations where identified: FGFR1 (6%), IDH (2%), BRCA1 (2%), BRCA2 (2%), CCNE (2%), CCND1 (2%), RAF (2%), AR (2%), ALK(2%). Also, the pattern of gene amplifications presented an increased rate of MYC and FGFR1 amp. Patients with progression of disease before 6 months of CDK-i therapy presented baseline higher number and variation of mutations compared to patients with disease controlled beyond 6 months of therapy.

Conclusion: Longitudinal assessment with ctDNA analysis suggest that a genomic alteration landscape consisting of persistent detection of driver and acquired mutations along with emergent new abnormalities in regulatory genes could potentially be related to primary or secondary resistance to CDK-Is in ER+ MBC patients. Future investigation of these alterations should be conducted.

Citation Format: Cruz MR, Limentani K, Taxter T, Santa-Maria CA, Behdad A, Gradishar WJ, Nagy RJ, Cristofanilli M. Patterns of genomic alterations in ER-positive advanced breast cancer patients treated with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-05.