Abstract P5-01-15: Monitoring of CDK4/6 inhibitor treatment response through blood liquid biopsy in metastatic breast cancer
Authors: Shibayama Tomoko , Chin Yoon Ming , Ono Makiko , Kobayashi Takayuki , Chan Hiu Ting , Hara Fumitaka , Hosonaga Mari , Kobayashi Kokoro , Inagaki Rina , Ito Yoshinori , Ueno Takayuki , Takahashi Shunji , Oono Shinji , Nakamura Yusuke , Low Siew Kee 
Published: March 2020

Abstract
Background: Hormone receptor positive breast cancers accounts for approximately 70% of metastatic breast cancers (MBCs), and it is often treated with an anti-hormonal agent as long as possible unless with visceral and aggressive metastasis.CDK4/6 inhibitorsare effective as first- or second-line treatments for metastatic hormone receptor positive HER2 negative breast cancer (HR+ HER2-). When disease progression due to resistance to CDK4/6 treatment occurs, treatment modification is required. Currently, monitoring of treatment response relies solely on imaging.Therefore, through thisstudy, we aim to evaluate ctDNA as a potential biomarker to monitor response to CDK4/6 treatment. Materials & Methods: Patients were recruited from the Cancer Institute Hospital of Japan Foundation for Cancer Research (JFCR).Hormone positive HER2 negative (HR+ HER2-) MBC patients treated with CDK4/6 inhibitors were collected at different timepoints up till 24 months or if patient develops disease progression. These samples were sequenced using a targeted pan-cancer panel that utilizes ultradeep NGS with molecular barcodes.This panel is able to detect all classes of mutations such as single nucleotide variants (SNV), copy number variants (CNV) and fusions. Results:A total of 78 samples from 20patients was sequenced. CDK4/6 was administered as early line treatments. The average total coverage was 56,933X and average molecular coverage was 4,442X.The majority of mutations detected prior to CDK4/6 treatment were TP53, PIK3CAand ESR1. The ctDNA profile is consistent with the clinical status in most patients. ctDNA showed greater dynamics of tumor response to CDK4/6 inhibitor compared to tumor markers CEA and CA15-3.ctDNA was also more sensitive at detecting onset of progression disease compared to imaging. We observed an increase in ctDNA mutation frequency 2-3 months earlier than imaging in 2 patients. From the 20 patients, 7 patients developed progression disease(PD) during our evaluation and required a different treatment. 5 of the 7 patients (71.4%) have ESR1 mutations prior to start of treatment and these patients developed PD within 6 months of treatment. In contrast, no ESR1 mutations were detected in patients who did not develop disease progression. Discussion: In this study, we observed that ctDNA was more sensitive at detecting onset of progression disease compared to imaging. This is essential as early detection of poor response enables timely change of treatment for patients. Patients carrying ESR1mutations respond poorly to CDK4/6 treatment. This might be due to resistance of ESR1mutants to fulvestrant or aromatase inhibitor component of the CDK4/6 treatment regimen. Conclusion: Monitoring of ctDNA is useful to assess treatment response of CDK4/6 inhibitors in metastatic breast cancer patients.
Citation Format: Tomoko Shibayama, Yoon Ming Chin, Makiko Ono, Takayuki Kobayashi, Hiu Ting Chan, Fumitaka Hara, Mari Hosonaga, Kokoro Kobayashi, Rina Inagaki, Yoshinori Ito, Takayuki Ueno, Shunji Takahashi, Shinji Oono, Yusuke Nakamura, Siew Kee Low. Monitoring of CDK4/6 inhibitor treatment response through blood liquid biopsy in metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-15.