AUTHOR=Tang Yu , Li Jing , Liu Binliang , Ran Jialu , Hu Zhe-Yu , Ouyang Quchang 

TITLE=Circulating tumor DNA profile and its clinical significance in patients with hormone receptor-positive and HER2-negative mBC

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1075830

DOI=10.3389/fendo.2022.1075830

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>After early-line (first- and second-line) endocrine therapy, hormone-receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancers (mBCs) become resistant to endocrine therapy. Genetic alterations may underlie resistance to endocrine therapies. This study aims to investigate the circulating tumor DNA (ctDNA) alterations and the clinical implication in hormone-receptor-positive, HER2-negative metastatic breast cancer patients with multiline endocrine therapy failure.</p></sec><sec><title>Methods</title><p>This registered study (NCT05079074, ClinicalTrials.gov) enrolled 104 patients with hormone-receptor-positive, HER2-negative metastatic breast cancer who progressed after the early-line endocrine therapy. ctDNA alterations were analyzed by next generation sequencing (NGS). ctDNA alterations were ranked and clustered by using R ‘ComplexHeatmap’ and ‘hclust’ function. ctDNA-guided therapy was administrated. Progression-free survival (PFS) was assessed COX regression analysis, and Kaplan-Meier curves were plotted.</p></sec><sec><title>Findings</title><p>The top ctDNA altered genes were <italic>TP53</italic> (39%), <italic>PIK3CA</italic> (38%), <italic>BRCA1/2</italic> (13%), <italic>ESR1</italic> (12%), <italic>FGFR</italic> (11%), <italic>ERBB2</italic> (11%), and <italic>GATA3</italic> (9%). Among these genes, <italic>TP53</italic>, <italic>PIK3CA</italic> helix domain mutation (<italic>PIK3CA</italic>-HD), <italic>FGFR</italic>, <italic>ESR1</italic> and <italic>GATA3</italic> were related to endocrine therapy resistance. The genetic landscapes changed and tumor mutation burden increased in both <italic>TP53</italic>-altered and <italic>PIK3CA</italic>-altered patients. Both <italic>BRCA1/2</italic> and <italic>ERBB2</italic> alterations correlated with <italic>TP53</italic> alterations (<italic>P</italic>=0.02 and <italic>P</italic>=0.04, respectively). However, while 93% <italic>BRCA1/2</italic> alterations concentrated in <italic>PIK3CA</italic>-wildtype patients, 82% <italic>ERBB2</italic> alterations concentrated in <italic>PIK3CA</italic>-altered patients. Kaplan–Meier curves showed that patients who received druggable ctDNA alteration-guided treatment (DDAT) had significantly longer PFS than those who received physician-chosen therapy, with median PFS of 6.1 months versus 4.6 months (hazard ratio = 0.53, 95% CI: 0.34-0.85, Logrank <italic>P</italic> = 0.006).</p></sec><sec><title>Conclusion</title><p>Multiple genetic alterations were important reasons for the failure of endocrine therapy for HR-positive and HER2-negative mBC. Targeting these genes might restore the treatment sensitivity and benefit survival.</p></sec>