Assessing tumor heterogeneity using ctDNA to predict and monitor therapeutic response in metastatic breast cancer

Abstract

Tumor heterogeneity was associated with treatment outcome of metastatic cancers but few studies have examined whether tumor heterogeneity in circulating tumor DNA (ctDNA) can be used to predict treatment outcome. ctDNA analysis was performed in 37 HER2‐positive metastatic breast cancer patients treated with pyrotinib. Patients with high tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks vs. 60.0 weeks for patients with low tumor heterogeneity (hazard ratio [HR], 2.9; p = 0.02). Patients with trunk resistance mutations receiving pyrotinib monotherapy had worse outcomes (HR, 4.5; p = 0.03), with a median PFS of 7.8 weeks vs. 27.4 weeks for those with branch resistance mutations or without any resistance mutations in baseline ctDNA. Longitudinal monitoring of 21 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (p < 0.0001, Pearson r = 0.52) and detected disease progression 8–16 weeks earlier. Our current findings suggested that ctDNA could be used to assess tumor heterogeneity and predict treatment outcomes. Furthermore, the mTBI is better for assessing therapeutic response than single gene mutations and might supplement the current therapeutic response evaluation system.

<p>Pathological Complete Response from Pyrotinib Combined with Trastuzumab, Paclitaxel and Cisplatin in a Postpartum Woman with HER2-Positive Locally Advanced Breast Cancer: A Case Report</p>

“…Intriguingly, the biomarker analysis of previous trials suggested that PIK3CA and TP53 mutation status in ctDNA in tumor tissues correlated with response and even PFS. 3,[18][19][20] Interestingly, our patient had the PIK3CA H1047R mutation, but the value of the detection of biomarkers in the adjuvant setting still needs to be proven. In one study, pyrotinib had a manageable toxicity profile in patients with HER2-positive metastatic breast cancer.…”

Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer

“…PIK3CA mutations were reported to be a negative predictor of the response to HER2-targeted therapy in patients with HER2 amplification-positive breast cancer 25 , 26 . In the SUMMIT study 8 , the activation of the phosphatidyl inositol 3-kinase/AKT/mammalian target of rapamycin pathway did not adversely affect the likelihood of the clinical benefit of neratinib in patients with various cancers.…”

<p>Advances in the Detection Technologies and Clinical Applications of Circulating Tumor DNA in Metastatic Breast Cancer</p>

“…42 The molecular tumor burden index, a measure of the percentage of ctDNA in samples, was positively correlated with tumor size as evaluated by computed tomography (P < 0.0001) and detected disease progression 8-16 weeks earlier. 54 The ctDNA Concentration Dynamic changes in ctDNA levels closely reflect changes in tumor burden and increases in ctDNA levels may predict the progressive disease (PD) several months before the standard imaging. 55 In recent years, several methods were used to determine the ctDNA concentration in MBC and investigate its relationship with clinical outcomes.…”

“…The results indicated that patients with higher tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks vs. 60.0 weeks for patients with low tumor heterogeneity (P = 0.02). 54 Sub-clonal mutations are reported most commonly in ESR1. Multiple concurrent ESR1 genomic alterations including mutation, rearrangement, and amplification were observed in 40% of ESR1-altered cases, suggesting polyclonal origin.…”