Background Combination of eribulin and immune checkpoint inhibitor (ICI) showed durable response for HER-2 negative metastatic breast cancer (MBC) patients, but PD-L1 expression was not associated with efficacy. Here, we report the whole exome sequencing (WES) and whole transcriptome sequencing (WTS) analysis of pretreatment tumor tissues from the phase II clinical trial of the eribulin and nivolumab combination in patients with HER-2 negative MBC to find potential biomarker (KORNELIA trial, ClinicalTrials.gov Identifier: NCT04061863).
Methods We acquired whole exome sequencing (WES) data from 76 patients, and whole transcriptomic sequencing (WTS) data from 58 patients. Patients achieved progression free survival (PFS) ≥ 6 months were defined as PFS6-responders and otherwise as PFS6-nonresponders. We explored the potential biomarkers from WES and WTS, and analyzed how they are associated with efficacy.
Results PFS6 rate in this study cohort was 34.5%. PFS6-responders tended to have higher TMB compared with PFS6-nonresponders (median TMB 6.6 vs. 5.1 mut/Mb, p = 0.309). TMB-high patients (≥ 8 mut/Mb) showed showed tendency to higher PFS compared with TMB-low patients (median PFS 8.0 months, 95% confidence interval [CI] 5.6 ~ 14.6 for TMB-high and 4.3 months, 95% CI 3.0 ~ 5.6 for TMB-low, p = 0.07). Comprehensive analysis related to homologous recombination deficiency (HRD), which include mutational signature 3, somatic HRD-related gene mutation, and HRD scores, showed that overall HRD was associated with poor response to the combination regimen. Specifically, when patients were divided into two groups by median HRD score, patients with high HRD score showed significantly lower PFS6 rate (23.7% vs. 50.0%, p = 0.031) and significantly shorter PFS compared to patients with low HRD score (median PFS 4.2 months [95% CI 2.6 ~ 5.6] vs. 6.5 [95% CI 5.3 ~ 14.3], p = 0.025). WTS data showed antigen presentation (AP) gene set enrichment scores were high in PFS6-responders and the patients with high scores showed significantly longer PFS compared with the other patients. In addition, the proportion of naïve B-cell and plasma cell were significantly higher in the long responders (≥ 18 months).
Conclusions In conclusion, we found that high TMB and B-cell related enrichment were associated with good efficacy while HRD was associated with poor efficacy of eribulin plus nivolumab in patients with HER-2 negative metastatic breast cancer. The implications from our study would need to be considered when designing the clinical trial in terms of biomarker enrichment and inclusion/exclusion criteria.
Trial Registration NCT04061863
Ethics Approval Institutional review boards of Seoul National University Bundang Hospital
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.