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Exploratory biomarker analysis from a phase II clinical trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine for HER2-negative metastatic breast cancer patients (KCSG BR13-11)

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Abstract

Purpose

We conducted an exploratory biomarker study from a phase II clinical trial of eribulin plus gemcitabine (EG) versus paclitaxel plus gemcitabine (PG) in HER2-negative metastatic breast cancer (BC) patients.

Methods

We performed targeted deep sequencing with a customized cancer gene panel and RNA expression assay. Tumor mutation burden (TMB) and mutation signatures were determined based on genetic alteration in targeted regions. Gene set variation analysis was performed with PanCancer Immune Profiling and PanCancer Pathway Panels. Statistical analyses were conducted to identify the associations between genetic alterations and clinical outcomes.

Results

Of 119 patients, 40 had available biomarker data. Among the 40 patients, 4 supported their post-treatment tissues. In targeted deep sequencing, FAT3 (48%) was the most frequently mutated gene, followed by PKHD1, TP53, GATA3, PARP4, and PIK3CA. In terms of gene expression, low expression of epithelial-mesenchymal transition (EMT) pathway genes was associated with prolonged progression-free survival (PFS) in the EG group, while high expression of the EMT pathway was associated with good prognosis in the PG group. Median TMB was 6.5 (range 2.44–46.34) and there was no relationship between TMB and patient prognosis. Analysis of mutation signatures showed that signatures 3, 20, and 26 were frequently observed in our cohort. Further survival analysis according to mutation signature showed that mutation signature 3, as a homologous recombinant deficiency-related signature, was highly associated with disease progression (hazard ratio (log2 scale) 8.21, 95% confidence interval 2.93–13.48, p = 0.002). Kaplan–Meier plot also showed that BCs with signature 3 had short PFS compared to those without these signatures (median PFS (months) for signature 3 (low vs. high): 17.2 vs. 8.1, p = 0.0026).

Conclusions

Mutation signature 3, found in about 30% of MBCs regardless of hormone receptor status, was associated with short PFS for patients with cytotoxic chemotherapy.

Trial registry

ClinicalTrials.gov number: NCT02263495.

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Funding

This research was supported by a Grant from the National Research Foundation of Republic of Korea (NRF-2018R1A2B6004690), the Ministry of Health and Welfare, Republic of Korea (HA17C0055), and the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1720150). This study was also supported by a Grant from Eisai Korea Inc.

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Author notes

  1. Ji-Yeon Kim and Eunjin Lee have contributed equally.

Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea

    Ji-Yeon Kim & Yeon Hee Park

  2. Samsung Medical Center, Samsung Genome Institute, Seoul, 06351, Korea

    Eunjin Lee & Kyunghee Park

  3. Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University, College of Medicine, Seoul, 03080, Korea

    Seock-Ah Im & Tae-Yong Kim

  4. Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea

    Joohyuk Sohn

  5. Center for Breast Cancer, National Cancer Center, Goyang, 10408, Korea

    Keun Seok Lee

  6. Kyungpook National University Medical Center, Daegu, 41944, Korea

    Yee Soo Chae

  7. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 13620, Korea

    Jee Hyun Kim

  8. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea

    Kyung Hae Jung

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  1. Ji-Yeon Kim
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the Breast Cancer Committee of the Korean Cancer Study Group

Corresponding authors

Correspondence to Kyung Hae Jung or Yeon Hee Park.

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All procedures performed in studies involving human participants were in accordance with the ethical standards our institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Supplementary material 1 (PDF 112 kb)

Supplementary material 2 (XLSX 39 kb)

Supplementary material 3 (TIFF 1477 kb)

Supplementary Fig. 1. OS and PFS according to FAT3 mutation

Supplementary material 4 (TIFF 3252 kb)

Supplementary Fig. 2. DEG analysis for angiogenesis-related genes in immune panel according to treatment arm and disease progression

Supplementary material 5 (TIFF 2385 kb)

Supplementary Fig. 3. DEG analysis for angiogenesis-related genes in cancer panel according to treatment arm and disease progression

Supplementary material 6 (TIFF 1748 kb)

Supplementary Fig. 4. GSVA for nanostring (a) cancer panel and (b) immune panel

Supplementary material 7 (TIFF 2516 kb)

Supplementary Fig. 5. GSVA for (a) cancer panel and (b) immune panel using pre- and post-treatment samples

Supplementary material 8 (TIFF 1577 kb)

Supplementary Fig. 6. Cox-regression and KM analysis according to mutation signature 3 in (a) EG arm and (b) PG arm

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Kim, JY., Lee, E., Park, K. et al. Exploratory biomarker analysis from a phase II clinical trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine for HER2-negative metastatic breast cancer patients (KCSG BR13-11). Breast Cancer Res Treat 178, 367–377 (2019). https://doi.org/10.1007/s10549-019-05400-y

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