Comprehensive genomic profiling of triple-negative breast cancer metastases identifies role of PKD1 in immunotherapy resistance
Xiu-Zhi Zhu, Yi-Fan Zhou, Xiao-Han Ying, Yun-Yi Wang, Xiao-Hong Ding, Kun-Yu Zhang, Zhi-Ming Shao, Xi Jin, Yi-Zhou Jiang, Zhong-Hua Wang
Xiu-Zhi Zhu, Yi-Fan Zhou, Xiao-Han Ying, Yun-Yi Wang, Xiao-Hong Ding, Kun-Yu Zhang, Zhi-Ming Shao, Xi Jin, Yi-Zhou Jiang, Zhong-Hua Wang
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Research Article Genetics Oncology

Comprehensive genomic profiling of triple-negative breast cancer metastases identifies role of PKD1 in immunotherapy resistance

Abstract

The multi-omics data represented by genomic data from patients with metastatic triple-negative breast cancer (TNBC) is crucial for precision treatment, yet data on genomic alterations in metastatic cohorts and Chinese populations remains limited. We performed targeted sequencing of 296 metastatic TNBC samples from 296 patients treated at Fudan University Shanghai Cancer Center (October 2018 to November 2020) using a 484-gene panel, identifying 796 metastatic events across 18 organ sites. We characterized the genomic landscape of TNBC metastases and identified marked enrichment of polycystin-1 (PKD1) mutations in metastatic lesions — a finding validated in an independent paired primary metastasis cohort (n = 105). Notably, PKD1 mutations were associated with resistance to anti–PD-1 therapy, as validated across 3 clinical trials (NCT03805399, NCT04129996, and NCT04395989). Multi-omics analyses, combined with functional in vitro and in vivo mechanistic studies, revealed that PKD1 modulated the “desert” tumor immune microenvironment via C-C motif chemokine ligand 2 (CCL2), and targeting CCL2 could reverse immunotherapy resistance. This comprehensive genomic characterization of metastases enhances our understanding of tumor evolution, identifies PKD1 as a previously uncharacterized regulator of immune evasion to our knowledge, and suggests a potential therapeutic strategy to overcome immunotherapy resistance.

Authors

Xiu-Zhi Zhu, Yi-Fan Zhou, Xiao-Han Ying, Yun-Yi Wang, Xiao-Hong Ding, Kun-Yu Zhang, Zhi-Ming Shao, Xi Jin, Yi-Zhou Jiang, Zhong-Hua Wang

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Figure 3

Genomic profiling of TNBC metastases identifies PKD1 as a potential biomarker for immunotherapy.

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Genomic profiling of TNBC metastases identifies PKD1 as a potential biom...
(A) Comparative analysis of genomic mutations between large-scale unpaired metastatic (n = 296) and primary (n = 252) TNBC cohorts. P values were calculated via the χ2 test. (B) Validation of PKD1 mutation enrichment in metastases using a paired cohort of 52 metastatic and 53 primary TNBC samples. P values were calculated using Fisher’s exact test. (C) Association between the objective response (CR+PR) rate and PKD1 mutation status of immunotherapy in the FUSCC mTNBC cohort. Treatment responses were assessed according to RECIST v1.1 and systematically documented in electronic medical records based on radiographic evaluations. P values were calculated via the χ2 test. (D) Typical imaging of tissues from patients with advanced TNBC with PKD1 mutations before and after immunotherapy. Yellow arrows indicate tumor lesions at baseline (left panels) and post-treatment (right panels). (E) Progression-free survival of patients with advanced TNBC receiving immunotherapy in the FUTURE trial (NCT03805399). P values were calculated via the log-rank test. TNBC, triple-negative breast cancer; FUSCC, Fudan University Shanghai Cancer Center; mTNBC, metastatic triple-negative breast cancer; WT, wild-type; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.