Genomic Characterization of de novo Metastatic Breast Cancer
| Autor: | Ethan Cerami, Daniel Xia, Maxwell R. Lloyd, William T. Barry, Ian E. Krop, Nan Lin, Priti Kumari, Barrett J. Rollins, Yvonne Y. Li, Simona Di Lascio, Eric P. Winer, Andrew D. Cherniack, Romualdo Barroso-Sousa, Deborah A. Dillon, Ayesha Mohammed-Abreu, Nikhil Wagle, Colin Mackichan, Janet Files, Liam F. Spurr, Laura E. MacConaill, Bruce E. Johnson, Hao Guo, Max Krevalin, Brittany L. Bychkovsky, Esha Jain, Ana C. Garrido-Castro, Melissa E. Hughes, Neal I. Lindeman |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research medicine.medical_specialty business.industry Intrinsic resistance medicine.disease Metastatic breast cancer 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Breast cancer Text mining SETD2 030220 oncology & carcinogenesis Internal medicine medicine In patient Stage (cooking) business Gene |
| Zdroj: | Clinical Cancer Research. 27:1105-1118 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-20-1720 |
| Popis: | Purpose: In contrast to recurrence after initial diagnosis of stage I–III breast cancer [recurrent metastatic breast cancer (rMBC)], de novo metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS). Experimental Design: Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC. Results: When comparing primary tumors by subtype, MYB amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, P = 0.0005, q = 0.111). Mutations in KMTD2, SETD2, and PIK3CA were more prevalent, and TP53 and BRCA1 less prevalent, in primary HR+/HER2− tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; P = 0.008, q = 0.107), MYC (79.7 vs. 23.3 months; P = 0.0003, q = 0.011), and cell-cycle (122.7 vs. 54.9 months; P = 0.034, q = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC (P = 0.041). Conclusions: Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments. |
| Databáze: | OpenAIRE |
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