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Purpose <p>We aimed to characterize the genomic landscape of hormone receptor-positive (HR+)/HER2-negative breast cancer in patients with hormone therapy-resistant and -sensitive phenotypes.</p> Methods <p>HR+/HER2-negative patients who were disease-free for ≥2&#xa0;years were considered hormone therapy-sensitive (<i>n</i> = 19), while those who experienced disease progression within 2&#xa0;years were considered hormone therapy-resistant (<i>n</i> = 48). Whole-exome sequencing (WES) was performed on paired (treatment-naïve and relapse-site) tumor and germline-derived DNA from resistant patients (<i>n</i> = 19), and targeted next-generation sequencing (NGS) was performed on plasma-derived circulating tumor DNA (ctDNA) from resistant (<i>n</i> = 35) and sensitive (<i>n</i> = 19) patients.</p> Results <p>In 19 resistant patients, the mutation burden was higher in relapse-site compared with treatment-naïve samples (median 0.883 vs 0.655 mutations/mb, <i>p</i> = 0.03), there were 64 driver mutations (median treatment-naïve versus relapse-site; 2/sample vs. 3/relapse), of which 21 mutations in 8 genes in 15 (78.9%) patients were classified as actionable, and branching evolutionary trajectories were seen in 18 (94.7%) patients, with the presence of <i>PIK3CA</i> and/or <i>TP53</i> mutations in stem clones of 13 (68.4%) patients. ctDNA analysis in 35 resistant patients identified 27 actionable hotspot mutations, such as <i>PIK3CA</i> H1047X, <i>AKT1</i> p.E17K, <i>CDH1</i> p.R63X, <i>CDKN2A</i> p.X50*, <i>ERBB2</i> p.D769Y, and <i>ESR1</i> p.E380Q, in 25 (71.4%) patients. Among 19 patients with hormone therapy-sensitive disease who were in remission at the time of sample collection, ctDNA analysis showed driver mutations in 10 (52.6%) patients, of whom 2 patients subsequently experienced relapse and died.</p> Conclusion <p>Hormone therapy-resistant HR+/HER2-negative&#xa0;breast cancers are polyclonal, acquire actionable alterations at relapse, and moderate-depth ctDNA successfully identifies many clonal mutations, suggesting a role for liquid biopsy monitoring in these patients.</p>

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Genomic landscape of hormone therapy-resistant HR-positive, HER2-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月12日

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  • Rohan Chaubal,
  • Elizabeth Talker,
  • Jaya Chitra ,
  • Rasika Kadam,
  • Nilesh Gardi,
  • Riddhi Ursekar,
  • Anushree Kadam,
  • Ankita Singh,
  • Suhani Sale,
  • Shwetali Pandey,
  • Mrudula Madhav,
  • Aishwarya Raja,
  • Rushikesh Mukhare,
  • Pallavi Parab,
  • Nitin Shetty,
  • Kunal Gala,
  • Suyash Kulkarni,
  • Khushboo A. Gandhi,
  • Seema Gulia,
  • Shalaka Joshi,
  • Tanuja Shet,
  • Sudeep Gupta

摘要

Purpose

We aimed to characterize the genomic landscape of hormone receptor-positive (HR+)/HER2-negative breast cancer in patients with hormone therapy-resistant and -sensitive phenotypes.

Methods

HR+/HER2-negative patients who were disease-free for ≥2 years were considered hormone therapy-sensitive (n = 19), while those who experienced disease progression within 2 years were considered hormone therapy-resistant (n = 48). Whole-exome sequencing (WES) was performed on paired (treatment-naïve and relapse-site) tumor and germline-derived DNA from resistant patients (n = 19), and targeted next-generation sequencing (NGS) was performed on plasma-derived circulating tumor DNA (ctDNA) from resistant (n = 35) and sensitive (n = 19) patients.

Results

In 19 resistant patients, the mutation burden was higher in relapse-site compared with treatment-naïve samples (median 0.883 vs 0.655 mutations/mb, p = 0.03), there were 64 driver mutations (median treatment-naïve versus relapse-site; 2/sample vs. 3/relapse), of which 21 mutations in 8 genes in 15 (78.9%) patients were classified as actionable, and branching evolutionary trajectories were seen in 18 (94.7%) patients, with the presence of PIK3CA and/or TP53 mutations in stem clones of 13 (68.4%) patients. ctDNA analysis in 35 resistant patients identified 27 actionable hotspot mutations, such as PIK3CA H1047X, AKT1 p.E17K, CDH1 p.R63X, CDKN2A p.X50*, ERBB2 p.D769Y, and ESR1 p.E380Q, in 25 (71.4%) patients. Among 19 patients with hormone therapy-sensitive disease who were in remission at the time of sample collection, ctDNA analysis showed driver mutations in 10 (52.6%) patients, of whom 2 patients subsequently experienced relapse and died.

Conclusion

Hormone therapy-resistant HR+/HER2-negative breast cancers are polyclonal, acquire actionable alterations at relapse, and moderate-depth ctDNA successfully identifies many clonal mutations, suggesting a role for liquid biopsy monitoring in these patients.