Related Experiment Video
Updated: Nov 9, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Genomic landscape of extraordinary responses in metastatic breast cancer
Sun Min Lim1, Eunyoung Kim2, Kyung Hae Jung3
1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Abstract:
Extreme responders to anticancer therapy are rare among advanced breast cancer patients. Researchers, however, have yet to investigate treatment responses therein on the whole exome level. We performed whole exome analysis to characterize the genomic landscape of extreme responders among metastatic breast cancer patients. Clinical samples were obtained from breast cancer patients who showed exceptional responses to anti-HER2 therapy or hormonal therapy and from those who did not. Matched breast tumor tissue (somatic DNA) and blood samples (germline DNA) were collected from a total of 30 responders and 15 non-responders. Whole exome sequencing using Illumina HiSeq2500 was performed for all 45 patients (90 samples). Somatic single nucleotide variants (SNVs), indels, and copy number variants (CNVs) were identified for the genomes of each patient. Group-specific somatic variants and mutational burden were statistically analyzed. Sequencing of cancer exomes for all patients revealed 1839 somatic SNVs (1661 missense, 120 nonsense, 43 splice-site, 15 start/stop-lost) and 368 insertions/deletions (273 frameshift, 95 in-frame), with a median of 0.7 mutations per megabase (range, 0.08 to 4.2 mutations per megabase). Responders harbored a significantly lower nonsynonymous mutational burden (median, 26 vs. 59, P = 0.02) and fewer CNVs (median 13.6 vs. 97.7, P = 0.05) than non-responders. Multivariate analyses of factors influencing progression-free survival showed that a high mutational burden and visceral metastases were significantly related with disease progression. Extreme responders to treatment for metastatic breast cancer are characterized by fewer nonsynonymous mutations and CNVs.
Insights
Extreme responders to advanced breast cancer therapy have fewer genomic alterations. This whole exome sequencing study found fewer nonsynonymous mutations and copy number variations in exceptional responders to anti-HER2 or hormonal therapies.
Area of Science:
- Genomics
- Oncology
- Translational Research
Background:
- Extreme responders to advanced breast cancer treatments are rare.
- Genomic characterization of these patients at the whole exome level is lacking.
Purpose of the Study:
- To perform whole exome analysis on extreme responders with metastatic breast cancer.
- To characterize the genomic landscape associated with exceptional treatment responses.
Main Methods:
- Whole exome sequencing was conducted on matched tumor and blood samples from 30 responders and 15 non-responders.
- Somatic single nucleotide variants (SNVs), insertions/deletions (indels), and copy number variants (CNVs) were identified.
- Statistical analysis was performed to compare genomic profiles between responders and non-responders.
Main Results:
- Sequencing revealed a median of 0.7 mutations per megabase across all patients.
- Responders exhibited significantly lower nonsynonymous mutational burden (median 26 vs. 59) and fewer CNVs (median 13.6 vs. 97.7) compared to non-responders.
- High mutational burden and visceral metastases were linked to disease progression.
Conclusions:
- Extreme responders to metastatic breast cancer therapy are characterized by a reduced number of nonsynonymous mutations and copy number variations.
- Genomic mutational burden and CNVs may serve as potential biomarkers for treatment response in breast cancer.
