Cancer Res Treat.  2024 Apr;56(2):538-548. 10.4143/crt.2023.1059.

Genomic Characteristics and Its Therapeutic Implications in Breast Cancer Patients with Detectable Molecular Residual Disease

• Zhang S
• Jiang Y
• Zhou L
• Xu J
• Zhang G
• Shen L
• Xu Y

• KMID: 2554343
• DOI: http://doi.org/10.4143/crt.2023.1059

Abstract

Purpose
Molecular residual disease (MRD) is the main cause of postoperative recurrence of breast cancer. However, the baseline tumor genomic characteristics and therapeutic implications of breast cancer patients with detectable MRD after surgery are still unknown.
Materials and Methods
In this study, we enrolled 80 patients with breast cancer who underwent next-generation sequencing-based genetic testing of 1,021 cancer-related genes performed on baseline tumor and postoperative plasma, among which 18 patients had detectable MRD after surgery.
Results
Baseline clinical characteristics found that patients with higher clinical stages were more likely to have detectable MRD. Analysis of single nucleotide variations and small insertions/deletions in baseline tumors showed that somatic mutations in MAP3K1, ATM, FLT1, GNAS, POLD1, SPEN, and WWP2 were significantly enriched in patients with detectable MRD. Oncogenic signaling pathway analysis revealed that alteration of the Cell cycle pathway was more likely to occur in patients with detectable MRD (p=0.012). Mutational signature analysis showed that defective DNA mismatch repair and activation-induced cytidine deaminase (AID) mediated somatic hypermutation (SHM) were associated with detectable MRD. According to the OncoKB database, 77.8% (14/18) of patients with detectable MRD had U.S. Food and Drug Administration–approved mutational biomarkers and targeted therapy.
Conclusion
Our study reports genomic characteristics of breast cancer patients with detectable MRD. The cell cycle pathway, defective DNA mismatch repair, and AID-mediated SHM were found to be the possible causes of detectable MRD. We also found the vast majority of patients with detectable MRD have the opportunity to access targeted therapy.

Keyword

Breast neoplasms; Molecular residual disease; Genomic character; Cell cycle pathway; Defective DNA mismatch repair; Activation-induced cytidine deaminase

Figure

• 

  Fig. 1. Somatic mutational landscape of breast cancer patients with detectable molecular residual disease (MRD). (A) Oncoplot of top 20 genes altered in patients with detectable MRD. (B) Oncoplot of top 20 genes altered in patients with undetectable MRD. (C) Forest plot of different mutant genes between patients with detectable and undetectable MRD. Inf means infinity. *p < 0.05. (D) Co-bar plot of different mutant genes between patients with detectable and undetectable MRD. CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; OR, odds ratio; TMB, tumor mutation burden; TNBC, triple-negative breast cancer.

• 

  Fig. 2. Oncogenic signaling pathways were affected by somatic mutations. (A) The 10 cancer-related signaling pathways were affected by somatic mutations both in patients with detectable and undetectable molecular residual disease (MRD). *p < 0.05. (B) Mutational diagram of cell cycle pathways in patients with detectable MRD. (C) Mutational diagram of cell cycle pathways in patients with undetectable MRD.

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  Fig. 3. Mutational signatures of patients with detectable molecular residual disease (MRD). (A) The fraction and etiology of each signature in patients with detectable MRD. (B) The fraction and etiology of each signature in patients with undetectable MRD. AID, activation-induced cytidine deaminase.

• 

  Fig. 4. Clinical actionability for targeted therapy. (A) Schematic diagram of different targeted therapeutic levels in the OncoKB database. Patients with detectable (B) or undetectable (C) molecular residual disease (MRD) were classified according to their highest level of actionable alterations. (D) The number of patients with detectable MRD in different actionable alterations. FDA, U.S. Food and Drug Administration; gBRCA1, germline BRCA1 mutation; NCCN, National Comprehensive Cancer Network; sBRCA1, somatic BRCA1 mutation; sBRCA2, somatic BRCA2 mutation; TMB-H, TMB-high.

Reference

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