Genomic Characteristics and Its Therapeutic Implications in Breast Cancer Patients with Detectable Molecular Residual Disease
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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.
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.
참고문헌 (29)
- Loibl S, "Breast cancer", Lancet, 397, pp.1750~1769 (2021)
- Foulkes WD, "Triple-negative breast cancer", N Engl J Med, 363, pp.1938~1948 (2010)
- Coombes RC, "Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence", Clin Cancer Res, 25, pp.4255~4263 (2019)
- Garcia-Murillas I, "Assessment of molecular relapse detection in early-stage breast cancer", JAMA Oncol, 5, pp.1473~1478 (2019)
- Parsons HA, "Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer", Clin Cancer Res, 26, pp.2556~2564 (2020)
- Lipsyc-Sharf M, "Circulating tumor DNA and late recurrence in high-risk hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer", J Clin Oncol, 40, pp.2408~2419 (2022)
- Li S, "Circulating tumor DNA predicts the response and prognosis in patients with early breast cancer receiving neoadjuvant chemotherapy", JCO Precis Oncol, 4, pp.PO.19.00292~ (2020)
- "A trial using ctDNA blood tests to detect cancer cells after standard treatment to trigger additional treatment in early stage triple negative breast cancer patients (c-TRAK-TN)" (2017)[URL]
- "A prospective, phase II trial using ctDNA to initiate post-operation boost therapy after adjuvant chemotherapy in TNBC (Artemis)" (2017)[URL]
- "A prospective, phase II trial using ctDNA to initiate post-operation boost therapy after NAC in TNBC (Apollo)" (2020)[URL]
- Nik-Zainal S, "Landscape of somatic mutations in 560 breast cancer whole-genome sequences", Nature, 534, pp.47~54 (2016)
- Pereira B, "The somatic mutation profiles of 2, 433breast cancers refines their genomic and transcriptomic landscapes", Nat Commun, 7, pp.11479~ (2016)
- Lang GT, "Characterization of the genomic landscape and actionable mutations in Chinese breast cancers by clinical sequencing", Nat Commun, 11, pp.5679~ (2020)
- Kingston B, "Genomic profile of advanced breast cancer in circulating tumour DNA", Nat Commun, 12, pp.2423~ (2021)
- "NCCN clinical practice guidelines in oncology version 4" (2023)[URL]
- Zhang JT, "Longitudinal undetectable molecular residual disease defines potentially cured population in localized non-dmall vell lung cancer", Cancer Discov, 12, pp.1690~1701 (2022)
- Mayakonda A, "Maftools : efficient and comprehensive analysis of somatic variants in cancer", Genome Res, 28, pp.1747~1756 (2018)
- Sanchez-Vega F, "Oncogenic signaling pathways in The Cancer Genome Atlas", Cell, 173, pp.321~337 (2018)
- Rosenthal R, "DeconstructSigs : delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution", Genome Biol, 17, pp.31~ (2016)
- Alexandrov LB, "Signatures of mutational processes in human cancer", Nature, 500, pp.415~421 (2013)
- "Mutational Signatures (accessed version 2, 2015)" (2015)[URL]
- Chakravarty D, "OncoKB: a precision oncology knowledge base", JCO Precis Oncol, 2017, pp.PO.17.00011~ (2017)
- Powles T, "ctDNA guiding adjuvant immunotherapy in urothelial carcinoma", Nature, 595, pp.432~437 (2021)
- Fakhri N, "Risk factors for breast cancer in women : an update review", Med Oncol, 39, pp.197~ (2022)
- van Leeuwen FE, "Anthracyclines and alkylating agents : new risk factors for breast cancer in childhood cancer survivors?", J Clin Oncol, 34, pp.891~894 (2016)
- Olave MC, "Mismatch repair deficiency : the what, how and why it is important", Genes Chromosomes Cancer, 61, pp.314~321 (2022)
- Bonneville R, "Landscape of microsatellite instability across 39cancer types", JCO Precis Oncol, 2017, pp.PO.17.00073~ (2017)
- Sajjadi E, "Mismatch repair-deficient hormone receptor-positive breast cancers : biology and pathological characterization", Cancer Cell Int, 21, pp.266~ (2021)
- Cakan E, "Activation induced cytidine deaminase : an old friend with new faces", Front Immunol, 13, pp.965312~ (2022)