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Comprehensive assessment of actionable genomic alterations in primary colorectal carcinoma using targeted
Yi-Hua Jan1, Kien Thiam Tan1, Shu-Jen Chen1
1Cancer Genomics, ACT Genomics, Co. Ltd., Taipei City, Taiwan.
Background:
The clinical utility of comprehensive genomic profiling (CGP) for guiding treatment has gradually become the standard-of-care procedure for colorectal carcinoma (CRC). Here, we comprehensively assess emerging targeted therapy biomarkers using CGP in primary CRC.
Methods:
A total of 575 primary CRCs were sequenced by ACTOnco® assay for genomic alterations, tumour mutational burden (TMB), and microsatellite instability (MSI).
Results:
Eighteen percent of patients were detected as MSI-High (MSI-H), and the remaining cases were classified as microsatellite stable (MSS). Driver mutation prevalence in MSS CRCs were APC (74%), TP53 (67%), KRAS (47%), PIK3CA (21%) and BRAF (13%). The median TMBs for MSI-H and MSS patients were 37.8 mutations per mega base (mut/Mb) and 3.9 mut/Mb, respectively. Forty-seven percent of MSI-H CRC harboured at least one loss-of-function mutations in genes that may hamper immune checkpoint blockade. Among MSS RAS/RAF wild-type CRCs, 59% had at least one actionable mutation that may compromise the efficacy of anti-EGFR therapy. For late-stage CRC, 51% of patients are eligible for standard care actionability and the remaining 49% could be enrolled in clinical trials with investigational drugs.
Conclusions:
This study highlights the essential role of CGP for identifying rational targeted therapy options in CRC.
Insights
Comprehensive genomic profiling (CGP) is crucial for colorectal cancer (CRC) treatment. This study identified actionable mutations in CRC patients, guiding targeted therapy and clinical trial enrollment.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Colorectal carcinoma (CRC) treatment is increasingly guided by comprehensive genomic profiling (CGP).
- CGP has become a standard-of-care procedure for identifying targeted therapy options in CRC.
- Emerging targeted therapy biomarkers require comprehensive assessment in primary CRC.
Purpose of the Study:
- To comprehensively assess emerging targeted therapy biomarkers using CGP in primary colorectal carcinoma (CRC).
- To identify actionable mutations for guiding treatment decisions in CRC patients.
- To evaluate the utility of CGP in stratifying CRC patients for standard care or clinical trials.
Main Methods:
- Sequencing of 575 primary CRCs using the ACTOnco® assay.
- Analysis of genomic alterations, tumor mutational burden (TMB), and microsatellite instability (MSI).
- Classification of tumors as MSI-High (MSI-H) or microsatellite stable (MSS).
Main Results:
- Eighteen percent of CRCs were MSI-H; 82% were MSS.
- Prevalence of driver mutations in MSS CRC: APC (74%), TP53 (67%), KRAS (47%), PIK3CA (21%), BRAF (13%).
- Median TMB was 37.8 mut/Mb for MSI-H and 3.9 mut/Mb for MSS CRC.
- 47% of MSI-H CRC had mutations potentially affecting immune checkpoint blockade efficacy.
- 59% of MSS RAS/RAF wild-type CRC had actionable mutations impacting anti-EGFR therapy efficacy.
- 51% of late-stage CRC patients were eligible for standard care; 49% could enter clinical trials.
Conclusions:
- Comprehensive genomic profiling (CGP) is essential for identifying rational targeted therapy options in colorectal carcinoma (CRC).
- CGP facilitates personalized treatment strategies by revealing actionable biomarkers.
- The study underscores the importance of genomic assessment for optimizing CRC patient management.
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