An Early-Onset Advanced Rectal Cancer Patient With Increased KRAS Gene Copy Number Showed A Primary Resistance to...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are standard treatments for metastatic colorectal cancer (CRC).
• Primary resistance to these therapies is often linked to specific genetic mutations like KRAS, NRAS, BRAF, and amplifications in ERBB2 and MET, accounting for 70-80% of cases.
• However, the full spectrum of biomarkers predicting primary resistance remains incomplete.

Observation:

• This report details a case of metastatic CRC with wild-type RAS/BRAF, initially showing no common resistance mutations.
• Despite standard mutation testing and subsequent treatment with cetuximab and FOLFIRI chemotherapy after platinum-based adjuvant therapy failure, the patient experienced disease progression.
• Advanced molecular profiling revealed increased KRAS copy number and mutations in SMAD4, RNF43, and PREX2.

Findings:

• This is the first reported case of advanced CRC with increased KRAS copy number exhibiting primary resistance to anti-EGFR therapy (cetuximab) and chemotherapy.
• The presence of KRAS copy number alterations, alongside mutations in SMAD4, RNF43, and PREX2, may contribute to treatment failure and poor prognosis.
• These genetic alterations were identified in postoperative tumor tissue.

Implications:

• KRAS copy number alterations should be considered as a potential biomarker for primary resistance to anti-EGFR therapy in colorectal cancer.
• Routine examination of KRAS copy number may improve patient selection for anti-EGFR treatments and guide therapeutic strategies.
• Further research is warranted to elucidate the role of KRAS copy number variations and other identified mutations in CRC treatment resistance and outcomes.