In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis.

PURPOSE To identify novel genetic markers predictive of clinical benefit from epidermal growth factor receptor-directed antibody therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Seventy-six consecutive patients who received cetuximab or panitumumab, either alone or in combination with chemotherapy, with available tumor tissue were included. Tumor tissue was tested for mutations at known hotspots in the KRAS, BRAF, PIK3CA, PIK3R1, AKT1, and PTEN genes by pyrosequencing. PTEN promoter methylation status was analyzed by methylation-specific PCR, and expression determined by immunohistochemistry (IHC). Forty-four patients had ≥ 4 weeks of therapy and were considered for clinical correlates. RESULTS Consistent with previous studies, KRAS gene mutations were associated with a shorter progression free (PFS) and overall survival (OS). Among the KRAS wild type patients, preservation of PTEN expression and PIK3CA WT status was associated with improved OS (median OS, 80.4 vs 32.5 weeks, HR: 0.33, p=0.0008) and a trend towards improved PFS (median PFS, 24.8 vs 15.2 weeks, HR: 0.51, p=0.06), compared to PTEN negative or PIK3CA mutant tumors. PTEN methylation was more common in the metastases than the primary (p=0.02). Simultaneous presence of methylation and mutation in the PTEN gene was associated with IHC negativity (p=0.026). CONCLUSION In addition to KRAS mutation, loss of PTEN expression (by IHC) and PIK3CA mutation is likely to be predictive of lack of benefit to anti-EGFR therapy in mCRC. PTEN promoter methylation and mutation status was predictive of PTEN expression, and may be utilized as an alternative means of predicting response to EGFR-targeted therapy.

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