SUMMARY: The role of adjuvant chemotherapy in patients with stage III ColoRectalCancer (CRC) has been well established, with improvement in Disease Free Survival (DFS) and Overall Survival (OS). The same however, cannot be stated for patients with Stage II CRC. Several Prognostic (outcome regardless of specific treatment) and Predictive (benefit from a specific therapy) molecular biomarkers have been developed to help make treatment decisions which include MSI (MicroSatellite Instability), LOH 18q (Loss of heterozygosity on the long arm of chromosome 18), P53, TS (Thymidylate Synthase), KRAS, BRAF, ERCC1 (Excision Repair Cross-Complementation group 1), Oncotype DX and Coloprint. Even though LOH 18q, P53, TS, KRAS, BRAF and ERCC1 are of prognostic value, they presently do not provide clinical utility in the management of early stage CRC. The biomarkers of interest are MSI, Oncotype DX Colon Cancer Assay and ColoPrint. MMR and MSI: MSI is the hallmark of defective/deficient DNA MisMatchRepair (MMR) system and develops following a germline mutation in one of the MMR genes. The MMR gene system consists of several proteins which are responsible for surveillance and correction of DNA errors. These genes include MLH1, MSH2, MSH6, PMS2 and EPCAM. MSI-high (MSI-H, MMR deficient) is actually a good prognostic marker in early stage CRC, with less likelihood of lymph node involvement, systemic metastases and with improved survival. These patients do not benefit from DNA inhibiting anti-metabolites such as 5-FluoroUracil (5-FU). In fact, treatment with 5-FU could be detrimental, whereas they may be more responsive to Irinotecan. This is in contrast to early stage CRC patients with tumors that are MicroSatelliteStable (MSS) or MSI-low (MSI-L) and MMR proficient, who benefit from 5-FU based adjuvant chemotherapy with significantly improved DFS. It should be noted that the prognosis for patients with early stage CRC, whose tumors harbor V600E BRAF mutation and are MSI-H, is similar to CRC patients with MSS tumors. MSI is a genetic marker of Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC) and approximately 15% of sporadic CRC share the genetics of Lynch Syndrome and are MSI-H and MMR-deficient. By evaluating the MMR/MSI status of a CRC patient, a clinician may be able to assess a patient’s prognosis, predict response to therapy and detect Lynch’s Syndrome, which constitutes about 3-5% of CRC cases. MSI is a functional assay and can be detected by PCR whereas ImmunoHistoChemistry (IHC) can confirm the presence or absence of MMR proteins.
ONCOTYPE DX COLON CANCER ASSAY: Oncotype DX Colon Cancer assay is a multigene expression assay and evaluates genes in the patient’s tumor, using paraffin slides. It consists of 7 potential recurrence genes and 5 internal reference genes and has been clinically validated from three prospective trials, to assess risk of recurrence, in patients with Stage II and III CRC. The Oncotype DX colon cancer assay is able to prognosticate the risk of recurrence of a particular CRC tumor but unlike the Oncotype DX assay for Breast Cancer, is unable to predict clinical benefit from adjuvant chemotherapy.
COLOPRINT: This assay uses an18 gene expression profile and requires fresh tissue. This assay is also able to assess the risk of recurrence in Stage II CRC but is unable to predict the benefit from adjuvant chemotherapy.
In summary, testing for MSI should be performed in all patients with Stage II CRC. Genetic signatures derived from Oncotype Dx Colon Cancer assay and ColoPrint may have limited clinical value for patients with early stage CRC. NCCN guidelines recommend adjuvant chemotherapy for high risk Stage II CRC. High risk for recurrence is defined as tumors that are poorly differentiated (except those tumors that are MSI-H), lymphovascular invasion, perineural invasion, bowel obstruction, localized perforation, close, indeterminate or positive margins and examination of less than 12 lymph nodes. Mettu NB, Hurwitz H and Hsu DS. Oncology 2013;27:746-754
