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Authors: DJ Sargent et al Date posted: June 26 2008

Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU based Chemotherapy in Adjuvant Colon Cancer. Authors: DJ Sargent et al Date posted: June 26 2008. Background/Rationale.

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Authors: DJ Sargent et al Date posted: June 26 2008

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  1. Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU based Chemotherapy in Adjuvant Colon Cancer Authors: DJ Sargent et al Date posted: June 26 2008

  2. Background/Rationale • Defective mismatch repair (MMR) is characterized by presence of MSI and loss of MLH1, MSH2, MSH6 or PMS2 expression • ~15% of sporadic colon cancer has evidence of dMMR • Clinical correlations: right sided, female, early stage, better outcome • Ribic/Gallinger NEJM 2003 demonstrated that patients with MSI-H have improved survival compared to MSS and MSI-L • Their data also suggested that patients with defective MMR tumours do not benefit from 5-FU based chemotherapy

  3. Methods • Sargent et al used data and tumour specimens from RCTs of 5-FU based treatment vs control that were not used in Ribic analysis • MMR determined by MSI testing if possible, otherwise IHC • Primary EP was DFS comparing 5-FU based treatment to control by MMR status; secondary EP was OS; primary focus was stage II patients Results • 5 RCT with n=491 patients • 49% stage II • 15% dMMR (as expected) • Findings validated the 2003 Ribic study • 5-FU based therapy of no value in dMMR patients • 5-FU based therapy of benefit in pMMR patients

  4. Results (cont’d) • Consistency of findings justified pooling the Sargent and Ribic datasets • Pooled data, n=1027 • Pooled data validated dMMR as a prognostic marker in untreated patients and showed no suggestion of benefit from 5-FU based treatment in dMMR patients • Significant OS decrement to 5-FU based treatment in stage II patients • Stage II dMMR 5 yr OS : Untreated=93%, Treated=75%, p=0.03 • p=0.014 for treatment by MMR status interaction • Sargent et al take home message was “In a patient being considered for 5-FU based therapy (stage II), mismatch repair status by MSI or IHC, should be tested to determine whom not to treat.”

  5. STUDY COMMENTARY • Due to limited tissue resources and low prevalence of dMMR this study included only 165 dMMR patients • This study lends supports the assertion that MMR is a potentially useful prognostic and predictive biomarker in colon cancer • These data are only for 5-FU/LV – and therefore would generally apply to low risk stage II and not to any stage II (ie hi risk stage II) patient being considered for oxaliplatin based adjuvant therapy

  6. BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS • Given the small numbers and retrospective nature of this study, it would be difficult to make definitive recommendations based on the results – however given the lack of prospective evidence and the significant detriment seen in treating selected patients, oncologists with access to MMR testing could use this information in a discussion regarding adjuvant therapy with their patients • HOWEVER – • since most clinicians do not yet have access to reliable and centralized MMR testing, and… • many Canadian oncologists do not routinely offer adjuvant chemotherapy to low risk stage II colon cancer patients … • The results of this study are unlikely to have much of an impact on Canadian oncology practice. • Ongoing E5202 (NCIC CRC.3) will contribute greatly to our understanding of this issue in the “FOLFOX” era

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