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Emerging Concepts in the Workup of Colorectal Cancer

Emerging Concepts in the Workup of Colorectal Cancer. APMG Pathologist, MD FCAP. Mismatch Repair System (MMR). During replication of each cell ’ s 3 billion DNA bases, mistakes are introduced The mismatch repair system (MMR) corrects errors during replication

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Emerging Concepts in the Workup of Colorectal Cancer

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  1. Emerging Concepts in the Workup of Colorectal Cancer APMG Pathologist, MD FCAP

  2. Mismatch Repair System (MMR) • During replication of each cell’s 3 billion DNA bases, mistakes are introduced • The mismatch repair system (MMR) corrects errors during replication • Functional protein complex composed of four subunits – MLH1, MSH2, MSH6 & PMS2 • Proteins can be detected using IHC • Normal cells express the proteins

  3. Defects in the Mismatch Repair System (dMMR) • Sporadic (2/3rd of cases) • Usually the result of methylation (DNA inactivation) of MLH1 gene • Biologic behavior of tumor similar to tumors in patients with inherited mutation • Inherited (1/3rd of cases) • Born with one defective copy of MMR gene • During life, second copy is mutated by chance during DNA replication • Most often MLH1 or MSH2 • Both result in microsatellite instability (MSI)

  4. Microsatellite Instability (MSI) • Develops as a result of defects in the mismatch repair system (MMR) • Cells that cannot repair their DNA acquire compounding defects with every cell division • Microsatellites are areas of highly repetitive DNA • Especially prone to errors during DNA replication

  5. Colorectal Cancer From: de la Chapelle A. Microsatellite Instability. N Engl J Med. 2003 Jul 17;349(3):209-10.

  6. dMMR and MSI • Same underlying biology of the tumor • Test for protein expression (IHC) or genetic abnormalities (MSI) • Significantly better prognosis identified in multiple studies • For stage II – III disease, help decision making for which patients should receive adjuvant chemotherapy

  7. EGFR inhibitors (e.g. cetuximab, panitumimab) • Monoclonal antibodies targeted at epidermal growth factor receptors (EGFR) • First line therapy for unresectable, inoperable or metastatic colorectal cancer • Second line therapy after failure of 1st line • No benefit in the presence of a mutation in the KRAS gene! • The targeted pathway is already activated downstream

  8. Antibodies approved for colorectal cancer therapy From: Gazdar FA. Cancer Metastasis Rev (2010) 29:37–48

  9. KRAS • Mutations in codons 12-13 associated with resistance to EGFR inhibitors • A codon is a set of 3 nucleic acids in a row that code for the amino acid to be inserted when building the protein • Mutations in codons 12-13 cause KRAS to continually signal downstream in the absence of upstream signal, i.e. “switch is stuck in the on position” • Test either the biopsy, primary resection, or metastasis • Mutation occurs early during oncogenesis and persists

  10. BRAF • BRAF, like KRAS, is in the EGFR pathway • One dominant mutation… V600E • Worse prognosis • Mixed data whether BRAF mutations confer resistance to EGFR inhibitors, but most believe it does • … the mutation appears to cause downstream signaling in the absence of ligand binding = resistance to anti-EGFR therapy

  11. When to test? • Select patients by request or at the time of metastasis? • Testing can take up to 2 weeks • Sequential testing takes longer • Select patients at the time of initial diagnosis or primary resection? • Clinical information and pathologic stage are often incomplete • Does not allow all prognostic values to be incorporated in decision making • All patients at the time of initial diagnosis or primary resection? • More comprehensive diagnostic classification • Determination of (in)eligibility for therapy in advance • Ideal if not for costs • But… there is growing recognition among payers of the need for testing and support for up-front algorithms • and… cost is relatively small in total cost of cancer care

  12. Consider Testing • All colorectal adenocarcinomas greater than stage I for: • KRAS Codon 12-13 Mutations • BRAF V600E Mutation • Microsatellite Instability (MSI) Added benefit… detection of inherited cases of colorectal cancer offers opportunity to screen family members.

  13. Questions • Contact pathologist with questions or to sort out appropriate testing on a patient: APMG Pathologist, MD FCAP tlpath@domain.com (888) 555-1212

  14. About these slides Provided by the CAP as an aid to pathologists Intended as a “starting point” from which customization / modifications can be made for personal use CAP requests to be notified when the presentation has been used via email to spec@cap.org Content has been reviewed by experts at the CAP, but does not necessarily reflect the official opinion of the College of American Pathologists. Version 1.0.1, rev. 4/27/2012 To obtain the latest version of this presentation, visit:http://www.cap.org/spec

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