1 / 14

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

thora
Download Presentation

Emerging Concepts in the Workup of Colorectal Cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related