It's Not Quite Prime Time for Up-Front Genomic Sequencing in Early-Stage CRC

Wafik S. El-Deiry, MD, PhD, FACP
Published: Monday, Jun 11, 2018
CarboneWafik S. El-Deiry, MD, PhD, FACP
Wafik S. El-Deiry, MD, PhD, FACP
 
Deputy Cancer Center Director
Coleader, Molecular Therapeutics Program
William Wikoff Smith Chair in Cancer Research
Fox Chase Cancer Center
Philadelphia, PennsylvaniaStrategic Partnership
Genomic aberrations are becoming increasingly significant in the diagnosis and treatment of patients colorectal cancer (CRC), but the optimal timing and nature of the testing needed for these biomarkers is the subject of robust debate. Although testing for some genetic defects has been incorporated into the treatment paradigm, particularly for advanced disease, the clinical utility of up-front tumor sequencing that would yield wide-ranging information has not yet been established.

Mismatch Repair Deficiency

In the past several years, universal testing for mismatch repair deficiency (dMMR) has been adopted as a standard for all patients diagnosed with CRC. Tumor tissue is stained by immunohistochemistry (IHC) for mismatch repair (MMR) proteins. If these proteins are present, it is consistent with microsatellite stability (MSS) or a lack of dMMR. If there is loss of expression of MMR proteins, tumor DNA can be subjected to classical microsatellite instability (MSI) testing, which involves polymerase chain reaction amplification across a number of repetitive sequences found in the human genome.

When the DNA from an MSI CRC sample is run on a gel, one observes a smear rather than discrete bands (1 from the female parent and 1 from the male parent in “normal individuals”). This is due to slippage during DNA replication and the highly polymorphic nature of these genomic regions. In addition to universal testing for dMMR, patients with stage IV CRC require tumor testing for KRAS, NRAS, and BRAF mutations. Patients with right-sided versus left-sided colon tumors have different prognoses and are now treated differently, most notably when the KRAS and NRAS genes are not mutated.

With immunotherapy for MSI-high tumors approved since 2017, finding dMMR is not just relevant to altered surveillance procedures but also actionable and could significantly affect patient survival. Extensive molecular analysis of tumors by including larger sequencing gene panels in stage IV CRC generally occurs later in the disease course after multiple lines of therapy and may identify actionable targets such as HER2, ALK, NTRK, DNA damage and repair pathways, and other DNA repair defects. When potentially actionable targets are identified for which therapeutics exist, patients can consider enrolling in open clinical trials (such as the NCI MATCH and ASCO TAPUR).

Growing Genomic Evidence

In 2017, our research team at Fox Chase Cancer Center in Philadelphia, Pennsylvania, reported that CRC tumors with dMMR have increased rates of BRCA2 mutations, as well as a higher frequency of activating EGFR and NTRK gene mutations.1 Although it remains unclear whether PARP inhibitors, anti-EGFR, or anti-NTRK therapeutics would be effective in dMMR tumors or add value if combined with immunotherapy in MSI-high tumors (those with biallelic BRCA2 mutations or activating mutations in EGFR or the NTRK genes), there is certainly compelling evidence that targeting activated NTRK genes is effective.2

Today, tumor sequencing with limited panels or a few genes is not performed in early-stage (I-III) CRC; such testing is not reimbursable because the results are not immediately actionable. Additionally, the current standard of therapy for stage II to III CRC is not tailored toward genetic abnormalities. For example, National Comprehensive Cancer Network guidelines for adjuvant therapy recommend that patients with dMMR stage III tumors be treated with 5-fluorouracil (5-FU) chemotherapy–based therapy. However, it is well known that MSI-high CRC tumors tend to be more resistant to 5-FU than other subtypes. (There is perhaps less concern for reduced 5-FU efficacy in MSI-high CRC tumors because oxaliplatin, which has been established as effective in this population, is frequently part of combination therapy, such as in the FOLFOX or CAPOX regimens used in the adjuvant setting.)


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