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GI Cancer Biomarkers
What I Want My Colleagues to Know About State-of-the-Art Biomarker Testing for GI Malignancies

Released: April 27, 2022

Expiration: April 26, 2023

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In the past decade, biomarker testing and targeted therapy for gastrointestinal (GI) malignancies have dramatically improved the standard of care. In this commentary, I will discuss best practices in contemporary testing and the use of targeted agents for patients with GI cancers.

Colorectal Cancer
For any patient diagnosed with metastatic colorectal cancer, it is important to test for several biomarkers that can directly affect treatment choices in the first-line setting and beyond. These include RAS and BRAF mutations, microsatellite instability (MSI)/mismatch repair deficiency (dMMR), HER2 amplifications, and NTRK fusions; primary tumor sidedness (left vs right vs transverse colon) also should be considered.

For example, if a patient has high MSI (MSI-H), they should now be considered for treatment with a PD-1 inhibitor in the first-line setting. The KEYNOTE-177 trial specifically assessed first-line pembrolizumab for patients with metastatic colorectal cancer and MSI-H or dMMR. Progression-free survival was significantly improved with this treatment, with a lower incidence of significant adverse events and an improvement in quality of life. These results changed practice, and today all patients with colorectal cancer should be tested for MSI status at the time of diagnosis.

Similarly, next-generation sequencing should be used to assess a tumor for specific alterations in KRAS, NRAS, and BRAF, as well as HER2. If patients have wild-type KRAS, NRAS, and BRAF V600E, they may be candidates to receive chemotherapy in combination with an anti‑EGFR antibody such as cetuximab or panitumumab (if they have a left‑sided tumor). If KRAS or NRAS are mutated, they should not receive EGFR-targeted therapy in any line of treatment. Patients with BRAF V600E mutations are candidates for encorafenib plus either cetuximab or panitumumab in the second‑line setting and beyond.

There is emerging evidence that HER2 amplification is associated with resistance to EGFR-targeted therapy. To manage this, combination strategies were developed with trastuzumab plus lapatinib or pertuzumab, and these approaches have shown significant responses in the refractory setting. Furthermore, data have suggested that the HER2-targeted antibody–drug conjugate trastuzumab deruxtecan may provide responses in heavily pretreated patients with HER2 amplification.

To summarize, it’s important to consider the sites of metastatic disease and the molecular features of the tumor (MSI/dMMR, alterations in KRAS, NRAS, BRAF, HER2, and NTRK) when selecting the most appropriate treatment for a patient with metastatic colorectal cancer.

Gastroesophageal Cancer
In metastatic gastroesophageal cancers, MSI testing also should be reflexively used in all newly diagnosed patients, as patients with MSI-H/dMMR cancers may be considered for immune checkpoint inhibitor therapy. All patients should now be considered for nivolumab in addition to standard chemotherapy based on the CheckMate 649 study; PD‑L1 testing may be helpful to select the patients most likely to benefit from the addition of immune checkpoint inhibitors.

HER2 amplification also is essential to assess in all patients with metastatic gastric cancer prior to selecting first-line and second‑line therapy. The KEYNOTE-811 trial recently demonstrated that the addition of pembrolizumab to chemotherapy and HER2-targeted trastuzumab may improve responses in patients with HER2-positive disease.

Cholangiocarcinoma
In cholangiocarcinoma, the mainstay of therapy continues to be chemotherapy, but emerging targets may influence treatment selection in the refractory setting. The FDA has approved—and the National Comprehensive Cancer Network has recommended—numerous targeted agents for specific patients with cholangiocarcinoma following progression with first-line therapy. Patients with FGFR2 fusions can receive infigratinib or pemigatinib, whereas those with an IDH1 mutation can receive ivosidenib. As with other patients with metastatic GI cancers, patients with NTRK fusions can receive larotrectinib and entrectinib, both of which have tumor-agnostic FDA approvals. Those with MSI-H tumors and high tumor mutational burden can receive pembrolizumab, which also has a tumor-agnostic approval.

Conclusion
Biomarker‑directed therapy for GI malignances has evolved dramatically in the past decade, and it is becoming even more critical that appropriate next-generation sequencing is ordered for our patients to ensure the appropriate selection of therapies that may increase survival and decrease treatment‑related toxicity. Further study is needed to guide biomarker‑directed therapies in pancreatic, hepatocellular, neuroendocrine, small bowel, and appendiceal tumors. Going forward, the hope is that as additional studies show survival benefit with targeted agents, a larger proportion of patients with GI cancers will be able to benefit from quality of life improvement, in addition to longer survival.

Your Thoughts?
How do you test for biomarkers in your patients with advanced GI cancers, and how do the results of this testing inform your treatment recommendations? What investigational strategies are you most excited about? Answer the polling question and join the conversation by posting a comment in the discussion section below.

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How do you currently recommend HER2-targeted therapies for your patients with HER2-amplified metastatic colorectal and gastric cancers, when possible?
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