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The Evolution of Biomarkers to Guide the Treatment of Metastatic Colorectal Cancer
Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
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The Evolution of Biomarkers to Guide the Treatment of Metastatic Colorectal Cancer

Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
Systemic treatment for CRC involves various cytotoxic drugs and monoclonal antibodies (mAbs), administered as single agents or in combination. At diagnosis of mCRC, tumor biomarkers should be tested (Table 1), as the choice of therapy is influenced by the mutational profile of the tumor.6 However, in clinical practice, the utility of these biomarkers is limited to identifying patients who should not receive anti-EGFR mAbs and patients for whom anti-PD-1/PD-L1 immunotherapy is appropriate. As more treatment options have become available, therapy response prediction and optimal patient selection is increasingly important to avoid unnecessary toxicities and healthcare costs.13 The clinical utility of using these 4 consensus molecular subtypes (CMS1-4) to predict therapy response requires validation in prospective, independent clinical trials. Although the NCCN does not recommend the use of CMS molecular subtype classifications in clinical practice, it warrants further study as a platform to help guide appropriate treatment.

Treatment Options for CRC

Both NCCN and the European Society for Medical Oncology (ESMO) have released updated guidelines for the treatment of mCRC.3,6 The treatment of mCRC is driven by disease presentation, features of the tumor, patient characteristics and expectations, and treatment preferences.3,6 No single treatment regimen is preferred over another for initial treatment of metastatic disease.6 Also, there are no data to suggest that clinical outcomes are different for patients who receive initial treatment with intensive therapy as compared with less intensive initial therapy followed by subsequent intensive therapies. This contrasts with the preferred initial approach to treatment for CRC in general, in which the use and types of systemic therapy are more limited. Also, the initial management of CRC is further defined by the primary tumor site. Treatment for patients with cancers that arise in the rectum (ie, rectal cancer) differs from treatment of cancers that arise in the colon (ie, colon cancer) in that treatment for nonmetastatic, resectable rectal cancer includes the use of radiotherapy.25 Radiotherapy is given to further decrease the risk of local tumor recurrence, which is higher for rectal cancers as compared with colon cancers. Radiotherapy may be administered pre- or postoperatively and either alone, sequentially, or concurrently with chemotherapy. The chemotherapeutic agents used are the same as those used for colon cancer.

Patients with nonmetastatic, resectable CRC who undergo complete surgical resection may be candidates for systemic postoperative adjuvant therapy, depending on the stage of their disease (Table 36). Adjuvant chemotherapy should be administered for 6 months following the surgery. If chemotherapy is given preoperatively, such as for rectal cancer, perioperative treatment should total 6 months. Recommended systemic therapies include only fluoropyrimidines (eg, capecitabine, fluorouracil) and oxaliplatin (discussed later in greater detail relative to mCRC). The use of other cytotoxic drugs or mAbs in the adjuvant setting outside of a clinical trial is not recommended.6 Biomarker testing for MSI-H tumors for stage II colon cancer is recommended, and can be useful to identify patients for whom adjuvant systemic therapy is not required.

Systemic therapy for advanced and mCRC involves the use of chemotherapy, targeted therapies, and immunotherapies. Surgery is not recommended for mCRC, but may be performed in selected cases for tumor-related symptoms or curative intent. Systemic therapies include multiple active drugs, either in combination or as single agents: fluorouracil (5-FU)/leucovorin, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, ramucirumab, regorafenib, trifluridine-tipiracil, pembrolizumab, and nivolumab.6 Broadly, these agents can be categorized as cytotoxic chemotherapy (5-FU, capecitabine, irinotecan, oxaliplatin, and trifluridine-tipiracil), targeted therapy (anti-EGFR: cetuximab, panitumumab; anti-VEGF/VEGFR: bevacizumab, ziv-aflibercept, ramucirumab, regorafenib), and immunotherapy (pembrolizumab, nivolumab).

Chemotherapy

Fluoropyrimidines, capecitabine, and 5-FU comprise the backbone of most chemotherapy regimens used for mCRC. These agents undergo metabolic conversion to inhibit thymidylate synthase, the rate-limiting enzyme for pyrimidine nucleotide synthesis, ultimately inhibiting DNA synthesis and repair.26 Leucovorin is given with 5-FU to potentiate thymidylate synthase inhibition, thus potentiating the cytotoxic effects of 5-FU. Capecitabine is an oral prodrug of 5-FU that, when given twice daily, mimics the pharmacologic effects of continuous infusion 5-FU. The spectrum of adverse events (AEs) common to both agents, primarily diarrhea, mucositis, myelosuppression (neutropenia), and hand-foot syndrome, can be modulated with the schedule of 5-FU infusion.

Irinotecan is converted to an active metabolite, SN38, which binds to topoisomerase I, an enzyme that is critical for DNA replication and transcription.27 Topoisomerase I inhibition causes DNA strand breaks, ultimately leading to DNA fragmentation and tumor cell death. SN38 is inactivated via glucuronidation by UDP-glucuronosyltransferase 1A1 (UGT1A1) and is then eliminated. A polymorphism in UGT1A1 (UGT1A1*28) is associated with reduced expression of UGT1A1 and hence there is increased toxicity due to decreased SN38 glucuronide. Predominant AEs include myelosuppression (neutropenia) and diarrhea.
Oxaliplatin is a platinum analog that acts as an alkylating agent forming cross-links between DNA strands, leading to DNA damage and tumor cell death.26 AEs include myelosuppression (neutropenia), cumulative peripheral neuropathy, and an acute, cold-related neuropathy. When used for CRC, oxaliplatin is always administered in combination with a fluoropyrimidine. Trifluridine-tipiracil is a newer fluoropyrimidine that will be discussed in greater detail.

Targeted Therapy

Molecular targets in CRC include the EGFR and the vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR). Cetuximab and panitumumab are mAbs that target the EGFR, which is overexpressed in the majority of CRC.6 Cetuximab is a chimeric mAb, whereas panitumumab is fully humanized. The epidermal growth factor (EGF) ligand activates the EGFR, subsequently activating downstream cell signaling pathways, including the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway, which drives cell proliferation, and promotes cell migration, angiogenesis, and cellular resistance to apoptosis.26 Cetuximab and panitumumab block the binding of EGF to the EGFR to inhibit its downstream cell proliferative signaling pathways. Mutations in KRAS and NRAS cause constitutive activation of the Ras/Raf/MAPK signaling pathway and resistance to EGFR inhibition; therefore, these agents are only recommended for KRAS and NRAS wild-type tumors. The BRAF V600E mutation also leads to constitutive activation of Ras/Raf/MAPK pathway and may represent a source of tumor resistance to cetuximab and panitumumab in KRAS and NRAS wild-type tumors. Severe infusion reactions, including anaphylaxis, have been observed with both cetuximab and panitumumab, although the incidence is lower with panitumumab.6 Dermatologic reactions, particularly skin rash, can be severe. Other AEs include diarrhea, electrolyte imbalances (magnesium, potassium, calcium), fatigue, ocular toxicities, and interstitial lung disease.28

VEGF represents a family of endothelial growth factors that promote angiogenesis by inducing endothelial cell proliferation, migration, permeability, and survival.26 In the setting of environmental hypoxia, VEGF and other proangiogenic factors are produced by tumor cells and associated stroma, and released into the circulation to stimulate new blood vessels that will support further tumor growth. VEGF binds to VEGF receptors (VEGFR), VEGF receptor-1 and VEGF receptor-2, and VEGF receptor-3, which are expressed on vascular endothelial cells, as well as some cancer cell surfaces.28 Binding of VEGF to the VEGF receptor activates intracellular signaling pathways that promote angiogenesis. Bevacizumab is a humanized mAb that has a high affinity for binding to circulating soluble VEGF-A, thereby preventing activation of signaling cascades that stimulate angiogenesis.29 Ziv-aflibercept is a recombinant fusion protein that binds to VEGF-A, VEGF-B, and the angiogenic protein placental growth factor, to inhibit angiogenesis. Ramucirumab, the most recently approved antiangiogenic mAb for colorectal cancer, binds to VEGFR-2. All of these agents can cause infusion-related reactions, hypertension, impaired wound healing, hemorrhage, gastrointestinal perforation, arterial and venous thrombotic events, proteinuria, and reversible posterior leukoencephalopathy syndrome.

Regorafenib is an orally administered small-molecule inhibitor of multiple kinases that regulate normal cellular functions as well as tumor oncogenesis, angiogenesis, and metastasis.30 AEs associated with regorafenib include diarrhea, hepatotoxicity, and hand-foot syndrome, in addition to those seen with the antiangiogenic mAbs. Regorafenib is a substrate CYP3A4 and, as such, strong CYP3A4 inducers or inhibitors should be avoided during treatment with regorafenib.

Immunotherapy

Pembrolizumab and nivolumab are both programmed cell death-1 (PD-1) blocking antibodies that have received approval by the FDA for use in MSI-H or tumors that are deficient in mismatch repair (dMMR) that has progressed following treatment with a fluoropyrimidine, irinotecan, and oxaliplatin.6

Initial Therapy Selection

 
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