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Subjects:
Surgery
Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in the United States. Despite best efforts, 5-year survival for unresectable metastatic CRC is only about 20%. CRC is a heterogeneous disease and the underlying genetic differences inform behavior, treatment strategy, and prognosis. Given the limitations of cytotoxic chemotherapy and the growing role of molecular profiling, research has focused on identifying and developing targeted therapies.
- colorectal cancer
- metastases
- targeted therapy
- liver
1. Introduction
Colorectal cancer (CRC) is the second most common cause of cancer-related mortality for men and women in the United States [1]. Among newly diagnosed patients with CRC, 20% will present with metastatic disease and at least another 25% will develop metastases [2]. The lung and liver are both common sites of metastatic CRC (mCRC), but there is a propensity to metastasize to the liver due to the veinous drainage of the gastrointestinal tract into the portal system [3]. While the foundation of treating mCRC, surgical resection only treats macrometastatic disease. In turn, patients are vulnerable to recurrence from occult, disseminated micrometastatic disease. As such, the combination of surgery, systemic therapy (e.g., fluoropyrimidine-based chemotherapy, biologic therapy, immunotherapy), and/or regional therapy (e.g., hepatic artery infusion pump, Yttrium-90 radioembolization) is often employed to treat mCRC [2]. Despite best efforts, long-term survival is still poor for unresectable mCRC with 1-, 3-, and 5-year survival rates of approximately 70–75%, 30–35%, and 20%, respectively [2].
2. Genetic Profiling of mCRC
2.1. Consensus Molecular Subtypes
2.1.1. CMS 1—Microsatellite Instability/Immune
Guinney et al. established four robust consensus molecular subtypes (CMS) of CRC using gene expression data from 4151 patients [8]. Prior to this study, CRC was primarily defined by individual gene mutations (e.g., RAS or BRAF mutations) or microsatellite instability status. Guinney et al. created a new taxonomy of CRC to facilitate research and advance drug development strategy. Studies have demonstrated that these molecular and immune signatures can be used to predict clinical behavior and response to therapy [9]. CMS 1 tumors are hypermethylated, hypermutated, and have an immune-rich tumor microenvironment [8]. The MLH1 promoter hypermethylation leads to defective mismatch repair (MMR) and microsatellite instability (MSI) [10].
2.1.2. CMS 2—Canonical
While CMS 1 tumors are characterized by hypermethylation, CMS 2, CMS 3, and CMS 4 tumors arise from increased chromosomal instability. CMS 2 tumors follow the traditional CRC carcinogenesis pathway secondary to APC, p53, and RAS mutations [8]. These tumors demonstrate the upregulation of the downstream targets of WNT and MYC and the increased expression of the oncogene epidermal growth factor receptor (EGFR), erythroblastic oncogene B-2 (ERBB2, also known as HER2), insulin-like growth factor 2 (IGF2), insulin receptor substrate 2 (IRS2), and transcription factor hepatocyte nuclear factor 4α (HNF4α) [16].
2.1.3. CMS 3—Metabolic
At the gene expression level, CMS 3 was the most similar to normal colon tissue. This tumor type commonly demonstrates the enrichment of several metabolic pathways secondary to the KRAS activating mutations [8]. On a pathologic assessment, these tumors display a papillary morphology [10]. Both CMS 2 and CMS 3 tumors are considered “cold” tumors with poor immune infiltration [18]. Given the high frequency of KRAS mutations, these tumors typically have a poor response to EGFR inhibitors [19].
2.1.4. CMS 4—Mesenchymal
CMS 4 tumors demonstrate the upregulation of genes linked to epithelial–mesenchymal transition and signatures associated with activation of transforming growth factor-β (TGF-β), angiogenesis through the activation of vascular endothelial growth factor receptor (VEGFR), and matrix-remodeling pathways [8]. On pathologic assessment, these tumors display a desmoplastic reaction with high stromal content [10]. Both CMS 1 and CMS 4 are considered “hot” tumors and are characterized by immune infiltration [18].
2.1.5. CMS Subtypes and Tumor Location
Loree et al. compared mutation prevalence by anatomic site through the next generation sequencing of 1876 CRC tumors [21]. Right-sided tumors had higher rates of BRAF, PIK3CA, CTNNB1, SMAD4, and KRAS mutations, mucinous histology, and increased incidence of MSI. Left-sided tumors had higher rates of TP53 mutations. There were differences in the mutational profile based on anatomic location beyond the classic right, left, and rectal locations. For example, even though both are considered “right”-sided tumors, cecal carcinomas had a higher rate of RAS mutations (70%) and lower rate of BRAFV600 mutations (10%) compared with hepatic flexure carcinoma (RAS: 43%, p = 0.0001, BRAFV600: 22%, p < 0.0001).
2.2. Genetic Profiling Can Predict Recurrence after Resection for CRC Liver Metastases
After the resection of CRC liver metastases (CRC-LM), there is still a high risk of recurrence or development of new metastatic disease. The 5- and 10-year OS is predicted to be up to 50% and 25%, respectively [22,23,24]. The Fong clinical risk score evaluates risk based on clinical factors: node positive primary tumor, number of hepatic tumors, largest hepatic tumor size, disease free interval between primary and metastases, and carcinoembryonic antigen (CEA) level [25]. A Fong score of ≥3 is considered high risk for recurrence and confers a 20% 5-year survival after metastectomy. However, given the progress in recent years with the genomic sequencing of tumors, specific mutational profiles can also be utilized to predict long term outcomes.
3. Vascular Endothelial Growth Factor (VEGF)
3.1. Bevacizumab
Bevacizumab is a monoclonal antibody that selectively binds to circulating VEGF-A and inhibits its ability to bind to VEGFR. This process causes the regression of existing tumor vasculature, decreases the development of new vessels to prevent tumor growth, and normalizes tumor vasculature to improve chemotherapy delivery [39,40]. The AVF2107 trial randomized 813 patients with previously untreated mCRC to receive either bevacizumab and irinotecan/fluorouracil/leucovorin (IFL) or chemotherapy alone [41]. Compared with chemotherapy alone, the combination of bevacizumab/IFL led to improved median OS (20.3 months vs. 15.6 months), median PFS (10.6 months vs. 6.2 months), and a median duration of response (10.4 months vs. 7.1 months). Based on results of this trial, bevacizumab with fluorouracil-based chemotherapy was approved by the FDA as a first-line therapy for patients with mCRC [41]. It should be noted, however, that bevacizumab can lead to poor wound-healing and an increased risk of bleeding in the surgical setting [42,43].
3.2. Aflibercept
Aflibercept is a human recombinant fusion protein that acts as a decoy receptor for VEGF-A, VEGF-B, and PGF [53]. Aflibercept has a higher affinity for VEGF-A than bevacizumab or VEGFR. In addition, its ability to target PIGF in addition to VEGF may lead to increased efficacy over other anti-angiogenic agents [54]. Phase II trials in patients with mCRC failed to show the efficacy of aflibercept as a monotherapy [55]. Given the success of combination bevacizumab and chemotherapy as first-line therapy in mCRC, a phase II trial randomized 236 patients with mCRC to receive modified FOLFOX6 with or without aflibercept as first-line therapy (AFFIRM trial) [56]. There was no difference in PFS between the two treatment groups and the addition of aflibercept was associated with higher toxicity (increased hypertension, proteinuria, and deep vein thrombosis/pulmonary embolism).
3.3. Ramucirumab
Ramucirumab is a humanized monoclonal that binds to VEGFR-2 and blocks the binding of VEGF-A and VEGF-B. The phase III RAISE trial enrolled 1072 patients with mCRC who progressed on first-line therapy and randomized patients to receive FOLFIRI with ramucirumab vs. placebo [58]. The ramucirumab cohort had improved median PFS (5.7 vs. 4.5 months) and OS (13.3 months vs. 11.7 months) compared with the placebo cohort. Ramucirumab was approved by the FDA for patients with mCRC who progressed on FOLFOX and bevacizumab.
3.4. Tyrosine Kinase Inhibitors That Target VEGF/VEGFR
Ligands bind tyrosine kinase receptors (TKR) and activate downstream signaling pathways required for cell growth and proliferation. Tyrosine kinase inhibitors (TKI) bind TKR at the ATP-binding pocket and block other proteins from binding [60]. Regorafenib inhibits multiple TKR targets, including VEGFR. Regorafenib did not demonstrate efficacy as a first-line therapy but is currently approved as a second-line therapy for mCRC based on the CORRECT trial [61,62]. The CORRECT phase III trial randomized 760 patients with mCRC who progressed on standard therapy to receive either regorafenib or a placebo. Patients treated with regorafenib had improved median OS (6.4 vs. 5 months) and PFS (1.9 vs. 1.7 months) compared with the placebo [61,62].
4. Epidermal Growth Factor Receptor (EGFR)
Erythroblastosis oncogene b (ERBB) is a family of four tyrosine kinase receptors with 11 growth factors. When ligands bind these receptors, downstream intracellular signaling pathways, including RAS/RAF/MEK/ERK, PI3K/AKT, and JAK/STAT3, are activated and lead to cell growth, survival, proliferation, metabolism, and migration. The four receptors include ERBB1 (EGFR/HER1), ERBB2 (Neu/HER2), ERBB3 (HER3), and ERBB4 (HER4) [69]. While the overexpression of EGFR has been noted in 25–77% of CRC, it is still unclear how EGFR impacts clinical outcomes [70].
RAS is a proto-oncogene in the EGFR signaling pathway that activates the MAPK pathway and subsequent cell proliferation and survival. However, RAS mutations lead to the constitutive activation of the MAPK pathway and uncontrolled cell growth. Aggressive tumors, metastatic disease, and poor survival are also associated with RAS mutations [75,76,77,78]. Understanding the relationship between EGFR and RAS is critical given the clinical implications. In the presence of EGFR inhibitors, mutated RAS remains activated because it is downstream of EGFR [79].
4.1. Cetuximab
Cetuximab is a chimeric mouse–human monoclonal antibody that binds to the external domain of EGFR. The EGFR receptor is then internalized and degraded. Cetuximab is currently approved for the treatment of mCRC based on the results of the BOND trial [80]. This study randomized 329 patients with mCRC who had progressed on an irinotecan-based regimen to receive either cetuximab and irinotecan-based therapy or cetuximab monotherapy. Patients who received combination therapy had a longer median time to progression (4.5 months vs. 1.5 months, p < 0.001), compared with the cetuximab monotherapy cohort, but a similar median OS (8.6 months vs. 6.9 months, p = 0.48). The CRYSTAL phase III trial randomized 1198 patients with EGFR positive mCRC to receive either FOLFIRI and cetuximab or FOLFIRI alone as first-line therapy [81].
Pre-clinical studies have suggested that treatment with VEGF inhibitors, like bevacizumab, may lead to resistance to anti-EGFR therapies, e.g., cetuximab [83]. Additionally, these early trials established that cetuximab is more effective in patients with KRAS wild-type mCRC. The recent TAILOR phase III trial was the first to evaluate the use of cetuximab/FOLFOX4 while prospectively choosing patients with RAS wild type mCRC [84]. Cetuximab/FOLFOX4 was associated with improved PFS and OS compared with FOLFOX4-only therapy.
4.2. Panitumumab
Panitumumab is a fully humanized monoclonal antibody that targets EGFR and has a lower risk of a hypersensitivity reaction compared with cetuximab [85]. The PRIME trial compared FOLFOX alone to FOLFOX/panitumumab in patients with KRAS wild-type mCRC [86]. The initial results demonstrated that the panitumumab cohort had a higher ORR and improved median PFS. The updated analysis confirmed an improvement in median OS for the panitumumab cohort.
4.3. BRAF Mutation
BRAF encodes the BRAF protein kinase in the MAPK signaling cascade and its activation drives cell proliferation, differentiation, angiogenesis, and survival. Mutations in the BRAF gene are commonly due to a transversion mutation in exon 15 that results in a valine amino acid substitution (V600E). This mutation mimics regulatory phosphorylation and increases BRAF activity [90]. There are two subtypes: BM1, which is secondary to the activation of the KRAS/AKT pathway, and BM2, which is secondary to the dysregulation of the cell cycle and cell cycle checkpoints. This mutation is present in about 10% of patients with mCRC and is commonly found in women with MSI right-sided tumors with mucinous features [62].
While proven to be effective in other malignancies, like melanoma, BRAF inhibitors have not had the same success in mCRC. Vemurafenib has not been effective as a monotherapy for mCRC [91,92,93]. Pre-clinical studies suggested that this was due to the feedback activation of EGFR in the presence of BRAF inhibition [94]. Therefore, subsequent trials have shifted to evaluate combination BRAF and EGFR inhibitors.
4.4. Human Epidermal Growth Factor Receptor (HER2, Also Known as ERBB2)
HER2 is a transmembrane growth factor receptor that does not bind a specific ligand but rather is the preferred dimerization partner for other ERBB receptors. This process leads to the activation of downstream transcription pathways, including RAS/RAF/MAPK and PI3K/AKT, that promote cell proliferation and apoptosis [97]. HER2 overexpression is seen in 2–3% of patients with CRC and commonly detected in left-sided tumors [98,99].
4.5. KRAS Targeted Therapy
While not yet approved for mCRC, KRAS-targeted therapy has demonstrated effectiveness in other cancers [79]. Combining a KRAS inhibitor and an EGFR inhibitor may be a path to overcoming anti-EGFR therapy resistance in KRAS mutated patients. However, the challenge lies in ensuring only mutant KRAS is targeted to avoid the potential toxicity of inhibiting wildtype KRAS, which is required for normal cell function. Sotorasib and Adagrasib are KRAS selective inhibitors that bind to G12C KRAS mutants. Both were recently approved by the FDA for use in non-small cell lung cancer [106,107]. These agents are currently being tested in clinical trials with patients with mCRC and KRAS-G12C mutations (NCT04793958, NCT05198934).
5. Mismatch Repair Mutations (Microsatellite Instability)
5.1. Pembrolizumab
In response to pro-inflammatory cytokines, programmed death ligand 1 (PD-L1) is expressed on somatic cells and binds to the programmed death 1 (PD-1) receptor to T cells, B cells, natural killer cells, dendritic cells, and myeloid-derived suppressor cells. When bound, there is the suppression of T cell migration, proliferation, and cytotoxin secretion [115]. Pembrolizumab is a PD-1 inhibitor and the first ICI demonstrated to be effective against dMMR mCRC. After several successful phase I trials, the phase II KEYNOTE-177 trial compared pembrolizumab to chemotherapy with or without bevacizumab as a first-line treatment in patients with MSI mCRC [116]. Pembrolizumab conferred superior median PFS (16.5 months) compared with chemotherapy/bevacizumab (8.2 months). Pembrolizumab is approved for dMMR/MSI high mCRC as first-line therapy.
5.2. Nivolumab
Nivolumab is also a PD-1 inhibitor and was approved in 2017 for MSI high or dMMR mCRC. The Checkmate-142 trial treated 74 patients with refractory MSI mCRC with nivolumab [117]. At a median follow-up of 12 months, the ORR was 31.1% and OS rate was 73.4%. A separate component of the Checkmate-142 trial evaluated the use of nivolumab and ipilimumab (CTLA-4 inhibitor) in patients with treatment-naïve MSI mCRC [118].
6. Hepatocyte Growth Factor (HGF)/Mesenchymal-Epithelial Transition Factor (MET) Pathway
6.1. Rilotumumab
Rilotumumab is a monoclonal antibody against HGF, which has mainly been studied in gastric and gastroesophageal cancers. Phase III studies examining rilotumumab (RILOMET-1 and RILOMET-2) were halted due to an increase in disease-related deaths [120,121,122]. In a randomized phase I/II trial of patients with KRAS wild-type mCRC, combination panitumumab with rilotumumab, ganitumab (anti-insulin-like growth factor 1 receptor), or placebo were assessed. Combination panitumumab and rilotumumab had an ORR of 31% versus 22% for patient treated with panitumumab/ganitumab [123].
6.2. Onartuzumab
Onartuzumab is a monoclonal antibody against the MET receptor, which has been evaluated in several malignancies. Unfortunately, onartuzumab has failed to demonstrate efficacy in phase III trials [124,125,126]. There was no differences in outcomes among patients with mCRC who were treated with FOLFOX/onartuzumab or FOLFOX/placebo. Sub-analysis of patients who were MET-positive on IHC staining similarly failed to demonstrate an effect for onartuzumab. As such, MET IHC was not a predictive biomarker [125].
7. Conclusions
Metastatic CRC requires a multidisciplinary approach involving the potential combination of surgery, cytotoxic chemotherapy, liver-directed therapy, and now targeted therapy. The underlying differences in the molecular profile of tumors and the microenvironments inform tumor biology, response to treatment, and prognosis. Targeted therapy allows for a more personalized approach by tailoring treatment to the unique features of the tumor. We are still in the early stages of understanding how to appropriately select patients who will best respond to individual therapies, but continued translational work is crucial to moving the field forward. In the pre-clinical setting, understanding the mechanisms of carcinogenesis, identifying novel targets, and developing new drugs will be important. Through large, multicenter clinical trials, tissues for sequencing should be obtained to elucidate the subtypes of mCRC and better identify the unique tumor characteristics that are associated with response to targeted therapy.
This entry is adapted from the peer-reviewed paper 10.3390/cancers15133513
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