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Ruff, S.M.; Shannon, A.H.; Pawlik, T.M. Multi-Disciplinary Approach to Colorectal Liver Metastasis. Encyclopedia. Available online: (accessed on 07 December 2023).
Ruff SM, Shannon AH, Pawlik TM. Multi-Disciplinary Approach to Colorectal Liver Metastasis. Encyclopedia. Available at: Accessed December 07, 2023.
Ruff, Samantha M., Alexander H. Shannon, Timothy M. Pawlik. "Multi-Disciplinary Approach to Colorectal Liver Metastasis" Encyclopedia, (accessed December 07, 2023).
Ruff, S.M., Shannon, A.H., & Pawlik, T.M.(2023, July 12). Multi-Disciplinary Approach to Colorectal Liver Metastasis. In Encyclopedia.
Ruff, Samantha M., et al. "Multi-Disciplinary Approach to Colorectal Liver Metastasis." Encyclopedia. Web. 12 July, 2023.
Multi-Disciplinary Approach to Colorectal Liver Metastasis

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 [4]. Prior to the 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 [5]. CMS 1 tumors are hypermethylated, hypermutated, and have an immune-rich tumor microenvironment [4]. The MLH1 promoter hypermethylation leads to defective mismatch repair (MMR) and microsatellite instability (MSI) [6].

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 [4]. 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) [7].

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 [4]. On a pathologic assessment, these tumors display a papillary morphology [6]. Both CMS 2 and CMS 3 tumors are considered “cold” tumors with poor immune infiltration [8]. Given the high frequency of KRAS mutations, these tumors typically have a poor response to EGFR inhibitors [9].

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 [4]. On pathologic assessment, these tumors display a desmoplastic reaction with high stromal content [6]. Both CMS 1 and CMS 4 are considered “hot” tumors and are characterized by immune infiltration [8].

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 [10]. 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 [11][12][13]. 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 [14]. 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 [15][16]. The AVF2107 trial randomized 813 patients with previously untreated mCRC to receive either bevacizumab and irinotecan/fluorouracil/leucovorin (IFL) or chemotherapy alone [17]. 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 [17]. It should be noted, however, that bevacizumab can lead to poor wound-healing and an increased risk of bleeding in the surgical setting [18][19].

3.2. Aflibercept

Aflibercept is a human recombinant fusion protein that acts as a decoy receptor for VEGF-A, VEGF-B, and PGF [20]. 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 [21]. Phase II trials in patients with mCRC failed to show the efficacy of aflibercept as a monotherapy [22]. 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) [23]. 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 [24]. 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 [25]. 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 [26][27]. 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 [26][27].

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) [28]. While the overexpression of EGFR has been noted in 25–77% of CRC, it is still unclear how EGFR impacts clinical outcomes [29]

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 [30][31][32][33]. 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 [34].

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 [35]. The 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 [36].
Pre-clinical studies have suggested that treatment with VEGF inhibitors, like bevacizumab, may lead to resistance to anti-EGFR therapies, e.g., cetuximab [37]. 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 [38]. 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 [39]. The PRIME trial compared FOLFOX alone to FOLFOX/panitumumab in patients with KRAS wild-type mCRC [40]. 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 [41]. 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 [27].
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 [42][43][44]. Pre-clinical studies suggested that this was due to the feedback activation of EGFR in the presence of BRAF inhibition [45]. 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 [46]. HER2 overexpression is seen in 2–3% of patients with CRC and commonly detected in left-sided tumors [47][48].

4.5. KRAS Targeted Therapy

While not yet approved for mCRC, KRAS-targeted therapy has demonstrated effectiveness in other cancers [34]. 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 [49][50]. 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)


  1. Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 2023, 73, 17–48.
  2. Biller, L.H.; Schrag, D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA 2021, 325, 669–685.
  3. Tsilimigras, D.I.; Brodt, P.; Clavien, P.A.; Muschel, R.J.; D’Angelica, M.I.; Endo, I.; Parks, R.W.; Doyle, M.; de Santibañes, E.; Pawlik, T.M. Liver metastases. Nat. Rev. Dis. Prim. 2021, 7, 27.
  4. Guinney, J.; Dienstmann, R.; Wang, X.; de Reyniès, A.; Schlicker, A.; Soneson, C.; Marisa, L.; Roepman, P.; Nyamundanda, G.; Angelino, P.; et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015, 21, 1350–1356.
  5. Farooqi, A.A.; de la Roche, M.; Djamgoz, M.B.A.; Siddik, Z.H. Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights. Semin. Cancer Biol. 2019, 58, 65–79.
  6. Budinska, E.; Popovici, V.; Tejpar, S.; D’Ario, G.; Lapique, N.; Sikora, K.O.; Di Narzo, A.F.; Yan, P.; Hodgson, J.G.; Weinrich, S.; et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J. Pathol. 2013, 231, 63–76.
  7. Kim, J.C.; Bodmer, W.F. Genomic landscape of colorectal carcinogenesis. J. Cancer Res. Clin. Oncol. 2022, 148, 533–545.
  8. Piskol, R.; Huw, L.; Sergin, I.; Kljin, C.; Modrusan, Z.; Kim, D.; Kljavin, N.; Tam, R.; Patel, R.; Burton, J.; et al. A Clinically Applicable Gene-Expression Classifier Reveals Intrinsic and Extrinsic Contributions to Consensus Molecular Subtypes in Primary and Metastatic Colon Cancer. Clin. Cancer Res. 2019, 25, 4431–4442.
  9. Thanki, K.; Nicholls, M.E.; Gajjar, A.; Senagore, A.J.; Qiu, S.; Szabo, C.; Hellmich, M.R.; Chao, C. Consensus Molecular Subtypes of Colorectal Cancer and their Clinical Implications. Int. Biol. Biomed. J. 2017, 3, 105–111.
  10. Loree, J.M.; Pereira, A.A.L.; Lam, M.; Willauer, A.N.; Raghav, K.; Dasari, A.; Morris, V.K.; Advani, S.; Menter, D.G.; Eng, C.; et al. Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes. Clin. Cancer Res. 2018, 24, 1062–1072.
  11. Galjart, B.; van der Stok, E.P.; Rothbarth, J.; Grünhagen, D.J.; Verhoef, C. Posttreatment Surveillance in Patients with Prolonged Disease-Free Survival After Resection of Colorectal Liver Metastasis. Ann. Surg. Oncol. 2016, 23, 3999–4007.
  12. Kanas, G.P.; Taylor, A.; Primrose, J.N.; Langeberg, W.J.; Kelsh, M.A.; Mowat, F.S.; Alexander, D.D.; Choti, M.A.; Poston, G. Survival after liver resection in metastatic colorectal cancer: Review and meta-analysis of prognostic factors. Clin. Epidemiol. 2012, 4, 283–301.
  13. Kulik, U.; Plohmann-Meyer, M.; Gwiasda, J.; Kolb, J.; Meyer, D.; Kaltenborn, A.; Lehner, F.; Klempnauer, J.; Schrem, H. Proposal of Two Prognostic Models for the Prediction of 10-Year Survival after Liver Resection for Colorectal Metastases. HPB Surg. 2018, 2018, 5618581.
  14. Fong, Y.; Fortner, J.; Sun, R.L.; Brennan, M.F.; Blumgart, L.H. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann. Surg. 1999, 230, 309–318; discussion 318–321.
  15. Goel, S.; Wong, A.H.; Jain, R.K. Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease. Cold Spring Harb. Perspect. Med. 2012, 2, a006486.
  16. Rosen, L.S.; Jacobs, I.A.; Burkes, R.L. Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars. Target. Oncol. 2017, 12, 599–610.
  17. Hurwitz, H.; Fehrenbacher, L.; Novotny, W.; Cartwright, T.; Hainsworth, J.; Heim, W.; Berlin, J.; Baron, A.; Griffing, S.; Holmgren, E.; et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N. Engl. J. Med. 2004, 350, 2335–2342.
  18. Gordon, C.R.; Rojavin, Y.; Patel, M.; Zins, J.E.; Grana, G.; Kann, B.; Simons, R.; Atabek, U. A review on bevacizumab and surgical wound healing: An important warning to all surgeons. Ann. Plast. Surg. 2009, 62, 707–709.
  19. Scappaticci, F.A.; Fehrenbacher, L.; Cartwright, T.; Hainsworth, J.D.; Heim, W.; Berlin, J.; Kabbinavar, F.; Novotny, W.; Sarkar, S.; Hurwitz, H. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J. Surg. Oncol. 2005, 91, 173–180.
  20. Stewart, M.W.; Rosenfeld, P.J. Predicted biological activity of intravitreal VEGF Trap. Br. J. Ophthalmol. 2008, 92, 667–668.
  21. Ciombor, K.K.; Berlin, J. Aflibercept--a decoy VEGF receptor. Curr. Oncol. Rep. 2014, 16, 368.
  22. Tang, P.A.; Cohen, S.J.; Kollmannsberger, C.; Bjarnason, G.; Virik, K.; MacKenzie, M.J.; Lourenco, L.; Wang, L.; Chen, A.; Moore, M.J. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin. Cancer Res. 2012, 18, 6023–6031.
  23. Folprecht, G.; Pericay, C.; Saunders, M.P.; Thomas, A.; Lopez Lopez, R.; Roh, J.K.; Chistyakov, V.; Höhler, T.; Kim, J.S.; Hofheinz, R.D.; et al. Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: The AFFIRM study. Ann. Oncol. 2016, 27, 1273–1279.
  24. Tabernero, J.; Yoshino, T.; Cohn, A.L.; Obermannova, R.; Bodoky, G.; Garcia-Carbonero, R.; Ciuleanu, T.E.; Portnoy, D.C.; Van Cutsem, E.; Grothey, A.; et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): A randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015, 16, 499–508.
  25. Huang, L.; Jiang, S.; Shi, Y. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020). J. Hematol. Oncol. 2020, 13, 143.
  26. Argilés, G.; Saunders, M.P.; Rivera, F.; Sobrero, A.; Benson, A., III; Guillén Ponce, C.; Cascinu, S.; Van Cutsem, E.; Macpherson, I.R.; Strumberg, D.; et al. Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial. Eur. J. Cancer 2015, 51, 942–949.
  27. Grothey, A.; Fakih, M.; Tabernero, J. Management of BRAF-mutant metastatic colorectal cancer: A review of treatment options and evidence-based guidelines. Ann. Oncol. 2021, 32, 959–967.
  28. Xie, Y.H.; Chen, Y.X.; Fang, J.Y. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct. Target 2020, 5, 22.
  29. Roskoski, R., Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharm. Res. 2014, 79, 34–74.
  30. Tan, C.; Du, X. KRAS mutation testing in metastatic colorectal cancer. World J. Gastroenterol. 2012, 18, 5171–5180.
  31. Vauthey, J.N.; Zimmitti, G.; Kopetz, S.E.; Shindoh, J.; Chen, S.S.; Andreou, A.; Curley, S.A.; Aloia, T.A.; Maru, D.M. RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Ann. Surg. 2013, 258, 619–626; discussion 626–627.
  32. Margonis, G.A.; Spolverato, G.; Kim, Y.; Karagkounis, G.; Choti, M.A.; Pawlik, T.M. Effect of KRAS Mutation on Long-Term Outcomes of Patients Undergoing Hepatic Resection for Colorectal Liver Metastases. Ann. Surg. Oncol. 2015, 22, 4158–4165.
  33. Yaeger, R.; Cowell, E.; Chou, J.F.; Gewirtz, A.N.; Borsu, L.; Vakiani, E.; Solit, D.B.; Rosen, N.; Capanu, M.; Ladanyi, M.; et al. RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer. Cancer 2015, 121, 1195–1203.
  34. Tria, S.M.; Burge, M.E.; Whitehall, V.L.J. The Therapeutic Landscape for KRAS-Mutated Colorectal Cancers. Cancers 2023, 15, 2375.
  35. Cunningham, D.; Humblet, Y.; Siena, S.; Khayat, D.; Bleiberg, H.; Santoro, A.; Bets, D.; Mueser, M.; Harstrick, A.; Verslype, C.; et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 2004, 351, 337–345.
  36. Van Cutsem, E.; Köhne, C.H.; Hitre, E.; Zaluski, J.; Chang Chien, C.R.; Makhson, A.; D’Haens, G.; Pintér, T.; Lim, R.; Bodoky, G.; et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 2009, 360, 1408–1417.
  37. Derangère, V.; Fumet, J.D.; Boidot, R.; Bengrine, L.; Limagne, E.; Chevriaux, A.; Vincent, J.; Ladoire, S.; Apetoh, L.; Rébé, C.; et al. Does bevacizumab impact anti-EGFR therapy efficacy in metastatic colorectal cancer? Oncotarget 2016, 7, 9309–9321.
  38. Qin, S.; Li, J.; Wang, L.; Xu, J.; Cheng, Y.; Bai, Y.; Li, W.; Xu, N.; Lin, L.Z.; Wu, Q.; et al. Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients with RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial. J. Clin. Oncol. 2018, 36, 3031–3039.
  39. Addeo, R.; Caraglia, M.; Cerbone, D.; Frega, N.; Cimmino, G.; Abbruzzese, A.; Del Prete, S. Panitumumab: A new frontier of target therapy for the treatment of metastatic colorectal cancer. Expert. Rev. Anticancer 2010, 10, 499–505.
  40. Douillard, J.Y.; Siena, S.; Cassidy, J.; Tabernero, J.; Burkes, R.; Barugel, M.; Humblet, Y.; Bodoky, G.; Cunningham, D.; Jassem, J.; et al. Final results from PRIME: Randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann. Oncol. 2014, 25, 1346–1355.
  41. Caputo, F.; Santini, C.; Bardasi, C.; Cerma, K.; Casadei-Gardini, A.; Spallanzani, A.; Andrikou, K.; Cascinu, S.; Gelsomino, F. BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights. Int. J. Mol. Sci. 2019, 20, 5369.
  42. Kopetz, S.; Desai, J.; Chan, E.; Hecht, J.R.; O’Dwyer, P.J.; Maru, D.; Morris, V.; Janku, F.; Dasari, A.; Chung, W.; et al. Phase II Pilot Study of Vemurafenib in Patients with Metastatic BRAF-Mutated Colorectal Cancer. J. Clin. Oncol. 2015, 33, 4032–4038.
  43. Hyman, D.M.; Puzanov, I.; Subbiah, V.; Faris, J.E.; Chau, I.; Blay, J.Y.; Wolf, J.; Raje, N.S.; Diamond, E.L.; Hollebecque, A.; et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N. Engl. J. Med. 2015, 373, 726–736.
  44. Seligmann, J.F.; Fisher, D.; Smith, C.G.; Richman, S.D.; Elliott, F.; Brown, S.; Adams, R.; Maughan, T.; Quirke, P.; Cheadle, J.; et al. Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: Analysis from 2530 patients in randomised clinical trials. Ann. Oncol. 2017, 28, 562–568.
  45. Prahallad, A.; Sun, C.; Huang, S.; Di Nicolantonio, F.; Salazar, R.; Zecchin, D.; Beijersbergen, R.L.; Bardelli, A.; Bernards, R. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012, 483, 100–103.
  46. Strickler, J.H.; Yoshino, T.; Graham, R.P.; Siena, S.; Bekaii-Saab, T. Diagnosis and Treatment of ERBB2-Positive Metastatic Colorectal Cancer: A Review. JAMA Oncol. 2022, 8, 760–769.
  47. Richman, S.D.; Southward, K.; Chambers, P.; Cross, D.; Barrett, J.; Hemmings, G.; Taylor, M.; Wood, H.; Hutchins, G.; Foster, J.M.; et al. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: Analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials. J. Pathol. 2016, 238, 562–570.
  48. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012, 487, 330–337.
  49. Spira, A.I.; Riely, G.J.; Gadgeel, S.M.; Heist, R.S.; Ou, S.-H.I.; Pacheco, J.M.; Johnson, M.L.; Sabari, J.K.; Leventakos, K.; Yau, E.; et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non–small cell lung cancer (NSCLC) harboring a KRASG12C mutation. J. Clin. Oncol. 2022, 40 (Suppl. S16), 9002.
  50. Nakajima, E.C.; Drezner, N.; Li, X.; Mishra-Kalyani, P.S.; Liu, Y.; Zhao, H.; Bi, Y.; Liu, J.; Rahman, A.; Wearne, E.; et al. FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC. Clin. Cancer Res. 2022, 28, 1482–1486.
  51. Ai, L.; Chen, J.; Yan, H.; He, Q.; Luo, P.; Xu, Z.; Yang, X. Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy. Drug Des. Devel. 2020, 14, 3625–3649.
  52. André, T.; Shiu, K.K.; Kim, T.W.; Jensen, B.V.; Jensen, L.H.; Punt, C.; Smith, D.; Garcia-Carbonero, R.; Benavides, M.; Gibbs, P.; et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N. Engl. J. Med. 2020, 383, 2207–2218.
  53. Overman, M.J.; McDermott, R.; Leach, J.L.; Lonardi, S.; Lenz, H.J.; Morse, M.A.; Desai, J.; Hill, A.; Axelson, M.; Moss, R.A.; et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study. Lancet Oncol. 2017, 18, 1182–1191.
  54. Lenz, H.J.; Van Cutsem, E.; Luisa Limon, M.; Wong, K.Y.M.; Hendlisz, A.; Aglietta, M.; García-Alfonso, P.; Neyns, B.; Luppi, G.; Cardin, D.B.; et al. First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase II CheckMate 142 Study. J. Clin. Oncol. 2022, 40, 161–170.
  55. Catenacci, D.V.T.; Tebbutt, N.C.; Davidenko, I.; Murad, A.M.; Al-Batran, S.E.; Ilson, D.H.; Tjulandin, S.; Gotovkin, E.; Karaszewska, B.; Bondarenko, I.; et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017, 18, 1467–1482.
  56. Doi, T.; Kang, Y.-K.; Muro, K.; Jiang, Y.; Jain, R.K.; Lizambri, R. A phase 3, multicenter, randomized, double-blind, placebo-controlled study of rilotumumab in combination with cisplatin and capecitabine (CX) as first-line therapy for Asian patients (pts) with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The RILOMET-2 trial. J. Clin. Oncol. 2015, 33 (Suppl. S3), TPS226.
  57. Iveson, T.; Donehower, R.C.; Davidenko, I.; Tjulandin, S.; Deptala, A.; Harrison, M.; Nirni, S.; Lakshmaiah, K.; Thomas, A.; Jiang, Y.; et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: An open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 2014, 15, 1007–1018.
  58. Van Cutsem, E.; Eng, C.; Nowara, E.; Swieboda-Sadlej, A.; Tebbutt, N.C.; Mitchell, E.; Davidenko, I.; Stephenson, J.; Elez, E.; Prenen, H.; et al. Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer. Clin. Cancer Res. 2014, 20, 4240–4250.
  59. Shah, M.A.; Bang, Y.J.; Lordick, F.; Alsina, M.; Chen, M.; Hack, S.P.; Bruey, J.M.; Smith, D.; McCaffery, I.; Shames, D.S.; et al. Effect of Fluorouracil, Leucovorin, and Oxaliplatin with or without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial. JAMA Oncol. 2017, 3, 620–627.
  60. Bendell, J.C.; Hochster, H.; Hart, L.L.; Firdaus, I.; Mace, J.R.; McFarlane, J.J.; Kozloff, M.; Catenacci, D.; Hsu, J.J.; Hack, S.P.; et al. A Phase II Randomized Trial (GO27827) of First-Line FOLFOX Plus Bevacizumab with or without the MET Inhibitor Onartuzumab in Patients with Metastatic Colorectal Cancer. Oncologist 2017, 22, 264–271.
  61. Spigel, D.R.; Edelman, M.J.; O’Byrne, K.; Paz-Ares, L.; Mocci, S.; Phan, S.; Shames, D.S.; Smith, D.; Yu, W.; Paton, V.E.; et al. Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non-Small-Cell Lung Cancer: METLung. J. Clin. Oncol. 2017, 35, 412–420.
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