Colorectal Cancer – Pathophysiology
Pathophysiology of colorectal cancer
CRC usually does not produce symptoms in early stages of the disease. If symptoms are present, they usually depend on the site of the primary tumor. Cancers of the proximal colon tend to grow larger before symptoms appear than those in the left colon and rectum. The first symptoms of colon cancer may be iron-deficiency anemia and bleeding due to abnormal vasculature in the tumor and trauma from the fecal stream. The bleeding is usually occult in early stages. Tumors of the anus, sigmoid colon, and rectum may lead to hematochezia.1
Later stages of the disease may be associated with obstruction of the colonic lumen, abdominal distension, pain, nausea, and vomiting. Obstruction of the gastrointestinal (GI) tract suggests a larger tumor and a poorer prognosis. If the tumor has invaded the muscularis propria and adjacent tissue, pain and site-specific symptoms may be present. This may include tenesmus from rectal invasion, pneumaturia from bladder penetration, or perineal or sacral pain from pelvic invasion. Cachexia is also common in patients with advanced GI malignancies.1
Anatomical Site of CRC
Clinical data have shown disparities in incidence, outcomes, genetic alterations, and pathogenesis depending on the anatomical site of the tumor in CRC. Right-sided colon cancer (RCC) occurs in the proximal colon, which consists of cancers of the cecum and ascending and transverse colon. Left-sided colorectal cancer (LCRC) occurs in the distal colorectum and consists of cancers of the descending and sigmoid colon and the rectum.2
Tumors of the proximal colon tend to be larger, have a higher TNM-stage, and have increased frequency of vascular invasion than LCRC. Mucinous adenocarcinoma, which is characterized by abundant extracellular mucin, is more frequently found in the proximal colon and is associated with microsatellite instability (MSI). MSI-positive CRCs have a better overall outcome compared with microsatellite-stable tumors. KRAS and p53 mutations are more commonly found in LCRC than RCC.2
Although RCCs are more likely to be MSI positive, when adjusted for tumor stage, survival is significantly worse for RCC compared with LCRC. The higher mortality of RCCs is likely due to more aggressive microsatellite-stable RCC, which tend to have mutations in the BRAF gene. LCRC may have a lower mortality rate because it is more easily diagnosed due to screening of the distal colon and more apparent symptoms. RCC often presents with subtle signs and symptoms, such as microcytic anemia, weight loss, and occult bleeding. LCRC is more likely to lead to rectal bleeding and alterations in bowel habits.2
A retrospective analysis of the CALGB/SWOG 80405 study suggested that patients with left-sided tumors had significantly longer median overall survival (OS) versus those with right-sided tumors (33.3 vs 19.4 months; hazard ratio [HR] = 1.55; P<0.0001). This trial demonstrated longer OS with cetuximab than with bevacizumab when the primary tumor was on the left side (36.0 vs 31.4 months, respectively).3 A retrospective analysis of tumor sidedness in patients with RAS wild-type CRC in the CRYSTAL and FIRE-3 trials concurred with these findings, showing that OS is significantly longer in patients with left-sided versus right-sided mCRC. The addition of cetuximab to chemotherapy improved OS in left-sided tumors and had limited or no effect in right-sided tumors.4 A population-based study using Surveillance, Epidemiology, and End Results Program (SEER) data found similar effects of primary tumor sidedness on prognosis, with inferior survival in patients with right-sided tumors.5
The NCCN guidelines currently recommend cetuximab and panitumumab for the first-line treatment of left-sided tumors only, in combination with chemotherapy in KRAS wild-type mCRC. Bevacizumab may be preferred for right-sided tumors in this setting.6
Summary of differences between right-sided colon cancer and left-sided colorectal cancer2
Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis, the formation of new blood vessels from the endothelium of preexisting vasculature. Angiogenesis is an early event in tumorigenesis and plays an important role in promoting tumor growth by supplying nutrients, oxygen, and growth factors needed for tumor proliferation. VEGF expression is significantly associated with advanced stage and poor prognosis in patients with CRC. In a study of VEGF concentrations, 56% of CRC tumors expressed VEGF compared with 17% of normal mucosa cells, with significantly higher levels of expression in tumor cells. Lymph node and liver metastases were also significantly associated with elevated VEGF expression. The 5-year overall survival of patients with negative and positive expression of VEGF was 84% and 40%, respectively.7,8 Bevacizumab, ramucirumab, and aflibercept are anti-VEGF agents that have been shown to improve OS and clinical outcomes in patients with mCRC.
Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancer, especially CRC, and it is associated with a more aggressive disease. Activating mutations in KRAS, a small G-protein downstream of EGFR, correlates with poor response to anti-EGFR antibodies in mCRC.9 It is estimated that up to 80% of all sporadic CRC is due to chromosomal instability, characterized by mutational activation of oncogenes (KRAS) and the loss of tumor suppressor gene activity (APC, p53, SMAD4). This pattern of activity is characteristic of LCRC, particularly rectal cancer.2
Since the discovery that patients whose CRC tumors have KRAS mutations will not benefit from EGFR-antibody therapy, resistance to EGFR blockade in mCRC has been extensively studied.10 About 80% of all the KRAS mutations occur in exon 2 (codon 12 and 13). Multiple studies demonstrated that mutations in KRAS exons 3 and 4 or NRAS exons 2 to 4 can also predict lack of response to EGFR-targeted antibodies given in combination with first-line chemotherapy.11 In a study assessing the efficacy of panitumumab in mCRC, 43% of tumors were found to have KRAS mutations. The treatment effect on progression-free survival (PFS) in the wild-type KRAS group (HR = 0.45; 95% confidence interval [CI], 0.34–0.59) was significantly greater (P<0.0001) than in the mutant group (HR = 0.99; 95% CI, 0.73–1.36). Response rates were 17% for the wild-type group and 0% for the mutant group.9 After an initial response to EGFR-targeted antibodies, wild-type tumors invariably acquire KRAS point mutations leading to secondary resistance to therapy.10 CRC tumors should be tested for RAS mutations (KRAS or NRAS) before initiating treatment. Cetuximab and panitumumab are anti-EGFR antibodies that improve OS only in CRC patients with wild-type RAS genes.
Mutations in the BRAF gene may be found in up to 18% of CRC patients and are associated with shorter PFS and OS.12 Mutation of BRAF, the gene encoding the serine/threonine-specific protein kinase B-Raf, is a predominant event in cancers with poor prognosis such as melanoma and CRC.13 The BRAF mutation leads to a constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, which is essential for cell proliferation and tumor progression. Up to 80% of all BRAF mutations are V600E mutations.12
Several studies have confirmed the association of BRAF mutations with poor outcomes in CRC. A systematic review and meta-analysis investigating the correlation between the BRAF mutation and OS survival in patients with mCRC and melanoma has shown that the BRAF mutation more than doubles the risk of mortality in CRC patients.12 Approximately 60% of melanoma patients have BRAF mutations, and BRAF inhibitors have shown a response rate of 50–80% in these patients. However, in CRC patients, the response rate to BRAF inhibitors is approximately 5%. BRAF-mutated tumors are often right-sided and of higher grade and are associated with MSI and older age.14 Clinical trial data have demonstrated that EGFR inhibitors such as cetuximab and panitumumab are not effective in treating CRC unless given with a BRAF inhibitor such as vemurafenib.
Microsatellites (MS) are tandem repeats of short DNA sequences that are abundant throughout the human genome.15 In individuals with MSI, mutations in DNA mismatch-repair (MMR) proteins that normally identify and repair mismatched bases during DNA replication, lead to an accumulation of microsatellites. Microsatellites found within protein coding sequences cause frameshift mutations, producing highly altered and immunogenic proteins.16 Microsatellite instability-high (MSI-H) status is found in 10–15% of sporadic CRC and is a strong prognostic factor of favorable outcomes, such as lower stage at diagnosis.17,18 However, its prognostic value varies, depending on tumor stage, tumor location, and BRAF mutation status.
Assessing for somatic mutations in BRAF in conjunction with MSI status may be prognostically valuable.19,20 The V600E mutation renders BRAF constitutively active, resulting in a worse prognosis.12 One study stratified CRC patients based on MSI and BRAF status into three prognostic groups: MSI/BRAF-wild type or mutant (best prognosis), microsatellite stable (MSS)/BRAF-wild type (intermediate prognosis), and MSS/BRAF mutant (worst prognosis).19 Other studies have reached conflicting results, and no consensus exists to date on the best prognostic subgroupings.21
Clinical studies have shown that MMR status is associated with responsiveness to PD-1 blockade, with reported PFS rates up to 78% in MMR-deficient (dMMR) CRC patients, compared with 11% in MMR-proficient (pMMR) patients. It is believed that the dMMR CRC tumors are responsive to checkpoint inhibitors because MSI status is usually associated with increased neoantigen burden.22 Anti-PD-1 antibodies that are effective in metastatic CRC include pembrolizumab, nivolumab, and ipilimumab.
- Hopkins Medicine. Sporadic (nonhereditary) colorectal cancer. https://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/small_large_intestine/sporadic_nonhereditary_colorectal_cancer.pdf
- Lee GH, Malietzis G, Askari A, et al. Is right-sided colon cancer different to left-sided colorectal cancer?—a systematic review. Eur J Surg Oncol. 2015;41:300-308.
- Venook AP, Niedzwiecki D, Lenz H-J, et CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2014;32(5 suppl): abstract LBA3.
- Tejpar S, Stintzing, S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017;3:194-201.
- Schrag D, Weng S, Brooks G, et al. The relationship between primary tumor sidedness and prognosis in colorectal cancer. J Clin Oncol. 2016;34 (suppl): abstract 3505.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Colon Version 3.2018. https://www.nccn.org/professionals/physician_gls/default.aspx
- Cao D, Hou M, Guan YS, et al. Expression of HIF-1 alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC Cancer. 2009;9:432.
- Ishigami SI, Arii S, Furutani M, et al. Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer. 1998;78:1379-1384.
- Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634.
- Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532-536.
- Misale S, Di Nicolantonio F, Sartore-Bianchi A, et al. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov. 2014;4;1269-1280.
- Safaee Ardekani G, Jafarnejad SM, Tan L, et The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PLoS One. 2012; 7:e47054.
- Davies H, Bignell GR, Cox C, et Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.
- Barras D. BRAF mutation in colorectal cancer: an update. Biomark Cancer. 2015;7(suppl 1):9-12.
- Cortes-Ciriano I, Lee S, Park WY, et al. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;8:15180.
- Lee JJ, Chu E. Recent advances in the clinical development of immune checkpoint blockade therapy for mismatch repair proficient (pMMR)/non-MSI-H metastatic colorectal cancer. Clin Colorectal Cancer. 2018;17:258-273.
- Dietel M, Jöhrens K, Laffert MV, et al. A 2015 update on predictive molecular pathology and its role in targeted cancer therapy: a review focussing on clinical relevance. Cancer Gene Ther. 2015;22:417-430.
- Goldstein J, Tran B, Ensor J, et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol. 2014;25:1032-1038.
- Lochhead P, Kuchiba A, Imamura Y, et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst. 2013;105:1151-1156.
- Phipps AI, Limburg PJ, Baron JA, et al. Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology. 2015;148:77-87.e2.
- Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22:813-820.
- Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-2520.