Colorectal cancer

Exploring dysfunctional pathways, mechanisms, and biomarkers in colorectal cancer (CRC) to discover new insights into the progression of the disease.

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estimated new cases of CRC in 20161

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of U.S. men and women will be diagnosed with colorectal cancer at some point during their lifetime2

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5-year survival rate in patients with metastatic colorectal cancer2

Incidence & Mortality

In 2016, there were an estimated 1,324,922 people living with colorectal cancer in the United States alone.2

Between 2006 and 2016, annual global incidence of CRC increased by 34%, from 1.3 million to 1.7 million cases. Most of this increase can be explained by an aging and growing population (19% and 12%, respectively).1

Only 38% of CRC patients are diagnosed with localized-stage disease, defined as a tumor confined to the primary site. In contrast, 35% of patients have regional disease (spread to regional lymph nodes) at diagnosis, and 22% have distant or metastatic disease – 4% of patients are unstaged or the stage is unknown.2

Localized colorectal cancer is highly treatable, primarily by surgery. Resection results in cure in approximately 50% of patients.3

For the nearly one-quarter of patients who present with metastatic colorectal cancer, treatment can be far more difficult than localized disease. Additionally, 40-50% of patients diagnosed initially with localized CRC will eventually develop metastatic disease.4

The overall 5-year survival rate of CRC from diagnosis is ~65%. Patients with localized disease have a 5-year relative survival of ~90%, while patients with metastatic disease have a 5-year relative survival of ~14%.2

Overall, colorectal cancer is the 2nd most common cancer diagnosis (2nd in women; 3rd in men) and has the 3rd highest death rate among cancer deaths.1,2

Risk factors associated with CRC include5:

  • Increasing age
  • Personal history of inflammatory bowel disease, CRC, or colorectal polyps
  • High BMI (overweight or obesity)
  • Diet high in red or processed meats
  • Long-term cigarette smoking
  • Heavy alcohol consumption
  • Low physical activity
  • History of CRC or adenomatous polyps in first-degree relatives
  • Lynch syndrome [LS; an inherited defect in DNA mismatch repair (MMR) genes, which leads to high microsatellite instability (MSI)]
  • Familial adenomatous polyposis (FAP; a genetic condition that leads to the development of adenomatous polyps throughout the colon)

African Americans have the highest colorectal cancer incidence and mortality rates of all racial groups in the US.5,6

CRC progression is a stepwise histological sequence, most commonly initializing with a transformation from adenoma to carcinoma over a period of ~10 years.5

One or more of the following mechanisms give rise to CRC7:

  • Chromosomal instability (CIN); associated with FAP cases involving germline APC gene mutations and with most (~85%) sporadic CRCs
    • CIN tumors are characterized by aneuploidy and loss of heterozygosity (LOH).
    • Begins with acquisition of adenomatous polyposis coli (APC) mutations, followed by mutational activation of the KRAS oncogene and inactivation of TP53 tumor suppressor gene.
  • CpG island methylator phenotype (CIMP); CIMP positive tumors are defined as those with three or more of the panel gene promoters methylated
    • Characterized by hypermethylation in the promoter region of tumor suppressor genes, such as MGMT and MLH1, or cell-cycle genes, resulting in their inactivation.
    • This hypermethylation is often associated with BRAF mutations and microsatellite instability (MSI).
  • Microsatellite instability (MSI); involves the inactivation of genetic alterations which is a hallmark condition in familial Lynch syndrome (LS) (3%) and appearing in ~15% of the sporadic CRC cases - MSI is often associated with proximal colon and poor differentiation, albeit with a better prognosis7,9
    • Cells with inactivating mutations in DNA mismatch repair (MMR) genes (usually from hypermethylation of the MLH 1 gene promoter) are unable to correct single-base mismatches and insertion-deletion loops that form during DNA replication. The accumulation of these errors causes the creation of microsatellite DNA fragments.
    • Analysis of a panel of MSI markers stratifies patients as MSI-High (MSI-H; >30% of unstable MSI biomarkers), MSI-Low (MSI-L; <30% of unstable MSI biomarkers), or Microsatellite Stable (MSS). Those with MSI-H tumors have a more positive prognosis compared with MSI-L or MSS tumors.

The three mechanisms that promote CRC are often interdependent.7

  • For example, hypermethylation of MMR genes may lead to MSI via the CIMP pathway.

The three characteristics that form the basis for the TNM staging system of CRC include3,8:

  • The degree of penetration of the tumor (T) through the bowel wall.
  • The presence or absence of nodal (N) involvement.
  • The presence or absence of distant metastases (M).

Definitions for T, N, M Classification

Staging

Allele loss at or mutation of DCC, TP53, and KRAS are all associated with a poorer prognosis and these abnormalities are not common in tumors with MSI.9 Lymphovascular invasion on pathology of the primary tumor, as well as elevated carcinoembryonic antigen (CEA), have a negative prognostic implication as well.10

CRC molecular subtypes represent biologically and clinically distinct subgroups.11

  • Consensus molecular subtype (CMS) 1: Hypermutated due to defective DNA mismatch repair with MSI and MLH1 silencing.
  • CMS2: Predominantly displayed epithelial signatures with prominent WNT and MYC signaling activation.
  • CMS3: Predominantly epithelial gene expression signatures and evidence of metabolic dysregulation in several pathways.
  • CMS4: Increased expression of epithelial-mesenchymal transition (EMT) genes and evidence of prominent transforming growth factor-β activation.
  • Samples with mixed features possibly represent either a transition phenotype or intratumoral heterogeneity.

Most patients with advanced or metastatic CRC are not candidates for tumor resection.4

Chemotherapy forms the backbone of treatment for advanced (late stage) and metastatic CRC, either with or without targeted agents.12

  • Median overall survival with chemotherapy alone was ~18 months.4,13
  • With the addition of targeted agents to the chemotherapy regimen, median overall survival increased to ~20 to 24 months.4
  • Immunotherapy was recently approved for use in microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic CRC patients.14
    • MSI-H is present in ~12-15% of metastatic CRC patients.15

As the complicated signaling pathways and network cross-talk involved in CRC tumorigenesis are better understood, agents that target these emerging key biomarkers may continue to increase the survival expectations for patients with metastatic CRC.15,16

  1. Global Burden of Disease Cancer Collaboration; Fitzmaurice C; Akinyemiju TF, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2018;4(11):1553–1568.
  2. National Cancer Institute. Cancer Stat Facts: Colon and Rectum Cancer. https://seer.cancer.gov/statfacts/html/colorect.html. Accessed November 2020.
  3. National Cancer Institute: Colon Cancer Treatment (PDQ®)–Health Professional Version. https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq. Accessed November 2020.
  4. Moriarity A, et al. Current targeted therapies in the treatment of advanced colorectal cancer: a review. Ther Adv Med Oncol. 2016;8(4):276–293.
  5. Colorectal cancer risk factors. American Cancer Society Web site. https://www.cancer.org/cancer/colon-rectal-cancer/causes-risks-prevention.html. Last revised February 21, 2018. Accessed July 2019.
  6. Amersi F, Agustin M, Ko CY. Colorectal cancer: epidemiology, risk factors, and health services. Clin Colon Rectal Surg. 2005;18(3):133-140.
  7. Tariq K, Ghias K. Colorectal cancer carcinogenesis: a review of mechanisms. Cancer Biol Med. 2016;13(1):120-135.
  8. American Joint Committee on Cancer. Colon and Rectum. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2016.
  9. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23(3):609-618.
  10. Sofocleous CT, et al. Radioembolization as a salvage therapy for heavily pre-treated patients with colorectal cancer liver metastases: factors affecting outcomes. Clin Colorectal Cancer. 2015;14(4):296–305.
  11. Müller MF, Ibrahim AEK, Arends MJ. Molecular pathological classification of colorectal cancer. Virchows Arch. 2016;469:125-134.
  12. DeSantis CE, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64(4):252-71.
  13. Goldberg R, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 22(1):23–30.
  14. Chang L, et al. Microsatellite instability: a predictive biomarker for cancer immunotherapy. Appl Immunohistochem Mol Morphol. 2017 Sep 4. doi: 10.1097/PAI.0000000000000575. [Epub ahead of print]
  15. Kawakami H, et al. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol. 2015 Jul;16(7):30.
  16. Taieb J, et al. The Evolving Biomarker Landscape for Treatment Selection in Metastatic Colorectal Cancer. Drugs (2019). https://doi.org/10.1007/s40265-019-01165-2.

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