Colorectal cancer

Exploring dysfunctional pathways, mechanisms, and biomarkers in colon cancer to discover new insights into the progression of the disease.

0

estimated new cases of CRC in 2015.1

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5-year survival rate in patients with metastatic colorectal cancer.2

Incidence & Mortality

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

Nearly 25% of patients present with metastatic colorectal cancer, which is far more difficult to treat than localized disease. Additionally, 40-50% of patients diagnosed initially with localized CRC will eventually develop metastatic disease.4

The number of diagnosed cases of CRC is expected to increase annually by ~1.7% across the US and the European Union Five (EU5; France, Germany, Italy, Spain, United Kingdom).3

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

Risk factors associated with CRC include5:

  • Increasing age.
  • Inflammatory bowel disease and history of CRC in first-degree relatives.
  • High BMI.
  • Diet high in red/processed meat and/or low in fruits and vegetables.
  • Cigarette smoking.
  • Low physical activity.
  • Personal history of colorectal polyps.
  • 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).

CRC progression is a stepwise histological sequence over a period of generally >10 years.6 One or more of the following mechanisms give rise to CRC7:

  • Chromosomal instability (CIN); associated with up to 85% of 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); incidence varies for genes involved.
    • Characterized by hypermethylation in the promoter region of tumor suppressor genes, such as MGMT and MLH1, or cell-cycle genes, resulting in their inactivation.
    • Hypermethylation is often associated with BRAF mutations and microsatellite instability (MSI).
  • Microsatellite instability (MSI); found in 15% of CRCs.8
    • 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:

  • The degree of penetration of the tumor through the bowel wall.
  • The presence or absence of nodal involvement.
  • The presence or absence of distant metastases.

Definitions for T, N, M Classification

Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor invades through the muscularis propria into the pericolorectal tissues
T4a Tumor penetrates to the surface of the visceral peritoneum
T4b Tumor directly invades or is adherent to other organs or structures
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1a Metastasis in one regional lymph node
N1b Metastasis in 2 to 3 regional lymph nodes
N1c Tumor deposit(s) in the submucosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis
N2a Metastasis in 4 to 6 regional lymph nodes
N2b Metastasis in ≥7 regional lymph nodes
Distant Metastasis (M)
M0 No distant metastasis
M1a Distant metastasis confined to one organ or site without peritoneal metastasis
M1b Metastasis in >1 organ/site or the peritoneum without peritoneal metastasis
M1c Metastasis to the peritoneal surface alone or with other site or organ metastases

Staging

Stage T N M
0 Tis N0 M0
I T1-T2 N0 M0
IIA T3 N0 M0
IIB T4a N0 M0
IIC T4b N0 M0
IIIA T1-T2 N1/N1c M0
T1 N2a M0
IIIB T3-T4a N1/N1c M0
T2-T3 N2a M0
T1-T2 N2b M0
IIIC T4a N2a M0
T3-T4a N2b M0
T4b N1-N2 M0
IVA Any T Any N M1a
IVB Any T Any N M1b
IVC Any T Any N M1c

Bowel obstruction and perforation, as well as elevated carcinoembryonic antigen (CEA), have a negative prognostic implication.10,11

CRC molecular subtypes represent biologically and clinically distinct subgroups.12

  • 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.
Hypermutated CRC Chromosomal Instability CIN Ultramutated CRC
Consensus Molecular Subtype (CMS) CMS1: MSI (14%) CMS2: Canonical (37%)
CMS3: Metabolic (13%)
CMS4: Mesenchymal (23%)
Mixed features (13%)
Description
  • Involves overexpression of genes specific to cytotoxic lymphocytes
  • Abundant tumor-infiltrating lymphocytes (TILs), highly immunogenic tumors
  • Common mutations include MSI+ and V600E
  • Chromosomal instability
  • Low inflammatory and immune signatures
  • Arise from oncogenic activation
  • KRAS mutations common
  • Transition phenotype/intratumoral heterogeneity
Hypermutated CRC
Consensus Molecular Subtype (CMS)
MS1: MSI (14%)
Description
  • Involves overexpression of genes specific to cytotoxic lymphocytes
  • Abundant tumor-infiltrating lymphocytes (TILs), highly immunogenic tumors
  • Common mutations include MSI+ and V600E
Chromosomal Instability CIN
Consensus Molecular Subtype (CMS)
CMS2: Canonical (37%)
CMS3: Metabolic (13%)
CMS4: Mesenchymal (23%)
Description
  • Chromosomal instability
  • Low inflammatory and immune signatures
  • Arise from oncogenic activation
  • KRAS mutations common
Ultramutated CRC
Consensus Molecular Subtype (CMS)
Mixed features(13%)
Description
Transition phenotype/intratumoral heterogeneity

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

  • As a result, treatment is primarily limited to palliative care.

Chemotherapy forms the backbone of treatment for metastatic CRC, either with or without targeted agents.13

  • Median overall survival with chemotherapy alone was ~18 months.14
  • 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 MSI-High metastatic CRC patients.15
    • MSI-H is present in ~12-15% of metastatic CRC patients.16

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.16

Relevant Biomarker Pathways

  1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524-548.
  2. National Cancer Institute. Cancer Stat Facts: Colon and Rectum Cancer. https://seer.cancer.gov/statfacts/html/colorect.html. Accessed November 27, 2017.
  3. National Cancer Institute: Colon Cancer Treatment (PDQ®)–Health Professional Version. https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq. Accessed November 2017.
  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/colonrectal-cancer/causes-risks-prevention/risk-factors.html. Last revised July 6, 2017. Accessed December 22, 2017
  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. Benson AB, et al. American Society of Clinical Oncology Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer. J Clin Oncol. 22(16):3408–3419.
  9. 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.
  10. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23(3):609-618.
  11. 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.
  12. Müller MF, Ibrahim AEK, Arends MJ. Molecular pathological classification of colorectal cancer. Virchows Arch. 2016;469:125-134.
  13. DeSantis CE, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64(4):252-71.
  14. 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.
  15. 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 aheadof print]
  16. 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.

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