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Posts Tagged ‘Colorectal cancer (CRC)’


Author Tilda Barliya PhD

Hepatic metastatic disease from colorectal cancer (CRC) is a significant clinical problem. The liver is the dominant metastatic site for patients with CRC, and although two-thirds of affected patients have extrahepatic spread, some have disease that is isolated to the liver. For patients with isolated liver metastases, regional treatment approaches may be considered as an alternative to systemic chemotherapy (1).

Metastases from CRC most commonly develop within 2 years of resection of the primary tumor and are usually asymptomatic; rarely, patients may complain of vague upper abdominal pain. Hepatic metastases associated with CRC may occur regardless of the initial stage of the primary tumor although nodepositive primary lesions are more likely to precede hepatic metastasis (2).

The available regional treatments for hepatic metastases from CRC include (1):

  • Surgical resection
  • Local tumor ablation (ie, instillation of alcohol or acetic acid directly into the metastatic lesions
  • Radiofrequency ablation [RFA])
  • Regional hepatic intraarterial chemotherapy or chemoembolization
  • Radiation therapy (RT)

**Among these treatments, only surgery is associated with a survival plateau.

Screening for Hepatic metastasis (3):

  • A biopsy may be indicated to confirm the diagnosis, depending upon the clinical picture. However, fine needle aspiration cytology has not been advocated as a screening test, because of its high risk of complications. It has been shown that the incidence of needle tract metastases is 0.4%-5.1% after fine needle aspiration and use of the procedure in abdominal tumors is fatal in 0.006%-0.031% of cases.  Most deaths are due to hemorrhage of liver tumors (3).
  • Laparoscopy has not been advocated as a screening test for colorectal liver metastases due to its invasiveness.
  • Imaging modalities, such as contrast enhanced computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography CT (PET-CT), may establish the diagnosis of liver metastasis of colorectal cancer. However, it is more difficult to make the clinical diagnosis of early liver metastases of colorectal cancer due to the absence of typical symptoms or signs.
  • Serological examination including tumor and biochemical markers for liver function evaluation is routinely performed, though its accuracy is not high.  In that aspect, carcinoembryonic antigen (CEA) levels is elevated in 63% of patients, while the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) is increased in about 30% of patients with liver metastases of colorectal cancer.

Surgical Resection (1)

Resection offers the greatest likelihood of cure for patients with liver-isolated CRC. In surgical case series, five-year survival rates after resection range from 24 to 58 percent, averaging 40 percent and surgical mortality rates are generally <5 percent (1). It’s worth noted that subgroups with advanced age, comorbid disease, and synchronous hepatic and colon resection may have higher procedure-related mortality and worse long-term outcomes.

The five-year survival rate was only 25 percent, Even so, five-year survival rates with the most active systemic chemotherapy regimens are only 10 to 11 percent, only about one-fifth of whom have a sustained disease remission. More so, approximately one-third of five-year survivors suffer a cancer-related death, while those who survive 10 years appear to be cured (4).

Because of its clear survival impact, surgical resection is the treatment of choice when feasible. Unfortunately, no more than 20 percent of patients with isolated hepatic metastases are amenable to potentially curative resection. Most are not surgical candidates because of tumor size, location, multifocality, or inadequate hepatic reserve.

Patient candidates for resection – The criteria for resectability differ among individual liver surgeons regarding borderline cases, from center to center and from country to country. One consensus statement defined absolute unresectability as nontreatable extrahepatic disease, unfitness for surgery, or involvement of more than 70 percent of the liver or six segments (1,2).  Patients are evaluaed using preoperative liver MRI and intraoperative ultrasound which offer the optimal assessment of the number, size, and proximity of tumors to key vascular and biliary structures.

Modern multidisciplinary consensus for resectable CRC liver metastases:

  • Tumors that can be resected completely (leaving an adequate liver remnant)
  • No  involvement of the hepatic artery, major bile ducts, main portal vein, orceliac/paraaortic lymph nodes
  • Adequate predicted functional hepatic reserve postresection

Criteria for unresectable liver metastases (5):

  • Pateitns with more than three lesions, those
  • Patients with bilobar distribution (ie, tumor involving any segments of the left and right hemi-liver),
  • Patients in whom it was not possible to achieve 1 cm margins,
  • Patients with portal lymph node or other extrahepatic metastases, and
  • Patients with liver metastases from cancers other than colorectal tumors

Some of these exclusion criteria have been challenged.

  • Better and safer surgical techniques are now more suitable for patients with multiple, even bilobar tumors.
  • A two-stage approach to hepatic resection may be needed in the presence of multiple bilobar metastases
  • Achieving wide margins doesn’t increase the 5-year survival. **** Only patients with a positive margin had worse survival and a higher intrahepatic recurrence rate.
  • Presence of portal lymph node metastases – still been challenged and results are controversy.
  • A major problem is the prediction of metastatic lymph nodes in the hepatic pedicle in patients with CRC liver metastases.  The presence of portal node metastases is not inevitably associated with distant metastases.  Outcome was more favorable if nodal involvement was limited to the porta as compared to along the common hepatic artery.
  • The presence of other sites of limited extrahepatic metastases (particularly lung) should not be considered a contraindication to resection as long as the disease is amenable to complete extirpation. However, outcomes in this group are not as favorable, particularly when there are >6 liver metastases.

Diagnostic Laparoscopy

In modern treatment paradigms, laparoscopy is infrequently performed, particularly since many patients have undergone surgical exploration of the peritoneum at the time of resection of a synchronous primary tumor. Laparoscopy is usually reserved for those thought to be at the highest risk for occult metastatic disease.

A growing number of authors report that staging laparoscopy (including laparoscopic US) performed under general anesthesia just prior to planned resection will identify 16 to 64 percent of patients with unresectable disease.

This approach is particularly useful in identifying small peritoneal metastases, additional hepatic metastases, and unsuspected cirrhosis. Laparoscopy in this setting is less likely to identify lymph node metastases, vascular compromise, and extensive biliary involvement that might render a patient unresectable (2,6).

Neoadjuvant chemotherapy

The availability of increasingly effective systemic chemotherapy has prompted interest in preoperative or neoadjuvant systemic chemotherapy prior to liver resection.  It may  be considered as a means of “downsizing” liver metastases prior to resection to lessen the complexity of hepatic metastasectomy or for initially unresectable metastatic disease (1). Chemotherapy, has many side effects including liver toxicity such as:  steatosis (chemotherapy-associated steatohepatitis, CASH), vascular injury, and nodular regenerative hyperplasia in the livers.

Due to high number of patients with liver toxicity and morbidity, these instructions have been suggested:

  • For low-risk (medically fit, four or fewer lesions), potentially resectable patients, initial surgery rather than neoadjuvant chemotherapy should be chosen, followed by postoperative chemotherapy.
  • For patients who have higher risk, borderline resectable or unresectable disease, neoadjuvant chemotherapy is the preferred approach.

Neoadjuvant Chemotherapy Guidelines from the National Comprehensive Cancer Network (NCCN) suggest any of the following:

  • FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or
  • FOLFOX or CAPOX or FOLFIRI plus cetuximab (wild-type K-ras only) or
  • FOLFOXIRI alone

Bevacizumab – Its addition to traditional chemotherapy results in a modestly higher frequency of tumor regression compared to regimens that do not include bevacizumab. However, these benefits have come at the cost of significant treatment-related toxicity. Such as: such as stroke and arterial thromboembolic events, bowel perforation and bleeding.  Data regarding the need and timing of use of bevacizumab is somewhat conflicting.

Cetuximab (if K-ras wild type) and panitumumab (if K-ras wild type) are also suggested as part of the  chemotherapy regimen in certain clinics are regional dependent.

Intraarterial (HIA) chemotherapy – The administration of chemotherapy into the hepatic artery. The benefit of this approach is remains unclear. A combined approach of HIA floxuridine plus systemic chemotherapy (oxaliplatin plus irinotecan) was explored in a single institution study of 49 patients with initially unresectable CRC liver metastases. Overall, 92 percent had either a complete or partial response rate to chemotherapy, and 23 (43 percent) were able to undergo a later resection, 19 with negative margins. The median overall survival from pump placement for the entire cohort was 40 months (1, 7).  Another approach is HIA oxaliplatin combined with systemic 5-FU and leucovorin for patients with initially unresectable but isolated hepatic CRC metastasis.

It should be noted that this approach is not used by many clinicians outside of New York City. The only way to assess the contribution of HIA chemotherapy to neoadjuvant systemic chemotherapy is with a randomized controlled trial.

Portal vein infusion — Because HIA FUDR carries a risk for biliary sclerosis, administration into the portal vein has been explored as an alternative. hepatic micrometastases (as well as the biliary tree) are primarily dependent on the portal vein for their blood supply. Like HIA infusion, portal vein infusion (PVI) carries with it a significant regional exposure advantage.

The potential benefit of adjuvant PVI with FUDR after resection or ablation of isolated hepatic metastases was evaluated in two trials conducted at the City of Hope Medical Center (1, 8).  The benefit of this approach was somewhat lower than has been reported with HIA FUDR and systemic 5-FU. Therefore, the use of this approach is limited.

Hepatic radiotherapy — The use of external beam radiotherapy and internal application of radiation therapy through the use of yttrium-labeled microspheres.  Radiation therapy (RT) has traditionally had a limited role in the treatment of liver tumors, primarily because of the low whole-organ tolerance of the liver to radiation (9).   When radiation is applied to the entire liver, RT doses of 30 to 33 Gy carry about a 5% risk of radiation-induced liver disease (RILD). The risk rises rapidly, such that by 40 Gy, the risk is approximately 50%.  Considering that most solid tumors require RT doses higher than 60 Gy to provide a reasonable chance for local control, it is not surprising that wholeorgan liver RT provides only a modest palliative benefit rather than durable tumor control. Hepatic dysfunction after RT is a very frequent event.

Summary:

Liver metastasis are a very tough disease to battle and the outcome is not encouraging. Currently, surgical resection is the only potentially curative option for patients with liver-isolated metastatic colorectal cancer. For appropriately selected patients with four or fewer metastases, five-year relapse-free survival rates average 30 percent.  Diagnostic laparoscopy is suggested only in patients with a suspicion of low-volume carcinomatosis based on preoperative radiographic imaging and for selected other cases at high risk for intraperitoneal metastatic disease. The optimal chemotherapy regimen is still not fully established but some suggestions have been made and the benefits of using HIA is still not clear.

Standardization of scoring, timing, surgical techniques , results from clinical trials and advanced research will offer better hope for these patients, who now, have a very bad prognosis and survival rates.

Reference:

1.  Venook AP and Curley SA. Management of potentially resectable colorectal cancer liver metastases. UpToDate Jun 2013. http://www.uptodate.com/contents/management-of-potentially-resectable-colorectal-cancer-liver-metastases

2. Smith AJ., DeMatteo RP., Fong Y and Blumgart LH.  Metastatic Liver Cancer.  HEPATOBILIARY CANCER. http://web.squ.edu.om/med-Lib/MED_CD/E_CDs/Hepatobiliary%20Cancer/DOCS/Ch4.pdf

3. Wu XZ., Ma F., and Wang XL. Serological diagnostic factors for liver metastasis in patients with colorectal cancer. World J Gastroenterol. 2010 August 28; 16(32): 4084–4088. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928464/

4. Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, Kemeny N, Brennan MF, Blumgart LH, D’Angelica M. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575. http://www.ncbi.nlm.nih.gov/pubmed?term=17925551

5. Tanabe KK. Palliative liver resections. J Surg Oncol. 2002;80(2):69. http://onlinelibrary.wiley.com/doi/10.1002/jso.10108/abstract;jsessionid=F19964733A4A1A2708A0BA0E274CF586.d01t03

6.  Ravikumar TS. Laparoscopic staging and intraoperative ultrasonography for liver tumor management. Surg Oncol Clin N Am 1996;5:271–282. http://www.ncbi.nlm.nih.gov/pubmed/9019351

7, Kemeny NE, Melendez FD, Capanu M, Paty PB, Fong Y, Schwartz LH, Jarnagin WR, Patel D, D’Angelica M.  Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2009;27(21):3465. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646304/

8.  Faynsod M, Wagman LD, Longmate J, Carroll M, Leong LA. Improved hepatic toxicity profile of portal vein adjuvant hepatic infusional chemotherapy.J Clin Oncol. 2005;23(22):4876. http://www.ncbi.nlm.nih.gov/pubmed?term=16009960

9. I. Frank Ciernik and Theodore S. Lawrence. Radiation Therapy for Liver Tumors. Book: Systemic and Regional Therapies. Chapter 7.  http://www.jblearning.com/samples/0763718572/Chapter_07.pdf

Other articles from our open journal access

I.  By: Dr. Sudipta Saha PhD . Treatment for Endocrine Tumors and Side Effects. https://pharmaceuticalintelligence.com/2013/06/24/treatment-for-endocrine-tumors-and-side-effects/

II. By: Dr. Stephen J. Williams PhD. Differentiation Therapy – Epigenetics Tackles Solid Tumors. https://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

III. By: Dr.  Ritu Saxena, PhD. In focus: Circulating Tumor Cells. https://pharmaceuticalintelligence.com/2013/06/24/in-focus-circulating-tumor-cells/

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Personalized Medicine and Colon Cancer

Author: Tilda Barliya, PhD

According to Dr. Neil Risch a leading expert in statistical genetics and the director of the UCSF Institute for Human Genetics,  “Personalized medicine, in which a suite of molecules measured in a patient’s lab tests can inform decisions about preventing or treating diseases, is becoming a reality” (7).

Colorectal cancer (CRC) is the third most common cancer and the fourth-leading cause of cancer death worldwide despite advances in screening, diagnosis, and treatment. Staging is the only prognostic classification used in clinical practice to select patients for adjuvant chemotherapy. However, pathological staging fails to predict recurrence accurately in many patients undergoing curative surgery for localized CRC (1,2). Most of the patients who are not eligible for surgery need adjuvant chemotherapy in order to avoid relapse or to increase survival. Unfortunately, only a small portion of them shows an objective response to chemotherapy, becoming problematic to correctly predict patients’ clinical outcome (3).

CRC patients are normally being tested for several known biomarkers which falls into 4 main categories (5):

  1. Chromosomal Instability (CIN)
  2. Microsatellite Instability (MSI)
  3. CpG Island methylator phynotype (CIMP)
  4. Global DNA hypomethylation

In the past few years many studies have exploited microarray technology to investigate gene expression profiles (GEPs) in CRC, but no established signature has been found that is useful for clinical practice, especially for predicting prognosis.  Only a subset of CRC patients with MSI tumors have been shown to have better prognosis and probably respond differently to adjuvant chemotherapy compared to microsatellite stable (MSS) cancer patients (6).

Pritchard & Grady have summarized the selected biomarkers that have been evaluated in colon cancer patients (10).

Table 1

Selected Biomarkers That Have Been Evaluated in Colorectal Cancer

Biomarker Molecular Lesion Frequency
in CRC
Prediction Prognosis Diagnosis
KRAS Codon 12/13 activating
mutations; rarely codon
61, 117,146
40% Yes Possible
BRAF V600E activating
mutation
10% Probable Probable Lynch
Syndrome
PIK3CA Helical and kinase
domain mutations
20% Possible Possible
PTEN Loss of protein by IHC 30% Possible
Microsatellite Instability (MSI) Defined as >30%
unstable loci in the NCI
consensus panel or
>40% unstable loci in a
panel of mononucleotide
microsatellite repeats9
15% Probable Yes Lynch
Syndrome
Chromosome Instability (CIN) Aneuploidy 70% Probable Yes
18qLOH Deletion of the long arm
of chromosome 18
50% Probable Probable
CpG Island Methylator
Phenotype (CIMP)
Methylation of at least
three loci from a selected
panel of five markers
15% +/− +/−
Vimentin (VIM) Methylation 75% Early
Detection
TGFBR2 Inactivating Mutations 30%
TP53 Mutations Inactivating Mutations 50%
APC Mutations Inactivating Mutations 70% FAP
CTNNB1 (β-Catenin) Activating Mutations 2%
Mismatch Repair Genes Loss of protein by IHC;
methylation; inactivating
mutations
1–15% Lynch
Syndrome

CRC- colorectal cancer; IHC- immunohistochemistry; FAP- Familial Adenomatous Polyposis

Examples for the great need of personalized medicine tailored according to the patients’ genetics is clearly seen with two specific drugs for CRC:  Cetuximab and panitumumab are two antibodies that were developed to treat colon cancer. However, at first it seemed as if they were a failure because they did not work in many patients. Then, it was discovered that if a cancer cell has a specific genetic mutation, known as K-ras, these drugs do not work.  This is an excellent example of using individual tumor genetics to predict whether or not treatment will work (8).

According to Marisa L et al, however, the molecular classification of CC currently used, which is based on a few common DNA markers as mentioned above (MSI, CpG island methylator phenotype [CIMP], chromosomal instability [CIN], and BRAF and KRAS mutations), needs to be refined.

Genetic Expression Profiles (GEP)

CRC is composed of distinct molecular entities that may develop through multiple pathways on the basis of different molecular features, as a consequence, there may be several prognostic signatures for CRC, each corresponding to a different entity. GEP studies have recently identified at least three distinct molecular subtypes of CC (4). Dr. Marisa Laetitia and her colleagues from the Boige’s lab however, have conducted a very thorough study and identifies 6 distinct clusters for CC patients. Herein, we’ll describe the majority of this study and their results.

Study  Design:

Marisa L et al (1) performed a consensus unsupervised analysis (using an Affymertix chip) of the GEP on tumor tissue sample from 750 patients with stage I to IV CC. Patients were staged according to the American Joint Committee on Cancer tumor node metastasis (TNM) staging system. Of the 750 tumor samples of the CIT cohort, 566 fulfilled RNA quality requirements for GEP analysis. The 566 samples were split into a discovery set (n = 443) and a validation set (n = 123).

Several known mutations were used as internal controls, including:

  • The seven most frequent mutations in codons 12 and 13 of KRAS .
  • The BRAF c.1799T>A (p.V600E)
  • TP53mutations (exons 4–9)
  • MSI was analyzed using a panel of five different microsatellite loci from the Bethesda reference panel
  • CIMP status was determined using a panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1)

Results:

The results revealed six clusters of samples based on the most variant probe sets. The consensus matrix showed that C2, C3, C4, and C6 appeared as well-individualized clusters, whereas there was more classification overlap between C1 and C5. In other words:

  • Tumors classified as C1, C5, and C6 were more frequently CIN+, CIMP−TP53 mutant, and distal (p<0.001), without any other molecular or clinicopathological features able to discriminate these three clusters clearly.
  • Tumors classified as C2, C4, and C3 were more frequently CIMP+ (59%, 34%, and 18%, respectively, versus <5% in other clusters) and proximal.
  • C2 was enriched for dMMR (68%) and BRAF- mutant tumors (40%).
  • C3 was enriched for KRAS- mutant tumors (87%).

Note: No association between clusters and TNM stage (histopathology) was found, except enrichment for metastatic (31%) tumors in C4.

Figure: These signaling pathways associated with the molecular subtype (by cluster)

Figure 2 Signaling pathways associated with each molecular subtype.

Marisa L et al. Signaling pathways associated with each molecular subtype

These clusters fall into several signaling pathways:

  • up-regulated immune system and cell growth pathways were found in C2, the subtype enriched for dMMR tumors
  • C4 and C6 both showed down-regulation of cell growth and death pathways and up-regulation of the epithelial–mesenchymal transition/motility pathways. displaying “stem cell phenotype–like” GEPs (91%)
  • Most signaling pathways were down-regulated in C1 and C3.
  • In C1, cell communication and immune pathways were down-regulated.
  • In C5, cell communication, Wnt, and metabolism pathways were up-regulated.

These results are further summarized in table 2:

Figure 3 Summary of the main characteristics of the six subtypes.

Marisa L et al. Gene Expression Classification of Colon Cancer into Molecular Subtypes

The authors have identified six robust molecular subtypes of CC individualized by distinct clinicobiological characteristics (as summarized in table 2).

This classification successfully identified the dMMR tumor subtype, and also individualized five other distinct subtypes among pMMR tumors, including three CIN+ CIMP− subtypes representing slightly more than half of the tumors. As expected, mutation of BRAF was associated with the dMMR subtype, but was also frequent in the C4 CIMP+ poor prognosis subtype. TP53– andKRAS-mutant tumors were found in all the subtypes; nevertheless, the C3 subtype, highly enriched in KRAS-mutant CC, was individualized and validated, suggesting a specific role of this mutation in this particular subgroup of CC.

Current Treatments for colon cancer- Table 3 (11) .

Constant S et al. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

Exploratory analysis of each subtype GEP with previously published supervised signatures and relevant deregulated signaling pathways improved the biological relevance of the classification.

The biological relevance of our subtypes was highlighted by significant differences in prognosis. In our unsupervised hierarchical clustering, patients whose tumors were classified as C4 or C6 had poorer RFS than the other patients.

Prognostic analyses based solely on common DNA alterations can distinguish between risk groups, but are still inadequate, as most CCs are pMMR CIMP− BRAFwt.

The markers BRAF-mutant, CIMP+, and dMMR may be useful for classifying a small proportion of cases, but are uninformative for a large number of patients.

Unfortunately, 5 of the 9 anti-CRC drugs approved by the FDA today are basic cytotoxic chemotherapeutics that attack cancer cells at a very fundamental level (i.e. the cell division machinery) without specific targets, resulting in poor effectiveness and strong side-effects (Table 3) (11).

An example for side effects induction mechanisms have also been reported in CRC for the BRAF(V600E) inhibitor Vemurafenib that triggers paradoxical EGFR activation (12).

Summary:

The authors of this study “report a new classification of CC into six robust molecular subtypes that arise through distinct biological pathways and represent novel prognostic subgroups. Our study clearly demonstrates that these gene signatures reflect the molecular heterogeneity of CC. This classification therefore provides a basis for the rational design of robust prognostic signatures for stage II–III CC and for identifying specific, potentially targetable markers for the different subtypes”.

These results further underline the urgent need to expand the standard therapy options by turning to more focused therapeutic strategies: a targeted therapy-for specific subtype profile.. Accordingly, the expansion and the development of new path of therapy, like drugs specifically targeting the self-renewal of intestinal cancer stem cells – a tumor cell population from which CRC is supposed to relapse, remains relevant.

Therefore, the complexity of these results supports the arrival of a personalized medicine, where a careful profiling of tumors will be useful to stratify patient population in order to test drugs sensitivity and combination with the ultimate goal to make treatments safer and more effective.

References:

1. Marisa L,  de Reyniès A, Alex Duval A,  Selves J, Pierre Gaub M, Vescovo L, Etienne-Grimaldi MC, Schiappa R, Guenot D, Ayadi M, Kirzin S, Chazal M, Fléjou JF…Boige V. Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value. PLoS Med May 2013 10(5): e1001453. doi:10.1371. http://www.plosmedicine.org/article/info%3Adoi/10.1371/journal.pmed.1001453

2. Villamil BP, Lopez AR, Prieto SH, Campos GL, Calles A, Lopez- Asenjo JA, Sanz Ortega J, Perez CF, Sastre J, Alfonso R, Caldes T, Sanchez FM and Rubio ED. Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer 2012, 12:260.  http://www.biomedcentral.com/1471-2407/12/260/

3. Diaz-Rubio E, Tabernero J, Gomez-Espana A, Massuti B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, et al.: Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 2007, 25(27):4224-4230. http://jco.ascopubs.org/content/25/27/4224.long

4. Salazar R, Roepman P, Capella G, Moreno V, Simon I, et al. (2011) Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 29: 17–24. http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&doptcmdl=Citation&defaultField=Title%20Word&term=Salazar%5Bauthor%5D%20AND%20Gene%20expression%20signature%20to%20improve%20prognosis%20prediction%20of%20stage%20II%20and%20III%20colorectal%20cancer

5.  By: Global Genome Knowledge. Colorectal Cancer- Personalized Medicine, Now a Clinical Reality.  http://www.srlworld.com/innersense/Voice-135-Colorectal-Cancer-Sept-2012-IS.pdf

6. Popat S, Hubner R and Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005 Jan 20;23(3):609-618. http://www.ncbi.nlm.nih.gov/pubmed/15659508

7. By: Jeffrey Norris. Value of Genomics and Personalized Medicine Is Wrongly Downplayed.http://www.ucsf.edu/news/2012/04/11864/value-genomics-and-personalized-medicine-wrongly-downplayed

8. By: James C Salwitz. The Future is now: Personalized Medicine. http://www.cancer.org/cancer/news/expertvoices/post/2012/04/18/the-future-is-now-personalized-medicine.aspx

9. Jeffrey A. Meyerhardt., and Robert J. Mayer. Systemic Therapy for Colorectal Cancer. N Engl J Med 2005;352:476-487. http://www.med.upenn.edu/gastro/documents/NEJMchemotherapycolorectalcancer.pdf

10. Pritchard CC and Grady WM. Colorectal Cancer Molecular Biology Moves Into Clinical Practice. Gut. Jan 2011 60(1): 116-129.  Gut. 2011 January; 60(1): 116–129http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006043/

11. Constant S, Huang S, Wiszniewski L andMas C. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies.  Pharmacology, Toxicology and Pharmaceutical Science » “Drug Discovery”, book edited by Hany A. El-Shemy, ISBN 978-953-51-0906-8.  http://www.intechopen.com/books/drug-discovery/colon-cancer-current-treatments-and-preclinical-models-for-the-discovery-and-development-of-new-ther

12. Prahallad, C. Sun, S. Huang, F. Di Nicolantonio, R. Salazar, D. Zecchin, R. L. Beijersbergen, A. Bardelli, R. Bernards, 2012 Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature Jan 2012 483 (7387): 100-103. http://www.nature.com/nature/journal/v483/n7387/full/nature10868.html

Other related articles on this Open Access Online Scientific Journal include the following:

*. By Tilda Barliya PhD. Colon Cancer. https://pharmaceuticalintelligence.com/2013/04/30/colon-cancer/

**. By: Tilda Barliya PhD. CD47: Target Therapy for Cancer. https://pharmaceuticalintelligence.com/2013/05/07/cd47-target-therapy-for-cancer/

I. By: Aviva Lev-Ari, PhD, RNCancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed. https://pharmaceuticalintelligence.com/2013/04/21/cancer-genomic-precision-therapy-digitized-tumors-genome-wgsa-compared-with-genome-native-germ-line-flash-frozen-specimen-and-formalin-fixed-paraffin-embedded-specimen-needed/

II. By: Aviva Lev-Ari, PhD, RN. Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection. https://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

III.  By: Stephen J. Williams, Ph.DIssues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. https://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

IV. By: Ritu Saxena, Ph.DIn Focus: Targeting of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

V.  By: Ziv Raviv PhD. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv. https://pharmaceuticalintelligence.com/2013/03/25/tel-aviv-sourasky-medical-center-cancer-prevention-center-excellent-example-for-adopting-prevention-of-cancer-as-a-mean-of-fighting-it/

VI. By: Ritu Saxena, PhD. In Focus: Identity of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

VII. By: Dror Nir, PhD. State of the art in oncologic imaging of Colorectal cancers. https://pharmaceuticalintelligence.com/2013/02/02/state-of-the-art-in-oncologic-imaging-of-colorectal-cancers/

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Colon Cancer

Author/Editor: Tilda Barliya PhD

 

Colorectal cancer is the third most common type of cancer diagnosed in the United States and is the third most common cause of cancer-related death. The majority of cases are sporadic, with hereditary colon cancer contributing up to 15% of all colon cancer diagnoses. Treatment consists of surgery for early-stage disease and the combination of surgery and adjuvant chemotherapy for advanced-stage disease. Management of metastatic disease has evolved from primary chemotherapeutic treatment to include resection of single liver and lung metastases in addition to resection of the primary disease and chemotherapy (1-4).

Courtesy WebMD site

In the United States, colorectal cancer (CRC) is the third most common type of cancer diagnosed and the third most common cause of cancer-related death in men and women. In 2010, an estimated 102,900 new cases of colon cancer were diagnosed (49,470 male, 53,430 female) and 51,370 patients (26,580 male, 24,790 female) died from CRC. The death rate from colon cancer decreased over the preceding decade, from 30.77 per 100,000 people to 20.5 per 100,000 people. The lifetime risk of developing colon cancer in industrialized nations is 5% and is stable or decreasing. In contrast, the incidence in developing countries continues to rise, hypothesized to be due to increased exposure to risk factors. It has been estimated that 1.5 million people in the United States will be living with CRC by 2020.The financial burden of caring for this population is significant: $4.5 to $9.6 billion per year.

Colon Cancer is divided into 5 types:

  1. Sporadic: 60-85%
  2. Familial: 10-30%
  3. Hereditary non-Polyposis Colon Cancer (HNPCC): 5%
  4. Familial Adenomatous Polyposis (FAP): 1%
  5. Autosomal Dominant Inheritance

The molecular defects are of two types:

  • alterations that lead to novel or increased function of oncogenes
  • alterations that lead to loss of function of tumor-suppressor genes (TSGs)

Multiple genes are associated with the initiation and progression of the different syndromes of colon cancer and are summarized by Fearon ER in Table 1 (6):

Table 1  Genetics of inherited colorectal tumor syndromesa
Syndrome Common features Gene defect(s)
FAP Multiple adenomatous polyps (>100) and carcinomas of the colon and rectum; duodenal polyps and carcinomas; fundic gland polyps in the stomach; congenital hypertrophy of retinal pigment epithelium APC (>90%)
Gardner syndrome Same as FAP; also, desmoid tumors and mandibular osteomas APC
Turcot’s syndrome Polyposis and colorectal cancer with brain tumors (medulloblastomas); colorectal cancer and brain tumors (glioblastoma) APC
MLH1PMS2
Attenuated adenomatous polyposis coli Fewer than 100 polyps, although marked variation in polyp number (from 5 to >1,000 polyps) observed in mutation carriers within a single family APC(predominantly 5′ mutations)
Hereditary nonpolyposis colorectal cancer Colorectal cancer without extensive polyposis; other cancers include endometrial, ovarian and stomach cancer, and occasionally urothelial, hepatobiliary, and brain tumors MSH2
MLH1
PMS2
GTBPMSH6
Peutz-Jeghers syndrome Hamartomatous polyps throughout the GI tract; mucocutaneous pigmentation; increased risk of GI and non-GI cancers LKB1STK11(30–70%)
Cowden disease Multiple hamartomas involving breast, thyroid, skin, central nervous system, and GI tract; increased risk of breast, uterus, and thyroid cancers; risk of GI cancer unclear PTEN (85%)
Juvenile polyposis syndrome Multiple hamartomatous/juvenile polyps with predominance in colon and stomach; variable increase in colorectal and stomach cancer risk; facial changes DPC4 (15%)
BMPR1a(25%)
PTEN (5%)
MYH-associated polyposis Multiple adenomatous GI polyps, autosomal recessive basis; colon polyps often have somatic KRAS mutations MYH

aAbbreviations: FAP, familial adenomatous polyposis; GI, gastrointestinal.

Essentially all of the genes discussed above are conclusively implicated in subsets of CRC due to specific somatic defects that either activate or inactivate gene and protein function. It is hypothesized that essentially any gene with dysregulated expression in CRC—either increased or decreased expression—may have a functionally significant role as an oncogene or a TSG, respectively. The aggregate data on the mutations and function of any given gene must be carefully evaluated to establish whether the gene truly contributes to CRC pathogenesis and whether it should be designated as an oncogene or a TSG (5,6).

The first proposed genetic model of CRC assumed that most CRCs arise from preexisting adenomatous lesions and that the accumulation of multiple gene defects is required for CRCs.

Benign GI tumors are a varied group, but localized lesions that project above the surrounding mucosa are commonly termed polyps. In humans, most colorectal polyps, particularly small polyps less than 5 mm in size, are hyperplastic (6). Most data indicate that hyperplastic polyps are not a major precursor to CRC; rather, the adenomatous polyp, or adenoma, is probably the important precursor lesion (7).

” Adenomas arise from glandular epithelium and are characterized by dysplastic morphology and altered differentiation of the epithelial cells in the lesion. The prevalence of adenomas in the United States is approximately 25% by age 50 and approximately 50% by age 70 (8)”. Only a fraction of adenomas progress to cancer, and progression probably occurs over years to decades. Individuals affected by syndromes that strongly predispose to adenomas, such as FAP, invariably develop CRCs by the third to fifth decade of life if their colons are not removed”.

A more recent and modified version of the genetic model postulate that each gene defect described in the model occurs at high frequency only at particular stages of tumor development. This observation is the basis for assigning a relative order to the defects in a multistep pathway.

Colon Cancer and clinical Trails:

Mutations in the KRAS proto-oncogene are found in 40-45% of patients with CRC and occur mainly in exon 2 (codon 12 and 13) and to a lesser extent in exon 3 (codon 61) and exon 4 (codon 146). A number of studies have evaluated a potential prognostic role of KRAS  in clinical practice for the treatment of colorectal cancer. However, clinical study design, reproducibility, interpretation and reporting of the clinical data remain important challenges.

Laurent-Puig’s group was the first to show the negative predictive value of KRAS mutations for response to the EGFR monoclonal antibody (mAb) cetuximab (11, 12, 13). Ever since then, a number of large phase II-III randomized studies have confirmed the negative predictive value of KRAS mutations for response to cetuximab and panitumumab treatment.

The role of KRAS mutations in predicting response to other therapies remains unclear. A subset analysis of patients treated in the phase III study of bevacizumab plus IFL (irinotecan, bolus 5-FU, and folinic acid) versus IFL showed that the clinical benefit of bevacizumab is independent of KRAS mutational status (11, 14).

The KRAS biomarker story is unique in several ways. It represents the first biomarker integrated into clinical practice in CRC“.

The high prevalence of KRAS mutations in CRC and its strong negative predictive value for EGFR mAb therapies, has led to its rapid acceptance as a valuable biomarker. The EMEA, FDA and ASCO47 now recommend that all patients with metastatic CRC who are candidates for anti-EGFR mAb therapy should be tested for KRAS mutations and, if a KRAS mutation in codon 12 or 13 is detected, then patients should not receive anti-EGFR antibody therapy.

More so, Data from the PETACC-3 trial, presented at ASCO 2010, have shown that KRAS and BRAF mutant CRC tumors induce different gene-expression profiles, further reiterating that these tumors have a distinct underlying biology. Despite intensive progress in the field of genomic research, none of these genomic markers are used routinely in clinical trials.  Only, nowadays, trials are starting to use specific gene-pathway” target in CRC clinical trials.

Samuel Constant et al. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

Summary:

Early studies are underway to understand the role of DNA methylation, chromatin modification, changes in the patterns of mRNA and noncoding RNA expression, and changes in protein expression and posttranslational modification. However,  we do not yet have an indepth and comprehensive understanding of the pathogenesis of the biologically and clinically distinct subsets of CRC. Careful design of clinical trials end points and validation of the genes as potential prognostic markers will allow a better outcome for these patients.

Ref:

1. Sarah Popek, MD, and Vassiliki Liana Tsikitis, MD. Colorectal Cancer: A Review. OncLive  November 10, 2011. http://www.onclive.com/publications/contemporary-oncology/2011/fall-2011/Colorectal-Cancer-A-Review

x. Martin Hefti.,  H.Maximilian Mehdorn., Ina Albert and Lutz Dörner. Fluorescence-Guided Surgery for Malignant Glioma: A Review on Aminolevulinic Acid Induced Protoporphyrin IX Photodynamic Diagnostic in Brain Tumors.  Current Medical Imaging Reviews, 2010, 6, 1-5. http://www.hirslanden.ch/content/global/en/startseite/gesundheit_medizin/mediathek_bibliothek/fachartikel/verschiedenes/fluorescence_guidedsurgeryformalignantglioma/_jcr_content/download/file.res/FluorescenceGuidedSurgeryforMalignantGlioma.pdf

2. Oguz Akin, Sandra B. Brennan., D. David Dershaw., Michelle S. Ginsberg., Marc J. Gollub., Heiko Sch€oder., David M. Panicek, and Hedvig Hricak. Advances in Oncologic Imaging: Update on 5 Common Cancers. CA CANCER J CLIN 2012;62:364–393. http://onlinelibrary.wiley.com/doi/10.3322/caac.21156/pdf

3. O’Donnell, Kevin et al. Nanoparticulate systems for oral drug delivery to the colon. International Journal of Nanotechnology, 2010, 8, 1/2, 4-20. “Colonic Navigation: Nanotechnology Helps Deliver Drugs to Intestinal Target”. http://www.sciencedaily.com/releases/2010/11/101104154553.htm

4. Perumal V. Molecular Therapy and Nanocarrier Based Drug Delivery to Colon Cancer: Targeted Molecular Therapy (AEE788 and Celecoxib) and Drug Delivery (Celecoxib) To Colon Cancer. http://www.amazon.com/Molecular-Therapy-Nanocarrier-Delivery-Cancer/dp/3659162558

5. Xiaoyun Liao, Paul Lochhead, Reiko Nishihara, Teppei Morikawa, Aya Kuchiba, Mai Yamauchi, Yu Imamura, Zhi Rong Qian, Yoshifumi Baba, Kaori Shima, Ruifang Sun, Katsuhiko Nosho, Jeffrey A. Meyerhardt, Edward Giovannucci, Charles S. Fuchs, Andrew T. Chan, Shuji Ogino. Aspirin Use, TumorPIK3CAMutation, and Colorectal-Cancer Survival. New England Journal of Medicine, 2012; 367 (17): 1596 DOI:10.1056/NEJMoa1207756http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532946/

Gene Mutation Identifies Colorectal Cancer Patients Who Live Longer With Aspirin Therapy. http://www.sciencedaily.com/releases/2012/10/121024175357.htm

6. Fearon ER. Molecular Genetics of Colorectal Cancer. Annual Review of Pathology: Mechanisms of Disease 2011; 6: 479-507.http://www.annualreviews.org/doi/pdf/10.1146/annurev-pathol-011110-130235

7.  Jass JR. 2007. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Hisopathology 50:113–130. http://www.amedeoprize.com/ap/pdf/histopathology.pdf

8.  Rex DK, Lehman GA, Ulbright TM, Smith JJ, Pound DC, et al.  Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am. J. Gastroenterol 1993. 88:825–831.http://www.ncbi.nlm.nih.gov/pubmed/8503374

9. Kerber RA, Neklason DW, Samowitz WS, Burt RW. Frequency of familial colon cancer and hereditary nonpolyposis colorectal cancer (Lynch syndrome) in a large population database. Fam. Cancer 2005; 4:239–44. http://www.ncbi.nlm.nih.gov/pubmed/16136384

10. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996: 87:159–170. http://users.ugent.be/~fspelema/les%204-5%20HMG/kinzler%20clon.pdf

11. Sandra Van Schaeybroeck, Wendy L. Allen, Richard C. Turkington & Patrick G. Johnston. Implementing prognostic and predictive biomarkers in CRC clinical trials.(colorectal cancer)(Clinical report). Nature Reviews Clinical Oncology 2011: 8; 222-232. http://www.nature.com/nrclinonc/journal/v8/n4/abs/nrclinonc.2011.15.html

12. Lievre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66 2006: 3992-3995. http://hwmaint.cancerres.aacrjournals.org/cgi/content/full/66/8/3992

13. Lievre, A. et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 2008: 26, 374-379. http://jco.ascopubs.org/content/26/3/374.full.pdf

14. Hurwitz, H. I., Yi, J., Ince, W., Novotny, W. F. & Rosen, O. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist  2009: 14, 22-28. http://theoncologist.alphamedpress.org/content/14/1/22.full

Other related articles on this Open Access Online Scientific Journal include the following:

I. By: Aviva Lev-Ari, PhD, RNCancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed. https://pharmaceuticalintelligence.com/2013/04/21/cancer-genomic-precision-therapy-digitized-tumors-genome-wgsa-compared-with-genome-native-germ-line-flash-frozen-specimen-and-formalin-fixed-paraffin-embedded-specimen-needed/

II. By: Aviva Lev-Ari, PhD, RN. Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection. https://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

III.  By: Stephen J. Williams, Ph.DIssues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. https://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

IV. By: Ritu Saxena, Ph.DIn Focus: Targeting of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

V.  By: Ziv Raviv PhD. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv. https://pharmaceuticalintelligence.com/2013/03/25/tel-aviv-sourasky-medical-center-cancer-prevention-center-excellent-example-for-adopting-prevention-of-cancer-as-a-mean-of-fighting-it/

VI. By: Ritu Saxena, PhD. In Focus: Identity of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

VII. By: Dror Nir, PhD. State of the art in oncologic imaging of Colorectal cancers. https://pharmaceuticalintelligence.com/2013/02/02/state-of-the-art-in-oncologic-imaging-of-colorectal-cancers/

Other posts by the group: Please see https://pharmaceuticalintelligence.com/?s=colon+cancer

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