Launch Training Phase I Lesson 1
Introduction to Colon Cancer
AACP0424-1
Introduction to Colon Cancer
Introduction to Colon Cancer •
Additional required reading: PDF files (click links to open) - ACS Colorectal Cancer - ACS Colorectal Cancer Facts and Figures - AJCC 7th Staging Overview - NCCN Guidelines (see especially page Col-3) - NCI booklet “what you need to know about colon cancer”
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Optional reading: Web pages that are good for further information: - http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001308/ (with more figures) - The NCI web page http://www.cancer.gov/cancertopics/types/colon-and-rectal - Less US-focus but always a good summary http://en.wikipedia.org/wiki/Colorectal_cancer - The SEER database if you are into statistics http://seer.cancer.gov/statfacts/html/colorect.html
1. Anatomy Reading and Pictures: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001308/ To simplify the anatomy, the different segments of the colon (also called large bowel) are often lumped together into three major groups: right, left and rectum. Ascending and transverse colon are part of the right colon while descending and sigmoid colon are part of the left colon. .
Currently, ColoPrint has been validated only in colon cancer and cannot be used in rectal cancer patients. Colon and Rectal Cancer are often grouped together as colorectal cancer. This is due to the fact that the colon and rectum are histologically and biologically very similar. However, the treatment of rectal cancer is different than the treatment of colon cancer. Patients with rectal cancer can receive local radiation since the cancer is accessible for radiation. Therefore, many rectal cancer patients receive radiation prior to surgery (which has a big impact on the gene expression pattern). Because rectal cancer surgery is very difficult, the experience and the skill of the surgeon is often the most important risk factor to determine relapse (and that cannot be read out by microarray!). Since the introduction of the
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so called Total Mesorectal Excision (TME) surgery, the surgical procedure for rectal cancer became more standardized. Therefore Agendia is considering validation of ColoPrint in rectal cancer patients.
2. Incidence and Survival Reading: ACS Colorectal Cancer Facts and Figures 2012 • Colorectal cancer is the third most common cancer in men and women worldwide. In 2010, approximately 100,000 people in the United States were expected to be diagnosed with colon cancer (ACS Facts and Figures 2012), and estimates of the worldwide total of colon cancer incidence run as high as 1.2 million (ACS Global Facts and Figures 2008). • Incidence and death rates for colon cancer increase with age. Overall, 90% of new cases and 94% of deaths occur in individuals 50 and older. The median age of colon cancer patients is ~70 years. • More men (~60%) than women (~40%) have colon cancer • Incidence and mortality rates are highest in African American men and women • As with most cancers, the stage at which colon cancer is diagnosed is a key factor in determining longterm survival outcomes. For example, patients with stage I have better 5-year survival chances than patients with stage II. And patients with stage IIA have a better outcome than stage IIB patients. However, stage IIIA patients have the same outcome as patients with stage IIA.
Stage
% of patients
% 5-year survival
I
~15
90-95%
II A
~30
~80-85%
II B
6
~75%
III A
~2-3
80-85%
III B
~16
~65%
III C
~10
~45%
IV
~20-25
~10%
3. Stages Reading: AJCC 7th Staging Overview • The stage of cancer is determined by 3 main characteristics, the TNM staging (Tumour, Node, Metastasis) o T-stage (describing the size and how deep the tumor grew into the surrounding tissue) o N-stage (describing the number of lymph nodes that are positive for cancer) o M-stage (describing if the cancer has spread to other organs – or has metastasized)
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Simplified Staging (for more details see AJCC Staging Overview) • • • •
Stage I = T1 or T2, N0, M0 Stage II = T3 or T4, N0, M0 Stage III = T1-4, N1 or N2, M0 Stage IV = T1- 4, N0-2, M1
ColoPrint is indicated for all Stage II and Stage IIIA patients
4. Treatment and Guidelines Reading: NCCN Guidelines (page Col-3) In most US centers, physicians follow the NCCN guidelines for treatment recommendation. ASCO also releases guidelines for treatment but no recent recommendations or guidelines have been released for stage II patients. Confidential – For Internal Use Only – Not intended for Duplication/Distribution
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Stage I patients: Colon cancer treatment is relatively uniform in all hospitals and among physicians. Because of a favorable prognosis, patients with Stage I colon cancer are generally treated with surgery alone. Stage II patients: All patients with Stage II colon cancer are treated with surgery but whether the patients should receive chemotherapy as well is very controversial for 3 reasons: - The prognosis of patients is good (~80%) even without any additional treatment - The benefit of chemotherapy is very small (~3%) that means that 100 patients need to be treated and many of them suffer through toxic side effects so that 3 patients benefit - There are no clinical factors that help to identify those patients who are more likely to benefit The number of patients receiving adjuvant chemotherapy varies significantly from physician to physician and hospital to hospital. Approximately 30-50% of stage II patients receive adjuvant chemotherapy in the US today. Stage III patients: All patients are treated with Surgery and adjuvant chemotherapy is recommended for all stage III patients. Treatment is always 5-FU based treatment, either with or without oxaliplatin. However, it is acknowledged that a small subset of stage III patients has a very good prognosis (mainly stage IIIA) and might not need additional therapy. Confidential – For Internal Use Only – Not intended for Duplication/Distribution
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Drugs used to treat colorectal cancer Several drugs can be used to treat colorectal cancer. Often, 2 or more of these drugs are combined to try to make them more effective. Chemo drugs are very strong medicines that can also affect some healthy cells in the body. Doctors give the drugs in cycles, with each period of treatment followed by a rest period to allow the body time to recover. Chemotherapy cycles generally last about 2 to 4 weeks, and people usually get at least several cycles of treatment. For most chemotherapy regimens, treatment is repeated every 2 weeks, over a period of 6 months to a year. 5-Fluorouracil (5-FU) and leucovorin: 5-FU has been in use for several decades, and it is part of most chemotherapy regimens for colorectal cancer. It is usually given together with a drug called leucovorin (or folinic acid), which makes it more effective. This drug may be given as an infusion into a vein over 2 hours, or (more commonly) as a quick injection followed by continuous infusion over 1 or 2 days. For continuous infusions, the patient wears a small battery-operated pump that infuses 5-FU into an intravenous (IV) catheter. Capecitabine (Xeloda®): This is a chemotherapy drug in pill form. Once inside the body and inside the cell, it is converted to 5-FU.. This drug seems to be as effective as giving continuous intravenous 5-FU with leucovorin, however it is much more expensive. Capecitabine is usually taken twice a day for 2 weeks, followed by a week off. Irinotecan (Camptosar®): This drug is often combined with 5-FU and leucovorin (known as the FOLFIRI regimen) to treat advanced colorectal cancer. In some cases it may be tried by itself as a second-line treatment if other chemotherapy drugs are no longer effective. It is given as an IV infusion over 30 minutes to 2 hours. Oxaliplatin (Eloxatin®): This drug is usually combined with 5-FU and leucovorin (known as the FOLFOX regimen) or with capecitabine (known as the CapeOX regimen) to treat colorectal cancer. Oxaliplatin is given as an IV infusion over 2 hours, usually once every 2 or 3 weeks. Oxaliplatin can have severe side effects and is most often used in stage III. Its efficacy in stage II patients has not been demonstrated.
5. Clinical Need in stage II and clinical risk factors Clinical Need: Based on large randomised clinical studies such as QUASAR (study on a population of 3,239 colorectal cancer patients in the UK), it was shown that the benefit of treating Stage II colon cancer patients with chemotherapy is relatively small (Quasar Collaborative Group, Lancet. 2007 Dec 15;370(9604):2020-9.). The meta-analysis of many clinical studies confirms that the benefit for stage II patients is around 3-5% (see below or Sargent et al (2009) J Clin Oncol;27 :872-7). Note: In stage III patients, the benefit of chemotherapy is bigger (~10-15%) – more similar to the benefit we know from breast cancer.
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A recent study has shown that among Medicare stage II colon cancer patients, adjuvant chemotherapy did not substantially improve overall survival. This means in older patients (Medicare patients are usually older than the population of patients in clinical studies), there was no benefit of chemotherapy at all (O’Connor et al (2011) JCO 29;25). Clinical Risk Factors: Considering the very small benefit of chemotherapy, it would be very helpful to identify patients with a higher risk of recurrence and only treat those patients. There has been much effort put into identifying reliable risk factors to assess the individual risk of stage II patients so that only those patients who might benefit would be treated. A number of poor prognostic clinical factors have been identified: -
inadequately low number of assessed lymph nodes (<12), T4 tumors obstruction or perforation at diagnosis, vascular, lymphatic or perineural invasion, poor histological differentiation (high grade) and the presence of positive resection margins
Molecular markers also have been investigated for their potential to predict the outcome of patients. High microsatellite instability (MSI-H), is the most promising factor to identify a small group of patients who have a good prognosis and may derive no benefit from adjuvant therapy (see below for explanation on MSI).
ColoPrint stratifies patients with good prognosis and poor prognosis better than any of the clinical factors alone or combined. Considering that most stage II patients today have tumor-free resection margins (R0), more than 12 lymph nodes assessed and no signs of perforation or obstruction, T4 tumors remain as the most reliable high risk factor and MSI-H status as low risk factor to assess the risk of relapse in stage II patients. Since approximately 15-20% of all patients are MSI-H and approximately 10-15% of all stage II patients are T4, this leaves nearly 70% of patients with an undetermined risk.
6. Other important facts to know The human body is genetically equipped to ensure proper replication and repair of DNA. This DNA repair is performed by proteins belonging to the Mismatch Repair (MMR) System. However the process can be imperfect or “broken”, especially in patients with cancer. Mutations or silencing of the body’s mismatch repair (MMR) system that normally helps correct improper DNA copying, can cause mistakes in the DNA replication. One of the mistakes is the so-called Microsatellite instability (MSI) , a condition in which Confidential – For Internal Use Only – Not intended for Duplication/Distribution
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replicated strands of DNA accumulate errors and become longer and shorter than they should be. MSI is a measurable sign that the cell has a defect MMR system. . MSI-H (High Microsatellite Instability) MSI-H is a complicated concept. But it is a very important molecular factor for stage II patients, and testing for MSI-status becomes more and more clinical routine. If you only want to remember two things about MSI-H, then remember that ~15% of all stage II patients are MSI-H and that MSI-H patients have a better prognosis than MSS patients. Since they also do not seem to benefit from chemotherapy, current practice is to NOT treat MSI-H patients. For more explanation: The microsatellite instability (MSI) is a form of genome destabilization. It is commonly caused by DNA mismatch repair (MMR) deficiency. Consequently, the MSI phenotype is also referred to as the MRR deficient (dMRR) phenotype. Tumors typically display various insertions or deletions , most common in short tandem repeats, the so-called microsatellites. MSI occurs in 10-20% of colon tumors and has been attributed predominantly to gene silencing of DNA mismatch repairs (MMR) genes by mutation or methylation, including MSH2, PMS2 and in particular MLH1. Patients with no instability in those microsatellites are called microsatillite stable (MSS). Clinical studies have demonstrated that MSI rates vary with tumor stage, and in stage II, MSI-H have been associated with longer survival than patients with MSS tumors. The deficiencies in MMR genes leads to loss of function of tumor suppressor genes and is associated with activating mutations in oncogenes such as BRAF. The molecular background of patients plays an important role in their response to treatment. Patients with MSI-H cancers have no benefit and maybe even have a worse outcome with chemotherapy. Familial adenomatous polyposis (FAP) FAP accounts for approximately 1% of colorectal cancers in the west and is characterised by the presence of multiple (often thousands) of adenomas in the large bowel. FAP patients have an almost 100% risk of developing colorectal cancer by their 40s. The gene for FAP is the APC tumour suppressor gene on chromosome 5q21. Prophylactic surgery is offered to affected individuals, usually in their teens. Hereditary non-polyposis colorectal cancer (HNPCC) HNPCC, or Lynch syndrome, is estimated to be responsible for 2–5% of colorectal cancers. HNPCC is caused by a fault in a DNA mismatch repair (MMR) gene – they are therefore part of the patients with MSI-H cancers. HNPCC is characterised by early onset of colon cancer and is associated with non-colorectal cancers, including cancers of the endometrium, ovaries, stomach, pancreatico-biliary system and urinary tract. Genetic testing for predisposing mutations in people with a strong family history of these cancers enables screening and prevention to be targeted to those most at risk. For people with a known mutation, especially young patients from HNPCC families, prophylactic surgery may be recommended.
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7. Differences between Colon Cancer and Breast Cancer Although ColoPrint is very similar to MammaPrint in providing more accurate risk assessment for early stage cancer patients to help making treatment decisions, there are some important differences between colon and breast cancer: a. Stage II: MammaPrint is for stage I and II, ColoPrint for stage II and IIIA. While the definition of stage II in breast cancer can include patients with negative lymph node (N0) and positive lymph nodes (N1), all colon cancer patients with stage II are by definition lymph node negative b. Patient population: Obviously, men and women can have colon cancer. Generally, patients with colon cancer are older than patients with breast cancer. Old(er) age is one of the reasons why patients often do NOT want chemotherapy. c. Treatment: Treatment benefit in stage II colon cancer patients (~3%) is much lower than in stage II breast cancer (~10%). This is another reason why patients and physicians are more willing to withhold treatment. Younger physicians usually treat more stage II patients than older physicians, but most physicians will agree that they would like to find reasons to NOT treat patients or only treat patients with high risk. d. Relapse: 80% of all relapses in colon cancer occur in the first 3 years. There are nearly no relapses after 5 years. While in breast cancer, recurrences happen after 5, 10 or even 15 years. Note: in breast cancer, the description of “relapses” usually refers to the development of distant metastasis. In colon cancer, “relapses” can refer to local (in the colon), regional (in the abdomen) and/ or distant recurrences. e. Clinical factors: Breast Cancer has more prognostic and predictive clinical markers than colon cancer. In breast cancer, hormonal status, size, grade etc. play a big role in determining who is high risk and how patients should be treated. In colon cancer, T3 versus T4 plays a role but not many other clinical factors have consistently shown significance in prognosis. No clinical or molecular factor has yet shown predictive power in colon cancer. f. Adjuvant!Online: Adjuvant Online for colon cancer exists and is used but not to the same extent as in breast cancer. This is probably due to the fact that colon cancer does not have so many clinical (like size, grade etc.) and molecular factors (ER, PR, Her2 expression) as breast cancer and also not so many treatment options. Hence there are less varierty to make a “personalized” treatment decision. But tools/ apps to be used for personalized medicine will become more and more popular. Check out for example http://www.collabrx.com/colorectal
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Colorectal Cancer Glossary
Glossary Abdominoperineal resection: the surgical removal of the anus, rectum, and sigmoid colon, resulting in the need for a permanent colostomy. Adenoma: benign (non-cancerous) polyps, or growths, that are considered the first step toward colon and rectal cancer. Adjuvant therapy: Additional treatment after surgery, or add-on treatment, provided to prevent cancer recurrence; usually refers to chemotherapy treatment Antibodies in colon cancer only play a role as treatment in mCRC Antibodies: proteins produced by the body to protect itself from foreign substances, such as bacteria or viruses. Antibodies can also be given as therapy to target cancer-specific molecules. Antigens: substances that provoke an immune response in the body. The body produces antibodies to fight antigens, or harmful substances, to try to eliminate them. Anastomosis: a surgical joining of two ducts, blood vessels, or bowel segments to allow flow from one to the other. Carcinoma: a malignant (cancerous) growth that begins in the lining or covering of an organ and tends to invade surrounding tissue and travel to and grow in other regions of the body. Colectomy, partial: a surgical procedure that involves removing part of the colon and joining the ends that remain. This is used to treat colon cancer or severe, chronic ulcerative colitis. Colectomy, segmental: a surgical procedure that involves removing segments of the colon. Colectomy, total: a surgical procedure that involves removing the entire colon, with the small intestine being attached to the rectum. Desmoid tumors: growths of scar tissue that are very tough and firm. Desmoid tumors are rare among the general public. This is not colon cancer but a very different form of cancer found in up to 13% of people with familial adenomatous polyposis, or FAP, who are at increased risk of also getting colorectal cancer. Duodenum: the first part of the small intestine, connecting with the lower opening of the stomach and extending to the jejunum. Familial adenomatous polyposis (FAP): a syndrome in which a gene mutation that influences the development of colon, rectal, and other cancers is inherited. People with FAP usually have hundreds, and sometimes thousands of pre-cancerous polyps, or growths developing at a very early age. FAP is defined as the presence of more than 100 benign (adenomatous) polyps in the large intestine at one examination. Some people with FAP with a mild version of the disease have less than 100 adenomas; in these individuals the diagnosis is made by family history, or by finding the mutation during genetic testing.
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Hereditary non-polyposis colorectal cancer (HNPCC): a syndrome in which a gene mutation influences the development of colon, rectal, and other cancers. Colon and rectal cancer occurs frequently in HNPCC families. Ileum: the lower three fifths of the small intestine from the jejunum to the ileocecal valve. Jejunum: the second portion of the small intestine extending from the duodenum to the ileum. Large intestine (or large bowel): the digestive organ made up of the ascending (right) colon, the transverse (across) colon, the descending (left) colon the sigmoid (end) colon and the rectum. The colon receives the liquid contents from the small intestine and absorbs the water and electrolytes from this liquid to form feces, or waste. Feces are then stored in the rectum until elimination from the body through the anus. Microsatellite instability (MSI): The microsatellite instability is a form of genome destabilization that is caused by a defect in the DNA repair system (see MMR). Microsatellites are small segments in the chromosomes that usually have a very defined length. However, when the DNA repair system is broken, these segments are no longer replicated properly and their length vary. In other words, the microsatellites become instable. Since the mismatch repair system is usually only broken in cancer but not in normal cells, the length of the microsatellites in normal and cancer cells are measured and compared. If the lengths vary, the patient is classified as MSI-H. MSI therefore indicates that the cell has a defective mismatch repair (MMR) system. Mismatch repair genes: genes responsible for correcting errors in DNA when cells divide. In hereditary nonpolyposis colorectal cancer (HNPCC), mutations in a variety of genes that are part of the DNA mismatch repair system are responsible for a defect in the DNA repair system , therefore predisposing families with HNPCC to the development of cancer. However, more common is the “sporadic” form mismatch repair deficiency. In approximately 15% of patients, the genes of the mismatch repair system are not mutated but ‘silenced’. The silencing of genes causes the same effect as the mutation: the DNA repair no longer functions properly and the tumor will acquire many “mistakes” in its genome. One of the mistakes is the Microsatellite Instability. Mismatch repair (MMR): DNA constantly has to produce new strands of itself. When this is done incorrectly, there are special genes involved in correcting the mistake. If this is not done, or not done properly, a tumor can grow in the place of normal cells. MMR-D (deficient) = MSI-H MMR-P (proficient anti-tumor response) = MSS (Microsatellite stable) Mutation: mutations are changes in a genomic sequence. This change can be inherited from the parents and then is called “germline mutation”. Mutations in the FAP or HPNCC patients are examples. More often in cancer however are “somatic mutations”. These are mutations that the cancer acquires during its progression and that often gives the cancer cell an advantage to grow. This mutation could not be found in surrounding normal tissue but is cancer-specific. Somatic mutations can be caused by a mismatch repair system deficiency. Polyps (colon): small growths on the inner colon lining. Certain types of polyps, such as adenomas, may develop into cancer. Other types of polyps have no risk of developing into cancer. Colorectal screening is important to detect polyps and early cancer. Proctocolectomy: the surgical removal of the entire colon and rectum. Rectum: an ~8-inch chamber connected to the large intestine that receives solid waste (feces) from the descending colon to be expelled from the body. The rectum connects the colon to the anus. It is the rectum's job to receive stool from the colon, to let the person know that there is stool to be evacuated, and to hold the stool until evacuation happens.
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Small intestine: the portion of the digestive tract that first receives food from the stomach. It is divided into three sections: the duodenum, the jejunum, and the ileum. As food travels through the small intestine it is further broken down by enzymes, and nutrients from the food are absorbed into the bloodstream. Cancer in the small intestine is rare and not part of the colorectal cancer group. Total abdominal colectomy: surgical removal of the entire colon.
Chemotherapy Glossary FOLFOX : combination therapy oxaliplatin, 5-FU, leucovorin FOLFIRI: combination therapy infusional 5-FU, leucovorin, and irinotecan Fluorouracil (5-FU) belongs to the family of drugs called antimetabolites. It is a pyrimidine analog. The chemotherapy agent 5-FU (fluorouracil), which has been in use against cancer for about 40 years, acts in several ways, but principally as a thymidylate synthase inhibitor, interrupting the action of an enzyme which is a critical factor in the synthesis of pyrimidine-which is important in DNA replication. As a pyrimidine analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle arrest and apoptosis by inhibiting the cell's ability to synthesize DNA. It is an S-phase specific drug and only active during certain cell cycles. Oxaliplatin (Eloxatin) is a platinum-based chemotherapy drug in the same family as cisplatin and carboplatin. It is typically administered in combination with fluorouracil and leucovorin in a combination known as FOLFOX for the treatment of colorectal cancer. Compared to cisplatin the two amine groups are replaced by cyclohexyldiamine for improved antitumour activity. The chlorine ligands are replaced by the oxalato bidentate derived from oxalic acid in order to improve water solubility. Oxaliplatin is marketed by Sanofi-Aventis under the trademark Eloxatin®. Capecitabine (INN) is an orally-administered chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor by the tumor-specific enzyme PynPase, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-fluorouracil. Capecitabine is marketed under the trade name Xeloda (Roche). Irinotecan (Camptosar®) is a chemotherapy agent that is a topoisomerase 1 inhibitor. Chemically, it is a semisynthetic analogue of the natural alkaloid camptothecin. Its main use is in colon cancer, particularly in combination with other chemotherapy agents. This includes the regimen FOLFIRI which consists of infusional 5-fluorouracil, leucovorin, and irinotecan. I received accelerated FDA approval in the United States, where it is now marketed by Pfizer as Camptosar®. It is also known as CPT-11. Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibitions of DNA replication and transcription. Leucovorin: Trade Name(s): Citrovorum Factor, FA, Folinic acid . Leucovorin calcium belongs to the general group called vitamins. It enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase.
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