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Expand Collapse Colorectal Cancer  - General Description A cancer that begins in the colon is often called colon cancer and a cancer that begins in the rectum is often called rectal cancer, but sometimes the term colorectal cancer is used for a cancer that begins in either place. This year about 132,700 people in the U.S. will be diagnosed with cancer of the colon or rectum. However, nearly 1.1 million remain alive today after having been diagnosed with colorectal cancer.

The colon and rectum are parts of the large intestine. In the colon, which accounts for most of the length of the large intestine, water and nutrients are extracted from partly-digested food before the food is turned into waste. The waste then enters the rectum before being pushed out of the body, leaving via the short anal canal and the anus (cancers also develop in the anus and anal canal, but they aren't classified as colorectal cancers). Most colon cancers and rectal cancers are adenocarcinomas, tumors that begin in gland-like cells lining the colon or rectum. Other types of cancerous tissues account for only 2% to 5% of colorectal cancers.

Colorectal cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the colon/rectal cancer cells cause secondary tumors to grow. The main sites to which colorectal cancer spreads are the liver, lungs and peritoneum. To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist examines it to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include chest x-rays, MRI, CT scans and PET scans.

The FDA has approved several targeted therapies for treatment of patients with metastatic colorectal cancer. These include bevacizumab (Avastin), cetuximab (Erbitux), panitumumab (Vectibix) and ziv-afibercept (Zaltrap).

Despite significant improvements in the treatment of colorectal cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
The prognosis of patients with colon cancer is clearly related to the degree of tumor penetration through the bowel wall, the presence or absence of nodal involvement, and the presence or absence of distant metastases. These three characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. The American Joint Committee on Cancer and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor. This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.

Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, though most have not been prospectively validated (including allelic loss of chromosome 18q or thymidylate synthase expression). Microsatellite instability, also associated with hereditary nonpolyposis colon cancer (HNPCC), has been associated with improved survival (independent of tumor stage) in a population-based series of 607 patients younger than 50 years of age with colorectal cancer. Treatment decisions generally depend on factors such as physician/patient preferences and the stage of the disease, rather than the age of the patient. Racial differences in overall survival after adjuvant therapy have been observed (although not in disease-free survival), suggesting that comorbid conditions play a role in survival outcome in different patient populations.

Source: National Cancer Institute, 2012
A cancer that begins in the colon is often called colon cancer and a cancer that begins in the rectum is often called rectal cancer, but sometimes the term colorectal cancer is used for a cancer that begins in either place. This year about 132,700 people in the U.S. will be diagnosed with cancer of the colon or rectum. However, nearly 1.1 million remain alive today after having been diagnosed with colorectal cancer.

The colon and rectum are parts of the large intestine. In the colon, which accounts for most of the length of the large intestine, water and nutrients are extracted from partly-digested food before the food is turned into waste. The waste then enters the rectum before being pushed out of the body, leaving via the short anal canal and the anus (cancers also develop in the anus and anal canal, but they aren't classified as colorectal cancers). Most colon cancers and rectal cancers are adenocarcinomas, tumors that begin in gland-like cells lining the colon or rectum. Other types of cancerous tissues account for only 2% to 5% of colorectal cancers.

Colorectal cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the colon/rectal cancer cells cause secondary tumors to grow. The main sites to which colorectal cancer spreads are the liver, lungs and peritoneum. To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist examines it to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include chest x-rays, MRI, CT scans and PET scans.

The FDA has approved several targeted therapies for treatment of patients with metastatic colorectal cancer. These include bevacizumab (Avastin), cetuximab (Erbitux), panitumumab (Vectibix) and ziv-afibercept (Zaltrap).

Despite significant improvements in the treatment of colorectal cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
The prognosis of patients with colon cancer is clearly related to the degree of tumor penetration through the bowel wall, the presence or absence of nodal involvement, and the presence or absence of distant metastases. These three characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. The American Joint Committee on Cancer and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor. This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.

Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, though most have not been prospectively validated (including allelic loss of chromosome 18q or thymidylate synthase expression). Microsatellite instability, also associated with hereditary nonpolyposis colon cancer (HNPCC), has been associated with improved survival (independent of tumor stage) in a population-based series of 607 patients younger than 50 years of age with colorectal cancer. Treatment decisions generally depend on factors such as physician/patient preferences and the stage of the disease, rather than the age of the patient. Racial differences in overall survival after adjuvant therapy have been observed (although not in disease-free survival), suggesting that comorbid conditions play a role in survival outcome in different patient populations.

Source: National Cancer Institute, 2012
Expand Collapse KRAS  - General Description
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KRAS is a gene that provides the code for making a protein, KRAS, which is involved primarily in controlling cell division. This protein is part of the MAP kinase signaling cascade (RAS/RAF/MEK/ERK) that relays chemical signals from outside the cell to the cell's nucleus and is primarily involved in controlling cell division. KRAS is an enzyme (a GTPase) that converts a molecule called GTP into GDP. When KRAS is attached (bound) to GDP, it's in its "off" position and can't send signals to the nucleus. But when a GTP molecule arrives and binds to KRAS, KRAS is activated and sends its signal, and then it converts the GTP into GDP and returns to the "off" position.

When mutated, KRAS can act as an oncogene, causing normal cells to become cancerous. The mutations can shift the KRAS protein into the "on" position all the time. KRAS mutations are common in pancreatic, lung and colorectal cancers. These KRAS mutations are said to be somatic, because instead of coming from a parent and being present in every cell (hereditary), they are acquired during the course of a person's life and are found only in cells that become cancerous.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified KRAS mutations across a broad-spectrum of cancer types. The highest incidence of KRAS mutations have been found in pancreatic cancer (70%), colon cancer (30%), lung cancer (25%), cholangiocarcinoma (15-20%), acute myeloid leukemia (15-20%) and endometrial cancer (15-20%). Across the other major tumor types, KRAS mutations have been found in less than 10% of cases that have been tested.

Source: Genetics Home Reference
KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a member of the closely related RAS gene family that includes NRAS and HRAS. These RAS members are small GTPases that transduce extracellular signals to the downstream effectors RAF, PI3K and RALGDS. Ras members are involved in regulating diverse cellular processes including survival, proliferation and differentiation. While activating mutations in the RAS genes lead to sustained GTPase activation and are tumorigenic, each oncogene exerts clear phenotypic differences. KRAS is the most frequently mutated gene from the RAS family, occurring in approximately 20% of all human cancers. Mutational hotspots in KRAS reside primarily in amino acid residues 12, 13 or 61 and function to promote hyperproliferation and suppress differentiation.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified KRAS mutations across a broad-spectrum of cancer types. The highest incidence of KRAS mutations have been found in pancreatic cancer (70%), colon cancer (30%), lung cancer (25%), cholangiocarcinoma (15-20%), acute myeloid leukemia (15-20%) and endometrial cancer (15-20%). Across the other major tumor types, KRAS mutations have been found in less than 10% of cases that have been tested.

Source: Genetics Home Reference
Expand Collapse G13S (c.37G>A)  in KRAS
The KRAS G13S mutation arises from a single nucleotide change (c.37G>A) and results in an amino acid substitution of the glycine (G) at position 13 by a serine (S).
The KRAS G13S mutation arises from a single nucleotide change (c.37G>A) and results in an amino acid substitution of the glycine (G) at position 13 by a serine (S).

There is no clear association between activating KRAS mutations and poor prognosis in colorectal cancer. This may be attributed to allele-specific differences, as the KRAS G12V mutation has specifically been associated with worse survival. In addition, the presence of BRAF mutations significantly worsens the prognosis and clinical trials looking for the effect of KRAS on long-term outcomes should control for this factor.

Currently, the presence of KRAS mutations in colorectal cancer is used more as a negative marker of treatment selection. Based on FDA guidelines, metastatic colorectal patients harboring a KRAS mutation should NOT be treated with the anti-EGFR agent cetuximab or panitumumab, regardless of EGFR expression status. Furthermore, preclinical studies have strongly indicated that clinical BRAF inhibitors should NOT be used in the treatment of KRAS-mutant colorectal cancer, due to unexpected compensatory mechanisms.

The role of KRAS mutations in predicting response to other targeted therapies has not yet been determined. While it remains unclear whether KRAS mutation will predict response to current MEK and/or ERK inhibitors being tested in clinical trials, a combination therapy approach that additionally targets the PI3K/AKT/mTOR or insulin growth factor receptor pathways may confer more robust treatment effects.

There is no clear association between activating KRAS mutations and poor prognosis in colorectal cancer. This may be attributed to allele-specific differences, as the KRAS G12V mutation has specifically been associated with worse survival. In addition, the presence of BRAF mutations significantly worsens the prognosis and clinical trials looking for the effect of KRAS on long-term outcomes should control for this factor.

Currently, the presence of KRAS mutations in colorectal cancer is used more as a negative marker of treatment selection. Based on FDA guidelines, metastatic colorectal patients harboring a KRAS mutation should NOT be treated with the anti-EGFR agent cetuximab or panitumumab, regardless of EGFR expression status. Furthermore, preclinical studies have strongly indicated that clinical BRAF inhibitors should NOT be used in the treatment of KRAS-mutant colorectal cancer, due to unexpected compensatory mechanisms.

The role of KRAS mutations in predicting response to other targeted therapies has not yet been determined. While it remains unclear whether KRAS mutation will predict response to current MEK and/or ERK inhibitors being tested in clinical trials, a combination therapy approach that additionally targets the PI3K/AKT/mTOR or insulin growth factor receptor pathways may confer more robust treatment effects.

PubMed ID's
20133499, 19934290, 20008640, 11531254, 18316791, 18946061, 19339720, 19114683, 20921465, 19884549, 20130576, 19194827, 20179705, 18946061, 1911468
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 28 Per Page:
123Next »
Protocol # Title Location Status Match
NCT02327169 A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies MGH Open DGM
NCT02079740 Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors MGH Open DGM
NCT02279433 A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b MGH Open D
NCT02099058 A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors MGH Open D
NCT02219724 A Phase I, Open-Label Study of MOXR0916 in Patients With Locally Advanced or Metastatic Solid Tumors A Phase I, Open-Label Study of MOXR0916 in Patients With Locally Advanced or Metastatic Solid Tumors MGH Open D
NCT02365662 A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor MGH Open D
NCT01714739 A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors MGH Open D
NCT01633970 A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors MGH Open D
NCT02467361 A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers MGH Open D
NCT02228811 A Study of DCC-2701 in Participants With Advanced Solid Tumors A Study of DCC-2701 in Participants With Advanced Solid Tumors MGH Open D
Trial Status: Showing Results: 1-10 of 28 Per Page:
123Next »
Our Colorectal Cancer Team

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