A recent study by the German HNPCC Consortium confirmed the effectiveness of annual colonoscopies to find colorectal cancers at a curable stage.  Regular colonoscopies found early cancers more often than did patient symptoms.

Current recommendations are for surveillance colonoscopies to begin by age 25, be repeated every 1 to 2 years until age 40, and then annually.

Over 1,100 individuals from families with HNPCC were scheduled for annual colonoscopies, and more than 80 percent were completed in less than 15 months.  Ninety-nine colorectal cancers were found in ninety patients.

Of those cancers:

• 17 (17 percent) were identified by symptoms:  8 before the first baseline colonoscopy, 8 when the time between colonoscopies was more than 15 months, and 1 in an interval between tests less than 15 months.
• 43 were found during follow-up colonoscopies, only 2 of which regionally advanced (stage III)

Tumor stages were significantly lower among those whose cancers were found by colonoscopy compared to those identified after patients experienced symptoms.

The researchers divided the study patients into three groups:

• Those with an identified inherited genetic mutation for one of the Lynch mismatch repair genes (MUT group)
• Those without a mutation but with microsatellite instability (MSI group)
• Those with a strong family history that met the Amsterdam criteria but did not have MSI (MSS group)

By the age of 60, the mutation and MSI group combined had a 23 percent risk of getting colorectal cancer.  However, risk for the MSS group was only 1.8 percent.

Patients who had an adenomatous polyp removed during the first colonoscopy had a risk of another polyp that was two and a half times as great as those without that first polyp.  Their risk of subsequent colorectal cancer was almost four times as high.

The Amsterdam II criteria is used to detect families at risk for Lynch-related mutations. Each of the following criteria must be fulfilled:

• 3 or more relatives with an associated cancer (colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis)
• 2 or more successive generations affected
• 1 or more relatives diagnosed before the age of 50 years
• 1 should be a first-degree relative of the other two (first degree relatives are parents, siblings, or children)
• Familial adenomatous polyposis (FAP) should be excluded in cases of colorectal carcinoma

However, genetic testing is necessary to confirm a mutation.

Christoph Engel and his colleagues in the German HNPCC Consortium concluded,

Annual colonoscopic surveillance is recommended for individuals with HNPCC. Less intense surveillance might be appropriate for MSS families.

SOURCE: Engel et al., Clinical Gastroenterology and Hepatology, Volume 8, Number 2, pages 174-182, February 2010.

The drug targeted and destroyed cells that contained mutated MSH2 genes. Inherited mutations in MSH2 prevent mistakes in correct copying of DNA during cell division allowing cancer to develop and grow, particularly inherited colorectal and endometrial cancers.  In addition, MSH2 mutations can occur in some colorectal cancers that are not inherited.

Based on the work done in cancer cells, a Phase II clinical trial has begun recruiting patients with advanced colorectal cancer at the Royal Marsden Cancer Hospital in the United Kingdom.  To be part of the trial, patients need to have changes in MSH2 genes either in their tumor tissue or in their blood.

Scientists in the Institute of Cancer Research in London explored the effect of over 1,110 chemicals, most chemotherapy drugs on the market, on cells that lacked a working MSH2 gene and found that methotrexate destroyed DNA and made it impossible for the cells to divide.  Because the MSH2 gene wasn’t functioning to repair DNA mistakes, methotrexate was particularly effective in the deficient cells.

Their goal was to identify drugs or other compounds that could be moved quickly into clinical trials.  Based on the laboratory work,  Professor David Cunningham and his team at the Royal Marsden are recruiting patients with advanced colorectal cancer and mutated MSH2 for a clinical trial to measure their response to methotrexate.  The trial will also measure the time until cancer progresses, overall survival, quality of life, and methotrexate side effects.

Perhaps 40 percent of Lynch syndrome-related colorectal cancers are caused by inherited mutations in the MSH2 gene.  Other genetic mutations known to be connected to Lynch syndrome are found in the MLH1, MSH6, and PMS2 genes.  Although methotrexate targeted and killed MSH2-deficient cells, it was not similarly effective in cell lines with mutated MLH1.

Because Lynch syndrome tumors are microsatellite instable (MSI), they do not respond well to standard treatments with 5-FU.  Methotrexate could provide an alternative treatment that could reduce recurrences in early stage cancers and extend life for patients with advanced cancer.

Professor Alan Ashworth, who led the study, said,

The MSH2 gene plays a vital role in repairing DNA damage but if it is faulty, mistakes accumulate in cells and increase the risk of cancer developing.

What’s exciting about methotrexate is that it selectively destroys the cells lacking the MSH2 function. This indicates that it may make an excellent treatment for patients with the genetic alteration. With our colleagues at The Royal Marsden Hospital, we have set up clinical trials to test this.

Sarah Martin and the team at the Institute of Cancer Research reporting their study in EMBO Molecular Medicine concluded,

While methotrexate has been used for many years as a cancer therapy, our observations suggest that this drug may have particular utility for the treatment of a subset of patients with tumours characterized by MSH2 mutations.

SOURCE:  Martin et al., EMBO Molecular Medicine, online August 27, 2009.

Clinical Trial:  Methotrexate in Metastatic Colorectal Cancer With MSH2 Deficiency (MESH)

Even after adjusting for possible bias, lifetime risks for both cancers was high and the need for special surveillance was critical.

In 147 families with diagnosed Lynch syndrome (hereditary nonpolyposis colon cancer or HNPCC) there were 638 cases of colorectal cancer and 155 cases of endometrial cancer. All families had a mismatch repair (MMR) gene mutations (55 MLH1, 81 MSH2, and 11 MSH6).

For men in the study:

• There was a 66 percent lifetime risk of colorectal cancer.
• Median age at diagnosis was 42.
• Highest lifetime risk was for men with an MLH1 mutation.

For women studied:

• There was a 43 percent risk of colorectal cancer.
• Median age at diagnosis of colorectal cancer was 47.
• Lifetime risk for endometrial cancer was 39 percent.
• Median age for endometrial cancer diagnosis was 47.5 years.
• Risk for either colorectal or endometrial cancer was 73 percent.

Elena Stoffel, MD,MPH, and her colleagues concluded,

Lifetime risks of CRC and EC in mismatch repair gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer surveillance is necessary.

Another study in Canada that analyzed risk for colorectal cancer for families in Ontario with Lynch Syndrome found a 60 percent risk by age 70 for men and  a 47 percent risk for women.  Men who carried a MLH1 gene had a 67 percent risk, while women had a 35 percent risk.  By age 90 risk of having colorectal cancer increased to 81 percent for men and 72 percent for women.

Carriers of the MLH1 gene had a fairly consistent increase of risk over the general population over their lives.  They were about 5 times more likely to get colorectal cancer at any age.  However, relative risk decreased for MSH2 carriers.  At age 30, they were thirteen times more likely to have cancer, decreasing to about 5 percent at age 70.

SOURCES:  Stoffel et al., Gastroenterology, published online July 18, 2009.

Choi et al., Hereditary Cancer in Clinical Practice, published online August 23, 2009.

The Santa Cruz was the third of eight half marathons, Martinez plans to run to honor of eight members of her family diagnosed with Lynch syndrome cancers.  Sunday’s race was for her sister Noemi Garza who survived colon and endometrial cancer.

Martinez’ website Detect the Mutation provides information about recognizing and testing for Lynch syndrome. She is also raising funds for the University of California at San Francisco’s Gastrointestinal Cancer Prevention Program, which offers screenings to those in need.

Selena, a lab specialist at UC San Francisco. told the Mercury News,

We are very lucky to still have my sister. A lot of families don’t get properly diagnosed. I just thought, this is not acceptable. I’m a scientist, I have to do something.

In the last fourteen years, eight members of the Martinez family have been diagnosed with ten different Lynch-related cancers: five colon, two endometrial, two gastric, and one pancreatic.

Lynch syndrome is caused by an inherited mutation in one of several genes that repair DNA errors that occur during cell division.  Normally such mistakes are either fixed or cells with errors are destroyed by the body itself to prevent cancer developing.

Patients with Lynch syndrome are at a very high lifetime risk for colorectal cancer.  Women also have a high risk for uterine and ovarian cancer.  Risk is increased for other cancers of the stomach, small intestine, pancreas, kidney, brain, and skin.

Lynch cancers occur much earlier than normal, with risk beginning in the early twenties, and develop rapidly.  Early and frequent screenings for colorectal, uterine, and ovarian cancer  are critical to detecting polyps or cancer when they can be treated successfully.  Genetic counseling and testing is available for families who might carry the gene.

Thus far Martinez has participated in three half marathons, one for her father, Nazarío P. Martínez, Jr. and and anotherr for her Uncle Juan P. Martínez in addition to the Santa Cruz Half in honor of her sister, Noemí Martínez Garza.

Danish researchers reviewed records of more than 400 people with Lynch associated cancers in families in the Danish HNPCC registry.  There were 290 parent-child pairs.  Two-thirds of the cancers in the entire group were colon or rectal, the rest cancers linked to Lynch syndrome.

Using a simple statistical method,  the average difference between the age of cancer diagnosis of a parent and the child was 9.84 years. When the first cancer in both parent and child was colorectal, the children were diagnosed 10.85 years earlier than their parent.

There was little difference in time gaps for various mutated genes — MLH1, MSH2, or MSH6.  It also made no difference if the parent was father or mother.

Only 24 individuals in the registry had colorectal cancer diagnosed during a surveillance colonoscopy.  All the rest had cancer diagnosed because of symptoms.  When surveillance diagnoses were excluded from calculations, there was still a difference of 9.54 years.

Lynch syndrome (also referred to as HNPCC or hereditary nonpolyposis colon cancer) is caused by inherited defects in DNA mismatch repair genes.  People who carry one of these mutations have a greatly increased lifetime risk of both colorectal and uterine cancer (80 percent and 50 percent, respectively).  They also are at risk for other associated cancers including ovarian, gastric, kidney, small intestine, and brain.

Mef Nilbert M.D., Ph.D. and colleagues in Denmark concluded,

The effect from anticipation demonstrated in this large, population-based Lynch syndrome cohort underscores the need to initiate surveillance programs at young age. It should also stimulate research into the genetic mechanisms that determine age at onset and whether the genetic instability that characterizes Lynch syndrome can be linked to anticipation.

SOURCE: Nilbert et al., Journal of Clinical Oncology, Volume 27, Number 3, January 20, 2009.

When doctors in four research centers immediately followed up Lynch syndrome patients after a regular colonoscopy with more intense colonoscopy scrutiny, they discovered they had missed more polyps than they found.  During the first exam, their miss rate for adenomas, polyps with the greatest risk of developing into cancer, was 55 percent.

In the study, patients with Lynch syndrome had a conventional colonoscopy and then were randomly assigned for an immediate follow-up test.  One half had colonoscopies enhanced with a blue dye that makes polyps easier to see (chromoendoscopy).  In the other group, doctors spent a longer time, more than 20 minutes, searching for polyps (intensive inspection).

• Fifty-four patients had an initial colonoscopy where 10 adenomas and 7 hyperplastic polyps were found and removed.  Hyperplastic polyps are usually benign with little risk of becoming cancer.  During the second exam, there were 12 more adenomas and 11 hyperplastic polyps.
• Twenty-eight patients had their colons sprayed with a blue dye during their follow-up exam.  Fifteen more polyps — 5 adenomas and 11 hyperplastic – were found.
• Twenty-six patients had intensive inspections that lasted longer than regular colonoscopies.  Doctors found 7 adenomas and 1 hyperplastic polyp.

Although more polyps were found with chromoendoscopy, when all factors were taken into consideration there was little difference between the adenomas uncovered between the two techniques.  Chromoendoscopy takes longer than intensive inspection, about 30 minutes compared to 25 minutes to complete an intensive exam.

The researchers pointed out that this was a small pilot trial and that larger, randomized studies are necessary to show that chromoendoscopy will not, in fact, find more missed polyps.

Dr. Elena M. Stoffel, gastroenterologist at Brigham and Women’s Hospital in Boston, and her colleagues concluded,

Small adenomas are frequently missed in patients with Lynch syndrome. Although chromoendoscopy did not detect more missed adenomas than intensive inspection in this pilot study, larger trials are needed to determine optimal surveillance techniques in this high-risk population.

SOURCE: Stoffel et al.,Cancer Prevention Research, Volume 1, Number 6, November 1, 2008.

Italian researchers studied all patients with colorectal cancer treated at a cancer institute in Rome between 1970 and 1993.  Patients who met the Amsterdam I criteria were diagnosed as having Lynch syndrome (HNPCC).  During that time 40 patients, 25 women and 15 men, had Lynch syndrome. 573 patients, 312 women and 261 men had sporadic colon or rectal cancer.

The average age at diagnosis for sporadic cancer patients was 61, while Lynch syndrome patients were diagnosed younger at an average age of 47.  Lynch patients were more likely to have right-sided tumors than sporadic colorectal cancer patients (85 percent versus 57 percent.)

Stage at diagnosis did not differ significantly with 70 percent of Lynch patients and 62 percent of sporadic patients diagnosed with stage I or II cancers.

• For early stage I and II cancers, 96 percent of Lynch and 84 percent of sporadic patients survived five years.
• At stage III, 93 percent of Lynch and 64 percent of sporadic patients were alive five years later

Vittoria Stigliano and her colleagues concluded,

Our results show that overall survival of colorectal cancer in patients with HNPCC is better than sporadic CRC patients. The different outcome probably relates to the specific tumorigenesis involving DNA mismatch repair dysfunction.

Lynch syndrome is an inherited cancer syndrome, passed directly from parent to child, and caused by mutations in the genes that repair damaged DNA.  It is responsible for 3 to 5 percent of colorectal cancer, as well as some uterine, ovarian, and other associated cancers.  Lynch syndrome colon cancers are usually diagnosed in younger people, in the right side of the colon, and have high microsatellite instability.  Genetic testing can identify the genes that cause them to make a definite diagnosis.

In the Italian study, the Amsterdam I criteria (below) based on family history was used to select patients with Lynch syndrome.  However, some patients whose families meet Amsterdam criteria do not, in fact, test positive for known mismatch repair genes.

Amsterdam I Criteria

• Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
• Two successive affected generations
• One or more colon cancers diagnosed under the age of 50
• Familial adenomatous polyposis (FAP) has been excluded

Source: Stigliano et al., Journal of Experimental and Clinical Cancer Research, September 19, 2008.

Sometimes called the disease that whispers, ovarian cancer symptoms are often not recognized until its late stages when it is most deadly.  Found early, ovarian cancer is 90 percent curable but most cases are found after the cancer is already advanced.

President Bush has proclaimed September 2008 ass National Ovarian Cancer Awareness Month.  During September, advocates will be working to raise awareness of ovarian cancer, let women know about its symptoms, and work toward early detection and effective treatment.

Although there is no screening test for ovarian cancer, being aware of its symptoms and following up with a CA-125 blood test, transvaginal ultrasound, and rectal/vaginal pelvic exam can find ovarian cancer early when it is most treatable.  Pap smears are not a test for ovarian cancer, and the CA-125 blood test does not effectively screen for it alone.

Symptoms of ovarian cancer include

• Bloating
• Pelvic or abdominal pain
• Difficulty eating or feeling full quickly
• Urinary symptoms (urgency or frequency)

When these occur for more than two weeks and are a new occurrence for a woman, a visit to a gynecologist for further testing can help find ovarian cancer so it can be treated.

Recent research has found that combining a simple four point questionnaire about symptoms combined with the CA-125 blood test will find 80 percent of early stage ovarian cancer and 95 percent of late-stage disease.

Women with Lynch syndrome (hereditary non-polyposis colon cancer or HNPCC) have about a 10 percent lifetime risk for ovarian cancer.  Guidelines suggest that women with a Lynch syndrome mutation begin annual screening for ovarian cancer between 25 and 35 years of age and consider preventive removal of their ovaries and uterus after they finish childbearing.

More information about ovarian cancer is available from:

• National Cancer Institute: Ovarian Cancer
• National Ovarian Cancer Coalition including a short video.
• Ovarian Cancer National Alliance
• Marsha Rivkin Center for Ovarian Cancer Research

If you have more questions about ovarian cancer you can call the SHARE Ovarian Cancer Hotline at (866)537-4273.

Kicking off National Ovarian Cancer Awareness month, the Seventh Biennial Ovarian Cancer Research Symposium will be held in Seattle on September 4-5, 2008 at the Marsha Rivkin Center.

Researchers in Australia studied tumors from 146 women who were diagnosed with endometrial cancer before the age of 51.  They stained the tumor sections for proteins expression by mismatch repair genes, a genetic mutation that leads to Lynch syndrome cancers.  They also tested tumor DNA for other changes that can identify or exclude Lynch syndrome, and reviewed family medical history where it was available.

They found 26 tumors that were presumed to be due to Lynch syndrome or 18 percent of all the early endometrial cancers.  The tumors were more likely to be poorly differentiated, stage II, have rapidly dividing cells, and invade the wall of the uterus more deeply.

Patients with the presumptive Lynch syndrome tumors were also more likely to have a family history of cancer, Lynch associated cancer in a first-degree relative, or family colon cancer histories that met the Amsterdam criteria for Lynch syndrome.

The research team concluded that endometrial cancers diagnosed in women fifty or younger should be routinely tested by immunohistochemistry for proteins associated with Lynch syndrome.

Michael Walsh and his colleagues wrote,

Presumptive Lynch syndrome was identified in 18% of early-onset endometrial cancer. A risk of this magnitude would argue for routine immunohistochemical testing of tumors in patients diagnosed with EC at or before the age of 50 years.

SOURCE: Walsh et al., Clinical Cancer Research, March 15, 2008.