Breast cancer may actually be with in the spectrum of Lynch cancers.

An Australian team reviewing the pathology of breast cancers in women who carried a mutation for Lynch syndrome ( hereditary non-polyposis colon cancer) found that half of the breast tumors were mismatch repair deficient — a hallmark of Lynch cancers.

The team found 107 cases of breast cancer and 90 families in the Colorectal Cancer Family Registry where

• both breast and colon cancer co-occurred
• families met either modified Amsterdam criteria, or had at least one colorectal cancer occurring before age 50
• breast tissue was available in the tissue bank for mismatch repair (MMR) testing

Among those breast cancers, 35 women with a Lynch mutation had been diagnosed with breast cancer.  Of these, 18 (51%) showed deficient mismatch repair and immunohistochemical testing found proteins missing that were the same as the family mutation.

Michael D. Walsh from the  Familial Cancer Laboratory at the  Bancroft Centre in Queensland, Australia, wrote,

Mismatch repair deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking.

SOURCE: Walsh et al. , Clinical Cancer Research, Volume 16,  Number 7, April 1,2010.

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.

While subtotal colectomy didn’t reduce deaths from Lynch-related colon cancer, it did cut down on additional colorectal cancer diagnoses and the need for other abdominal surgery.

Five years after surgery, 93 percent of patients who had subtotal colectomy were alive compared to 88 percent of those who had more limited operations or no surgery.  This wasn’t a significant difference.  However, 84 percent survived the five years without needing additional abdominal surgery compared to 63 percent of the group who had limited or no surgery.

Researchers analyzed people with Lynch syndrome in the Creighton University database.  Cases included those who had subtotal colectomy, either at the time of colon cancer diagnosis or as preventive surgery. They were compared to controls who had limited operations to remove only part of the colon (segmental colectomy).

In subtotal colectomy the colon is removed and the small intestine is attached to the rectum, which remains in place.

Five years after surgery, comparing those who had subtotal colectomy to those with limited resection:

• 94 percent were alive without another colorectal cancer compared to 74 percent of the controls alive and without subsequent colorectal cancer.
• 84 percent survived without needing abdominal surgery compared to 63 percent of controls.
• 93 percent lived five years compared to 88 percent of controls.
• Time to another colorectal cancer or the need for abdominal surgery was shorter for those who had a limited resection.

Their conclusion:

Even though no survival benefit was identified between the cases and controls the increased incidence of metachronous colorectal cancer and increased abdominal surgeries among controls warrant the recommendation of subtotal colectomy in patients with Lynch syndrome.

Lynch syndrome is a highly increased risk for colorectal and other related cancers caused by an inherited mutation in one of the mismatch repair genes.  People with a Lynch syndrome genetic mutation have a lifetime risk for colorectal cancer as high as 80 percent.

SOURCE: Natarajan et al., Diseases of the Colon and Rectum, Volume 53, Issue 1, pages 72-82, January 2010.

About 4 in every 1000 colorectal cancers are due to an inherited mutation in the MSH6 gene.  It accounts for about 10 to 20 percent of Lynch syndrome mutations.

By the time they are 80 years old, men have eight times the risk of getting colorectal cancer and women have 26 times the risk of endometrial cancer — cancer that begins in the lining of the uterus.

A research team identified 113 families with inherited MSH6 mutations in five countries, including 3,104 relatives.  They estimated the risk that they would have been diagnosed with a Lynch-related cancer by the time they were 70 and by the age of 80.  They also compared the risk of a cancer diagnosis in Lynch carriers to the general population.

• Men had a 22 percent risk of colorectal cancer by age 70 which rose to 44 percent by age 80.
• Women had a 10 percent risk of colorectal cancer by 70 which was 20 percent by 80.
• Women had a 26 percent risk of endometrial cancer by 70, 44 percent by 80.

For any Lynch-related cancer

• Men had a 24 percent risk by 70 with a 47 percent risk by 80.
• Women had a 40 percent risk by 70 and a 65 percent risk by 80.

Compared to other people without the Lynch-related MSH6 gene:

• Men had 8 times the risk of getting colorectal cancer in their lifetime.
• Women had 26 times the risk of endometrial cancer and 6 times the risk of any Lynch-related cancer.

Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), is an increased cancer risk, inherited directly from parent to child.  Changes in the genes that repair damaged DNA increase the chances that cells can grow out of control and develop into cancer.

SOURCE:  Baglietto et al., Journal of the National Cancer Institute, Advance Access, December 22, 2009.

Sgt. Joshua T. Rose and Iron (Photo by Tina Susman)

Briefly: Pancreatic cancer occurs in about on in five Lynch syndrome families, increasing risk for the cancer substantially.

Colorectal cancer patients whose tumors don’t have EGFR on immunohistochemical testing can still benefit from Erbitux treatment.

Patients learn more and like medical consultations better when doctors sit side-by-side with them to view tests.

Gastroenterologists deployed in Iraq are using their skills to help military working dogs.

Research Reports

• Among families with Lynch syndrome, one in five had at least one person with pancreatic cancer.  Data from 6,342 individuals in 147 families in familial cancer registries at Dana-Farber Cancer Institute in Boston and University of Michigan Comprehensive Cancer Center in Ann Arbor included 47 cases of pancreatic cancer in Lynch families, evenly spread between men and women.  There was a 3.68 percent risk of having pancreatic cancer before age 70, almost nine times the risk in the general population. Fay Kastrinos, MD, MPH and her team reported their study results in the October 28, 2009 issue of the Journal of the American Medical Association.
• Some colorectal cancer patients whose tumors did not express the epidermal growth factor receptor (EGFR) when tested with immunohistochemical staining still responded to treatment with Erbitux© (cetuximab), when given as a single drug (monotherapy). Seven of 85 patients (8.2 percent) had tumors shrink.  For the group, median time to cancer progression was 2.1 months with median overall survival of 10 months.  About 40 percent of patients were alive one year after treatment began.  Study results were similar to other clinical trials of cetuximab monotherapy restricted to patients with EGFR positive tumors.Rafal Wierzbicki and colleagues published their phase II clinical trial results in Investigational New Drugs, online October 15, 2009.

Other Headlines

• When doctors and patients sat side by side at a semicircular table facing a computer screen during a consultation, they shared more information and patients said they were more satisfied with the visit than in a conventional office.  The computer displayed the patient’s electronic medical record, test results, and Internet pages with other health information.  Watch Dr. Victor Montori of the Mayo Clinic who led the randomized Space and Interaction Trial (SIT) discuss the results.
• Gastroenterologists in Iraq are using their skills — and their colonoscopes — to help military working dogs return to duty.  Deployed in Iraq, the doctors removed buttons, tacks, and rocks swallowed by the dogs.  They also stemmed bleeding, found fungal infections, and discovered a large cancer in one dog, who died.  Leon Kundrotas, MD, FACG and Timothy Cassidy, DO presented their work with military dogs in a poster at the American College of Gastroenterology Annual Meeting in San Diego last week.

Disclosure: C3 has accepted funding for projects and educational programs from Bristol-Myers Squibb and ImClone Systems in the form of unrestricted educational grants. C3 has ultimate authority over website content.

Although initial reports found no reduction in polyps or cancer in people with Lynch syndrome who took aspirin and/or resistant starch supplements, longer follow-up tells a difference story.

About five years after trial participants began taking aspirin or a placebo, differences began to emerge. Even though patients in the trial only took aspirin for four years, later followup found significantly fewer colon colon cancers among those who had used  aspirin, as well as fewer Lynch-related cancers overall.   There were almost three times as many colon cancers in Lynch carriers who took a placebo compared to those who used aspirin.

The Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2) enrolled over 1,000 patients worldwide who carried a mutated gene that causes Lynch syndrome in a randomized study to compare daily aspirin use with or without resistant starch supplements to placebos.  Participants in the trial took aspirin, starch supplements, or placebos for four years.  An initial report in the New England Journal of Medicine found that neither aspirin or Novolose (resistant starch) made any difference in the development of polyps or cancer.

However, when the research team contacted over 600 of the original study members again, they found that, with longer follow-up, there was a significant difference in the development of colon cancer and other Lynch-related cancers.  Six patients who had taken aspirin had colon cancer compared to 16 who didn’t use it.  There was a reduction in endometrial cancer, as well.  Overall, there were 18 Lynch-related cancers in all among the aspirin-users, compared to 31 who didn’t take aspirin during the four years of the study.

Aspirin protected the people who took it for at least 6 years after they stopped.

Participants in the trial took 600 mg of aspirin daily.

Professor John Burn, from the Institute of Human Genetics at Newcastle University in the United Kingdom,who reported the newest results of CAPP2 at the ECCO/ESMO meeting in Berlin said,

Our original design allowed for long term post trial follow-up. We have managed to track down most of those who completed the trial – around 75% of the original consent cohort – with information extending up to 10 years from randomisation. We found that, around four years after randomisation, there was a divergence in the incidence of cancers between the aspirin and placebo groups. To date, there have been only six colon cancers in the aspirin group as opposed to 16 who took placebo. There is also a reduction in endometrial cancer. This is a statistically significant result and we are delighted – all the more so because we stopped giving the aspirin after four years, yet the effect is continuing, and is directly correlated with the duration of aspirin use on the trial.

Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is a type of inherited cancer of the digestive tract, particularly the colon and rectum. People with Lynch syndrome have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women carriers also have a high risk of developing endometrial and ovarian cancers.

Patients with Lynch-related cancers are often diagnosed at a younger age, and their tumors develop more quickly.

Concluding, Prof.  Burn and his team recommended,

All those at risk of Lynch syndrome related cancer should consider long term aspirin use. Plans for a large scale randomised dose finding study of aspirin in Lynch syndrome will be presented.

SOURCE:  Burn et al., European Journal of Cancer Supplements, Volume 7 Number 2, September 2009, Page 320.

In 2009 there will be an estimated 80,720 new cases of GYN cancers and 28,120 deaths.

Women with Lynch syndrome (also known as hereditary non-polyposis colon cancer or HNPCC)  have a high lifetime risk of endometrial cancer, reaching 71 percent by the age of 70.  This is much higher than the general population whose risk is less than 2 percent.

Lynch syndrome women also have a 10 to 12 percent lifetime risk of ovarian cancer, again larger than the other women with a risk is about 1.5 percent.

Women who have been identified as carrying one of the Lynch syndrome genes — MLH1, MSH2, MSH6, or PMS2 — should plan annual screening for both ovarian and endometrial cancer beginning about age 30 to 35.  A pelvic-rectal examination, transvaginal ultrasound, CA-125 blood test, and endometrial biopsy should be part of that exam.

On the other hand, women who are diagnosed with endometrial cancer before menopause or the age of 50 are at high risk for Lynch syndrome and colorectal cancer.  They should consider genetic counseling and testing.  Tumor testing may identify older women who need further genetic testing, as well.

Symptoms of endometrial cancer that should prompt a visit to a gynecologist and endometrial biopsy include:

• Abnormal vaginal bleeding:  heavier than usual menstrual periods, bleeding between periods, or prolonged periods.
• Vaginal bleeding after menopause.

Symptoms of ovarian cancer can be subtle, but according to the Ovarian Cancer National Alliance, they are more likely to occur in women with ovarian cancer than other women.  They exist even in early stages.  When symptoms are persistent and are a change from a woman’s normal patterns, they should be investigated.  Symptoms include:

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

Cervical cancer is not part of the Lynch syndrome.  However, all women should schedule regular pap smears to detect changes in cells that may lead to cervical cancer.  Such screening can prevent cervical cancer. However, pap smears do not detect or prevent ovarian or endometrial cancer.

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.

A Johns Hopkins team has developed SUDS — a device for cleaning ER equipment that wipes out dangerous bacteria and keeps it from returning for several days.  The Caring Connection will help you find advance directive forms and instructions for your state.

Research Reports

• People with Lynch syndrome don’t benefit from either aspirin or resistant starch (Novelose) even when aspirin is given at a high dose of 600 mg a day.  Over four years, Lynch patients on aspirin, Novelose, or a combination of the two had no fewer polyps than clinical trial participants on placebo.  Serious adverse events, gastric bleeding, strokes, and heart attacks, weren’t any different between the two groups either.  Dr. John Burn and the CAPP2 team report their results in the New England Journal of Medicine, December 11, 2008.
• Almost 9 out of 10 patients in treatment asked about cancer-related advertising directed at consumers had seen ads, mostly on television.  A majority of surveyed patients felt that the ads made them “aware of treatments they did not know about“, presented information “in a balanced manner“, and helped them have “better discussions” with their doctor.  One in ten felt that the ads reduced their confidence in their doctor’s judgment.  Of those who were aware of ads, 1 in 5 discussed an advertised medicine with their doctor, but of those only 20 percent actually received a prescription for the drug. Gregory A. Abel and the team at Harvard Medical School report the results of the survey in an early online edition of the Journal of Clinical Oncology August 3, 2009.
• People prone to colorectal polyps who were “super-compliers” in following a recommended low-fat, high-fiber diet with high amounts of fruits and vegetables had 35 percent fewer new polyps than people who were not on the diet at all.  However, most trial participants didn’t report that level of compliance.  Of 1,900 people in the trial, only 210 consistently reported success in following all three diet recommendations:  low fat, high fiber, and high fruit/vegetable intake.  Dr. Leah B. Sansbury and her team from the Polyp Prevention Trial Study Group reported their results in the American Journal of Epidemiology online July 30, 2009.

Other Headlines

• A team at Johns Hopkins has developed a device, similar to a shower cubicle, that can clean and decontaminate hard-to-clean emergency room equipment from electrocardigram machines to  cell phones.  SUDS or  the Self-cleaning Unit for the Decontamination of Small instruments beats manual scrubbing for removing bacteria and keeping it away for at least two days.  Two days after manual cleaning, 1 in 4 devices had new bacterial growth, but SUDS-cleaned devices were bacteria-free even in heavy ER settings.  Treatment inside the 7 foot high SUDS machine didn’t appear to damage electronics, and its use can replace expensive  and wasteful disposables.  Development and testing of the SUDS device is described in Annals of Surgical Innovation and Research, online July 30, 2009.
• Caring Connections, a program of the National Hospice and Palliative Care Organization, provides free advance directives and instructions for each state that can be downloaded and filled out.  The packets include information about the HIPAA Privacy Rule and the specific forms and information you’ll need for your own state.  Depending on the state, advance directives allow you to appoint an advocate or proxy to make health care decisions if you are unable to speak for yourself and to specify what health care you do or do not want if you are critically ill.