45,000 women were diagnosed with endometrial cancer in the United States in 2010 — and for nearly 900, cancer was due to Lynch syndrome.

Women who have Lynch syndrome have an increased risk of getting endometrial cancer during their lifetime that is as high as 60 percent. Often endometrial cancer (cancer of the lining of the uterus) is the first Lynch-related cancer diagnosed, earlier than colon or rectal cancer.

Identifying a mutation in these women can prevent future colorectal cancers and discover ovarian, gastric, and other Lynch cancers early when they can be treated successfully.

And not only does this help the woman with endometrial cancer, it helps her family as well if they are tested for the inherited mutation and take steps to reduce their risk of future cancers.

Now, a research team has found the most cost-effective way to identify those women with endometrial cancer with Lynch syndrome is to screen their tumors for missing Lynch proteins only if they also have a first-degree relative with a Lynch-related cancer.

Researchers from the University of British Columbia and MD Anderson Cancer Center in Texas built a computer model to study ways to find women with Lynch syndrome among all women diagnosed with endometrial cancer.  Their goal was to decide on the best strategy to identify both:

• The most women with Lynch syndrome at risk for future colorectal cancer.
• The most cost-effective way of finding those women.

The six strategies they considered were:

• Direct referral for genetic testing for women with Amsterdam II family histories.
• Direct referral to genetic testing for women diagnosed under age 50 with at least one first-degree relative with a Lynch-related cancer.
• Immunohistochemical triage (IHC) of tumors in women under age 50 with genetic testing for those positive.
• IHC triage for women under age 60, followed by genetic testing for positive results.
• IHC triage for women diagnosed at any age with one first-degree relative with a Lynch cancer, followed by genetic testing.
• IHC triage for all women with endometrial cancer, with follow-up of positive results with genetic testing.

While using immunohistochemical testing for all women with diagnosed at any age with endometrial cancer would find 100 percent of Lynch syndrome, it is extremely expensive with an incremental cost-effectiveness ratio (ICER) of $648,494 for each life-year gained.

A better strategy was to use IHC triage for all women diagnosed at any age, but limit the tests to those who had a first-degree relative (parent, child, sibling) with a Lynch-related cancer.  The ICER for this plan was $9,126 — well within the range of cost-effective public health benefits.  It would also find more than 91 percent of women with Lynch syndrome

• Using the Amsterdam family history criteria would miss about a third of women (35%) who have Lynch syndrome.
• Direct genetic testing without IHC triage for women under 50 with a first-degree relative with a Lynch cancer would also miss 36% of potential Lynch mutations.
• IHC triage of women under 50 and under 60 would miss 38% and 34% of women with Lynch syndrome respectively.

Colonoscopy screening saves lives

Both women with Lynch syndrome and women with sporadic endometrial cancer benefit from colonoscopy screeningto reduce their subsequent risk for colorectal cancer and death from colorectal cancer:

• Lynch syndrome women who have annual colonoscopies have a 15% risk of getting colorectal cancer and a 6% risk of dying from it.
• LS women who don’t get the critical annual colonoscopy surveillance have a 40% risk of getting colorectal cancer and a 47% chance of dying.
• Women with sporadic endometrial cancer who have at least one colonoscopy every 10 years cut their risk of colorectal cancer from 5% to 3% compared to women who don’t get a colonoscopy.  Their chances of dying of colorectal cancer are cut down from 37% to 15%.

Janice S. Kwon, MD, MPH, FRCSC and her colleagues concluded,

Immunohistochemical (IHC) triage of women with endometrial cancer at any age having at least 1 first-degree relative (FDR) with a Lynch-associated cancer is a cost-effective strategy for detecting Lynch syndrome. IHC triage of women with endometrial cancer at any age having at least 1 FDR with a Lynch-associated cancer is a cost-effective strategy for detecting Lynch syndrome.

SOURCE

Kwon et al., Journal of Clinical Oncology, Volume 29, Number 16, June 1, 2011.

What This Means for Patients

If you have been diagnosed with endometrial cancer — cancer of the uterine lining — at any age and also have a parent, sister or brother, or child who has been diagnosed with a Lynch-syndrome related cancer, you should ask to have your tumor tested first by immunohistochemistry to see if you might have Lynch syndrome.

If that initial test is positive, you should follow-through with genetic testing to see if you have an inherited mutation for Lynch syndrome.

This is a better strategy than depending on family history alone or being diagnosed under age 50.

Lynch syndrome related cancers include colon, rectal, ovarian, endometrial, gastric, small bowel, and brain cancer as well as some kidney and skin cancers.  Newer evidence points to breast cancer as also related to Lynch syndrome.

Everyone needs to be aware of of how important including anyone with endometrial cancer when family histories are taken

Screening all new colon and rectal cancer tumors for markers that might indicate Lynch syndrome not only saves future lives, it is cost effective according to a new study.

In order for tumor screening to be cost-effective, not only should new tumors be tested, but family members need to follow through with genetic testing after a new Lynch mutation is found.  Finally people with Lynch syndrome mutations need to follow surveillance guidelines to prevent cancer or find it early,

Testing both tumors and at least three to four family members could cost as little of $36,000 per life year saved — well within the value of preventive health strategies.

Researchers used a computer model to predict costs of  testing tumors using several strategies, upper age limits, and assumptions about family members following up with genetic testing.

In order to fall beneath the $50,000 per life year saved threshold for cost-effectiveness, three to four family members needed to follow up with DNA testing for an identified Lynch syndrome mutation.

Women with Lynch syndrome could improve their life expectancy by about four years if they had their uterus and ovaries removed and followed the colorectal cancer surveillance guidelines, the study found.

The researcher team said that the ideal testing strategy was for pathologists to:

1. Use immunohistochemistry (IHC) tumor tests to look for missing protein expression  related to Lynch syndrome (MLH1, MSH2,MSH6, PMS2).
2. If IHC is positive, followup with tumor tests for a BRAF V600E  mutation.  (Inherited Lynch mutations don’t have BRAF mutations.)
3. If IHC is positive and BRAF is negative, do DNA blood tests for an inherited germline Lynch syndrome mutation.

Once an individual is identified with an inherited Lynch syndrome mutation, it is critical to inform close family members — siblings, children, and parents — of their own potential risk.  Since Lynch syndrome is passed directly from parent to child (autosomal dominant), children of an affected parent have a 50-50 chance of inheriting the gene.

When they know they are at risk, family members should also have DNA testing.  However, they only need to be tested for the gene discovered in their family — a much less expensive process.  Genetic counseling after their test can help them understand what the test results mean and, if positive, what steps they can take to protect themselves against cancer.

Study leader, Uri Ladabaum, M.D., from Stanford University, said,

A systematic approach to identify families with Lynch syndrome makes sense clinically, because it can save lives, and economically, because its costs are comparable to other things we choose to spend our health-care dollars on, We advocate establishing similar tumor-screening systems on a national level.

The study team, led by Dr. Ladabaum, included members from Stanford, University of California, Baylor University, and Memorial Sloan Kettering Cancer Center.  They concluded,

Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome.

Although family history can help identify individuals and families that may carry a Lynch syndrome mutation, it is not foolproof.  About half of families with mutations don’t meet the criteria and another half who do have histories that meet Amsterdam criteria don’t have one of the identified Lynch mutations.

In an editorial accompanying the study report in Annals of Internal Medicine, Dr. Randall Burt  from the University of Utah and the Huntsman Cancer Center points out:

The Amsterdam criteria were developed to identify persons and families who are likely to have the syndrome. The criteria include the following: 3 relatives in a family must have colorectal cancer, and 2 of them must be first-degree relatives of the third; at least 2 generations must be affected; and 1 of the cases must be diagnosed at an age younger than 50 years (2). These criteria have been successfully used to identify families with the Lynch syndrome but have also proven to be insensitive. At least 50% of families with the condition do not meet the criteria. About one half of families meeting the criteria will have a disease-causing mutation in one of the mismatch repair genes ( MLH1, MSH2, MSH6, or PMS2).

The Annals of Internal Medicine includes a summary for patients that describes the study and what it means.

SOURCES:

Ladabaum et al., Annals of Internal Medicine, Volume 155, Number 2,  July 19, 2011.

Burt, Annals of Internal Medicine, Volume 155, Number 2,  July 19, 2011.

What This Means for Patients

This study looks at how costly a testing strategy to identify people with Lynch syndrome is for a large population.  The cost isn’t for one individual or one family, but for everyone in a national health care system.

However, it does support the idea that people who have surgery for colon or rectal cancer should have simple, inexpensive tests done on their tumor tissue to see if they might have Lynch syndrome.

This not a definitive test for Lynch syndrome.  It will also be positive for people who don’t have Lynch, but it will also screen and find those who do.

About 15 out of 100 of people with colon or rectal cancer will have tumors that suggest Lynch syndrome, but only 3 to 5 of them will actually carry a Lynch mutation.

Many of these people with Lynch mutations won’t have strong family cancer histories, so tumor testing is the only way the syndrome would be uncovered.

If you have had surgery to remove a colon or rectal tumor, check with  your doctor to see if testing for microsatellite instability (MSI) has been done.  It will be part of the pathology report from the surgical specimen.  Many hospitals are now doing this test automatically after surgery at the same time they look for lymph nodes and other tumor information.

If it wasn’t done, you might want to request it.  The tumor block saved by the pathology department should still be available for the test.

If testing does indicate you might carry a Lynch mutation, you’ll want to talk to a genetic counselor about DNA testing to either confirm or rule out Lynch syndrome.

The test can save your life by changing the way your cancer is followed up.  And it can save the lives of your brothers, sisters, and children if they also have the mutation.

September is set aside to raise awareness of gynecological cancers.  GYN cancers affect women’s reproductive organs including the cervix, endometrium, uterus, fallopian tubes, vagina, vulva, and ovaries.

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.