Endometrial cancer is a female cancer that has been steadily increasing in recent years, accounting for 2.7 percent of all female cancer cases, according to the National Cancer Registry. Various mechanisms have been reported, and it is traditionally thought to be caused by disproportionate exposure to the female hormone estrogen. Recently, however, hereditary endometrial cancer has gained attention. If you have a family history of colon or endometrial cancer, you may have to suspect “Lynch syndrome.”

In the 19th century, Dr. Aldred Warthin, a pathologist at the University of Michigan in the United States, first suggested that cancer is inherited by predicting that an acquaintance's family members will develop cancer, based on the fact that they have many cases of gastrointestinal and gynecological cancers. In the mid-20th century, Dr. Henry T. Lynch reported that certain families had a high incidence of cancer, particularly colorectal cancer without accompanying colon polyps. This experience and theory became known as Lynch syndrome in the 1980s when the genetic factor was scientifically identified.

Lynch syndrome is an inherited cancer syndrome caused by mutations in mismatch repair genes (MMR genes, MLH1, MSH2, MSH6, PMS1, PMS2) that repair damage during DNA replication. It is caused by a mutation or deletion of a gene that prevents it from performing its normal function. It has a prevalence of one in 279. In addition to colorectal and endometrial cancers at a young age, there is an increased risk of ovarian, stomach, urinary tract (kidney, renal, ureter, bladder, prostate), pancreatic, small bowel, brain, and female breast cancer.

When mismatch repair genes are mutationally inactivated, they cannot correct errors during DNA synthesis at sites with repeated sequences called microsatellites. This causes the length of the repeated sequences to vary. This situation is called microsomal instability (MSI).

Lynch syndrome -- how is it diagnosed?

Lynch syndrome is diagnosed by testing for mutations in these genes, protein expression, and microsomal instability. If one of the parents has the mutation, there’s a 50 percent chance of passing it on to their children. In women, the risk of colorectal cancer is 40-60 percent, endometrial cancer 40-60 percent, and breast cancer 5-20 percent.

So, what percentage of endometrial cancer patients have Lynch syndrome? These gene mutations are identified in 25-30 percent of endometrial cancer patients in Korea, similar to other ethnicities.

There are two ways to diagnose the gene mutations associated with Lynch syndrome.

First, the expression of the proteins made by the mismatch repair genes is checked by tissue immunostaining, and if none is observed, a deficiency of the mismatch repair genes is diagnosed.

Second is the microsomal instability PCR method. This checks for changes in length due to the errors in the microsomal subunits and uses a total of five markers. You can also use next-generation sequencing (NGS).

There are two ways to recognize a family history of Lynch syndrome that should raise suspicion.

First, using the revised Bethesda guidelines, it should be suspected if one or more of the following are true

-You are younger than 50 years of age at the time of your colorectal cancer diagnosis 2) You are younger than 60 years of age at the time of your colorectal cancer diagnosis and pathologic evidence of microsomal instability 3) You have two or more colorectal cancers or cancers associated with Lynch syndrome, either simultaneously or over multiple years 4) At least one of your brothers, sisters, or children was diagnosed with colorectal cancer or a cancer associated with Lynch syndrome before the age of 50 5) At least two of your brothers, sisters, or children were diagnosed with colorectal cancer or a cancer associated with Lynch syndrome.

-In addition, if three or more family members have been diagnosed with colorectal cancer or Lynch syndrome-associated cancer using the Amsterdam criteria: 1) at least one is related to two other siblings, sisters, or children; 2) at least one was diagnosed before age 50; 3) the disease spans two or more generations; and 4) the disease is not familial polyposis syndrome.

If you have Lynch syndrome, what could be the prevention and treatment?

If Lynch syndrome is identified based on family history, it’s important to start regular screenings at a young age to detect cancer early or prevent it before it occurs. To prevent endometrial and ovarian cancer, women should undergo annual ultrasounds, tumor marker tests, and endometrial biopsies, if necessary, starting at age 30, and consider hysterectomy after childbearing.

Colorectal cancer can be prevented by colonoscopy every one to two years starting at age 20-25 or whenever the youngest person in the family was diagnosed with colorectal cancer, and by taking aspirin for at least two years. Other screening recommendations include a gastroscopy and urinalysis every one to three years starting at age 30 to 35, and quitting smoking. These tests are recommended in consultation with your primary care physician, who will discuss the age at which to begin screening, as well as the frequency and type of screening, to determine a personalized schedule for you.

The primary treatment of endometrial cancer in women with Lynch syndrome is no different than it has been in the past, and most cases are successfully treated when detected at stage 1. However, advanced or recurrent cancer remains difficult to treat, and recent advances in research and the development of new cancer therapies have led to a breakthrough in treatment. This is the use of immunotherapy. Immunotherapy drugs have recently been approved and partially covered by health insurance in Korea due to the excellent therapeutic effects of immunotherapy drugs in patients with mismatch repair gene deficiency (MMRd) or high microsomal instability (MSI-H).

Pembrolizumab (Keytruda) and dostarlimab (Jemperli) are currently available in Korea.

The addition of pembrolizumab demonstrated superior efficacy in the Keynote-868 study, reducing the risk of cancer death by 36 percent in patients with endometrial cancer. Dostalimumab showed promise in the RUBY and GARNET studies, reducing the risk of disease progression or death by 72 percent when used in endometrial cancer with confirmed mismatch repair gene deficiency or high microsatellite instability.

For advanced cancer, immunotherapy is given in combination with conventional chemotherapy after surgery, followed by a schedule of immunotherapy alone every six weeks as maintenance therapy after completing six cycles of chemotherapy.

For recurrent cancer, immunotherapy can be used for treatment if it has not been used before. However, although it is approved for first-line treatment, it is not covered by health insurance, so it is expensive.

Pembrolizumab costs about 4.2 million won ($3,054) and dostalimumab costs about 3.8 million won for a single dose in combination with chemotherapy, and pembrolizumab costs about 840 million won and dostalimumab costs about 760 million won for maintenance therapy every six weeks. In the case of dostalimumab, if you have never used an immunotherapy drug before and have had a recurrence, it is now covered by health insurance, and the cost has been significantly reduced to about 5 percent of the original price or about 190,000 won per dose.

Women with a family history of Lynch syndrome or a genetic predisposition to Lynch syndrome discovered after a colorectal cancer diagnosis are encouraged to consult with their doctors to proactively prevent and manage the development of cancer and protect their health and the health of their families.