Endometrial cancer on the rise in US, obesity epidemic a major factor
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Key takeaways:
- There are no general screening guidelines for endometrial cancer, except for women with genetic or familial risk.
- Addressing the obesity epidemic in the U could have a significant impact on endometrial cancer mortality.
Endometrial cancer has become the number one cancer diagnosis among U.S. women, particularly among the younger population, with nearly 68,000 cases and 14,000 deaths expected annually, according to Robert Wenham, MD.
“Endometrial cancer has become the number one gynecologic cancer killer and is largely driven by the obesity epidemic,” Wenham, chair of the department of gynecologic oncology at Moffitt Cancer Center, told Healio. “ number one for patients with endometrial cancer is abnormal bleeding but that can be difficultin younger women for whom we find an increasing shift of cases happening primarily due to our obesity epidemic.”
![a white background with a Healio green bar going across the top and one on the bottom that stops right before the bottoms right corner where the Healio logo is located. In the middle of the background on the left hand side is an image of Dr. Robert Wenham and on the right hand side is a quote from his in black text that reads "[Endometrial cancer] is disproportionately hitting some parts of the population more than others" beneath his quote in Healio Green text reads "Robert Wenham, MD""](/~/media/images/collections/hematology-oncology/resources/editorial-features/gynecologic-cancer-central/wenham_pullquote_infographic.jpg?w=800)
Screening recommendations
No general screening guidelines exist for endometrial cancer, according to Wenham, except for certain recommendations for a small subset of patients who have genetic or familial risk.
“The primary genetic syndrome is hereditary non-polyposis cancer syndrome, or Lynch syndrome, which only makes up about 3% to 5% of all endometrial cancer cases,” he said. “Screening without symptoms, although widely recommended by ASCO and SGO, ha not been shown to impact mortality or morbidity for endometrial cancer. is still recommended that these women have an exam and endometrial biopsy starting around the age of 30 to 35 years. There are also some suggestions for ultrasound once every year or years.”
As part of the endometrial evaluation, physicians look for the inner lining of the uterus to be very thin for post-menopausal women who have bleeding after menopause.
“The converse, a thickened endometrium, particularly in younger, pre-menopausal women, where we expect to have fluctuating endometrial thickness throughout the menstrual cycle, is not helpful and often will not help us diagnose endometrial cancer,” Wenham said.
Moreover, performing random biopsies in women without abnormal bleeding has been problematic in demonstrating that it helps to make earlier diagnoses, or impacts outcome, because most endometrial cancer presents with uterine bleeding early in its course, he continued.
“That’s what makes universal screening for endometrial cancer difficult — the number of patients present with [this cancer type] usually have abnormal bleeding to bring them in and many of those patients are earlystage,” Wenham said. “Therefore, when we start doing the math, we see that we impact a very small number of patients with random screening.”
It is therefore for physicians and other providers to ask key questions, he continued.
“For patients who have had endometrial cancer, we perform immunohistochemistry, which is where we stain the cancer, looking for protein products of the genes that are responsible for mismatch repair,” Wenham said. “If that screen is positive, we go over genetic counseling and testing for those patients.”
When a patient is suspected of having Lynch syndrome, there are screening guidelines that utilize AmsterdamII and modified Bethesda criteria.
“These are all familial risk screening criteria, so whether you had cancer, a firstdegree relative, more than one seconddegree and firstdegree relative, there are all of these complicated algorithms physicians can go through,” he said. “For physicians, must at least make the back of their brain wonder if a patient falls . Other cancer types that are common with Lynch syndrome should also be considered, colorectal being the number one. There is up to an 80% lifetime risk for that, up to a 60% lifetime risk for endometrial cancer, about a 10% to 20% risk for ovarian cancer, and then a splattering of other less common cancer types.”
Obesity and race
Obesity increases estrogen in the body, and “that bombarding of estrogen over time leads to an increased risk for endometrial cancer,” according to Wenham.
“Being more than 50 pounds overweight can raise the risk tenfold — [obesity] a really strong risk factor,” Wenham said. “For patients who are younger with a higher body mass index who come in with irregular bleeding, that really has to be taken seriously. They are the type of patient that I would consider biopsy or some other type of endometrial cancer screening for, especially if I tried regulating their [menstrual] cycle and it didn’t work. Make sure to rule out pathology, because it’s not uncommon to find pre-cancer or cancer in those patients.”
Race is another known risk factor for endometrial cancer.
“We see a correlation even among certain races,” he said. “Particularly Native Americans, African American and Hispanic Americans have some of the greatest increases in obesity. We also see it in Southern white women, that’s where we really see the same increase in parallel over time with obesity.”
As Healio previously reported, data presented during the 2020 virtual American Association for Cancer Research Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, showed uterine microbial diversity appeared higher among Black women diagnosed with endometrial cancer compared with their white counterparts.
Researchers specifically found distinct microbiota profiles between endometrial cancers of Black women with obesity and white women with obesity.
“[Black] women suffer a 55% higher overall mortality from endometrial cancer compared with white women,” Gabrielle M. Hawkins, MD, fellow in gynecologic oncology at The University of North Carolina at Chapel Hill, said during a presentation. “Potential biological causes for this disparity in Black women include a higher risk for more lethal tumor histology, molecular subtypes such as TP53 mutations, and higher rates of obesity and diabetes. However, we hypothesized that another biological factor driving this racial disparity could be the uterine microbiome, as it is thought to have a complex role in human health and disease, including obesity and cancer.”
In another study published in 2021 in JAMA Oncology, Kemi M. Doll, MD, MSCR, and colleagues sought to determine the accuracy of transvaginal ultrasonography endometrial thickness thresholds in identifying cases of endometrial cancer among Black vs. white women. They developed a simulated cohort using SEER registry data between 2012 and 2016 including women with postmenopausal bleeding.
As Healio previously reported, 36,708 women in the simulated cohort had endometrial cancer. Among them, the 4 mm-or-greater endometrial thickness threshold prompted biopsy for less than half of Black women with endometrial cancer, for a sensitivity of 47.5% (95% CI, 46-49).
In addition, among Black women referred for biopsy, 13.1% were diagnosed with endometrial cancer, for a positive predictive value of 13.1% (95% CI, 12.5-13.6) and an area under the curve for the 4 mm-or-more threshold of 0.57 (95% CI, 0.56-0.57).
Conversely, the 4 mm-or-more threshold led to biopsy among most white women with endometrial cancer, for a sensitivity of 87.9% (95% CI, 87.6-88.3). Among white women referred for biopsy, 14.6% were diagnosed with endometrial cancer, for a positive predictive value of 14.6% (95% CI, 14.4-14.7) and an AUC of 0.73 (95% CI, 0.73-0.74).
“This startling difference is due to the higher prevalence of fibroids and nonendometrioid histology type among Black women, both of which decrease the accuracy of the transvaginal ultrasound strategy,”Doll, researcher in the department of obstetrics and gynecology at University of Washington School of Medicine, previously told Healio. “This places Black women at higher risk for false-negative results, which is unacceptable in a group that already is most vulnerable to the worst outcomes in endometrial cancer. A false-negative result could easily lead to delays in diagnosis and treatment, allowing more time for cancer growth and spread, ultimately making surviving an endometrial cancer diagnosis much less likely.”
Guiding treatment
Treatment for high grade pre-cancers and/or early endometrial cancers has improved in recent years, according to Wenham.
“We’ve gotten better and more comfortable at conservative management of highgrade precancers or even very early endometrial cancers, using hormonal therapy and a series of biopsies for patients,” he said. “Many of these patients may be able to go on and have successful pregnancies with their uterus intact. It is certainly something that we have been developing some comfort with and are willing to work a bit outside the standard box of a hysterectomy as treatment for all patients.”
Moreover, diagnosing Lynch syndrome can help guide therapy for patients.
“For those patients who have those genes, they actually respond better to immunotherapy, and so we’re incorporating that into treatment for patients who have advanced cancers. Outcomes have certainly changed for patients with advanced endometrial cancers who we know about genetics, but I’m afraid that outcomes overall have gotten worse for patients, and that’s because there’s more cancer and there’s more late-stage cancer as a result of that, which is particularly to the obesity problem. [Endometrial cancer] is disproportionately hitting some parts of the population more than others, both in terms of access to care and in terms of just overall diet.”
Needed research
Looking ahead, Wenham said he is looking forward to more discoveries in using the immune system to help treat endometrial cancer and a better understanding for biopsies of early endometrial cancer in terms of the molecular genetics within the cancer to better tailor initial staging and treatment of patients.
“That is coming. We are on the precipice of being able to do that we are just trying to gather more data to feel confidence in being able to do that,” he said. “For patients presenting with late-stage cancers, we’re going to continue to figure out how to make the cold tumors hot so we can harness the body’s immune system to help fight them.”
ore research is also needed to address the obesity problem in the United States.
“That would have the most impact on endometrial cancer death far and above anything I can do as an oncologist,” Wenham said. “We have it in our power that if we get these drugs that are really impacting weight loss become affordable, and have longer safety data, where there’s better uptake and good access, along with healthy, well-balanced weight loss programs, we can make a dramatic impact where we’re seeing significantly fewer cases of endometrial cancer in this country.”
Reference:
- Doll KM, et al. JAMA Oncol.2021;doi:10.1001/jamaoncol.2021.1700.
- Hawkins G, et al. Abstract PR-07. Presented at: American Association for Cancer Research Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved (virtual); Oct. 2-4, 2020.
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