Cover Story

Increased endometrial cancer incidence prompts calls for more screening, research funding

Endometrial cancer incidence has increased dramatically in many parts of the world, and the United States is no exception.

Lortet-Tieulent and colleagues analyzed international patterns of age-standardized endometrial cancer incidence in 43 countries from 1978 to 2013.

Their results — published last year in Journal of the National Cancer Institute — showed the rate among U.S. white women reached 19 cases per 100,000 by the end of the study period, tied with Slovakia for highest in the world.

Endometrial cancer incidence among black women in the United States historically has trailed that of white women. However, the gap has narrowed considerably since the turn of the century.

This trend has prompted some experts to call for greater emphasis on screening. In addition, NCI funding for research into endometrial cancer and other gynecologic malignancies is incredibly scarce, even though the optimal treatment for the women with the greatest need — those with intermediate- to high-risk disease — has not been established.

“Some may say, ‘Endometrial cancer can be found early and most patients are cured, so do we really need to focus on new treatments?” Pamela T. Soliman, MD, MPH, associate professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center and medical director of the institution’s gynecologic medical center, told HemOnc Today. “But those of us who treat these patients know they do not all have great outcomes, and we do see a significant need.”

HemOnc Today spoke with researchers and clinicians about the potential explanations for increased endometrial cancer incidence in the United States; the factors that are driving the spike among black women; whether greater incidence should result in more screening; how the treatment landscape is evolving; and the calls for more research funding for endometrial cancer and other gynecologic malignancies.

Incidence and outcomes

Endometrial cancer — the most common type of uterine cancer — is the fourth most common malignancy among women in the United States, trailing only breast, lung and colorectal cancers.

It typically occurs among women aged 55 years or older; however, the experts with whom HemOnc Today spoke said they are seeing more women diagnosed at younger ages.

“In many countries, especially in the United States, we are seeing year-over-year increases in incidence of endometrial cancer ... across many age groups, including those between the ages of 25 and 49 years. [This encompasses] both premenopausal and postmenopausal women,” Ryan J. Spencer, MD, MS, assistant professor in the division of gynecologic oncology and the department of obstetrics and gynecology at University of Wisconsin School of Medicine and Public Health, said in an interview.

Approximately 63,230 U.S. women are expected to be diagnosed with uterine cancer this year, and more than 57,000 of them will have endometrial cancer, according to American Cancer Society.

Nearly 90% of women diagnosed with stage 0 or stage Ia endometrial cancer survive at least 5 years. However, that percentage drops to precipitously as stage at diagnosis increases (stage II, 69%; stage III, approximately 50%; stage IV, approximately 15%).

“I want to cure every woman [with endometrial cancer], so there is a definite need for improvement,” Jennifer Mueller, MD, gynecologic oncologist at Memorial Sloan Kettering Cancer Center, said in an interview. “However, compared with other female reproductive cancer types — such as ovarian or cervical cancers — endometrial cancer is one of the more treatable types, as the vast majority of women present with early-stage disease.”

“One could potentially get 10 different answers from 10 different gynecologic oncologists regarding what may be contributing to increased endometrial cancer incidence, yet all 10 oncologists would say obesity is a clear contributing factor,” Jennifer Mueller, MD, said.
High BMI is estimated to account for nearly half of endometrial cancer cases in North America. “One could potentially get 10 different answers from 10 different gynecologic oncologists regarding what may be contributing to increased endometrial cancer incidence, yet all 10 oncologists would say obesity is a clear contributing factor,” Jennifer Mueller, MD, said.

Source: Memorial Sloan Kettering Cancer Center.

Incidence likely will continue to rise over the next decade, according to a study by Sheikh and colleagues. The researchers analyzed endometrial cancer incidence from 1990 through 2013 and — after accounting for temporal changes in obesity, hysterectomy and smoking — determined incidence will continue to increase through 2030.

However, it is unclear how increased incidence may disproportionately affect certain patient populations.

“When comparing or evaluating endometrial cancer incidence rates, it is important to consider whether the rates account for hysterectomy practices in the population,” Britton Trabert, PhD, MS, Earl Stadtman investigator in the division of cancer epidemiology and genetics at NCI, told HemOnc Today. “The denominator typically includes women who have had a hysterectomy and are not at risk for having endometrial cancer because their uterus has been removed.”

Not removing them from the denominator of the population at risk leads to underestimated rates of disease.

Siegel and colleagues found that failure to adjust uterine cancer incidence rates for hysterectomy prevalence underestimates the disease burden. They showed hysterectomy-corrected rates in the United States were 61% higher for white women, 78% higher for black women and 47% higher for Hispanic women.

“The cited studies are important to focus on when comparing incidence or projections of endometrial cancer rates because they have attempted to correct for hysterectomy practices in the population,” Trabert said.

Risk factors

Endometrial cancer is a hormone-driven malignancy, and nearly 80% of cases are attributable to excess estrogen or lack of progesterone, according to Carlson and colleagues.

Greater prevalence of key risk factors — such as obesity and shifts in reproductive trends among women, including delayed childbirth and having fewer children — likely are driving increased incidence, according to experts.

Other risk factors include increased use of exogenous estrogen among peri- and postmenopausal women; endogenous estrogen exposure associated with obesity; early age at menarche; late menopause; history of infertility; diabetes; hypertension; and personal or family history of polycystic ovary syndrome or hereditary nonpolyposis colon cancer, also known as Lynch syndrome.

Lortet-Tieulent and colleagues cited greater prevalence of established risk factors in most areas of the world. Obesity rates doubled in less than 30 years globally, and high BMI alone is estimated to account for more than one-third (34%) of endometrial cancer cases worldwide and nearly half (48%) of cases in North America.

“One could potentially get 10 different answers from 10 different gynecologic oncologists regarding what may be contributing to increased endometrial cancer incidence, yet all 10 oncologists would say obesity is a clear contributing factor,” Mueller told HemOnc Today. “Obesity provides peripheral estrogen that stimulates the lining of the uterus and can drive the endometrial lining into an environment that is quite hospitable for cancer progression.”

A 2017 study by Juhua Luo, PhD, associate professor of epidemiology and biostatistics at Indiana University School of Public Health, and colleagues suggested intentional weight loss could dramatically reduce endometrial cancer risk among postmenopausal women.

During mean follow-up of 11.4 years, researchers confirmed 566 incident endometrial cancer cases among 36,794 women enrolled in the Women’s Health Initiative observational study.

Multivariable analysis showed women with weight loss ( 5%) demonstrated significantly reduced endometrial cancer risk (HR = 0.71; 95% CI, 0.54-0.95), especially among obese women who lost weight intentionally (HR = 0.44; 95% CI, 0.25-0.78).

“Many older adults think it’s too late to benefit from weight loss, or [they] think that — because they are overweight or obese — the damage has already been done,” Luo said in a press release. “Our findings show that’s not true. It’s never too late, and even moderate weight loss can make a big difference when it comes to cancer risk.”

Although these findings support the concept that maintaining a healthy body weight can help prevent endometrial cancer, it is important to be mindful of the risk associated with exogenous menopausal hormone use among women who have not had a hysterectomy — specifically taking estrogen hormone therapy without a progestogen, Trabert said.

“In general, with respect to exogenous hormones used around the time of menopause, it is important to consider the risks and benefits,” Trabert said. “The current recommendation is that hormone therapy should only be used as necessary for the shortest duration possible.”

Racial disparities

Endometrial cancer incidence traditionally had been lower among black women in the United States than white women. However, that has changed over the past 2 decades.

When Lortet-Tieulent and colleagues analyzed global trends, they determined incidence in the United States increased more than twice as fast among black women than white women from 2003 through 2012 (average annual percent change, 3.1 vs. 1.4).

Today, rates of endometrial and other uterine malignancies are only slightly higher among white women in the U.S. than black women.

However, white women are considerably more likely than black women to survive 5 years after diagnosis (84% vs. 62%), according to data from Cancer.Net, ASCO’s patient information website.

“The question we are asking ourselves is: Why are black women more likely to have endometrial cancer and die of endometrial cancer than white women?” Mueller said. “This is a very complex question and not something that our research has yet been able to successfully definitively answer.”

Black women are less likely than white women to be diagnosed with early-stage disease, and they are more likely than women of other racial or ethnic groups to present with more aggressive subtypes. Differences in access to care and other factors associated with socioeconomic status also may contribute.

“A rich body of work from the social sciences — including anthropology, sociology and social epidemiology — have broadened the understanding of and research approaches to the study of health and health care inequity experienced by black Americans. Yet, these intellectual advancements in understanding are virtually absent from the gynecologic oncology literature,” Kemi Doll, MD, MSCR, assistant professor in the division of gynecologic oncology at University of Washington School of Medicine, wrote in an analytic essay published this year in Gynecologic Oncology.

Doll discussed three frameworks for the study of racial inequity in gynecologic oncology.

The ecosocial theory of disease distribution can be used to design and interpret racial differences in molecular and genetic studies.

The fundamental cause theory explains the relationship of socioeconomic position with the evolving treatability of a given disease over time and provides understanding into the contrast in racial disparities within ovarian, endometrial and cervical cancers.

The public health critical race praxis is an iterative methodology that helps frame how to study the impact of racism on health care delivery.

“Doll discusses racial disparities in research in a practical, culturally expanded way of thinking through theoretical and oncologic frameworks,” Mueller said. “She writes so succinctly and helps to explain this so that we can ask how anthropology and social sciences have advanced the understanding of how race may be influencing not just someone’s economic advantage, but their actual physical health at the cellular level.”

Screening

The American Cancer Society recommends women be told about the risks for and symptoms of endometrial cancer when they reach menopause.

The society also recommends that women who have or are likely to have hereditary nonpolyposis colon cancer be offered annual testing with endometrial biopsy starting by age 35 years.

However, there is no standard screening tool for endometrial cancer.

An NCI-funded study by Wang and colleagues showed PapSEEK — a liquid biopsy designed to identify cancer-related alterations in DNA from fluids collected during routine Pap tests — may detect some early-stage endometrial and ovarian cancers.

The test incorporates assays for mutations in 18 genes, as well as an assay for aneuploidy.

Wang and colleagues used the test to analyze Pap brush samples from 382 patients with endometrial cancer and 714 women without cancer.

Researchers reported sensitivity of 81% (95% CI, 77-81), including 78% among patients with early-stage disease. The sensitivity increased when investigators also tested DNA collected from blood and other tissue samples. The specificity was approximately 99%.

“These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable,” they wrote.

However, prospective randomized trials are needed to determine whether endometrial cancer screening could be worthwhile, according to Otis W. Brawley, MD, MACP, FASCO, FACE, chief medical officer at American Cancer Society and a HemOnc Today Editorial Board member.

Otis W. Brawley, MD, MACP, FASCO, FACE
Otis W. Brawley

“We do not have the data to show screening for endometrial cancer saves lives,” Brawley said in an interview. “We do not want to repeat the mistakes that occurred in screening for prostate and other cancers. Before we start large-scale endometrial screening, we need to perform a prospective randomized trial comparing a group of women screened to a group that is aware of symptoms. Widespread screening is appropriate only after such a study shows a mortality advantage among those screened.”

More intense efforts by the clinical community to improve awareness of endometrial cancer symptoms could pay dividends.

“We need to better educate women and physicians about the symptoms of endometrial cancer, including bleeding after menopause or a bleeding profile that is different than normal,” Mueller said. “We need to put this at the front of our minds when patients come into the office for their annual exam. These are the opportunities we have to perform biopsy, diagnose disease and ideally to treat endometrial cancer as soon as it arises. We want to be practical and intervene as soon as possible.”

Lynch syndrome

Lynch syndrome — caused by germline mutations in DNA mismatch repair genes — is the most common hereditary cause of endometrial cancer, accounting for an estimated 3% to 5% of cases. The condition also is associated with elevated risk for colorectal cancer.

Lynch syndrome screening among patients with these malignancies and their relatives can provide tremendous insights into how genetics contributes to risk for and prevalence.

Although Lynch syndrome screening is recommended for all patients with colorectal cancer, uptake is inconsistent for women with endometrial cancer.

Adar and colleagues sought to determine the added value of an immunohistochemistry-based screening program for Lynch syndrome among patients with these malignancies.

The analysis included 1,290 patients with colorectal cancer and 484 patients with endometrial cancer, all of whom underwent Lynch syndrome screening. Investigators recommended genetic testing for 137 (10.6%) patients with colorectal cancer and 32 (6.6%) with endometrial cancer.

Genetic testing identified Lynch syndrome among 16 (1.2%) patients with colorectal cancer and eight (1.7%) patients with endometrial cancer.

Among the group who underwent genetic testing, the rate of Lynch syndrome diagnosis was more than twice as high for those with endometrial cancer than colorectal cancer (25% vs. 11.7%).

The PREMM5 model — intended to help assess a person’s likelihood of carrying one of the gene mutations that drives Lynch syndrome — would have missed 12.5% of the Lynch syndrome cases detected through the universal screening approach used in this study.

Two other commonly used diagnostic tools — the Amsterdam II criteria and revised Bethesda criteria — would have missed at least half of the patients found to have Lynch syndrome, thereby supporting the value of universal Lynch syndrome screening for patients with endometrial and colorectal cancers, researchers wrote.

Treatment controversies

More than 80% of women with endometrial cancer survive at least 5 years after diagnosis, with survival outcomes correlated strongly with disease stage.

Hysterectomy — surgical removal of the uterus — is the primary treatment. However, some women experience serious complications.

Infection is the most common, with rates ranging from approximately 10% for abdominal or laparoscopic hysterectomy to 13% for vaginal hysterectomy.

Venous thromboembolism, injury to the genitourinary tract and bleeding complications are less common but still possible.

Although the benefits largely outweigh the risks, it may not always be appropriate for younger patients who want to preserve their fertility, women who are obese and those who have cardiovascular risk factors, Soliman said.

“These are the situations when we ask ourselves if surgery is the right thing to do or if we need to look at alternative treatment options,” she said.

For patients with localized disease, adjuvant chemotherapy — typically carboplatin and paclitaxel — and radiation often are administered after surgery to reduce recurrence risk.

Surgery may not be helpful if the cancer has spread to the liver, lungs or other organs. In those cases, chemotherapy and radiation may be used instead.

The use of chemotherapy for women with intermediate- to high-risk disease — which places them at greater risk for recurrence — remains controversial.

“A clear benefit has not been shown with chemotherapy for these patients in clinical trials,” Soliman said. “We still do not know the right answer for how best to treat these patients.”

The value of adjuvant radiation therapy also is debated, partly because of the variations in data interpretation at different cancer centers.

“Most studies have shown that giving radiation in this setting does not necessarily benefit overall survival, but there is decreased risk for local recurrence,” Soliman said. “Some centers suggest that — because radiation does not affect OS — there is no benefit to using it. Other centers argue that, if radiation decreases the risk for local recurrence, it most certainly is warranted.”

Several studies are underway to identify newer, more effective treatment options. Pathway inhibition, targeted treatments and immunotherapy offer the most promise.

“One of the most exciting breakthroughs for endometrial cancer is checkpoint blockade inhibitors for mismatch repair-deficient tumors,” Mueller said.

Last year, FDA granted accelerated approval to the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) for unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors that progressed after prior treatment and have no satisfactory alternatives.

This marked the agency’s approval of an agent indicated for patients with a specific genetic feature, independent of tumor type or site.

“We see mismatch repair-deficient tumors in endometrial cancers, so our patients can benefit significantly from this FDA approval,” Mueller said. “Although we are not using pembrolizumab in the frontline setting, we are using it for women who have progressed on previous treatments. We are still exploring this medication’s role in endometrial cancer, but we will see more clinical trials using this agent. This is a very exciting area.”

Bevacizumab (Avastin, Genentech), an angiogenesis inhibitor, is approved for women with recurrent platinum-treated ovarian cancer, as well as women with advanced cervical cancer.

Results of several prospective trials have suggested the agent is active among women with endometrial cancer.

Fader and colleagues conducted a multicenter, randomized phase 2 trial to evaluate the addition of the monoclonal antibody trastuzumab (Herceptin, Genentech) to chemotherapy for patients with advanced or recurrent HER-2-positive uterine serous carcinoma, an aggressive variant of endometrial cancer.

Researchers randomly assigned 61 women to six cycles of carboplatin-paclitaxel with or without trastuzumab.

The results showed women who received trastuzumab achieved significantly longer median PFS (12.6 months vs. 8 months; HR = 0.44; 90% CI, 0.26-0.76).

Trastuzumab extended median PFS among the 41 patients with stage III or stage IV disease who were undergoing primary treatment (17.9 months vs. 9.3 months; HR = 0.4; 90% CI, 0.2-0.8), as well as the 17 patients with recurrent disease (9.2 months vs. 6 months; HR = 0.14; 90% CI, 0.04-0.53).

“This is a very specific group of women,” Mueller said. “This was very exciting to see, but there needs to be phase 2 and phase 3 trials to confirm this benefit.”

PI3 kinase, AKT and mTOR pathway inhibitors also are under investigation for treatment of endometrial cancer.

“Initially, mTOR inhibitors were looked at in the endometrial cancer setting, but there are a lot of pathway escape mechanisms,” Mueller said. “We are now looking at dual inhibition of PI3K/AKT/mTOR.”

Funding frustrations

Because of increased incidence and the need for more effective therapies, endometrial cancer is “a fertile area” for scientific investigation, Mueller said.

However, research funding remains scarce.

“It is so frustrating to think how much farther along we could be — and how much more utility of those therapies could be understood — if endometrial cancer research was funded to the level that research for other cancer types is being funded,” Spencer said.

National Comprehensive Cancer Network guidelines offer only one level one recommendation for endometrial cancer.

“I find this appalling, and a lot of my colleagues do, too,” Spencer told HemOnc Today. “I do not say this because I want to take away money from research into other cancer types, but I want a cancer moonshot for every cancer. I do not want this group of women to be left out, but they are getting left out.”

Spencer and colleagues used data from the NCI SEER database, Cancer Trends Progress Report and funding statistics to assess NCI funding received across 13 cancer types from 2007 to 2014.

Researchers calculated funding-to-lethality scores for each cancer site. These scores measured funding received per years of life lost from 100 incident cases.

Scores would be the same across cancer types if funding was equitably allocated based on considerations of incidence and mortality.

However, the results showed scores for prostate cancer and breast cancer were nearly 32 times higher than uterine cancer (P < .00001).

Prostate cancer had the most funding with an 8-year average of $1.81 million received per years of life lost from 100 incident cases (funding-to-lethality score, 1.81). Breast cancer followed closely with a score of 1.8.

Of the 13 cancers analyzed, funding for ovarian cancer research ranked ninth, with a score of 0.097, followed by cervix cancer with a score of 0.087. Uterine cancer ranked next to last with a score of 0.057.

“As with any important cause, we need constant effort to make both administration and lay persons aware of the inequalities,” Spencer said. “It is critical to recruit people to champion the case that gynecologic cancers deserve more funding to keep pace with the transformative discoveries that we are seeing for other cancers.”

Spencer said he and his coinvestigators want these findings to serve as “a call to action.”

“Complete results of this project should be published soon, and we are engaging in ongoing research to understand how to best highlight this concern and develop suggestions and systems to correct the problem,” he said.

Soliman suggested endometrial cancer receives less research funding because incidence of other malignancies — namely breast, colon and lung cancers — is much higher.

“The potential impact of a clinical trial [for those malignancies] applies to a higher number of patients,” Soliman said. “We are sort of competing with that as far as research dollars go.”

Amid calls for additional research funding, Brawley cautioned against what he called “disease Olympics” — the process by which funding for investigations into one cancer takes away from funding for other malignancies.

“There are important examples when [research into] a particular disease has benefited research in another area,” Brawley said.

He cited the discovery in the 1990s of the role ALK plays in acute lymphoma. In the early 2000s, researchers learned the ALK gene is involved in certain thyroid cancers and, subsequently, investigators discovered the ALK gene is rearranged in 2% of lung cancers. This finding led to the development of crizotinib (Xalkori, Pfizer), which has been FDA-approved for ALK-positive lung cancer since 2010.

“These patients have been alive for 8 years because of this discovery,” Brawley said. “This lung cancer research would not have happened if the thyroid cancer research had not been funded, and the thyroid cancer research would not have happened if the lymphoma research had not been funded.

“This is an example for why we should advocate for more research funding for all cancer types, and we should see how we can apply the research that is done to other cancer types,” Brawley added. “Our philosophy should be that we should be trying to answer the questions that are most answerable and keep a broad open mind to application of what we learn.” – by Jennifer R. Southall

Click here to read the POINTCOUNTER, “Does increased endometrial cancer incidence warrant more intensive screening?”

References:

Adar T, et al. Cancer. 2018;doi:10.1002/cncr.31534.

American Cancer Society. Endometrial cancer survival rates by stage. Available at: www.cancer.org/cancer/endometrial-cancer/detection-diagnosis-staging/survival-rates.html. Accessed on June 13, 2018.

Cancer.net. Uterine cancer: Statistics. Available at: www.cancer.net/cancer-types/uterine-cancer/statistics. Accessed on June 13, 2018.

Carlson MJ, et al. Discov Med. 2012;14:215-222.

Clarke-Pearson DL and Geller EJ. Obstet Gynecol. 2013;doi:10.197/AOG.0b013e3182841594.

de Haydu C, et al. Expert Opin Pharmacother. 2016;doi: 10.1517/14656566.2016.1127351.

Doll KM. Gynecol Oncol. 2018;doi:10.1016/j.ygyno.2017.10.002.

Fader AN, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.76.5966.

Flegal KM, et al. JAMA. 2016;doi:10.1001/jama.2016.6458.

Lortet-Tieulent J, et al. J Natl Cancer Inst. 2018.doi:10.1093/jnci/djx214.

Luo J, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.70.5822.

Sheikh MA, et al. Future Oncol. 2014;doi:10.2217/fon.14.192.

Siegel RL, et al. Cancer Epidemiol Biomarkers Prev. 2013;doi:10.1158/1055-9965.EPI-12.0991.

Spencer R, et al. Abstract 3. Presented at: Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 24-27, 2018; New Orleans.

Wang Y, et al. Sci Transl Med. 2018;doi:10.1126/scitranslmed.aap8793.

For more information:

Otis W. Brawley, MD, MACP, FASCO, FACE, can be reached at American Cancer Society, 250 Williams St., Atlanta, GA 30303; email: otis.brawley@cancer.org.

Jennifer Mueller, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., H-1310, New York, NY 10065; email: muellerj@mskcc.org.

Pamela T. Soliman, MD, MPH, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: psoliman@mdanderson.org.

Ryan J. Spencer, MD, MS, can be reached at University of Wisconsin School of Medicine and Public Health, 600 Highland Ave., CSC H4/664, Madison, WI 53792; email: rjspencer2@wisc.edu.

Britton Trabert, PhD, can be reached at National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850; email: britton.trabert@nih.gov.

Disclosures: Brawley, Mueller, Soliman, Spencer and Trabert report no relevant financial disclosures.

Endometrial cancer incidence has increased dramatically in many parts of the world, and the United States is no exception.

Lortet-Tieulent and colleagues analyzed international patterns of age-standardized endometrial cancer incidence in 43 countries from 1978 to 2013.

Their results — published last year in Journal of the National Cancer Institute — showed the rate among U.S. white women reached 19 cases per 100,000 by the end of the study period, tied with Slovakia for highest in the world.

Endometrial cancer incidence among black women in the United States historically has trailed that of white women. However, the gap has narrowed considerably since the turn of the century.

This trend has prompted some experts to call for greater emphasis on screening. In addition, NCI funding for research into endometrial cancer and other gynecologic malignancies is incredibly scarce, even though the optimal treatment for the women with the greatest need — those with intermediate- to high-risk disease — has not been established.

“Some may say, ‘Endometrial cancer can be found early and most patients are cured, so do we really need to focus on new treatments?” Pamela T. Soliman, MD, MPH, associate professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center and medical director of the institution’s gynecologic medical center, told HemOnc Today. “But those of us who treat these patients know they do not all have great outcomes, and we do see a significant need.”

HemOnc Today spoke with researchers and clinicians about the potential explanations for increased endometrial cancer incidence in the United States; the factors that are driving the spike among black women; whether greater incidence should result in more screening; how the treatment landscape is evolving; and the calls for more research funding for endometrial cancer and other gynecologic malignancies.

Incidence and outcomes

Endometrial cancer — the most common type of uterine cancer — is the fourth most common malignancy among women in the United States, trailing only breast, lung and colorectal cancers.

It typically occurs among women aged 55 years or older; however, the experts with whom HemOnc Today spoke said they are seeing more women diagnosed at younger ages.

“In many countries, especially in the United States, we are seeing year-over-year increases in incidence of endometrial cancer ... across many age groups, including those between the ages of 25 and 49 years. [This encompasses] both premenopausal and postmenopausal women,” Ryan J. Spencer, MD, MS, assistant professor in the division of gynecologic oncology and the department of obstetrics and gynecology at University of Wisconsin School of Medicine and Public Health, said in an interview.

PAGE BREAK

Approximately 63,230 U.S. women are expected to be diagnosed with uterine cancer this year, and more than 57,000 of them will have endometrial cancer, according to American Cancer Society.

Nearly 90% of women diagnosed with stage 0 or stage Ia endometrial cancer survive at least 5 years. However, that percentage drops to precipitously as stage at diagnosis increases (stage II, 69%; stage III, approximately 50%; stage IV, approximately 15%).

“I want to cure every woman [with endometrial cancer], so there is a definite need for improvement,” Jennifer Mueller, MD, gynecologic oncologist at Memorial Sloan Kettering Cancer Center, said in an interview. “However, compared with other female reproductive cancer types — such as ovarian or cervical cancers — endometrial cancer is one of the more treatable types, as the vast majority of women present with early-stage disease.”

“One could potentially get 10 different answers from 10 different gynecologic oncologists regarding what may be contributing to increased endometrial cancer incidence, yet all 10 oncologists would say obesity is a clear contributing factor,” Jennifer Mueller, MD, said.
High BMI is estimated to account for nearly half of endometrial cancer cases in North America. “One could potentially get 10 different answers from 10 different gynecologic oncologists regarding what may be contributing to increased endometrial cancer incidence, yet all 10 oncologists would say obesity is a clear contributing factor,” Jennifer Mueller, MD, said.

Source: Memorial Sloan Kettering Cancer Center.

Incidence likely will continue to rise over the next decade, according to a study by Sheikh and colleagues. The researchers analyzed endometrial cancer incidence from 1990 through 2013 and — after accounting for temporal changes in obesity, hysterectomy and smoking — determined incidence will continue to increase through 2030.

However, it is unclear how increased incidence may disproportionately affect certain patient populations.

“When comparing or evaluating endometrial cancer incidence rates, it is important to consider whether the rates account for hysterectomy practices in the population,” Britton Trabert, PhD, MS, Earl Stadtman investigator in the division of cancer epidemiology and genetics at NCI, told HemOnc Today. “The denominator typically includes women who have had a hysterectomy and are not at risk for having endometrial cancer because their uterus has been removed.”

Not removing them from the denominator of the population at risk leads to underestimated rates of disease.

Siegel and colleagues found that failure to adjust uterine cancer incidence rates for hysterectomy prevalence underestimates the disease burden. They showed hysterectomy-corrected rates in the United States were 61% higher for white women, 78% higher for black women and 47% higher for Hispanic women.

“The cited studies are important to focus on when comparing incidence or projections of endometrial cancer rates because they have attempted to correct for hysterectomy practices in the population,” Trabert said.

PAGE BREAK

Risk factors

Endometrial cancer is a hormone-driven malignancy, and nearly 80% of cases are attributable to excess estrogen or lack of progesterone, according to Carlson and colleagues.

Greater prevalence of key risk factors — such as obesity and shifts in reproductive trends among women, including delayed childbirth and having fewer children — likely are driving increased incidence, according to experts.

Other risk factors include increased use of exogenous estrogen among peri- and postmenopausal women; endogenous estrogen exposure associated with obesity; early age at menarche; late menopause; history of infertility; diabetes; hypertension; and personal or family history of polycystic ovary syndrome or hereditary nonpolyposis colon cancer, also known as Lynch syndrome.

Lortet-Tieulent and colleagues cited greater prevalence of established risk factors in most areas of the world. Obesity rates doubled in less than 30 years globally, and high BMI alone is estimated to account for more than one-third (34%) of endometrial cancer cases worldwide and nearly half (48%) of cases in North America.

“One could potentially get 10 different answers from 10 different gynecologic oncologists regarding what may be contributing to increased endometrial cancer incidence, yet all 10 oncologists would say obesity is a clear contributing factor,” Mueller told HemOnc Today. “Obesity provides peripheral estrogen that stimulates the lining of the uterus and can drive the endometrial lining into an environment that is quite hospitable for cancer progression.”

A 2017 study by Juhua Luo, PhD, associate professor of epidemiology and biostatistics at Indiana University School of Public Health, and colleagues suggested intentional weight loss could dramatically reduce endometrial cancer risk among postmenopausal women.

During mean follow-up of 11.4 years, researchers confirmed 566 incident endometrial cancer cases among 36,794 women enrolled in the Women’s Health Initiative observational study.

Multivariable analysis showed women with weight loss ( 5%) demonstrated significantly reduced endometrial cancer risk (HR = 0.71; 95% CI, 0.54-0.95), especially among obese women who lost weight intentionally (HR = 0.44; 95% CI, 0.25-0.78).

“Many older adults think it’s too late to benefit from weight loss, or [they] think that — because they are overweight or obese — the damage has already been done,” Luo said in a press release. “Our findings show that’s not true. It’s never too late, and even moderate weight loss can make a big difference when it comes to cancer risk.”

Although these findings support the concept that maintaining a healthy body weight can help prevent endometrial cancer, it is important to be mindful of the risk associated with exogenous menopausal hormone use among women who have not had a hysterectomy — specifically taking estrogen hormone therapy without a progestogen, Trabert said.

PAGE BREAK

“In general, with respect to exogenous hormones used around the time of menopause, it is important to consider the risks and benefits,” Trabert said. “The current recommendation is that hormone therapy should only be used as necessary for the shortest duration possible.”

Racial disparities

Endometrial cancer incidence traditionally had been lower among black women in the United States than white women. However, that has changed over the past 2 decades.

When Lortet-Tieulent and colleagues analyzed global trends, they determined incidence in the United States increased more than twice as fast among black women than white women from 2003 through 2012 (average annual percent change, 3.1 vs. 1.4).

Today, rates of endometrial and other uterine malignancies are only slightly higher among white women in the U.S. than black women.

However, white women are considerably more likely than black women to survive 5 years after diagnosis (84% vs. 62%), according to data from Cancer.Net, ASCO’s patient information website.

“The question we are asking ourselves is: Why are black women more likely to have endometrial cancer and die of endometrial cancer than white women?” Mueller said. “This is a very complex question and not something that our research has yet been able to successfully definitively answer.”

Black women are less likely than white women to be diagnosed with early-stage disease, and they are more likely than women of other racial or ethnic groups to present with more aggressive subtypes. Differences in access to care and other factors associated with socioeconomic status also may contribute.

“A rich body of work from the social sciences — including anthropology, sociology and social epidemiology — have broadened the understanding of and research approaches to the study of health and health care inequity experienced by black Americans. Yet, these intellectual advancements in understanding are virtually absent from the gynecologic oncology literature,” Kemi Doll, MD, MSCR, assistant professor in the division of gynecologic oncology at University of Washington School of Medicine, wrote in an analytic essay published this year in Gynecologic Oncology.

Doll discussed three frameworks for the study of racial inequity in gynecologic oncology.

The ecosocial theory of disease distribution can be used to design and interpret racial differences in molecular and genetic studies.

The fundamental cause theory explains the relationship of socioeconomic position with the evolving treatability of a given disease over time and provides understanding into the contrast in racial disparities within ovarian, endometrial and cervical cancers.

The public health critical race praxis is an iterative methodology that helps frame how to study the impact of racism on health care delivery.

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“Doll discusses racial disparities in research in a practical, culturally expanded way of thinking through theoretical and oncologic frameworks,” Mueller said. “She writes so succinctly and helps to explain this so that we can ask how anthropology and social sciences have advanced the understanding of how race may be influencing not just someone’s economic advantage, but their actual physical health at the cellular level.”

Screening

The American Cancer Society recommends women be told about the risks for and symptoms of endometrial cancer when they reach menopause.

The society also recommends that women who have or are likely to have hereditary nonpolyposis colon cancer be offered annual testing with endometrial biopsy starting by age 35 years.

However, there is no standard screening tool for endometrial cancer.

An NCI-funded study by Wang and colleagues showed PapSEEK — a liquid biopsy designed to identify cancer-related alterations in DNA from fluids collected during routine Pap tests — may detect some early-stage endometrial and ovarian cancers.

The test incorporates assays for mutations in 18 genes, as well as an assay for aneuploidy.

Wang and colleagues used the test to analyze Pap brush samples from 382 patients with endometrial cancer and 714 women without cancer.

Researchers reported sensitivity of 81% (95% CI, 77-81), including 78% among patients with early-stage disease. The sensitivity increased when investigators also tested DNA collected from blood and other tissue samples. The specificity was approximately 99%.

“These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable,” they wrote.

However, prospective randomized trials are needed to determine whether endometrial cancer screening could be worthwhile, according to Otis W. Brawley, MD, MACP, FASCO, FACE, chief medical officer at American Cancer Society and a HemOnc Today Editorial Board member.

Otis W. Brawley, MD, MACP, FASCO, FACE
Otis W. Brawley

“We do not have the data to show screening for endometrial cancer saves lives,” Brawley said in an interview. “We do not want to repeat the mistakes that occurred in screening for prostate and other cancers. Before we start large-scale endometrial screening, we need to perform a prospective randomized trial comparing a group of women screened to a group that is aware of symptoms. Widespread screening is appropriate only after such a study shows a mortality advantage among those screened.”

More intense efforts by the clinical community to improve awareness of endometrial cancer symptoms could pay dividends.

“We need to better educate women and physicians about the symptoms of endometrial cancer, including bleeding after menopause or a bleeding profile that is different than normal,” Mueller said. “We need to put this at the front of our minds when patients come into the office for their annual exam. These are the opportunities we have to perform biopsy, diagnose disease and ideally to treat endometrial cancer as soon as it arises. We want to be practical and intervene as soon as possible.”

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Lynch syndrome

Lynch syndrome — caused by germline mutations in DNA mismatch repair genes — is the most common hereditary cause of endometrial cancer, accounting for an estimated 3% to 5% of cases. The condition also is associated with elevated risk for colorectal cancer.

Lynch syndrome screening among patients with these malignancies and their relatives can provide tremendous insights into how genetics contributes to risk for and prevalence.

Although Lynch syndrome screening is recommended for all patients with colorectal cancer, uptake is inconsistent for women with endometrial cancer.

Adar and colleagues sought to determine the added value of an immunohistochemistry-based screening program for Lynch syndrome among patients with these malignancies.

The analysis included 1,290 patients with colorectal cancer and 484 patients with endometrial cancer, all of whom underwent Lynch syndrome screening. Investigators recommended genetic testing for 137 (10.6%) patients with colorectal cancer and 32 (6.6%) with endometrial cancer.

Genetic testing identified Lynch syndrome among 16 (1.2%) patients with colorectal cancer and eight (1.7%) patients with endometrial cancer.

Among the group who underwent genetic testing, the rate of Lynch syndrome diagnosis was more than twice as high for those with endometrial cancer than colorectal cancer (25% vs. 11.7%).

The PREMM5 model — intended to help assess a person’s likelihood of carrying one of the gene mutations that drives Lynch syndrome — would have missed 12.5% of the Lynch syndrome cases detected through the universal screening approach used in this study.

Two other commonly used diagnostic tools — the Amsterdam II criteria and revised Bethesda criteria — would have missed at least half of the patients found to have Lynch syndrome, thereby supporting the value of universal Lynch syndrome screening for patients with endometrial and colorectal cancers, researchers wrote.

Treatment controversies

More than 80% of women with endometrial cancer survive at least 5 years after diagnosis, with survival outcomes correlated strongly with disease stage.

Hysterectomy — surgical removal of the uterus — is the primary treatment. However, some women experience serious complications.

Infection is the most common, with rates ranging from approximately 10% for abdominal or laparoscopic hysterectomy to 13% for vaginal hysterectomy.

Venous thromboembolism, injury to the genitourinary tract and bleeding complications are less common but still possible.

Although the benefits largely outweigh the risks, it may not always be appropriate for younger patients who want to preserve their fertility, women who are obese and those who have cardiovascular risk factors, Soliman said.

“These are the situations when we ask ourselves if surgery is the right thing to do or if we need to look at alternative treatment options,” she said.

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For patients with localized disease, adjuvant chemotherapy — typically carboplatin and paclitaxel — and radiation often are administered after surgery to reduce recurrence risk.

Surgery may not be helpful if the cancer has spread to the liver, lungs or other organs. In those cases, chemotherapy and radiation may be used instead.

The use of chemotherapy for women with intermediate- to high-risk disease — which places them at greater risk for recurrence — remains controversial.

“A clear benefit has not been shown with chemotherapy for these patients in clinical trials,” Soliman said. “We still do not know the right answer for how best to treat these patients.”

The value of adjuvant radiation therapy also is debated, partly because of the variations in data interpretation at different cancer centers.

“Most studies have shown that giving radiation in this setting does not necessarily benefit overall survival, but there is decreased risk for local recurrence,” Soliman said. “Some centers suggest that — because radiation does not affect OS — there is no benefit to using it. Other centers argue that, if radiation decreases the risk for local recurrence, it most certainly is warranted.”

Several studies are underway to identify newer, more effective treatment options. Pathway inhibition, targeted treatments and immunotherapy offer the most promise.

“One of the most exciting breakthroughs for endometrial cancer is checkpoint blockade inhibitors for mismatch repair-deficient tumors,” Mueller said.

Last year, FDA granted accelerated approval to the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) for unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors that progressed after prior treatment and have no satisfactory alternatives.

This marked the agency’s approval of an agent indicated for patients with a specific genetic feature, independent of tumor type or site.

“We see mismatch repair-deficient tumors in endometrial cancers, so our patients can benefit significantly from this FDA approval,” Mueller said. “Although we are not using pembrolizumab in the frontline setting, we are using it for women who have progressed on previous treatments. We are still exploring this medication’s role in endometrial cancer, but we will see more clinical trials using this agent. This is a very exciting area.”

Bevacizumab (Avastin, Genentech), an angiogenesis inhibitor, is approved for women with recurrent platinum-treated ovarian cancer, as well as women with advanced cervical cancer.

Results of several prospective trials have suggested the agent is active among women with endometrial cancer.

Fader and colleagues conducted a multicenter, randomized phase 2 trial to evaluate the addition of the monoclonal antibody trastuzumab (Herceptin, Genentech) to chemotherapy for patients with advanced or recurrent HER-2-positive uterine serous carcinoma, an aggressive variant of endometrial cancer.

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Researchers randomly assigned 61 women to six cycles of carboplatin-paclitaxel with or without trastuzumab.

The results showed women who received trastuzumab achieved significantly longer median PFS (12.6 months vs. 8 months; HR = 0.44; 90% CI, 0.26-0.76).

Trastuzumab extended median PFS among the 41 patients with stage III or stage IV disease who were undergoing primary treatment (17.9 months vs. 9.3 months; HR = 0.4; 90% CI, 0.2-0.8), as well as the 17 patients with recurrent disease (9.2 months vs. 6 months; HR = 0.14; 90% CI, 0.04-0.53).

“This is a very specific group of women,” Mueller said. “This was very exciting to see, but there needs to be phase 2 and phase 3 trials to confirm this benefit.”

PI3 kinase, AKT and mTOR pathway inhibitors also are under investigation for treatment of endometrial cancer.

“Initially, mTOR inhibitors were looked at in the endometrial cancer setting, but there are a lot of pathway escape mechanisms,” Mueller said. “We are now looking at dual inhibition of PI3K/AKT/mTOR.”

Funding frustrations

Because of increased incidence and the need for more effective therapies, endometrial cancer is “a fertile area” for scientific investigation, Mueller said.

However, research funding remains scarce.

“It is so frustrating to think how much farther along we could be — and how much more utility of those therapies could be understood — if endometrial cancer research was funded to the level that research for other cancer types is being funded,” Spencer said.

National Comprehensive Cancer Network guidelines offer only one level one recommendation for endometrial cancer.

“I find this appalling, and a lot of my colleagues do, too,” Spencer told HemOnc Today. “I do not say this because I want to take away money from research into other cancer types, but I want a cancer moonshot for every cancer. I do not want this group of women to be left out, but they are getting left out.”

Spencer and colleagues used data from the NCI SEER database, Cancer Trends Progress Report and funding statistics to assess NCI funding received across 13 cancer types from 2007 to 2014.

Researchers calculated funding-to-lethality scores for each cancer site. These scores measured funding received per years of life lost from 100 incident cases.

Scores would be the same across cancer types if funding was equitably allocated based on considerations of incidence and mortality.

However, the results showed scores for prostate cancer and breast cancer were nearly 32 times higher than uterine cancer (P < .00001).

Prostate cancer had the most funding with an 8-year average of $1.81 million received per years of life lost from 100 incident cases (funding-to-lethality score, 1.81). Breast cancer followed closely with a score of 1.8.

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Of the 13 cancers analyzed, funding for ovarian cancer research ranked ninth, with a score of 0.097, followed by cervix cancer with a score of 0.087. Uterine cancer ranked next to last with a score of 0.057.

“As with any important cause, we need constant effort to make both administration and lay persons aware of the inequalities,” Spencer said. “It is critical to recruit people to champion the case that gynecologic cancers deserve more funding to keep pace with the transformative discoveries that we are seeing for other cancers.”

Spencer said he and his coinvestigators want these findings to serve as “a call to action.”

“Complete results of this project should be published soon, and we are engaging in ongoing research to understand how to best highlight this concern and develop suggestions and systems to correct the problem,” he said.

Soliman suggested endometrial cancer receives less research funding because incidence of other malignancies — namely breast, colon and lung cancers — is much higher.

“The potential impact of a clinical trial [for those malignancies] applies to a higher number of patients,” Soliman said. “We are sort of competing with that as far as research dollars go.”

Amid calls for additional research funding, Brawley cautioned against what he called “disease Olympics” — the process by which funding for investigations into one cancer takes away from funding for other malignancies.

“There are important examples when [research into] a particular disease has benefited research in another area,” Brawley said.

He cited the discovery in the 1990s of the role ALK plays in acute lymphoma. In the early 2000s, researchers learned the ALK gene is involved in certain thyroid cancers and, subsequently, investigators discovered the ALK gene is rearranged in 2% of lung cancers. This finding led to the development of crizotinib (Xalkori, Pfizer), which has been FDA-approved for ALK-positive lung cancer since 2010.

“These patients have been alive for 8 years because of this discovery,” Brawley said. “This lung cancer research would not have happened if the thyroid cancer research had not been funded, and the thyroid cancer research would not have happened if the lymphoma research had not been funded.

“This is an example for why we should advocate for more research funding for all cancer types, and we should see how we can apply the research that is done to other cancer types,” Brawley added. “Our philosophy should be that we should be trying to answer the questions that are most answerable and keep a broad open mind to application of what we learn.” – by Jennifer R. Southall

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Click here to read the POINTCOUNTER, “Does increased endometrial cancer incidence warrant more intensive screening?”

References:

Adar T, et al. Cancer. 2018;doi:10.1002/cncr.31534.

American Cancer Society. Endometrial cancer survival rates by stage. Available at: www.cancer.org/cancer/endometrial-cancer/detection-diagnosis-staging/survival-rates.html. Accessed on June 13, 2018.

Cancer.net. Uterine cancer: Statistics. Available at: www.cancer.net/cancer-types/uterine-cancer/statistics. Accessed on June 13, 2018.

Carlson MJ, et al. Discov Med. 2012;14:215-222.

Clarke-Pearson DL and Geller EJ. Obstet Gynecol. 2013;doi:10.197/AOG.0b013e3182841594.

de Haydu C, et al. Expert Opin Pharmacother. 2016;doi: 10.1517/14656566.2016.1127351.

Doll KM. Gynecol Oncol. 2018;doi:10.1016/j.ygyno.2017.10.002.

Fader AN, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.76.5966.

Flegal KM, et al. JAMA. 2016;doi:10.1001/jama.2016.6458.

Lortet-Tieulent J, et al. J Natl Cancer Inst. 2018.doi:10.1093/jnci/djx214.

Luo J, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2016.70.5822.

Sheikh MA, et al. Future Oncol. 2014;doi:10.2217/fon.14.192.

Siegel RL, et al. Cancer Epidemiol Biomarkers Prev. 2013;doi:10.1158/1055-9965.EPI-12.0991.

Spencer R, et al. Abstract 3. Presented at: Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 24-27, 2018; New Orleans.

Wang Y, et al. Sci Transl Med. 2018;doi:10.1126/scitranslmed.aap8793.

For more information:

Otis W. Brawley, MD, MACP, FASCO, FACE, can be reached at American Cancer Society, 250 Williams St., Atlanta, GA 30303; email: otis.brawley@cancer.org.

Jennifer Mueller, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., H-1310, New York, NY 10065; email: muellerj@mskcc.org.

Pamela T. Soliman, MD, MPH, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: psoliman@mdanderson.org.

Ryan J. Spencer, MD, MS, can be reached at University of Wisconsin School of Medicine and Public Health, 600 Highland Ave., CSC H4/664, Madison, WI 53792; email: rjspencer2@wisc.edu.

Britton Trabert, PhD, can be reached at National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850; email: britton.trabert@nih.gov.

Disclosures: Brawley, Mueller, Soliman, Spencer and Trabert report no relevant financial disclosures.