Cancer couldn’t have been further from Sandy Facinoli’s mind when she noticed something odd.

“I had just found a little itsy, bitsy, teeny, weeny spot in my undies. I mean, no flow. No big thing. It wasn't even red,” she says. “I don't know why I paid any attention.”

She didn’t have any pain and felt healthy, but, at 69 and well past menopause, she knew she shouldn’t be bleeding. So, she reached out to her primary care clinician, thinking — for no particular reason — that perhaps “something had popped.” Her physician recognized a warning sign that merited an ultrasound and a visit to a gynecologist. 

Later, while out shopping, Facinoli got a call from a nurse saying her gynecologist wanted to talk to her, and the possibility of cancer, which she had until this point dismissed, became real. 

“I said, ‘I'm at the grocery store. Can I get home and sit down?’” she says she told the nurse. When she spoke with the gynecologist 10 minutes later, the news confirmed her new fear: Facinoli had endometrial cancer. The gynecologist described next steps and sent her to Johns Hopkins’ Anna Beavis, an assistant professor of gynecology and obstetrics, for surgery.

Malignancies like Facinoli’s, which develop in the lining of the uterus known as the endometrium, account for more than 90% of cancers of the uterus. These cancers are generally heralded by abnormal vaginal bleeding, which for women in Facinoli’s stage of life means any sign of blood at all, no matter the amount or color. Uterine cancers rank as the fourth most common type of cancer affecting women, with more than 66,000 new patients diagnosed each year.

Many such tumors respond well to treatment, however, they stand out among cancers. While statistics show progress against many types of malignancies, those of the uterus are becoming more prevalent and more deadly. That’s driven by a handful of factors, including obesity and increases in more aggressive tumors, which take a disproportionate toll on Black women — who die from uterine cancer at nearly twice the rate as their white counterparts.

“There should be no reason for these trends,” says Amanda Nickles Fader, professor of gynecology and obstetrics at Johns Hopkins. “As medical providers, we need to raise awareness of what I think is one of the worst public health crises for women right now.” 

Just as efforts to raise the profile of breast cancer have called attention to this malignancy, she wants to see cancers that occur “below the belt” in the female reproductive system, including those of the endometrium, receive similar focus. She and others at Johns Hopkins are working to spread the word to patients and their clinicians, and to devise much-needed new tools for catching these tumors as early as possible, when doctors have the best odds of beating back the cancer. 

Above: Anna Beavis, left, and Amanda Nickles Fader

"Heading in the Wrong Direction"

In the big picture, medicine continues to make hard-won progress against cancer. Since 1991, declines in mortality rates have prevented an estimated 3.8 million deaths in the U.S. and the frequency of most solid tumors is plateauing or even decreasing, according to Fader.

However, cancers of the uterus buck this trend. Between 2010 and 2019, researchers estimate that new cases of uterine cancer rose by, on average, 0.7 percent each year. Likewise, from 2011 to 2020, death rates increased by an average of 1.6 percent per year. 

“We are heading in the wrong direction,” Fader says.

While this alarming trajectory has no single, simple explanation, the national increase in body weight has contributed, she says. This connection arises because fat cells influence reproductive hormones. During the menstrual cycle, the hormone estrogen tells the endometrium to thicken, while its counterpart, progesterone, prompts the buildup to slough off. If unchecked, the growth of the endometrium can turn malignant. By causing estrogen levels to increase, fat cells can encourage this transformation. What’s more, obese women are more likely to have irregular menstrual cycles, which also favor thickening of the endometrial layer. 

Researchers have estimated that being overweight for 10 years can increase the risk of developing endometrial cancer by 17%. Another study, meanwhile, has linked rising obesity in the U.S. with increases in endometrial cancer, including a 14-fold surge among women younger than 45. 

“With diagnosis occurring at younger ages, we’re seeing women being given this news at a time in their lives when planning a family is important to them,” Fader says. While often effective, standard treatment can rob them of their ability to become pregnant, an outcome she describes as “life altering.”

Much of Fader’s research and clinical care focuses on women in their reproductive years and on those affected by rare forms of endometrial cancer. While excess estrogen drives most endometrial cancers, some tumors arise without its influence. More aggressive than the common variety, these malignancies have an outsized impact on mortality, according to Fader, who directs the Center for Rare Gynecologic Cancers at Johns Hopkins. These tumors account for half of endometrial-cancer related deaths, but only about 20 percent of cases, she says.

As a rule, the earlier a tumor is caught, the better. Buried deep in the abdomen, the lining of the uterus does not readily lend itself to conventional screening approaches, and to date, physicians do not have a routine method for identifying endometrial cancer among apparently healthy patients. 

Researchers at Johns Hopkins are working on a solution (see below). However, in the meantime, doctors and patients must rely on a more rudimentary alert: abnormal bleeding. 

“Any postmenopausal patient who has any amount of bleeding, whether it's light pink spotting, bright red bleeding, or bleeding like a period, that is never normal,” says Katherine Ikard Stewart, an assistant professor of gynecologic oncology, who treats patients with endometrial cancer. “They should see their gynecologist to have it evaluated.”

For women who have not yet gone through menopause, “any bleeding between periods, prolonged periods, or any other persistent change to their periods, those are reasons to be evaluated,” she says. 

Not only may women not know to seek help, but their physicians may misattribute bleeding to a more benign condition, according to Fader. 

“I see quite a few women who are blown off by their providers, frankly, because they’re not familiar with the symptoms of endometrial cancer,” she says.

Last year, she and her colleagues at Hopkins hosted a conference aimed at educating physicians. Those who attended the Inaugural Endometrial Cancer Symposium learned about trends for this cancer, and the latest in treatment and research. To launch the first in what they intend to be a recurring event, Hopkins faculty received support from The Laughlin Family Foundation, established by a Hopkins endometrial cancer survivor and patient advocate, Linda Laughlin, and her family.

Partnering with patient advocates and others in the community is crucial to making progress against this disease, says Fader, who plans to emphasize building these relationships when she assumes the presidency of the Society of Gynecological Oncology in 2025.

“High Time for a Screening Test”

For certain types of cancer — breast, cervical, colon, skin — physicians routinely check patients in the hopes of catching malignancies early, or even before they start. Based on x-rays, swabs, and other means, these tests are typically given to people at elevated risk, often determined by age. 

In the past, a screening test wasn’t seen as necessary for endometrial cancer, according to Fader. These tumors weren’t all that common, could be caught early based on their symptoms, and readily treated. Given the trends in endometrial cancer, which is projected to overtake colorectal cancer as the third most common cancer among women, “it’s high time for a screening test,” she says. 

Currently, physicians like Fader have several means with which they can investigate abnormal bleeding, including by using ultrasound imaging to examine the reproductive system and collecting tissue samples, a procedure known as a biopsy. All are invasive and have other significant drawbacks that render them unsuitable for examining large numbers of symptom-free women.

To develop a workable option, Johns Hopkins researchers are looking to the Pap smear. Since the mid-20th century, physicians have used this test to detect cancer at the entry to the uterus, the cervix. By swabbing the cervix with a soft brush during an exam, they collect cells that are then examined under the microscope for signs of malignancy or precursors to it. More recently, physicians have also begun analyzing these samples for genetic material belonging to the human papillomavirus, or HPV, which causes cervical cancer. 

Pap smears, now augmented with HPV testing, have dramatically reduced both the occurrence of and deaths from cervical cancer. 

The Hopkins team is aiming to recapitulate some of this success against other gynecological cancers. For endometrial cancer, they want to flag likely cases based on mutations gleaned from genetic material in the same samples already collected during Pap smears. 

“A thickening of the endometrial lining can be associated with a lot of different things. But we know which mutations drive endometrial cancer, and the theory is that we can detect the cancer, or precancer, by detecting the mutations,” says Jonathan Dudley, an assistant professor of pathology. He began working on the new test after joining oncologist Bert Vogelstein’s group in 2018 and is now continuing the project in his own lab. 

While endometrial tumors can carry many mutations, two figure prominently into their genetic profiles. Errors in the tumor suppressor gene TP53 are hallmarks of the less common endometrial cancers, while changes to another tumor suppressor gene, this one called PTEN, typically characterize the predominant estrogen-driven variety. In a study published in 2018, Vogelstein and his colleagues tested their approach on samples collected from women with cancer. 

While the results initially looked promising, encountered a challenge: Other studies demonstrated that mutations like these aren’t nearly as specific to cancer as the team had believed. This research showed that TP53 and other cancer-driving mutations turn up frequently in the cells of people who do not have cancer. 

This discovery forced the team to rethink their methods, Dudley says, adding, “we think we’ve found ways to address these problems.” 

They are currently testing a revised approach, the details of which they have not yet made public, on more patient samples. If everything progresses well, Dudley anticipates that a test could become available in three to five years.

Beavis, who is not involved in the project, called the prospect of the test an “exciting technology,” but notes “we would still need to understand, from an epidemiological perspective, who should undergo it.”

This cancer screening test could be performed in women at heightened risk. However, this category hasn’t yet been carefully defined for endometrial cancer. In addition to treating patients like Facinoli, Beavis is studying how to better identify which women are most likely to develop this cancer based on characteristics such as level of BMI, race or ethnicity, and presence of other health conditions.

Clinical Trials to Improve Outcomes

Caught soon enough, endometrial cancer has a potential cure: a total hysterectomy, which removes not only the tumor but also a woman’s uterus, ovaries, fallopian tubes and cervix. Using a robotic platform, surgeons at Johns Hopkins and elsewhere can extract them through only a handful of small incisions. The surgeon also investigates whether or not the cancer has spread to nearby lymph nodes, which are often an early site for metastasis. 

However, surgery isn’t the only option. Depending on the aggressiveness and stage of the cancer, Fader and her team can offer young women an alternative that leaves their reproductive system, and their capacity to become pregnant, intact. Fertility-sparing therapy employs the hormone progesterone, estrogen’s counterpart. Delivered through pills or an intrauterine device, more commonly known as an IUD, progesterone thins the thickened endometrium and can reverse the disease.

Fader and her colleagues are launching a clinical trial focused on improving progesterone therapy. The Womb for Improvement study will enroll women of reproductive age diagnosed with pre- or early-stage endometrial cancer and examine if weight loss measures — specifically an exercise program and dietary changes — can improve their response to the hormone. The researchers will also follow the women after their treatment to see how this regimen affects their ability to have children.

Meanwhile, Fader and others at Hopkins are conducting clinical trials testing more selective strategies for treating advanced cases of these cancers. By leveraging insights into the molecular basis for endometrial cancer, their research is advancing the care physicians provide and so offering patients new hope.

In one ground-breaking trial, Fader and her colleagues found that a drug long used to treat certain breast cancers could also improve outcomes for women with an aggressive form of endometrial cancer. Trastuzumab, a type of monoclonal antibody, targets a protein known as HER2 that can drive breast cancer. Because problematic HER2 also occurs in certain rare, deadly endometrial tumors known as serous carcinomas, the team wanted to know if adding trastuzumab to standard chemotherapy would improve outcomes for these patients. It did; those who received the antibody went longer without their cancer progressing, the researchers reported in the Journal of Clinical Oncology. Later research reinforced the benefit of this therapy, and trastuzumab has now become a standard treatment for aggressive endometrial tumors with excess HER2.

Fader and others are following up with another clinical trial examining the effect of adding a second HER2-targeting antibody, pertuzumab, to the treatment regimen.

Likewise, studies at Hopkins are translating one of the most exciting developments in cancer — immune-system targeting therapies — into the realm of endometrial malignancies. Building on prior work showing that certain mutations make tumors more responsive to immune boosting drugs known as check point inhibitors, she and colleagues from the National Cancer Institute NRG Oncology cooperative group have shown that adding one such drug, pembrolizumab, to standard chemotherapy benefits patients with advanced or relapsed endometrial cancer. Perhaps not surprisingly, the most marked gains occurred in those whose tumors had the mutations associated with increased vulnerability to this approach. Described earlier this year in the New England Journal of Medicine, these results prompted physicians to add this immunotherapy to the treatment regimens they prescribe for these patients.

Studies like these must continue, Fader says. “If we are to move the needle on this disease, there must be a continued intensive focus on new therapies and new approaches to treating it.”

“Can I Say It’s Gone?”

At the end of March in 2021, Beavis performed Facinoli’s hysterectomy, removing all of her tumor, which belonged to the more common and less aggressive variety of endometrial cancer. However, because the tumor possessed certain features indicating a heightened risk it might return, Beavis recommended that Facinoli receive radiation therapy afterward to reduce that possibility. Since completing radiation in July of 2021, Facinoli’s follow-up examinations have not turned up any sign of cancer. During an appointment two years later, Beavis cleared her to visit less often, dropping her appointments from every three months, to every six. 

Facinoli’s progress has raised a new question in her mind. “I remember asking Dr. Beavis, ‘Can I say it’s gone? How do I say it?’” Facinoli says. “She said, ‘Well, you can say you’re a survivor.’” Beavis explained that to describe patients in her situation, oncologists use the phrase “no evidence of disease,” meaning there is no detectable cancer, but, even so, they continue doing check-ups to make sure it doesn’t come back. 

Facinoli now makes a point of telling her friends about her experience — to make sure they know not to ignore abnormal bleeding. 

“I certainly did not dream in a million years that the little thing I noticed would turn out to be cancer,” she says. 

To contact Amanda Fader: [email protected]