Katherine Malmo

After a single treatment of Keytruda for endometrial cancer, Stephenie Black-Grant was able to breathe better, didn’t need morphine for pain and was able to lie down again. 

In November 2021, Stephenie Black-Grant, a 50-year- old artist who lives in Orlando, Florida, was in Iowa caring for her father when she found a lump at the base of her neck near her collarbone. She soon learned she had a recurrence of the endometrial cancer that had been diagnosed years before. Her doctors planned to start this round of treatment with radiation followed by the immunotherapy drug Keytruda (pembrolizumab).

But the medical center’s radiation department was running behind and while it was able to map her egg-sized tumor, it couldn’t schedule her treatments. Finally, her doctor decided to start Keytruda while they waited.

“Before my second (Keytruda) treatment,” Black-Grant says, “the doctor comes into the exam room, she’s on her laptop while asking me questions about how I’m feeling. And me and the nurses are grinning because you can barely see the lump in my neck. So I was just waiting. She finally looks up and she almost falls off the freaking stool. It was hilarious. And I’m laughing. And when I laugh really hard, I still cough. So we are all just laughing and coughing and laughing.”

Black-Grant was already able to breathe a bit better, didn’t need morphine for her pain and was able to lie down again. She knew that at the very least, they’d have to remap the tumor if they planned to do radiation because it was much smaller. This was all from a single treatment of Keytruda.

Black-Grant’s experience is the result of some exciting new drugs and studies that are bringing about a shift in how doctors treat advanced endometrial cancer.

According to Dr. Linda R. Duska, gynecologic oncologist and professor of obstetrics and gynecology at the University of Virginia in Charlottesville, endometrial cancer is the most common gynecological cancer and is almost always symptomatic. It’s usually caught in the early stages by bleeding, staining or vaginal discharge in postmenopausal women and heavier bleeding or intermittent bleeding in premenopausal women. Cancers confined to the uterus can almost always be cured with surgery and radiation therapy.

Dr. Brian Slomovitz, director of gynecologic oncology at Mount Sinai Medical Center in Miami Beach, Florida, and professor at Florida International University, and the Uterine Cancer Clinical Trial Lead for GOG Foundation/ GOG Partners, says symptoms of advanced disease can include pelvic pain, abdominal swelling and an early sense of satiety or fullness.

An endometrial cancer diagnosis usually includes a uterine biopsy or sampling from a dilation and curettage procedure. Then the doctor may recommend scans to determine whether tumors have spread outside the uterus. If so, these patients receive a diagnosis of advanced disease.

Advanced and recurrent endometrial cancer cases have historically been treated with chemotherapy – combination carboplatin/ paclitaxel – and in some patients, trastuzumab and hormonal therapy.

Black-Grant’s story started 21 years earlier, in 2000, when heavy menstrual bleeding led to a diagnosis of uterine polyps that were treated with a dilation and curettage (D&C) procedure and progesterone tablets.

Then in 2017, Black-Grant began having pelvic discomfort and abdominal pressure. She started spotting, but her periods were still regular so she brushed it off. In 2020, her gynecologist performed a hysterectomy and removed three fibroids and a sizable uterine tumor. She received a diagnosis of stage 3, grade 3 advanced endometroid adenocarcinoma and had six months of chemotherapy as well as internal and external radiation that she described as painful and hard on her body.

According to Dr. Ramez N. Eskander, gynecologic oncologist and associate professor at the University of California San Diego, things began to change in uterine cancer research in 2013 when scientists began to understand the various subtypes of endometrial cancer. Among the discoveries, they found that certain tumors were categorized as hypermutated or mismatch repair deficient (dMMR) while others were less mutated or mismatch repair proficient (pMMR). Approximately 30% of endometrial cancers are dMMR, according to a study published in the journal 

In 2015, Eskander says Dr. Dung Le of Johns Hopkins Medicine presented a pivotal study that showed a type of immunotherapy medication called a checkpoint inhibitor (Keytruda) worked well on colon cancer tumors that were dMMR. Researchers hypothesized that these same checkpoint inhibitors would be effective for women with dMMR endometrial tumors.

In 2017, Keytruda received Food and Drug Administration approval for use on dMMR tumors found in any part of the body. This was big news, but what about people with tumors that were pMMR?

Duska says dMMR tumors that are hypermutated can be thought of as “hot” and pMMR tumors with fewer mutations as “cold”, implying that the higher number of mutations and resulting protein alterations can better stimulate the immune system and make immunotherapy more effective. Since we know that Keytruda works on hot tumors, we need to make cold tumors hot so that Keytruda works.

“There are different ways you can make a cold tumor hot,” Duska says. “You could do it with anything that disrupts the tumor’s microenvironment (the neighborhood of cells in which the tumor lives). So that can be radiation, chemotherapy or you could do it with a tyrosine kinase inhibitor, which is what lenvatinib (Lenvima) is.”

Dr. Vicky Makker, medical oncologist at Memorial Sloan Kettering Cancer Center in New York, was the lead author on the KEYNOTE-775 trial for patients with advanced endometrial cancer who had experienced a recurrence after prior chemotherapy.

Half these patients received additional chemotherapy alone and the other half received Keytruda and Lenvima without chemotherapy. Overall, Keytruda plus Lenvima reduced the risk of disease progression by 44% and the risk of death by 38%. This worked for patients with dMMR or pMMR tumors.

According to Slomovitz, this shows that immunotherapy can be used in all patients with endometrial cancer as a second-line treatment after progressing on prior chemotherapy. 

“Based on these studies, we need to investigate whether, at least in some patients, if immunotherapy can be moved to the first line,” he says.

In March 2023, the results of the NRG-GY018 trial, led by the National Cancer Institute with Eskander as lead author, were released. In the study of patients with advanced-stage endometrial cancer, one group started chemotherapy plus placebo. The other group received chemotherapy plus Keytruda.

The study found that 30% of the patients had dMMR tumors and of that group, 74% who received Keytruda were alive without progression of their cancer 12 months later while only 38% of the placebo group could say the same. But that wasn’t all. They also looked at the results for patients with pMMR tumors.

“Not only did we see a paradigm shift in the (dMMR) patients with that 70% reduction,” Eskander says, “but even in the (pMMR) patients, we saw statistically significant and clinically meaningful improvement in progression-free survival with a 46% reduction in the risk of disease progression or death.”

Around the same time, the RUBY study results were released at the European Society for Medical Oncology Virtual Plenary. This similar study found that using immunotherapy and chemotherapy for the treatment of advanced endometrial cancer previously treated with chemotherapy significantly improved progression-free survival (the time during and after treatment when a patient with cancer lives with the disease without worsening).

Eskander says the next step is to incorporate immunotherapy with chemotherapy-naive patients at initial diagnosis.

“Both RUBY and GY-018 were game- changing trials,” Slomovitz says. “Statistically, the results are some of the most convincing that we have seen in gynecologic cancers, ever. Not only were the results presented at major conferences on the same day, but they were also published in 

simultaneously. As far as medical breakthroughs go, you can’t get better than that. We’re looking forward to FDA approval to incorporate immunotherapy in the first-line management for women with endometrial cancer.”

Trials such as LEAP-001 will determine if doctors can use a combination of Keytruda and Lenvima instead of chemotherapy for first-line management.

One study Slomovitz is watching is the LEAP trial that will determine whether Keytruda and Lenvima, the combination that is approved in the second-line setting, works better in a first-line setting than chemotherapy. Researchers are also investigating whether patients with dMMR tumors can be treated with Keytruda alone in the first-line setting and whether there are any biomarkers that would indicate who benefit from such treatment.

“We were all very excited about the results from these trials,” she says. “It’s wonderful news for the MMR-deficient group for sure. In the MMR-proficient group, I think we still need to wait for the mature overall survival (the time from treatment until death of any cause) data from RUBY. I think we need to wait to see what things look like when we move immunotherapy into the front line instead of chemo. And then we need to think carefully about how we’re going to use immunotherapy in the second line if we’ve already used it in the first line.”

Black-Grant said the Keytruda did make her extremely tired, and she had frequent nausea, which was new for her. She also had some digestive and bowel issues that weren’t unusual but had become more bothersome. One side effect she really struggled with was itchy rashes.

“The side effects for immunotherapies, the checkpoint inhibitors, are well tolerated,” Slomovitz says. “Sometimes they can cause immune-related types of side effects like colitis, diarrhea or thyroiditis or cystitis, but in general they’re pretty well tolerated.”

Valerie Smith, a pseudonym to protect her privacy, was diagnosed with stage 3 clear cell advanced endometrial cancer in 2019 when she was in her late 50s, after years of symptoms and illnesses that required frequent doctors’ visits and painful procedures. She had surgery in February 2020 and underwent six chemotherapy treatments in the early days of the COVID-19 pandemic.

“It was overwhelming,” Smith says. “With mandatory isolation I was stripped of my ability to socially engage. I was experiencing isolation and a life-threatening event. It was traumatic.”

Smith says chemotherapy brought the usual side effects and hit her with nausea and vomiting that was hard to control even with antinausea meds.

Then she had 28 rounds of radiation that left her with the “most horrendous UTI (urinary tract infection) I’ve ever experienced.” She couldn’t even stand up to get to the medical center to provide a sample.

The one group that continues to be difficult to treat is women with high-risk histologies including uterine serous cancers and carcinosarcomas, Slomovitz says.

“Even though we’re getting better in the first-line management of all women with endometrial cancers,” Slomovitz says, “We still have very limited treatment options for those women with the aggressive histologies. And we find those types of histologies are more likely to affect Black women. That may be one
of the reasons why, in fact, Black women are more likely to die of this disease. We are committed to finding better treatment options for all women and to overcome disparities in our treatment options.”

Smith is one of these women. “No, the immunotherapies are not warranted in my case if there is a recurrence,” Smith says.

Finding out why Black and Hispanic women are more likely to receive a diagnosis of advanced or recurrent stage disease with high-risk histologies is something that Duska believes researchers need to explore further and understand so they can address the disparities. This is most likely to be done by helping Black and Hispanic women enroll in clinical trials.

Black-Grant never needed radiation the second time around. These days, she sees her oncologist a few times a year for scans that show she is still clear of disease.

Both women, Black-Grant and Smith, are active with the Endometrial Cancer Action Network for African-Americans (ECANA) and part of the Sister Study, which provides peer support to African- American women in treatment for endometrial cancer. Black-Grant is also on the ECANA board.

Smith is doing her best to recover physically, emotionally and financially. She wants all women to know that a cancer diagnosis isn’t anyone’s fault and that they should make sure they are receiving the best care possible.

“Because I didn’t know what I was doing at the onset,” Smith says. “And this was a total, total surprise. I did not receive the best care at the onset, so I had to become my own advocate, which is not an easy task.”

For more news on cancer updates, research and education, don’t forget to 

Articles

Treatments for advanced endometrial cancer have progressed and improved with the use of immunotherapy with chemotherapy.


Treatment Breakthroughs: Immunotherapy Comes for Advanced Endometrial Cancer

In 2002, 53-year-old David Sturges made an appointment with a cardiologist to screen for heart disease, which ran in his family. He underwent electron beam computed tomography (CT) to check calcification in the arteries, an indicator of the disease.

Although significant calcium buildup was not detected, he saw something else in the results.

“It was literally a note that said, ‘We noticed this mass ... on the lower lobe of the right lung,’” Sturges, now 75, recalls. “If it’s being followed (by a physician), good, keep following it. If not, we suggest the patient go in for further follow-
up,’ which I did.”

David Sturges, a lung cancer survivor, started advocacy work with the founding of a nonprofit organization, which focuses on raising money for lung cancer research.

Sturges’ biopsy was performed in February 2002 and showed that he had stage 1a non-small cell lung cancer. He underwent a lobectomy to remove the lower lobe of his right lung and continued with follow-up exams and scans, per his oncologist’s instructions, for a year after diagnosis, when another suspicious nodule was detected.

Some eight months later, his then-surgeon recommended the tumor be removed. 

Unfortunately, the night before surgery, Sturges had a heart attack, and the procedure was not performed. He ended up seeing another oncologist, this time at UCLA, who did not recommend surgery. 

Monitoring continued until late 2016, when imaging showed that the tumor had grown. Surgery was once again on the table and was finally performed in August 2017 at Mayo Clinic in Rochester, Minnesota.

The follow-up schedule that Sturges’ oncologists suggested, which included CT scans and blood tests, allowed them to monitor not only tumor growth, but also cancer recurrence.

There are two main types of lung cancer: non-small cell lung cancer (NSCLC), which constitutes some 85% of cases, and small cell lung cancer (SCLC), which accounts for the other 15%. 

According to Dr. Malcolm DeCamp, chair of the Division of Cardiothoracic Surgery at the University of Wisconsin School of Medicine and Public Health in Madison, SCLC usually grows and spreads more quickly and is often treated with chemotherapy and radiation because tumors are too large or widespread for surgical removal.

“Non-small cell lung cancers are broken down into stages 1, 2, 3 and 4,” DeCamp says. “If it’s under 5 centimeters without lymph nodes involved, it’s stage 1 and treated primarily with surgery, assuming the patient is fit enough. Stage 2 disease is typically treated with surgery plus chemotherapy, as lymph nodes within the lung near the tumor are now involved. Stage 3 disease is locally advanced and requires chemotherapy plus radiation or plus surgery, or maybe all three. Then stage 4 is metastatic disease that has spread outside the chest. This stage is rarely, if ever, cured and treated primarily with chemotherapy, (targeted therapy or immunotherapy) to extend survival.”

Catching a tumor in the early stages, when it can be removed, is optimal since it is potentially curable. Because Sturges’ cancer was diagnosed at stage 1a, he only underwent surgery and needed no further intervention, although afterward he learned that a different treatment plan may have been more beneficial.

“It was probably two or three years after my initial surgery when (doctors) said they were finding that adjuvant therapy in combination with surgery probably gave a better outcome for people in my situation,” he says.

As with many other cancers, the fear of recurrence can linger long after treatment is over. But how likely is lung cancer to come back, and how can doctors monitor it?

Dr. Xiuning Le, assistant professor of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston, explains that the disease typically does not return for most patients with stage 1 non-small cell lung cancer. The five-year survival rate for patients with stage 2 disease is 40% to 60%, which decreases to 15% to 35% in patients with stage 3 disease.

According to the American Cancer Society, most doctors recommend that patients who no longer show evidence of disease come in for follow-up, which may include CT scans and blood tests, every three months during the first two years, every six months for the next three years, and at least once annually after five years.

Dr. Dennis Wigle, clinician scientist and chair of thoracic surgery at Mayo Clinic in Rochester, puts it this way: “With the higher stages and potentially higher recurrence rates, we want to look more frequently right after someone’s finished ... treatment so that we can detect recurrences as early as possible.”

Screening with low-dose CT scans is also done to detect new cancers, not recurrences, which are more common in current and ex-smokers (for about five to 10 years, then the risk decreases). But new cancers are more curable than recurrences, which are rarely curable.

“Small cell lung cancer has a reputation of early metastasis and early recurrence,” Le says. “It often spreads to the brain.” 

The five-year survival rate is 29% if the cancer is localized, 18% if it has spread in the chest and 3% if it has spread beyond the chest.

“We don’t have a good way to predict where the cancer is going to recur,”
Le says. “It can recur at the same location, spread to the other side of the lung or spread to other organs like the liver, adrenal glands and colon. Most thoracic oncologists do a CT scan that includes the lungs but also the upper part of the abdomen because these are the high-risk locations for metastasis.”

Additionally, Le notes that oncologists say they don’t know exactly why NSCLC is more likely to spread to certain organs than others, but some experts hypothesize that it is because these locations are rich in blood circulation.

If a patient has a recurrence, Le takes a multidisciplinary approach.

“We start by evaluating the pattern of recurrence,” she says. “If the cancer comes back in one location, we may be able to offer local treatment, but if it comes back in multiple locations, there is still a role for aggressive treatment. In that case, we need to consult with medical oncology, surgery and radiation oncologists.”

After Sturges’ heart attack, his doctor recommended he have CT scans every three months and then yearly until late 2016, when the scan showed his tumor had grown. In August 2017, he underwent a wedge resection in the upper lobe of his right lung and has been disease-free ever since.

So how do physicians catch lung cancer in the beginning or in the early stage of a recurrence?

DeCamp says that people at high risk should be on the lookout for voice changes or a cough that doesn’t go away or worsens. However, by the time symptoms appear, the disease may already be advanced. So the best way of detecting early-stage tumors is with CT scans. This is primarily considered in individuals at high risk due to smoking history.

Wigle agrees and points to the National Lung Screening Trial, in which 53,454 patients who were current or former smokers were assigned to undergo regular CT scans or chest X-rays. Investigators found more lung cancers in the CT group, and those patients had better survival outcomes.

“Increasing the buy-in to screening, at least in the at-risk population, is the lowest-hanging fruit and is the easiest way to improve survival,” DeCamp says. “The next lowest-hanging fruit is preventing people from smoking and getting people who smoke to quit. Then it’s going to be getting a better understanding of that group that gets cancer despite not smoking.”

The U.S. Preventive Services Task Force recommends annual screening for adults aged 50 to 80 years who have a 20 pack-year smoking history.

Wigle says that much of his job entails determining the risk level for each patient’s lung mass. 

“The frequency of having any kind of nodule is relatively high,” he says. “I always tell patients if we randomly did 100 scans in people at risk for lung cancer, 25 would have some kind of lung nodule that would require more investigation, but (fewer) than one of those would actually have a lung cancer.”

Currently, there is no approved screening test for nonsmokers, but some interesting plans are in the works.

“Dogs have an incredible sense of smell,” DeCamp says. “Some can actually smell ... cancer (if they are trained to do so). We’re trying to understand what those neural pathways are in the canine. Then we can create a device that a patient can breathe into that can detect some of the byproducts of cancer metabolism to use as a screening test.”

DeCamp also says that because the entire respiratory tract can be at risk for lung cancer, it may be possible to develop a test that looks for a particular structure of cells swabbed from the nose or mouth that will show whether an individual is predisposed to it.

And there are a number of companies looking for molecular markers present in the blood of patients with cancer that disappear when the tumor is removed. If found, such biomarkers could be used to screen for lung cancer and test for recurrence.

Wigle suggests that this type of blood test could be used in combination with standard screening. “It might even take over as the screening protocol, meaning you wouldn’t get a CT scan until you had a positive result on some kind of blood test.”

Sturges had smoked for about 17 years but had stopped 15 or 20 years before his diagnosis.

“There’s ... an attitude that there’s nothing you can do for those patients,” DeCamp says. “That’s wrong. There’s something to do for almost all of them. And then there’s the stigma. ‘Oh, they did it to themselves; they smoked, right?’ Well, a growing population of lung cancer patients have never smoked. So we need to change the face of lung cancer. Our society views a woman with breast cancer as a victim. But people don’t often look at lung cancer patients as victims.”

According to DeCamp, of the 200,000 people in the U.S. who develop lung cancer every year, about 15% (30,000 patients) do so without having any known cancer risk. 

Two-thirds of those 30,000 are women, but it is not known why.

But is the number of nonsmokers with cancer growing, or is the number of smokers who are diagnosed with lung cancer decreasing?

“The epidemiology is changing over time,” Le says. “Smoking overall has declined in (the) U.S. ... in the last decade. We definitely see more nonsmoker lung cancer patients, but I don’t think this number is growing. They are proportionally more of the patients we see in the clinic.”

According to Wigle, lung cancers are the deadliest cancer in America and lead to more deaths annually than many other cancers combined. Nevertheless, research in the field suffers from low funding from the National Institutes of Health and other government agencies.

After undergoing two surgeries and witnessing the benefits of screening for himself, in 2009 Sturges and two others set up the Lung Cancer Foundation of America. This nonprofit organization raises money for research into innovative treatment modalities that may one day lead to a cure.

“I’ve been very active in terms of sounding the alarm on the need for research and money to support research,” Sturges says. “We started our foundation because we were concerned that we weren’t getting ... a fair share from the National Cancer Institute and others, not enough money, not enough focus. ... And we need the money for research, and hopefully we can find a cure or at least as many treatment options as other cancers, so we can live and go forward.”

To learn more about David Sturges's story of getting diagnosed with stage 1A non-small lung cancer from a footnote of a CT scan and hear his thoughts on how lung cancer treatments have changed in the past 21 years,

listen to this "Cancer Horizons" podcast episode

Tumors can spread from one lung to the other and beyond. How are possible cancer metastases diagnosed in early stages?

Detecting Lung Cancer on the Move

Has anyone ever thought that reading the fine print of a document would save their life?

When David Sturges, an attorney from New Ulm, Minnesota, went to the doctor for a CT scan to assess his risk for heart disease, he wasn’t expecting a lung cancer diagnosis. After all, he had quit smoking almost 20 years ago and was only 53 years old.

However, when the scan came back with a footnote noting there was a mass on the lobe of his right lung, Sturges immediately went in for a biopsy. In February 2002, he was diagnosed with stage 1A non-small lung cancer and shortly after, had a lobectomy (the removal of the lower lobe of the right lung).

A year later, his doctor noticed a new suspicious mass and recommended another surgery. When Sturges sought 

, the new oncologist stated that he did not recommend surgery at that time. With regular screening that monitored the growth of the tumor, Sturges was able to avoid another surgery until 2017.

On today’s episode of the “Cancer Horizons” podcast, Sturges, who is now 75, shares how cancer treatments have changed in the past 21 years, his advocacy work with the 

 (a research foundation based in New Ulm, Minnesota), the importance of seeking genetic testing, decreasing the stigma around smokers getting lung cancer and more.


Read more about Sturges's story and how possible cancer metastases can be 

For more news on cancer updates, research and education, don’t forget to 

Podcasts

A man shares how reading the footnote of a CT scan looking for heart disease alerted him to a mass in his right lung, leading to an unexpected diagnosis of lung cancer.

Reading the Fine Print: How a Footnote on a CT Scan Led to an Unexpected Lung Cancer Diagnosis

John Salata says he is grateful his prostate-specific antigen (PSA) was tested when it was, even if it was by accident.

When Salata was 48, his primary care doctor mistakenly checked the box for a PSA test when ordering his panel of bloodwork. When Salata’s score came back high, she referred him to a urologist who gave him an antibiotic.

John Salata's story shows the dangers of not testing for PSA. His prostate cancer could have been diagnosed later in life, at the recommended age for testing, when, as he said, it could have been too late.

A few months later, his PSA tested even higher. He had a biopsy and received a diagnosis of cancer. He had a radical prostatectomy (surgery to remove the prostate gland and seminal vesicles after a prostate cancer diagnosis) in January 2011.

“When the pathology came back, it was 60% cancerous and it had spread beyond the surgical margins,” Salata recalls. “If we hadn’t found it, then it probably would have spread outside the prostate within a few years. It would have spread throughout the body. Even at that point in time there are usually no symptoms, so there would’ve been no need for me to see a doctor. Because the guidelines didn’t recommend testing until (age) 55 or 60, it would have gone unnoticed for some time. Then once you’re at stage 4, the care is generally palliative.”

Changes in recommendations for PSA testing as a screen for prostate cancer are a frequent occurrence. Why is it so difficult to decide whether or when it should be done? And what do the changes mean for men over the age of 50 as they enter the risk zone for this cancer type?

PSA is a protein made by prostate cells and released into the bloodstream. It is produced by both cancerous and noncancerous cells, but cancer cells tend to secrete PSA more directly into the blood, so PSA levels are often higher in patients with prostate cancer, according to Dr. Michael S. Leapman, associate professor of urology at Yale School of Medicine and clinical program leader of the Prostate and Urologic Cancers Program at Yale Cancer Center in New Haven, Connecticut.

“The PSA test does not diagnose prostate cancer,” Leapman says. “If you have a higher than average PSA, you’re identified to be in a higher risk category that typically triggers further investigation.”

PSA is specific to the prostate but not to prostate cancer, notes Dr. Mihir M. Desai, professor of clinical urology and director of robotic urologic surgery at Keck Medicine of USC in Los Angeles. High PSA levels also can be caused by infections, inflammation and other prostate procedures.

Why PSA Screening Recommendations Keep Changing

As with many cancer types, some prostate cancers may be so slow growing that they will not affect a patient significantly in their lifetime, so their detection and treatment may end up being worse than the cancer having been left alone. To ensure that prostate cancer screening is focused on those who would benefit, there are multiple organizations that issue medical guidelines in the United States, including the American Urological Association, National Comprehensive Cancer Network and American Cancer Society. Each formulates its guidelines based on data from clinical trials that are available at that time.

A patient may find that their PSA test is ordered by a primary care doctor who consults one source, and then by a urologist who consults another.

The U.S. Preventive Screening Task Force (USPSTF), an organization made up of public health and primary care experts, changed its PSA recommendations in 2018. According to their website, that year, the recommendation for men 55 to 69 years old to undergo 

periodic PSA-based screening for prostate cancer should be an individual one

, and that clinicians should not screen men who do not express the preference.

Additionally, the recommendations were against PSA-based screening in men 70 years and older.

“In 2012, the USPSTF issued a statement saying that no one should be screened for prostate cancer with the PSA test. At the time, the judgment from the USPSTF was that the net harms of screening outweighed the potential benefit,” Leapman says.

This recommendation was based on the Prostate, Lung, Colorectal and Ovarian Cancer Screening (PLCO) trial. In the trial, investigators randomly assigned men into two groups: those who were given a PSA test and those who were not. The trial results, released in 2009, showed that the difference in number of deaths between the two groups was statistically insignificant.

Also in 2009, results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial were published. The trial was similar to the PLCO trial in that participants were randomly assigned into groups to receive PSA screening or not. However, results of the ERSPC showed a 29% relative reduction in mortality for the PSA-tested group.

“One question we asked was how was the U.S. study conducted?” Leapman adds. “The main concern was that there was significant contamination — about 90% of the people in the ‘do not screen’ group had actually received PSA testing at some point. It really minimized the potential benefit that could have been seen because men were getting diagnosed in both groups. That contamination was not as prevalent in the European study.”

“The test itself is just a blood test,” Leapman says. “It’s usually combined with other routine bloodwork. So it’s not the test itself that is dangerous; it’s really what happens downstream.”

Henry Wigglesworth recalls telling his doctor that he would not undergo another biopsy for prostate cancer after a previous one came back inconclusive. He notes that he didn't want to get poked with a needled again. 

Often, the next step after receiving a high PSA test score is a biopsy. Dr. Kenneth Lin, professor of clinical family medicine at MedStar Georgetown University Hospital in Washington, D.C., says there can be real harm in this.

“Many men can be told they don’t need a definitive intervention,” Lin explains. “But nonetheless, when someone is walking around thinking there is some probability they have cancer, it often pushes them into treatments they don’t need because they’re never absolutely certain they don’t have it. So a lot of men do have removal of the prostate or radiation therapy when they don’t need to.”

Henry Wigglesworth, 64, is one such patient. When he was 55, he started having his PSA level tested regularly, and it climbed slowly and steadily in the following years until it reached 5. A score between 4 and 10 is in the range of “suspicious,” and approximately 25% of these patients with a score in that range have prostate cancer. Wigglesworth received a diagnosis of a nonaggressive form of prostate cancer in 2017.

“I still remember getting the call,” Wigglesworth says. “My urologist said the results of my biopsy showed I had cancer. Nobody wants to hear that. Then he said the good news was that I had the least harmful type of cancer that exists. It was still very upsetting. I’m healthy in all other respects. I never thought I would have cancer.”

That doctor recommended active surveillance that included frequent monitoring, but then told Wigglesworth that most men usually ended up opting for some form of treatment after five years or so. This prompted Wigglesworth to enroll in a study through the National Institutes of Health (NIH), where they monitored his cancer with regular PSA tests, MRIs and biopsies. They didn’t find any signs of progression.

When Wigglesworth later went to a urologist about his enlarged prostate, he explained his history, and the urologist said he never would have ordered the biopsy because Wigglesworth’s inflamed prostate likely had caused the high PSA result.

Approximately a year after the first biopsy, Wigglesworth returned to NIH. His doctor found a lesion, and Wigglesworth had another biopsy. He left the NIH with a catheter that remained in for four days. When the results came back inconclusive, the doctor ordered another biopsy.

“And I said, ‘No,’” Wigglesworth recalls. “I’m sorry. I’m not going to let you poke me again with that needle.”

While Wigglesworth has opted for active surveillance for his prostate cancer, Salata’s story shows the dangers of not testing. His cancer could have been diagnosed later in life, at the recommended age for testing, when, as he said, it could have been too late.

After the results of the ERSPC trial in 2018, the USPSTF updated its recommendations to state doctors should discuss the benefits and risks of PSA screening with patients who are between the ages of 55 and 69.

“PSA testing shouldn’t be a knee-jerk reaction,” Desai explains. “If patients are warned upfront that ‘Look, even if we do detect prostate cancer, it may be low risk and low grade, and we don’t even need to treat it,’ then they’re much more accepting of that fact afterward, so you can minimize the risk of overtreatment.”

Leapman says the use of active surveillance (close monitoring) as a form of treatment increased in the years USPSTF did not recommend PSA screening. This means prostate cancer is less likely to be overtreated. Desai uses a number of tools to assess a patient’s prostate cancer risk, including looking at the trajectory of their PSA numbers.

“If somebody has a brisk upshoot that doesn’t go down, then that’s more concerning,” Desai says. “If it happens in somebody who has a strong family history, that is concerning. African American men have a higher risk of prostate cancer, so the trigger for a biopsy is lower.”

The general trigger, or signal, to do a biopsy is when the PSA is at 4 or higher. However, if there is a quick upshoot, if the patient is Black or if there is a family history of prostate cancer, physicians may decide to do a biopsy with a lower PSA level.

But even with discussion, there are still overlooked costs of running PSA tests.

“I’d rather spend five minutes counseling somebody about nutrition or exercise,” Lin says. “But I may not have that time because I’m committed to discussing this test, which I think has a pretty marginal benefit at best.”

Leapman says the number of men given PSA tests decreased by approximately 15% between 2012 and 2018.

“After 2018 when the guidelines were changed,” he says, “there was a significant increase. We estimate that rates of testing have approximately gone back to levels prior to 2012.”

There were fewer PSA tests given during those years, but was there a decrease in the number of prostate cancer cases diagnosed?

“Overall the total incidence of prostate cancer has gone down because less testing means fewer biopsies, which means less detection,” Desai says. “But there is also evidence that the incidence of advanced or metastatic disease has begun to go up.”

Lin says the studies for these years can be challenging to interpret.

“What I’ve seen is that the percentage of cancers being diagnosed at a more advanced stage has gone up relative to the lower, earlier-stage cancers,” Lin says. “But you would expect that to happen because we were no longer screening as much. The proportions have changed. I haven’t seen good data showing that the absolute number of late-stage cancers has gone up relative to the population.”

What’s Next for Prostate Cancer Screening

Although MRIs have been around for a while, Leapman says the quality of the image has improved and can reliably show cancer in the prostate. This makes the biopsy more targeted and accurate.

“I think the MRI will hopefully spare some men biopsies,” Lin says. “Or if they have to undergo a biopsy, it’ll be more definitive.”

There are also other blood and urine-based biomarkers that when taken together with a PSA, Leapman says, can help doctors calculate the patient’s prostate cancer risk.

Salata and Wigglesworth say they have moved on with their lives. Salata says he was the first in his family to receive a diagnosis of prostate cancer, but his uncle and cousin also received diagnoses not much later. Salata’s son, who is 26, is planning to have his first PSA test in the next few years.

Wigglesworth notes he recently talked to someone who received a diagnosis of late-stage prostate cancer due to an early PSA test.

“And I thought, Oh my gosh, this test is amazing,” he says. “Everybody should have it. But then there’s the other side, the harm that can be done, not from the test itself, but from this odyssey that you have to go on to identify how it should be treated.”

As PSA testing recommendations change and the debate surrounding testing continues, people with a high-risk of prostate cancer and their families need to stay informed.

Katherine Malmo

Treatment Breakthroughs: Immunotherapy Comes for Advanced Endometrial Cancer

Detecting Lung Cancer on the Move

Reading the Fine Print: How a Footnote on a CT Scan Led to an Unexpected Lung Cancer Diagnosis

To Test or Not to Test for PSA Levels, The Question Remains in Prostate Cancer

Latest News