On the Cusp of a Sea Change in Endometrial Cancer

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Researchers Are Finding New, More Targeted Ways to Thwart the Most Aggressive Forms of the Disease

From Turning Point 2019

By Nicole Davis

Panos Konstantinopoulos, MD, PhD

Four years ago, Elizabeth McCabe discovered she was among an unlucky minority of patients with endometrial cancer. After her initial diagnosis, McCabe underwent surgery to remove her uterus and hoped that would be the end of her cancer journey. But a couple of months later, her doctors in her hometown, discovered what her body already knew: Her cancer had metastasized to her liver and lymph nodes. Her tumors had blossomed in silence, sprouting from the lining of the uterus and spreading to other parts of her body.

Endometrial cancers like McCabe's are challenging to treat because they have breached the confines of the uterus, so standard therapies are often largely ineffective.

"The good news is that the vast majority of patients with endometrial cancer are diagnosed early and cured," explains Panos Konstantinopoulos, MD, PhD, director of translational research in gynecologic oncology at Dana-Farber's Susan F. Smith for Women's Cancers. "But about 10-15% of patients have tumors that are extraordinarily difficult to treat. And for those patients, we don't have enough options beyond the standard regimens."

After three different courses of chemotherapy, McCabe's cancer remained undeterred. "I was basically told to get my affairs in order," she recalled.

She did. She and her family also researched what more could be done, which led her to Dana-Farber. She met with Dr. Konstantinopoulos, who had recently launched a phase 2 clinical trial in endometrial cancer – one of a handful now underway at Dana-Farber focused on finding potent new therapies for advanced forms of endometrial cancer.

Expanding Immunotherapy's Reach

Today, one of the most promising areas of clinical investigation in endometrial cancer is immunotherapy, a relatively new approach that stokes the fires of a patient's own immune system – energizing it so it can help quash tumor growth. Immune checkpoint inhibitors, a form of immunotherapy, have yielded profound results in some cancers. Yet initial tests in endometrial cancer were less dramatic: Only a small percentage of patients responded. That left researchers wondering: How can endometrial tumors be made more vulnerable to immune checkpoint inhibitors?

In an earlier clinical trial, Dr. Konstantinopoulos and his colleagues found that the immune checkpoint inhibitor avelumab was highly effective when given to a subset of endometrial cancer patients whose tumors showed a high propensity for accumulating genetic mutations. For patients with this molecular feature, known as microsatellite instability (MSI), avelumab would likely be a treatment option.

In endometrial cancer, only about 30% of patients have MSI; the rest have microsatellite stable (MSS) disease. Nevertheless, MSI has become an important biomarker of endometrial tumors, and it has begun to open the door to new treatments for patients, including McCabe, with advanced endometrial cancer.

Shortly after her first visit to Dana-Farber, McCabe learned that her cancer exhibited MSI and she enrolled in a new clinical trial led by Dr. Konstantinopoulos. The trial involves a control group, where patients with MSI receive the immune checkpoint inhibitor avelumab and another group, comprising MSS patients, receive avelumab combined with a second drug, talazoparib (a PARP inhibitor that hinders cancer cells by interfering with their DNA repair). Dr. Konstantinopoulos and his colleagues hope that by combining these two drugs, they can make MSS tumors more susceptible to the effects of checkpoint inhibitors.

For McCabe, treatment with avelumab has been transformative. "Liz has had an extraordinary response," says Dr. Konstantinopoulos. "Her tumors began to shrink after just the first cycle of treatment."

McCabe says she feels like she has part of her old life back. "I got to see my daughters graduate from college and begin their first professional jobs," she said. "I look at all the things I've been given and I'm forever grateful for this trial."

Jennifer Veneris, MD, PhD, and Rameen Beroukhim, MD, PhD

Meanwhile, other Dana-Farber trials are examining targeted ways of attacking endometrial cancer. For example, the Smith Center's Jennifer Veneris, MD, PhD, is studying pembrolizumab, a checkpoint inhibitor, combined with mirvetuximab, a so-called antibody-drug conjugate. "Antibody-drug conjugates are antibodies hooked up to a chemotherapy agent, and they work kind of like a smart bomb, delivering chemo directly to cells," says Dr. Veneris.

Because antibodies recognize and bind to proteins that sit at the cell surface, they can be used therapeutically to home in on specific cell types. Mirvetuximab is designed to latch on to tumor cells that have a protein on their surface that is abundant on endometrial cancer cells.

Another challenge MSS tumors pose is that they are considered immunologically "cold." That is, they fail to provoke a strong response by the immune system. Antibody-drug conjugates, however, are believed to also fire up the immune system, particularly within and around a tumor. "We like to think of this as a way to make a tumor immunologically 'hot,'" says Dr. Veneris.

By pairing the antibody-drug conjugate with a checkpoint inhibitor – a kind of one-two punch – Veneris and her colleagues hope to make MSS tumors more susceptible to immune-mediated attack.

Additional trials underway also seek to address shortcomings of other existing treatments – from overcoming resistance to hormone-blocking therapy to targeting a highly aggressive subtype of endometrial cancer.

"These trials are all investigator-initiated, representing years of effort," said Ursula Matulonis, MD, director of gynecologic oncology in the Smith Center. "All of the drug combinations are entirely new, so we're in discovery mode. This is a critical unmet need, so we feel we're making a difference."

Reining in Metastasis

In addition to exploring new drug combinations, researchers are also delving into a fundamental question: What enables endometrial tumors like McCabe's to spread in the first place? Dana-Farber oncologist and researcher Rameen Beroukhim, MD, PhD, is leading a team of scientists probing the genomes of hundreds of endometrial tumors, including primary tumors and their corresponding metastases. What they have uncovered so far seems a bit surprising: Within individual patients, the metastases appear more similar to each other than to the primary tumor – like a cluster of leaves budding from a tree branch.

"That makes us think that only a small focus of the tumor is actually spreading and that much of the rest of the tumor is unable to do so," explains Dr. Beroukhim.

His team is carefully comparing the genomes of the metastases with those of their corresponding primary tumor, searching for a genetic "smoking gun." That is, gene mutations that appear in the metastases but not in the primary tumor, which could explain how those parts of the tumor gained the wherewithal to spread. If the team can pinpoint genes that drive metastasis, they offer potential fodder for future drug development. Indeed, drugs that could prevent metastasis would represent a fundamental advance for many cancer types.

Building a Better Model

As Dr. Beroukhim and his colleagues plumb the depths of endometrial tumor genomes, Dana-Farber researchers are also working to improve how these cancers are studied in the lab. That means developing animal models that more closely mimic the biology of human tumors.

Jean Zhao, PhD, leads a lab developing innovative models of gynecological cancers using meticulous genetic engineering approaches in mice. These models incorporate many of the same mutations and driver genes that fuel cancer in humans, often weaving together two or three mutations into the same tumor. In addition to common genetic origins, the tumors also share cellular and biological hallmarks of their human counterparts.

Importantly, Zhao's mice are immunologically intact, a crucial feature that enables researchers to carefully analyze the complex interplay between tumors and the immune system. "Once we have the right model for endometrial cancer, we can study it in a variety of ways, including with targeted therapies, immunotherapy, and even combinations of the two," says Dr. Zhao.

Unintended Consequences

While a lack of good models has plagued endometrial cancer researchers for decades, clinicians have faced another vexing problem: the unintended consequences of the hormone-modulating drug tamoxifen. The drug is often given to women over the course of several years to help treat or prevent breast cancer. But, like many therapies, its actions are not wholly beneficial.

"We've known for many years that tamoxifen treatment can increase the risk of endometrial cancer," said Rinath Jeselsohn, MD, an oncologist and researcher at Dana-Farber. "The overall risk is fairly low because endometrial cancer is not a common cancer, but tamoxifen can raise a patient's risk of the disease by anywhere from two- to six-fold."

In the breast, tamoxifen suppresses cell growth. But in the uterus, it has the opposite effect, nudging cells toward a cancerous fate. Now, Dr. Jeselsohn is spearheading an effort to figure out just how tamoxifen goads uterine cells – specifically, what genes and biological processes it causes to run amok. She is scrutinizing the genomes of tumors from patients with tamoxifen-associated endometrial cancer, searching for genomic signals that distinguish the disease from other forms of endometrial cancer. Her goal: to find a way to molecularly disarm the effects of tamoxifen on the uterus, perhaps by designing drugs that can be given together with the hormone modulator.

As Dr. Jeselsohn looks forward to this possibility, McCabe also anticipates what lies ahead. Her cancer is still in retreat. Every two weeks, she flies to Boston for an infusion of avelumab. Her care team has become like a second family, so she does not mind the trip. Most of all, McCabe is excited for the future.

"Before, I'd hesitate if someone asked me to do something in six months or a year, but now I can make longer range plans," she said. "It makes me feel very hopeful."

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