His labored breathing and exhaustion prompted him to see his physician, who ordered a battery of tests. Aster’s diagnosis: A rare cancer called a neuroendocrine tumor was causing a condition called carcinoid heart disease, and causing his heart to fail.

With treatment at the Cedars-Sinai Neuroendocrine Tumor Multidisciplinary Clinic, Aster is now back on the trail, his bike, his board and the court.

“I went from wondering how long I have to live to understanding that this can be managed,” Aster said. “I feel better than I have felt in years.”

Aster’s symptoms came on slowly over several months: crushing fatigue, bloating, loss of appetite and swelling in his legs and feet. Blood tests ordered by his primary doctor were normal, but a CT scan showed tumors in his liver, which were eventually diagnosed as stage 4 neuroendocrine cancer.

“We received the diagnosis the day we dropped the youngest of our four kids off at college,” Orr said. “We had other plans, so we just had to reset.”

Unable to sleep the night they got the news, Orr—who Aster said was his caregiver and support throughout this difficult time and credits with helping save his life—spent hours online. She clicked her way to the Neuroendocrine Tumor Research Foundation. The organization, a resource for research funding, patient education and support, directed the couple to  the Neuroendocrine Cancer Foundation, which referred them to Cedars-Sinai and its multidisciplinary clinic.

“We were concerned about Ken’s neuroendocrine tumors, which had spread to his liver and were making it difficult for his stomach to work normally,” said Andrew Hendifar, MD, who leads the clinic and is a professor of Medicine at Cedars-Sinai. “But we knew from experience that his heart failure would have to be treated first. We didn’t have a minute to lose.”

Neuroendocrine tumors begin in neuroendocrine cells, which connect the nervous system with the hormone-producing endocrine system. They can occur anywhere in the body.

Aster’s began in his small bowel and produced a hormone called serotonin, which thickened two of his heart valves and caused them to leak. The condition is called carcinoid heart disease.

Prashanth Venkatesh, MD, assistant professor of Cardiology in the Smidt Heart Institute at Cedars-Sinai, is the cardiologist on the neuroendocrine team.

“The pulmonary valve, which sends blood from the heart to the lungs, is notoriously difficult to evaluate with standard imaging techniques because of its location in the chest and the relative rarity of pulmonary valve disease in adults,” Venkatesh said. “Significant pulmonary valve involvement in carcinoid heart disease is hence very easily missed.”

Venkatesh, a congenital heart specialist, often employs more extensive imaging techniques for patients born with structural heart defects. Aster’s results showed there was a leak in his pulmonary valve as well as a leak in his tricuspid valve. Both valves needed to be replaced.

“When there is a leaky valve, which we call regurgitation, some of the blood in the heart goes in the wrong direction,” said Raj Makkar, MD, vice president of Cardiovascular Innovation and Intervention at Cedars-Sinai and the Karsh Distinguished Chair in Interventional Cardiology in the Smidt Heart Institute. “With leaky pulmonary and tricuspid valves, the blood that is supposed to go into the lungs can leak back toward the upper chamber of the heart.”

Aster’s pulmonary valve was replaced via a minimally invasive procedure in which a catheter was threaded up through an artery in the groin to maneuver the valve into its proper place. Four weeks later, Makkar replaced Aster’s tricuspid valve using a similar procedure. 

“Patients with carcinoid heart disease are going through a lot because of the neuroendocrine tumor, and traditional valve replacement surgery puts them at higher risk for complications,” Makkar said. “We pioneered testing of transcatheter tricuspid valve replacement around five years ago, and this was the option we chose for Mr. Aster.”

To address the neuroendocrine tumors on Aster’s liver, Alexandra Gangi, MD, director of the Division of Surgical Oncology and co-director of the Neuroendocrine Tumor Multidisciplinary Clinc, chose another minimally invasive approach: tumor embolization.

“We accessed the tumors with a catheter, through the artery in the groin,” Gangi said. “This allows us to block off the blood flow to the specific arteries that feed the tumors. This starves the tumors, and results in shrinking and tumor control.”

So far, Aster has avoided surgery and chemotherapy because of the nature of neuroendocrine tumors and the expertise of his care team in sequencing his therapies based on his sypmtoms.

“I think the difference between metastatic neuroendocrine tumors and most other types of gastrointestinal cancers is that we’re playing the long game,” Gangi said. “We often do the least invasive thing and save more aggressive options for when we really need them. These tumors tend to recur, but prognosis is generally good and patients can live a long time with them.”

Additional treatment or surgical procedures might be on the horizon, but today, Aster is doing well.

“We feel very fortunate that we were able to identify this as early as we did and intervene in the way that we did,” Hendifar said. “A few years ago, even six months ago, Ken wouldn't have been a candidate for minimally invasive valve replacements. He would have required open-heart surgery, and I'm not sure if the outcome would have been as good.”

Aster describes his current health as “great.”

“I just started cycling again in January, 13 months after the second valve replacement,” Aster said. “Now I'm doing a 25-mile ride in the hills two or three times a week with no problem. My heart feels as normal as can be.”

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Andrew Hendifar, MD, professor of Medicine and medical director of the Cancer Clinical Trials Office and the Gastrointestinal Oncology Disease Research Group at Cedars-Sinai, was a principal investigator on the trial and a co-author of the study, which was sponsored by Revolution Medicines, makers of the new drug. He sat down with the Cedars-Sinai Newsroom to talk about the study results.

How does this new drug work?

The medication, called daraxonrasib, is the first drug that targets cancer-causing mutations in pancreas cells.

The drug targets a mutation in the KRAS gene, part of the RAS genetic family. KRAS mutations are present in 92% of pancreatic cancers. KRAS genes normally act as an “on-off” switch for cell growth. Mutated KRAS genes are stuck in the “on” position and send out a signal that causes cells to divide and grow uncontrollably, allowing cancer to form.

Daraxonrasib blocks the KRAS signal by fitting into a keyhole-type spot on the gene. That spot has a complex shape and is difficult to reach within the cell. The drug gets around this problem by using a “passenger protein” as a Trojan horse. When the cell allows this protein in, daraxonrasib tags along.

Why are these clinical trial results so groundbreaking?

There are no targeted treatments approved for pancreas cancer, and we haven’t had any significant progress for a long time. We've only come up with different chemotherapy combinations, and those are only moderately effective. This new treatment is staggeringly better than chemotherapy. Usually, when we think of an improvement in pancreatic cancer survival, we think of 25% improvement. This medication actually doubled survival in patients with advanced disease. We have patients who participated in the trial who are still alive, which is unheard of because the five-year survival rate for pancreatic cancer patients is only 13%-14%. If the drug is approved by the FDA, it will most likely become the new standard of care for advanced pancreatic cancer and could replace chemotherapy as a first-line treatment.

What comes next?

We are now testing the drug in patients with earlier-stage pancreatic cancer, prescribing it while their tumors are still operable and before their cancer spreads.

Could daraxonrasib be effective against other cancer types?

RAS mutations are one of the most common cancer-causing genetic mutations, and the drug is now being studied in several cancer types. I think it's going to work especially well in tumors that are primarily RAS driven, including colon cancer and lung cancer. It might also work in other cancer types in combination with drugs targeting other genetic mutations, but further research is needed.

How will this discovery change cancer science?

This is a win for the field. Until now we have been focused on immune therapies that might make tumors more vulnerable to the body’s immune system, and on finding new chemotherapy combinations that kill cancer cells.

This new treatment has given us a new focus, and I think it will spur a lot of scientific discovery over the next few years. There have only been a handful of KRAS researchers and their relevance to therapy was always questioned. That is about to change.

The most important next step for the field is to better understand the biology of cancer. We know that many pancreatic tumors will eventually become resistant to daraxonrasib, and we need to understand how this happens. We also need to identify additional genetic pathways and treatments that can target them. That’s how we will turn pancreas cancer from a deadly, deadly cancer into something we can manage—and one day, even cure.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Andrew Hendifar, MD, medical director of the Cedars-Sinai Cancer Clinical Trials Office and professor of Medicine, is available to discuss late-breaking, embargoed results of a trial of a new therapy for advanced pancreatic cancer, as well as Phase II results from a trial of a combination therapy that targets specific genetic mutations in pancreatic cancer cells.

Additional Cedars-Sinai Experts

Leslie Ballas, MD, professor of Radiation Oncology, will participate in a panel discussion and can discuss evidence related to use of biomarkers or circulating tumor DNA in treatment decisions for patients with muscle-invasive bladder cancer.

Fahima Dossa, MD, PhD, a surgical oncologist, will present research on which patients with high-risk localized soft tissue sarcoma are most likely to benefit from chemotherapy.

Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle, will present a post hoc analysis of the EMBARK trial in advanced prostate cancer, detailing testosterone recovery following treatment suspension. Freedland can also discuss research from his lab on use of olaparib, an enzyme blocker, in metastatic castration-resistant prostate cancer, and statin use in prostate cancer patients receiving hormone treatment after prostate-removal surgery.

Lawrence Liu, MD, a hematology oncologist, will present research on recent advances in CAR T-cell therapies for patients with relapsed multiple myeloma. The work involves mezigdomide, part of a new drug class in myeloma, following infusion with idecabtagene vicleucel, a genetically modified CAR T therapy derived from the patient’s own cells.

Arsen Osipov, MD, associate professor of Medicine and medical director of Pancreatic Cancer, can discuss research from his lab on the comprehensive molecular profiles associated with variants of the KRAS gene and patient survival in pancreatic cancer. KRAS mutations are found in more than 90% of pancreatic cancer cases.

Karen Reckamp, MD, professor of Medicine and director of the Division of Medical Oncology, can discuss the treatment landscape for non-small cell and small cell lung cancer. She can explain research from her lab on a machine learning approach for predicting immune-related pneumonitis, a noninfectious lung inflammation that can occur following treatment with immune checkpoint inhibitors. She can also speak about new data from Lung MAP, a clinical trial designed to efficiently test treatments for advanced non-small cell lung cancers. And she will make a presentation on support of academic nonclinical efforts for cancer investigator faculty at the Association of American Cancer Institutes.

Kamya Sankar, MD, assistant professor of Medicine and co-director of the Thoracic Disease Research Group, will present an analysis of factors associated with early cachexia—also known as cancer wasting disease—in metastatic non-small cell lung cancer. She can also speak about treatment of both non-small cell and small cell lung cancer.

From The Angeles Clinic and Research Institute

Mark Faries, MD, surgical oncologist and professor of Surgery, can discuss a five-year update from the KEYNOTE-942 study in resected melanoma and a new study of lymph node resection versus therapeutic dissection in advanced melanoma, as well as recurrence in advanced melanoma across time.

Erwin Grussie, MD, a hematology oncologist, can discuss results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study testing targeted therapies in patients with solid tumors.

Omid Hamid, MD, professor of Medicine and chief of Translational Research and Immuno-Oncology, will present results from a study of a medication that blocks the action of cortisol in patients with advanced solid tumors, as well as a study of causes of limited immunotherapy response in melanoma. He can also discuss new results from three trials of therapies in advanced melanoma.

Inderjit Mehmi, MD, a hematology oncologist, can discuss the association of prior immunotherapy treatment with limited response to subsequent immunotherapy in melanoma.

Media Contact

To schedule an interview, contact Christina Elston at christina.elston@cshs.org or 626-298-0702.

If validated in further studies, the artificial intelligence-based platform could be used to improve treatment selection in virtually any cancer type. Results from a study of the platform’s effectiveness are published in the Journal of Clinical Oncology.

“Currently, we have no conclusive data to show which of the two approved chemotherapy regimens for patients with advanced pancreatic cancer is more effective,” said Andrew Hendifar, MD, medical director of Pancreatic Cancer at Cedars-Sinai Cancer and first author of the study. “So we start with one, do our best to quickly gauge the patient’s response, and switch if needed.”

The problem with this, Hendifar said, is that putting an ill patient on a chemotherapy regimen that isn’t working worsens their health rather than improving it. Biomarkers from blood or tissue can help predict treatment response and guide these decisions in other cancer types, but currently, no biomarkers exist for pancreatic cancer.

“This endeavor is an example of applying AI technology to an unmet clinical need, and offers tremendous translational potential,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “It aligns perfectly with our goal of personalizing cancer treatment for our patients and improving outcomes for all.”

To develop the tool, investigators used a platform called Computational Histology Artificial Intelligence, or CHAI. CHAI analyzes images of microscope slides containing samples of tumor tissue, which are stained to highlight minute details of the cells. Almost all patients have these samples taken when their tumors are biopsied.

The team analyzed tissue characteristics in samples from 25,000 pancreatic cancer patients who had received one chemotherapy regimen or the other. The platform’s AI capabilities made it possible to analyze more than 30,000 different features of the tissue samples. Investigators then matched tissue characteristics to treatment response to create the predictive tool.

When they tested the tool on data from a large clinical trial using the two pancreatic cancer treatment regimens, they found that it was able to accurately predict each patient’s response to the treatment received.

“Unlike most biomarker tests, where you need an extra sample of tissue or blood, this test requires only a scanned image of the patient’s existing biopsy slide,” Hendifar said. “You just send the image electronically and quickly receive a result with the treatment preference. And you don’t just learn which treatment is preferred. You learn how much more effective it is likely to be.”

The tool needs to be further validated in patients undergoing treatment before it is ready for clinical use, but Hendifar said that with that validation it could eventually be applied to other solid tumor types. It could even compare the potential benefit of different types of therapy, such as radiation therapy versus surgery.

“If the chance that a particular treatment will benefit a patient is 50-50, which is quite common in cancer therapy, then this may serve as a powerful tool to aid physician and patient decision-making,” Hendifar said. “And we can train the digital tool not just to choose between two available treatments, but to choose between multiple available treatments.”

Additional Cedars-Sinai authors include Brent K. Larson, DO; Vladimir Kazarov, MS; Natalie Moshayedi, BS; and Arsen Osipov, MD.

Other authors include Viswesh Krishna, BS; Vrishab Krishna, BS; Haochen Zhang, PhD; Katelyn Smith, BA; Kawther Abdilleh, PhD; Snehal Sonawane, MD; Akshay Neema, MS; Asit Tarsode, MS; Ekin Tiu, MS; Vivek Nimgaonkar, MD; Shawn Hutchinson, MSc; Daniela Bevacqua, BS; Sudheer Doss, PhD; Alejandra Alvarez, MS; Drew Watson, PhD, MBA; Waleed M. Abuzeid, MD; Barbara T. Grunwald, MD; Marcus Noel, MD; Rashmi Samdani, MD; Dove Keith, PhD; Rosalie C. Sears, PhD; Davendra Sohal, MD, MPH; Christos Fountzilas, MD; Grainne M. O’Kane, MD; Robert C. Grant, MD, PhD; Eric A. Collisson, MD; Lesli A. Kiedrowski, MS, MPH; Trevor J. Royce, MD, MS, MPH; Anirudh R. Joshi, MS; Aatur D. Singhi, MD, PhD; and Jennifer J. Knox, MD, MSc.

Funding: Supported in part by the Pancreatic Cancer Action Network (PanCAN - Know Your Tumor), the University Health Network, Toronto (COMPASS trial), and Valar Labs, Inc.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

A syndrome called cachexia, which triggers unexplained loss of weight and muscle mass, causes severe illness and death among patients with cancer and other serious health conditions.

November is a month designated for raising awareness about lung and pancreatic cancers, and Andrew Hendifar, MD, medical director of Pancreatic Cancer at Cedars-Sinai Cancer, sat down to talk with the Cedars-Sinai Newsroom about cancer cachexia. Hendifar is co-author of recent clinical trial results, published in The New England Journal of Medicine, that could yield the first Food and Drug Administration-approved medication for the condition.

Why is understanding cachexia so important?

More than 25% of cancer-related deaths can be attributed to cachexia. It affects 80% of patients with pancreatic cancer, and half of patients with advanced lung cancer. We also see it among patients with colon, kidney and stomach cancer, as well as heart, lung and kidney disease.

As many as 75% of patients with cancer have significant unexplained weight loss six months before they are diagnosed, but this clue is often missed. People just think the latest weight loss strategy they have tried is finally working. Unintentional weight loss is a significant health problem, and anyone who is losing weight unexpectedly should immediately seek the care of a health provider to investigate it further. It’s a huge problem and a huge unmet need. At this point, all we are really able to offer patients with cachexia is a referral to a dietitian.

What causes cachexia?

For decades we've been trying to figure out what causes cachexia and what we can do to treat it. After pursuing many different pathways, we recently made significant progress with a drug that targets the GDF-15/GFRAL pathway.

GDF-15, growth differentiation factor 15, is a hormone that is elevated in patients with cancer and certain other medical conditions, and in patients on certain types of chemotherapy. Its role in normal physiologic function is not yet fully understood. It seems to be associated with appetite and with stress, and there have been several attempts over the past few years to target GDF-15 with various therapies.

Tell us about the recent clinical trial.

The therapy we tested, a monthly injection that caused few side effects, blocks the action of GDF-15. Our Phase 2 clinical trial included patients with non-small cell lung, pancreatic and colorectal cancers. Patients taking this new drug had improved weight gain and physical activity as compared with patients receiving a placebo. Not only is this the first promising cachexia drug, it is also the first drug showing promise in blocking the action of GDF-15.

What will happen next with this drug?

Several new clinical trials should be opening soon at various institutions, targeting cachexia not only in patients with cancer, but in those with other diseases as well. Patients with cachexia should be referred to a dietitian and also work with a physical therapist to help recover muscle mass. And they can ask their health care provider about opportunities to participate in one of these clinical trials.

Have there been any other promising options for cachexia patients?

Cedars-Sinai was recently part of an international consortium that conducted a Phase 3 trial called the MENAC trial. This trial found that a combination of protein and omega 3 supplementation, dietary counseling, a home exercise program and ibuprofen improved weight by roughly 2 pounds. But this hasn’t yet become part of official guidelines for cachexia care.

Read more on the Cedars-Sinai Blog: The Link Between Pancreatic Cancer and Diabetes

Gastrointestinal cancers were once diagnosed primarily by location. A tumor in the liver was liver cancer, while one in the pancreas was pancreatic. The few chemotherapy treatments available affected the entire patient—sometimes causing difficult side effects. Today, these tumors are analyzed at the molecular level, and clinicians target them with precision treatments that fight the cancer cells and spare the healthy tissue.

Andrew Hendifar, MD, medical director of the Gastrointestinal Oncology Disease Research Group at Cedars-Sinai Cancer, is a physician-scientist who treats patients with cancers of the digestive tract and other abdominal organs and works to develop new therapies for these patients.

In advance of the fifth annual Cedars-Sinai Gastrointestinal Tumor Conference, an event for healthcare professionals seeking updates on the most recent advances in these therapies, Hendifar sat down with the Cedars-Sinai Newsroom to discuss the challenges and latest advances in treating this group of cancers.

What has changed about the way we diagnose gastrointestinal (GI) tumors?

We used to diagnose these tumors based on their approximate location and a review of the tissue under a microscope. Now we use molecular profiling. These tests look at the makeup of the tumor’s genes and protein expression through a biopsy or blood specimen. This helps us understand the biological underpinnings of the specific tumor. Molecular profiling is especially important in GI tumors because these tumors—liver, gastric, pancreatic, small bowel, colon—look similar and are often located in the same area.

Without molecular testing, it might not be possible to tell that you're dealing with a bile duct tumor rather than a liver cancer or a pancreatic cancer. The bile ducts travel through the liver, so a bile duct mass could be in the same position as a liver cancer, but the cellular makeup is quite different and the treatments they require are worlds apart.

We’re also using advanced imaging techniques that employ artificial intelligence to discern subtle pancreatic masses that might be invisible to the human eye, and special MRI sequences that can detect pancreas cancer at an earlier stage. Imaging can also tell us whether treatments are working and predict what a patient’s outcomes could be. Furthermore, we are working to develop blood and urine tests for early pancreas cancer detection.

How is treatment of GI tumors changing?

When I started treating patients 15 years ago, the only treatments available were a couple of different IV chemotherapies. Now, thanks to new diagnostic tools and more targeted forms of treatment, we can often turn a patient’s life around, and that's actually the best feeling in the world.

Immune therapy has been such a breath of fresh air. Treatment involves just an hourlong infusion with minimal side effects, so we no longer have to worry about whether a patient can tolerate the treatment. I have so many patients who are alive and well receiving immune therapy, who otherwise wouldn’t have made it. Through our continuing work to develop new biomarkers, we are able to pair more of our patients with immune therapy. And these biomarkers go across tumor boundaries, so we no longer need to think about the site of origin. If your tumor has the right biomarker, we can pair you with the right form of treatment.

At ASCO GI 2024 we presented a study comparing patients with localized liver cancer who received local therapy alone with those who received local therapy and immune therapy in combination. For patients receiving the combination therapy, progression-free survival was twice as long, so this has become the new standard of care.

There are also a lot of new antibody drug conjugates that are working their way through the pipelines, including options for various types of GI tumors. Antibody drug conjugates deliver chemotherapy directly to tumor cells by binding to specific proteins on the surface of the cells. This allows us to target the cancer without targeting healthy tissue. If we can identify the right protein on a patient’s tumor cells, we can use antibody drug conjugates to deliver very effective treatment.

What are some of the more challenging tumors to treat?

Bile duct tumors need more attention. They are often lumped in with pancreatic cancer but are completely different. And they are difficult to diagnose without advanced endoscopy.

We’re doing a lot of research to identify bile duct tumor biomarkers that help us pair patients with targeted therapy, especially antibody drug conjugates, to improve outcomes. There are many clinical trials now open for these therapies, and many patients do incredibly well.

What is the next frontier for GI tumor research?

The Molecular Twin Precision Oncology Platform, a unique precision medicine and AI tool developed at Cedars-Sinai, was validated on patients with pancreatic cancer and used to identify biomarkers that outperformed the current standard test for predicting patient survival. The platform has expanded to include all cancers, and we have enrolled at least 500 patients with GI cancers. All of my patients are enrolled and are contributing quite a bit to this project.

What topics will be covered at the upcoming conference, and what makes the event unique?

We are always thinking about the future of cancer treatment rather than about what’s currently available. We will be highlighting new technologies to detect and treat cancer, and will focus on using social media platforms to enhance the practice of medicine.

Read more on the Cedars-Sinai Blog: Pancreatic Cancer Clinic Saves Time and Lives