Cancer cachexia has long been one of oncology’s most stubborn unsolved problems. This severe, uncontrollable wasting affects roughly half of all cancer patients. It makes treatment harder to tolerate, erodes a person’s quality of life, and is associated with worse outcomes.
A team of researchers from Memorial Sloan Kettering Cancer Center (MSK) and their collaborators went looking for a more nuanced understanding of the condition by analyzing routine clinical data collected during the treatment of nearly 60,000 cancer patients — making it the largest human study to date.
The data included more than 2 million body weight measurements and millions of blood test results — combined with detailed treatment histories and the genetic profiles of patients’ tumors.
“Much of this was routine clinical information being collected to help understand how a patient is doing at different points of time over the course of their treatment,” says study senior author Ed Reznik, PhD, whose lab applies data science to the study of cancer metabolism. “It turns out the data had a lot to tell us.”
According to findings published October 12 in Nature Medicine, the team found that cachexia:
- Occurs across nearly all forms of cancer, not just those associated with eating and digestion.
- Occurs in episodes that potentially recur, many of which are linked to disease progression.
- Leaves a consistent pattern in routine blood tests.
- And is linked to specific tumor mutations.
Together, these discoveries could help predict which patients are most at risk and help facilitate timely support and interventions, the researchers say.
The study was co-led by two students from the Reznik Lab: Venise Jan Castillon, a member of MSK’s Bridge program, which helps trainees successfully transition into biomedical graduate programs, and Amy X. Xie, PhD, a recent graduate of the Biochemistry, Cell Biology, Molecular Biology Allied Program at Weill Cornell Medicine, where she focused on bioinformatics.
What is cancer cachexia?
Cachexia is more than just ordinary weight loss. It is a condition in which the body raids its own muscle tissue and fat for energy, and it can’t be reversed simply by eating more. Patients also frequently lose their appetite, energy, and zest for life — changes that evidence suggests are biologically driven and not merely a psychological response to being seriously ill.
As cachexia progresses, patients grow weaker, making cancer treatments harder to tolerate. Though cachexia affects more than half of all cancer patients, there are currently no U.S. Food and Drug Administration-approved therapies to treat it.
Dr. Reznik was inspired to pursue the project after attending a seminar at a cancer conference a few years ago. The speaker, Tobias Janowitz, MD, PhD, of Cold Spring Harbor Laboratory, began his presentation with a photo of a patient.
“It turned out to be his own mother, who died of cancer-related cachexia,” Dr. Reznik recalls. “There were about 1,000 people in the audience, and the room was silent. Like everyone else, I was gripped by his talk, and it dawned on me that investigating cachexia would be a good fit for my lab’s expertise in cancer metabolism.”
Dr. Janowitz, who is a coauthor of the MSK-led study, argues that patients should be seen as more than the passive recipients of new treatments — through their individual experiences, they have a lot to teach researchers seeking to understand the condition and develop new therapies.
“In my mother’s words, ‘whatever you do, make sure to listen to your patients,’ ” he wrote in a recent essay in the journal Neuron on neuroscience and cachexia.
And, in a somewhat abstracted way, that’s exactly what the Reznik Lab did: tuning in, for the first time, to what all those weight checks and blood tests and clinical data had to say about one of the most challenging problems for people with cancer.
Why wasting in cancer isn’t fully understood
Despite how common it is, researchers still don’t fully understand what drives cachexia at a biological level.
Much of the foundational science on cachexia has come from laboratory models, which are useful for understanding its basic biology, but limited in what they can tell us about how the condition unfolds in human patients over months and years, Castillon notes.
Most human studies have been relatively small and often focused on a single cancer type. The new study, spanning tens of thousands of patients and more than 650 cancer types, represents a significant step toward filling critical information gaps.
“That’s why we call our study an atlas,” says Castillon, who studied physics and worked on solar panels before joining MSK as a step toward a career in biomedicine. “We were able to look at broader patterns in cachexia that hold true across different cancer types and disease stages.”
In general, studying cachexia can be surprisingly difficult, Dr. Reznik adds. The clinical definition is a loss of at least 5% of body weight over six months. That can tell you that someone is losing weight, but not what kind of tissue is disappearing or what mechanism is driving the loss.
“Understanding why someone is losing weight is a challenge,” Dr. Reznik says. “The body’s energy needs can shift in response to changes caused by a tumor or cancer treatment. But patients with stomach or esophageal cancer, for example, may also have physical difficulty eating or digesting food. And cancer treatments themselves can suppress appetite. So, the hard question is how much of a person’s weight loss is really driven by something intrinsic to the cancer itself.”
A new way to look at old data
With this in mind, Dr. Reznik and his team turned to data already sitting in MSK’s medical records, applying rigorous statistical analyses to uncover patterns that would otherwise be invisible.
This work was enabled, in part, by MSK’s Cancer Data Science Initiative — which supports translational research by using artificial intelligence (AI) and other tools to remove identifying details and make anonymized data collected in the clinic available to clinicians, biologists, and computational scientists across the institution for research purposes.
The team began by searching each patient’s weight history for any six-month window that met the 5% weight loss criterion for cachexia. For a typical patient, the records contained about 40 weight measurements over a five-year period, making it a rich source for analysis.
“This allowed us to see that cachexia wasn’t always just a long, steady decline,” Dr. Xie says.
Cachexia comes in episodes
Cachexia, it turns out, often occurs in distinct episodes that can recur multiple times over the course of a patient’s illness — something that had not been widely appreciated prior to the analysis.
Cachexia episodes, the data show, are somewhat more likely to occur when a patient’s cancer is actively growing or when a treatment starts to fail — moments doctors call “disease progression.” But that doesn’t tell the whole story: Many episodes of cachexia happen independent of progression, suggesting additional factors are at play.
In colorectal cancer, for example, nearly a third of all disease progression events occurred while a patient was also experiencing cachexia — more than would be expected by chance. Similar patterns appeared in lung and pancreatic cancers.
Overall, cachexia often emerges toward the end of life and hastens a patient’s final decline. But in patients with pancreatic and gastric cancers, cachexia frequently happens earlier and recurs, the data showed.
This variability suggests that new strategies against cachexia will need to be tailored to each patient’s disease and circumstances, Dr. Reznik says.
A consistent blood signature
Another critical finding from the study is that cachexia has a consistent signature that shows up in routine blood work.
Across nearly all the cancer types studied, wasting episodes were accompanied by a remarkably consistent pattern in lab results:
- Lower albumin
- Low hemoglobin and red blood cell count, which are indicators of anemia
- Elevated liver enzymes
- Higher white blood cell and neutrophil counts — markers of inflammation and nutritional depletion
“Cachexia affects the whole body, so it makes sense that we see a variety of markers in patients’ blood,” Dr. Reznik says. “Across almost all cancer types, we saw this same signature associated with cachexic weight loss.”
Notably, even though levels of albumin (a vital protein produced by the liver) decreased during episodes of cachexia, they often remained within a normal range.
“So, even though these declines are real, they might also be subtle enough not to raise a red flag unless clinicians are actively looking for them,” Dr. Xie adds.
Tumor genetics play a role
The researchers also found that specific tumor mutations are significantly associated with the risk of developing cachexia — some increasing that risk, while a few others seem to reduce it.
Mutations in TP53, one of the most commonly altered genes in human cancer, were linked to higher cachexia risk across nine different cancer types, including lung, breast, and prostate cancers. In lung cancer, mutations in STK11 were also independently associated with elevated risk. And in colorectal cancer, mutations in SMAD4 and KRAS were tied to higher risk, while mutations in ARID1A and KMT2B appeared protective.
These associations held even after accounting for disease stage and overall health — pointing to something in the tumor’s biology itself, not just how far the cancer had advanced.
“Scientists haven’t been able to fully agree on what actually causes cachexia,” Dr. Reznik says. “Is it something the tumor is releasing into the bloodstream? Or is it more behavioral — a loss of energy and appetite that comes with being seriously ill for years on end?”
The team’s genetic findings suggest that tumor biology plays a significant role, he says.
“Once you correct for other factors like disease stage, the associations with specific mutations suggest there’s something about these tumors that is driving the weight loss,” he says.
Predicting who is at risk for cachexia
Building on these findings, the researchers developed predictive models for two common cancer types: lung adenocarcinoma and colorectal carcinoma. The models combine tumor genetic information, disease stage, ability to maintain daily activities, and baseline body weight to generate individualized risk scores for developing cachexia over one, two, and three years.
The models were moderately accurate at making predictions — enough, the team believes, to represent a meaningful step toward identifying high-risk patients early enough to intervene with additional nutritional and rehabilitation supports.
Ultimately, the findings and continuing work by the lab suggest that there may be distinct subtypes of cachexia, Dr. Reznik says. Further research could help identify which patients are at greatest risk and suggest which therapies or interventions would be most effective for individual patients.
“That’s really the dream — a precision trial for cachexia,” he says. “I don’t think we’re that far off.”
Dr. Reznik notes the research wouldn’t have been possible without generous philanthropic and foundation support, in addition to traditional science grants. The research was supported by the Society of MSK, a Pershing Square Sohn Cancer Prize, and was conducted as part of the work by team CANCAN, an international team of researchers established in 2020 through Cancer Grand Challenges to tackle the cachexia challenge.
“This support made it possible, for the first time, to study how cancer patients’ bodies waste away — to understand not just that it happens, but when, why, and in whom — and to start building the kinds of risk models that could one day enable earlier intervention and more targeted treatment,” Dr. Reznik says.
Additional authors, funding, and disclosures
Additional authors on the paper include Sonia Boscenco, Ethan Tse, Neil Ruthen, Jamie Wang, Ziad El Bakouny, Michele Waters, Chenlian Fu, Christopher Fong, Urvi Shah, Ari Hakimi, Justin Jee, Eileen White, and Marcus Goncalves.
The work was supported by the National Cancer Institute (1OT2CA278609-01, P30 CA008748), National Institutes of Health (R37 CA276200), Department of Defense (HT9425-23-1-0995), a Kidney Cancer Association Young Investigator Award, the Society of MSK, the Pershing Square Sohn Cancer Research Foundation, and Cancer Grand Challenges (CGCSDF-2021\100003).
Dr. Shah reports research funding support from Celgene/BMS and Janssen to the institution; research support from Sabinsa Pharmaceuticals and M&M Labs to the institution; and personal fees from Janssen Biotech, Sanofi, and i3Health outside this study.
Read the study: “A health-system-scale, episode-resolved multimodal atlas of cancer cachexia,” Nature Medicine. DOI: 10.1038/s41591-026-04689-9