How Can Cancer Cachexia Be Treated? Molecular Subtypes May Be Key

Cancer cachexia can be deadly, and due to AEs or the tumor itself, scientists are now looking at molecular subtypes to inform treatment decisions.

Sick asian senior woman suffering from anorexia,bored with meal,eating less food or discomfort in swallowing,disease of Dysphagia,Old elderly patient having lack of appetite,nutrition and health care | © Satjawat - stock.adobe.com

Cancer cachexia is a condition where the patient loses a significant amount of skeletal muscle and body fat. Additionally, it could impact the quality of life (QOL) or the ability to receive treatment.1 Cancer cachexia may affect up to 50% of patients with cancer, 75% of patients with stage IV cancer, and is responsible for 25% of cancer-related deaths.

Some symptoms of cancer cachexia include weight loss, appetite loss, fatigue, or weakness. According to the Cleveland Clinic, some causes may include cytokines, symptoms from cancer, like pain or nausea, adverse effects (AEs) from treatment, or increased protein turnover which may allow for cancer cachexia to occur.

The Cachexia Staging Score (CSS) included: weight loss in 6 months (score 0-3), SARC-F questionnaire to assess muscle function and sarcopenia (score 0-3), ECOG performance status (score 0-3), appetite loss (score 0-2), or abnormal biochemistry (score 0-2).2 Regarding patient-related outcomes, the CSS could differentiate the cachexia stages by body composition, symptom burden, QOL, and survival.

To try and prevent cancer cachexia, the National Cancer Institute suggests regular nutrition screening to catch malnutrition early.3 However, what if there were a way to determine those who would be most at risk and intervene early?

The Molecular Subtype Study

A recent study published in Nature sought to look at the biology behind cancer cachexia.4 RNAome plus unsupervised clustering and integrative non-negative matrix factorization were applied to the muscle in 84 patients with pancreatic or colorectal cancer. Samples were taken from the rectus abdominus.

Patients who were identified with subtype 1 had a lower body mass index and total adipose tissue index, a higher percentage of weight loss, and a low-medium skeletal muscle index. Additionally, poorer overall survival was noted among those with subtype 1, which led researchers to suggest that subtype 1 is a cachexia subtype. Of note, patients with subtype 1 had an increased risk of mortality (HR, 2.086; 98% CI, 1.255-3.466; log-rank P = .005), and were more likely to have a primary cancer diagnosis in the colon vs the pancreas (HR, 0.0468; 98% CI, 0.286-0.768; P = .003).

“This is the first time anyone has reported a complete analysis of the coding and non-coding RNA, so the entire RNAome of any human muscle under any condition. We have a first-ever data set that we have applied methodology to, which would allow us to understand whether there are clusters of expression behavior, and that effort to understand clusters of expression behavior is something very well documented in the literature,” Vickie Baracos, MD, professor and Faculty of Medicine and Dentistry-Oncology Department at the University of Alberta, and an author on this study, said in an interview with CancerNetwork.

To assess the effectiveness of this method, a cross-sectional CT image was used. A single axial image at lumbar vertebra 3 (L3) was assessed. Prior to surgery, the CT images were reviewed for the muscle and fat tissue.

Of the 84 patients who underwent surgery for resection of pancreatic cancer or hepatic metastases of colon cancer at a single clinic in Alberta, CA, however, 3% declined participation. Prior to surgery, specimens from the rectus abdominis incision margin were collected to assess weight and skeletal muscle index.

The patient population was 57% male, and 45% had pancreatic cancer. At the median scan interval of 101 days, investigators found the population was losing muscle memory before the biopsy. Muscle loss was found to intercorrelate among different regions of the body, including thoracic vs thigh (Pearson’s r = 0.982), thoracic vs L3 (r = 0.982), and L3 vs thigh (r = 0.975).

Garnering the Psycho-social Aspect

As with anything, support from the psycho-oncology perspective is needed. As cancer cachexia is labelled a wasting disease and can lead to death, support is needed on multiple fronts.

“Whatever is treatable and will help [the disease], but not make [it] worse, we discuss with the patient and team and try to develop a plan, recognizing that there may need to be modifications.Patient’s caregivers, family, and supporters are often involved. If there are social determinants of health (such as food insecurity, financial problems, or hardships, etc), we want to address those,” Michelle Riba, MD, MS, clinical professor in the Department of Psychiatry and director of the PsychOncology Program at the University of Michigan Rogel Cancer Center and psycho-oncology editorial board member of ONCOLOGY, wrote in an email correspondence with CancerNetwork regarding treatment plans for patients with cancer cachexia.

The European Society of Medical Oncology (ESMO) has put in place a set of guidelines on how to best treat this.5 Depending on the patient’s probability of survival is where the focus of care should lie. If survival is more than 3 to 6 months, clinicians should continue regular screening and nutritional interventions; if it is less than 3 to 6 months decrease in nutritional interventions will occur, and counseling should be offered; and if it’s less than 3 to 6 weeks, comfort-directed care should be offered.

Part of successful cachexia care should include using a combination of physical activity, as well as psychological, oncological, and palliative support.

“Always collaborate with multidisciplinary colleagues regarding cancer cachexia since there are many etiologies, depending on the type of cancer and treatment, patient, or other co-occurring conditions. Depending on the above factors, we try to separate out what might be ways to help support and maintain functioning, strength,” Riba continued.

Further, the ESMO guidelines recommend that tailored information be provided to patients and caregivers regarding cancer cachexia, how to spot it, the stages of it, and the negative effects associated with it. This will allow for awareness and early multidisciplinary intervention.

Where Does Nutrition Come In?

The American Society of Clinical Oncology (ASCO) has guidelines pertaining to cancer cachexia and includes nutritional interventions.6 For those with advanced cancer or who have loss of appetite and/or body weight, a referral to a registered dietician may be needed. There, “practical and safe advice” regarding feeding, implementing high-protein/high-calorie, and nutrient-dense foods may occur.

“Because cancer cachexia is a complex syndrome, it is recommended to have a multidisciplinary approach. We have a team at Atrium Health Levine Cancer Institute to manage those with cachexia, including the Palliative Oncology [doctor] as well as the registered dietitian,” Denise Reynolds, RD, from Atrium Health Levine Cancer Institute said “More frequent meals and snacks are helpful, and adding liquid supplements such as Ensure or Boost can be easier to consume when appetite is poor. The [doctor] may add an appetite stimulant to help with intake.Our rehabilitation team may help with physical therapy to help build strength and possibly help counteract fatigue.”

The NCI Nutrition on Cancer Care looks at some basic principles.7 Malnutrition may occur in cancer care, with this occurring in 30% to 85% of patients. Malnutrition may also exacerbate AEs and worsen QOL.

The NCI also examines anorexia and cachexia as part of nutrition. For patients with cancer, anorexia or the loss of appetite is present in about 15% to 20% of all patients. Anorexia may occur as an AE from treatment or related to the disease itself. Because anorexia is the process of not eating, cachexia may occur quickly in this patient population. For patients who have primary protein or calorie intake, but have tumor-related factors that prevent the “maintenance of fat and muscle”, cachexia is likely to occur.

“Many times, the cancer itself will cause issues with appetite, [gastrointestinal] upset, things like that: it is different for everyone. Cancer treatment can make those situations worse, but some of the issues that they have start with weight loss, which is one of the reasons why they go to their doctor. They [may say] “I have lost this weight. I do not know why I am not eating.” They may know that they have a loss of appetite, but they do not feel like they have done anything to create that weight loss themselves. It was not intentional, and that is one of the things that drives them to the doctor to figure out what is going on with them,” Reynolds said.

In Conclusion

While the study published in Nature aimed to look at a molecular level, there are other avenues that are also being pursued to try and treat cachexia. Ponsegromab, a monoclonal antibody directed against differentiation factor-15, is being assessed in cancer cachexia.8,9 The primary end point of the phase 2 PROACC-1 trial (NCT05546476) was met with a change from baseline in body weight compared with the placebo, according to results published in the New England Journal of Medicine.

The results presented at ESMO 2024 showed an increase in body weight at 12 weeks across all doses by 2.02% (95% CI, –0.97% to 5.01%) in the 100 mg group, 3.48% (95% CI, 0.54%-6.42%) in the 200 mg group, and 5.61% (95% CI, 2.56%-867%) in the 400 mg group. Most notable in the 400 mg group was an increase in appetite, physical activity, and skeletal muscle index. There were no notable AEs.

Another study published in the Journal of the National Cancer Institute found clinicians may be able to diagnose cachexia within 3 months of a cancer diagnosis.10,11 This technique would allow for earlier clinical intervention.

The study looked at 8338 patients with advanced lung, pancreatic, and colorectal cancer between 2010 and 2012. Electronic health records were utilized to track weekly weight changes from 2 months before their advanced cancer diagnosis to 6 months after. Through this, 4 weight change categories were identified: weight stable, minor weight gains, moderate weight loss, and severe weight loss.

Weight trajectories mirrored findings from 3 months and 6 months. A total of 99% of patients who were in the severe weight loss group at 6 months were in the moderate or severe group at 6 months. Additionally, 85% of patients in the moderate weight loss group at 6 months were moderate or severe at 3 months.

“I would like to encourage clinicians to take a view of their patients, to understand if they have started cachexia and how quickly it’s rolling forward. I would like them to deploy whatever means they have access to support people experiencing cachexia and to record any feelings of distress or anxiety they may have about this issue. Then I would like to encourage everybody who is a researcher to participate in cachexia research. Start trials at your center. Encourage others to get involved in research. I hope that clinical and experimental cachexia researchers will find a common coffee pot that they can gather around so that we can build on the momentum that is happening now,” Baracos concluded.

References

1. Cancer cachexia. Cleveland Clinic. Updated January 30, 2024. Accessed October 30, 2025. https://tinyurl.com/56kxyya3
2. Dev R. Measuring cachexia—diagnostic criteria. Ann Palliat Med. 2019;8(1). doi: 10.21037/apm.2018.08.07
3. Cancer cachexia. National Cancer Institute. October 15, 2024. Accessed October 30, 2025. https://tinyurl.com/498r7hsj
4. Bhatt BJ, Ghosh S, Mazurak V, et al. Molecular subtypes of human skeletal muscle in cancer cachexia. Nature. 2025;646(8086):973-982. doi:10.1038/s41586-025-09502-0
5. Arends J, Strasser F, Gonella S, et al. Cancer cachexia in adult patients: ESMO Clinical Practice Guidelines☆. ESMO Open. 2021;6(3):100092. doi:10.1016/j.esmoop.2021.100092
6. Roeland EJ, Bohlke K, Baracos VE, et al. Management of cancer cachexia: ASCO guideline. J Clin Oncol. 2020;38(21):2438-2453. doi:10.1200/JCO.20.00611
7. Nutrition in cancer care. National Cancer Institute. Updated September 20, 2024. Accessed October 30, 2025. https://tinyurl.com/y9ubmzsn
8. Groarke JD, Crawford J, Collins SM, et al. Ponsegromab for the treatment of cancer cachexia. N Engl J Med. 2024;391(24):2291-2303. doi:10.1056/NEJMoa2409515
9. Pfizer presents positive data from phase 2 study of ponsegromab in patients with cancer cachexia. News release. Pfizer. September 14, 2024. Accessed October 30, 2025. https://tinyurl.com/5bf7zja8
10. Fuller S, Alexeeff S, Caan B, et al. Early identification of weight loss trajectories in advanced cancer and associations with survival. J Natl Cancer Inst. 2025;117(8):1729-1732. doi:10.1093/jnci/djaf030
11. Earlier identification of cachexia in advanced cancer possible. News release. Kaiser Permanente. February 18, 2025. Accessed October 30, 2025. https://tinyurl.com/yszm898t