A large cohort study with close to 160,000 men and women reported that “recent-onset diabetes accompanied by weight loss was associated with a substantial increase in risk for pancreatic cancer and may represent a high-risk group in the general population for whom early detection strategies would be advantageous.” Unintentional weight loss, particularly among those with a previously healthy weight, and older age further elevated the risk. The study was published in JAMA Oncology.1
Brian M. Wolpin, MD, MPH
The coexistence of recent-onset diabetes and weight loss often is not related to pancreatic cancer in the mind of the primary care doctor because these factors are not necessarily specific only for pancreatic cancer, according to Brian M. Wolpin, MD, MPH, Director of the Gastrointestinal Cancer Center and Hale Family Research Center, Dana-Farber Cancer Institute, Boston, and study senior author. “Even in this study, the majority of people who had diabetes and weight loss didn’t subsequently develop pancreatic cancer, but there was a subsegment that did. Since early diagnosis of pancreatic cancer is so uncommon, we want clinicians to be aware of this association,” Dr. Wolpin said in an interview with The ASCO Post. Other symptoms of pancreatic cancer, such as jaundice, are commonly recognized as abnormal, he noted, and may prompt a scan that might lead to detection of pancreatic cancer. “The pattern that is emerging of recent-onset diabetes, and unintentional weight loss in particular, should be a pattern that is recognized,” Dr. Wolpin said, and perhaps it should prompt an evaluation if symptoms persist.
More Than Sixfold Increase
The investigators looked at data from 112,818 women (mean age, 59.4 years) in the Nurses’ Health Study and 46,207 men (mean age, 64.7 years) enrolled in the Health Professionals Follow-up Study; they identified 1,116 incident cases of pancreatic cancers, an incident rate of 25 per 100,000. “Diabetes and recent weight loss were each independently associated with a modest increase in the risk for pancreatic cancer,” the researchers reported. “However, when weight loss co-occurred with recent-onset diabetes, the subsequent risk of pancreatic cancer increased by more than sixfold. In addition, the likelihood of a pancreatic cancer diagnosis was even further elevated among individuals with older age, healthy weight before weight loss, and unintentional weight loss.”
"When weight loss co-occurred with recent-onset diabetes, the subsequent risk of pancreatic cancer increased by more than sixfold."— Brian M. Wolpin, MD, MPH
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Compared with participants who did not have diabetes, those with recent-onset diabetes had an age-adjusted hazard ratio for pancreatic cancer of 2.97 (95% confidence interval [CI] = 2.31–3.82), and those with long-standing diabetes (≥ 4 years) had an age-adjusted hazard ratio of 2.16 (95% CI = 1.78–2.60). Age-adjusted hazard ratios for pancreatic cancer increased stepwise with the amount of weight lost when compared with those who did not lose weight: 1.25 (95% CI = 1.03–1.52) for those reporting a 1- to 4-lb weight loss, to 1.33 (95% CI = 1.06–1.66) for those with a 5- to 8-lb weight loss, and 1.92 (95% CI = 1.58–2.32) for those with more than an 8-lb weight loss.
Incident cases of pancreatic cancer per 100,000 person-years ranged from 16 cases for patients with neither recent-onset diabetes nor weight loss to 91 incident cases for those with recent-onset diabetes and a weight loss of 1 to 8 lb and 164 cases to those with recent-onset diabetes and a weight loss of more than 8 lb.
Unintentional Weight Loss
“Incidence rates were further increased among participants with recent-onset diabetes and weight loss with a body mass index of less than 25 kg/m2 before weight loss (400 incident cases per 100,000 person-years) or whose weight loss was not intentional judging from increased physical activity or healthier dietary choices (334 incident cases per 100,000 person-years),” the researchers wrote. Body mass index < 25 kg/m2 was considered a healthy or normal body weight.
“The main reason we looked at people who had a normal body weight is because we hypothesized that their weight loss was more likely to be unintentional,” Dr. Wolpin said. “If your weight was normal already, it is unlikely you are trying to lose a lot of weight to become healthier. It was essentially another way to try to tease out the intentionality of the weight loss.”
The researchers also created a composite index of physical activity and dietary patterns. “We assumed that if you were exercising more or your diet became healthier, your weight loss was more likely due to these factors, and that the weight loss was less likely to be due to cancer. Thus, both baseline patient weight and this index of physical activity and diet were trying to get at the same questions: Can we understand whether the weight loss was intentional or unintentional, and should unintentional weight loss be more concerning to clinicians.”
The researchers also “hypothesized that a particularly high-risk group would be older individuals, given pancreatic cancer is a disease of older age.” They found “particularly high incidence rates of pancreatic cancer in those 70 years or older (234 incident cases per 100,000 person-years) with recent-onset diabetes and weight loss.
Recent-Onset vs Long-Standing Diabetes
Recent-onset diabetes and weight loss “are symptoms in the sense that the cancer is causing them,” Dr. Wolpin noted. “The diabetes and the weight loss are likely occurring because the tumor is already there, and we just haven’t diagnosed it yet,” Dr. Wolpin added.
“At this time, screening average-risk individuals [for pancreatic cancer] has not been shown to be beneficial.”— Brian M. Wolpin, MD, MPH
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Conversely, long-standing type 2 diabetes is often accompanied by weight gain. “Over time, being overweight and having diabetes are risk factors” for pancreatic cancer, Dr. Wolpin said. “We presume—although there haven’t been interventional studies to test this—if people lost weight and took other measures to reduce their hyperglycemia, that likely would reduce their risk over time of pancreatic cancer. However, this is different from the weight loss and the recent-onset diabetes evaluated in the current study, which we believe are caused by the tumor itself, making earlier detection the key, rather than prevention.”
The authors cited a study that “found most patients with recent-onset diabetes who developed pancreatic cancer had early-stage cancer at the time they developed hyperglycemia, suggesting a window of opportunity for diagnosing and managing the cancer when it is still curable.2 Nevertheless, the authors commented, “the risk associated with recent-onset diabetes alone may be insufficient to warrant pancreatic cancer screening.”
The U.S. Preventive Services Task Force recommends against pancreatic cancer screening for asymptomatic individuals with average risk and without “certain inherited genetic syndromes or a history of familial pancreatic cancer” and points out that no other organization recommends such screening either. “At this time, screening average-risk individuals has not been shown to be beneficial,” Dr. Wolpin stated.
Additional Studies
“The question of whether recent-onset diabetes after age 50 in the context of weight loss should trigger pancreatic cancer surveillance should be evaluated in large prospective studies,” the authors wrote.
Two studies listed on ClinicalTrials.gov are now recruiting patients. One study, ClinicalTrials.gov identifier NCT03937453, aims “to explore the relationship between new-onset diabetes mellitus and a subsequent diagnosis of pancreatic cancer. Magnetic resonance imaging and magnetic cholangiopancreatography will be utilized to screen for early-stage pancreatic cancer or precursor lesions. Participants will be asked to donate a blood sample at specific intervals for the creation of a biobank necessary for the development of a blood-based screening test for pancreatic cancer.”
The other study (NCT03568630) is aiming to identify biomarkers of early pancreatic adenocarcinoma among those with higher-than-average risk, including those with a family history of pancreatic cancer, individuals with cystic pancreatic lesions or chronic pancreatitis, and those with new-onset diabetes.3 “Our study would suggest weight loss, and in particular unintentional weight loss, combined with recent-onset diabetes could be a symptom combination relevant to studies of pancreatic cancer early detection,” Dr. Wolpin said.
DISCLOSURE: Dr. Wolpin has received honoraria from, or consulted for, Celgene, G1 Therapeutics, BioLineRx, Genentech, and GRAIL and has received research funding from Celgene and Eli Lilly.
REFERENCES
1. Yuan C, Babic A, Khalaf N, et al: Diabetes, weight change, and pancreatic cancer risk. JAMA Oncol. August 13, 2020 (early release online).
2. Pelaez-Luna M, Takahashi N, Fletcher JG, et al: Resectability of presymptomatic pancreatic cancer and its relationship to onset of diabetes: A retrospective review of CT scans and fasting glucose values prior to diagnosis. Am J Gastroenterol 102:2157-2163, 2007.
3. Maitra A, Sharma A, Brand RE, et al: A prospective study to establish a new-onset diabetes cohort: From the consortium for the study of chronic pancreatitis, diabetes, and pancreatic cancer. Pancreas 47:1244-1248, 2018.
