Advancing the Early Detection of Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal of all cancers and is projected to be the second leading cause of cancer-related mortality by the year 2030. “The annual number of cases of pancreatic cancer continues to increase with estimates, according to the American Cancer Society, of close to 62,100, with some 49,830 people dying from the disease and its complications every year,” says Anil K. Rustgi, MD, Director of the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian/
However, even while sharing these somber statistics, Dr. Rustgi remains hopeful that he and his colleagues in the field of pancreatic cancer will continue to make inroads in combatting the disease. “There is absolutely no doubt we’re moving in the right direction in pancreatic cancer. For so long we were stuck at about a 5 percent overall survival at five years. Now we’re at about 11 percent,” says Dr. Rustgi, who has pursued pivotal work on the interplay of cancer driver genes and the microenvironment in pancreatic cancer. “That may not sound like a lot but in the context of pancreatic cancer, it’s dramatic. Currently, several things are being done and will continue to be done to build upon the advances we have made.”
Confronting Risk Through Genetics
“About 5 to 10 percent of pancreatic cancer patients have a hereditary basis and up to 10 percent have a first degree relative with the disease,” says Dr. Rustgi. “We have a very strong screening program at NewYork-Presbyterian/
Fay Kastrinos, MD, a gastroenterologist in the Division of Digestive and Liver Diseases at NewYork-Presbyterian/
“Here at Columbia we have one of the largest programs for hereditary pancreatic cancer, genetic testing, and counseling in the country.” — Dr. Anil Rustgi
Several hereditary cancer syndromes present an increased risk of PDAC, including:
- Hereditary breast and ovarian cancer syndrome (BRCA2, BRC1)
- Familial atypical multiple mole melanoma (CDKN2A)
- Lynch syndrome (MLH1, MS2, MSH6, PMS1)
- Peutz-Jeghers syndrome (STK11)
- Li-Fraumeni syndrome (TP53)
- Hereditary pancreatitis (PRSS1, SPINK1, CTRC, CFTR)
“Here at Columbia we have one of the largest programs for hereditary pancreatic cancer, genetic testing, and counseling in the country,” says Dr. Rustgi. “Pancreatic cancer can be associated with multiple familial cancer syndromes involving breast, ovarian, and colorectal cancers, as well as melanoma. The connections can be very broad. Now, because genetic testing has expanded to where we can simultaneously test multiple genes associated with cancer, we have more information beyond family history to define at-risk families.”
Screening and Surveillance for High-Risk Individuals
As the initial symptoms of pancreatic cancer are vague and non-specific, individuals may not seek medical attention, or if they do seek care, pancreatic cancer isn’t necessarily at the top of the suspicious diagnoses. More than 50 percent of pancreatic cancers therefore present at late stages, when the disease has spread or metastasized, making therapy challenging.
Experts have called for surveillance of high-risk individuals who generally have at least a five-fold relative risk of pancreatic ductal adenocarcinoma, which primarily includes those with a familial or genetic predisposition. The benefits of surveillance in this population allow for the likelihood of downstaging the cancer, an important concern given how often PDAC is diagnosed at a metastatic stage.
“Pancreatic cancer is not amenable to screening in the general population because the incidence isn’t high enough, unlike breast, colon, prostate, and lung, where there are guidelines based upon evidence of screening and surveillance,” says Dr. Rustgi. “Screening programs at major centers such as ours are focused on recognizing those individuals at highest risk and how to best monitor them so that the disease can be caught in its earliest stage or prevented. This is the focus of our clinical practice and with ongoing research we, as a national community, are going to be able to help more people and hopefully increase survival.”
Dr. Kastrinos, Dr. Rustgi, and Columbia colleagues recently took part in the multicenter Cancer of Pancreas Screening-5 (CAPS5) study to update outcomes of patients who were prospectively enrolled into one of eight CAPS5 study centers between 2014 and 2021. The primary end point of this study was the stage distribution of pancreatic ductal adenocarcinoma detected. Among the study results published in the October 1, 2022, issue of the Journal of Clinical Oncology are the following:
- Of 1,461 high-risk individuals enrolled into CAPS5, 48.5 percent had a pathogenic variant in a PDAC-susceptibility gene.
- 10 patients were diagnosed with PDAC, 1 of whom was diagnosed with metastatic PDAC 4 years after dropping out of surveillance.
- Of the remaining 9, 7 (77.8 percent) had a stage I PDAC detected during surveillance; 1 had stage II; and 1 had stage III disease. Seven of these 9 patients with PDAC were alive after a median follow-up of 2.6 years.
- In the entire CAPS cohort of 1,731 patients, 26 PDAC cases have been diagnosed, 19 within surveillance in which 57.9 percent of patients had stage I and 5.2 percent had stage IV disease.
- By contrast, 6 of the 7 patients with PDAC (85.7 percent) detected outside surveillance were diagnosed with stage IV.
- 5-year survival to date of the patients with a screen-detected PDAC is 73.3 percent and median overall survival is 9.8 years, compared with 1.5 years for patients diagnosed with PDAC outside surveillance.
The authors concluded that most pancreatic cancers diagnosed within the CAPS high-risk cohort in recent years have had stage I disease with long-term survival.
Additionally, some 20 to 30 percent of pancreatic cancer patients are linked to type 3c diabetes mellitus. “This type of diabetes has a sudden onset later in life and may be associated with pancreatic cancer,” says Dr. Rustgi. “Research has shown that type 3c diabetes could also be an early manifestation of pancreatic cancer. Epidemiological research is currently underway in this area that may uncover an additional way of diagnosing pancreatic cancer earlier in the course of the disease. The goal is to identify more precise biomarkers that enable us to classify patients with type 3c diabetes with an increased probability of having early-stage pancreatic cancer. If one could apply that more broadly, then screening could be done based on blood tests of glucose and hemoglobin A1c.”
The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival. Dbouk M, Katona BW, Brand RE, Chak A, Syngal S, Farrell JJ, Kastrinos F, Stoffel EM, Blackford AL, Rustgi AK, Dudley B, Lee LS, Chhoda A, Kwon R, Ginsberg GG, Klein AP, Kamel I, Hruban RH, He J, Shin EJ, Lennon AM, Canto MI, Goggins M. Journal of Clinical Oncology. 2022 Oct 1;40(28):3257-3266.
Familial Predisposition and Genetic Risk Factors Associated with Pancreatic Cancer. Rustgi SD, Hilfrank KJ, Kastrinos F. Gastrointestinal Endoscopy Clinics of North America. 2022 Jan;32(1):1-12.
Inherited Gastrointestinal Cancers: Identification, Management and the Role of Genetic Evaluation and Testing, An Issue of Gastrointestinal Endoscopy Clinics, 1st Edition. Ed: Fay Kastrinos. Elsevier. The Clinics: Internal Medicine, Volume 32-1. November 22, 2021.
Threshold Analysis of the Cost-effectiveness of Endoscopic Ultrasound in Patients at High Risk for Pancreatic Ductal Adenocarcinoma. Kumar S, Saumoy M, Oh A, Schneider Y, Brand RE, Chak A, Ginsberg GG, Kochman ML, Canto MI, Goggins MG, Hur C, Kastrinos F, Katona BW, Rustgi AK. Pancreas. 2021 Jul 1;50(6):807-814.
EUS-based Pancreatic Cancer Surveillance in BRCA1/BRCA2/PALB2/ATM Carriers Without a Family History of Pancreatic Cancer. Katona BW, Long JM, Ahmad NA, Attalla S, Bradbury AR, Carpenter EL, Clark DF, Constantino G, Das KK, Domchek SM, Dudzik C, Ebrahimzadeh J, Ginsberg GG, Heiman J, Kochman ML, Maxwell KN, McKenna DB, Powers J, Shah PD, Wangensteen KJ, Rustgi AK. Cancer Prevention Research (Phila). 2021 Nov;14(11):1033-1040.
Familial Pancreatic Cancer: Confronting the Risk. NewYork-Presbyterian Advances in Gastroenterology and GI Surgery, Issue 3, 2022.
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