麻豆传媒

In high-risk patients with a strong family history of pancreatic ductal adenocarcinoma (PDAC) or who are carriers of specific germline pathogenic variants (PVs), have shown that surveillance can lead to detection of pancreatic cancer at an earlier stage, boosting resectability rates and improving survival rates.

A recent of pancreatic cancer surveillance in carriers of high-risk PVs, however, has sparked debate, showing that although surveillance significantly increased the yield of PDAC diagnoses, it didn't improve survival outcomes.

Now, a 20-year prospective follow-up study of the most PDAC cases detected by surveillance to date provides new evidence that it leads to early disease detection, higher resectability rates, and substantially improved survival.

"We present outcomes that are notably better than what is currently reported for individuals diagnosed with PDAC in the general population," wrote Derk C.F. Klatte, MD, of Leiden University Medical Center, in Leiden, the Netherlands, and colleagues. "These data add to the accumulating evidence that surveillance for certain high-risk individual may be beneficial."

As shown in the study in the , the analysis of outcomes data from 347 carriers of CDKN2A PV showed that surveillance at a median age of 60 led to a diagnosis of 36 cases of primary PDAC in 31 patients. This included 12 patients with stage 1 disease. Surveillance consisting of annual magnetic resonance imaging with magnetic resonance cholangiopancreatography and optional endoscopic ultrasound also led to a determination of resectable disease in 30 of 31 patients.

In the 22 patients who underwent resection, the overall 5-year survival rate was 44.1%, and median survival after primary PDAC diagnosis was 32.4%.

The researchers explained that carriers of CDKN2A PV, a specific Dutch founder PV known as p16-Leiden, have a 15-20% lifetime risk of pancreatic cancer. The findings support this estimate, showing that about one fifth of the cohort of developed PDAC by age 70. "This cumulative risk is the highest currently reported for CDKN2A in the literature and is among the highest of all known PDAC susceptibility genes," Klatte and co-authors wrote.

Five of the 31 patients were diagnosed with a second primary PDAC up to 9 years later. Since the chances of long-term survival of course improve with the diagnosis of more early-stage disease, the number of these second primary tumors could increase, the study authors warned.

A retrospective assessment of previous uncovered evidence that direct or indirect signs of an incident or interval tumor had been missed in 75% of patients. "Awareness of these (often subtle) findings offers an opportunity for expert radiologists to detect these lesions at an earlier stage and will potentially result in a decrease of interval tumors," the researchers wrote.

In the following interview, Klatte discussed the findings in greater detail.

What do you consider the most significant barrier to improving pancreatic cancer surveillance?

Klatte: Timely detection. Currently, pancreatic cancer surveillance relies on magnetic resonance imaging and endoscopic ultrasound, but it remains difficult to characterize suspicious lesions.

We need to further improve our diagnostic imaging -- with the use of artificial intelligence, for example. We also need to develop highly sensitive and specific blood tests that can complement imaging.

Was the identification of CDKN2A PV carriers in the Netherlands significant in other ways?

Klatte: Our results show that national registries, such as our Dutch Hereditary Cancer Registry, can play an important role in the identification of families with hereditary cancer, and ensuring continuing participation in cancer surveillance programs.

To what do you attribute the substantial improvement in overall survival in your high-risk cohort?

Klatte: We believe that the improved overall survival is primarily due to diagnosis at an earlier stage, which has been shown to be the most important factor for improved survival in the general population. It is also likely that centralization of multidisciplinary PDAC care in the Netherlands, and the introduction of neoadjuvant chemotherapy were contributing factors.

Given that PDAC is expected to become a leading cause of cancer mortality by 2030, should surveillance be offered to the general population?

Klatte: I believe it is necessary to reserve pancreatic cancer surveillance for individuals who are at the highest risk of developing PDAC, such as those with specific hereditary cancer syndromes. The lifetime risk in the general population is too low, and in the absence of a sufficiently accurate screening test surveillance would very likely result in a large number of false positives and over-treatment.

Might other high-risk populations benefit from intensified pancreatic cancer surveillance?

Klatte: Further studies should investigate whether the risk of multiple PDACs is also present in other populations of CDKN2A PV carriers or other high-risk populations. If this is the case, intensified surveillance and potentially offering a total pancreatectomy, in case of histopathological-confirmed cases of early-stage PDAC, may also be warranted in other pancreatic cancer surveillance programs.

What is your main take-home message to physicians?

Klatte: Based on recent studies and the outcomes of this current study, surveillance appears to be of benefit, particularly in individuals with a proven PV, who are at highest risk of developing PDAC. In the case of suspected pancreatic cancer-associated hereditary cancer syndrome, physicians may wish to consider referral to an expert center to ensure that pancreatic cancer surveillance is offered to those who will benefit the most.

What's next for your research?

Klatte: We are currently conducting several studies exploring the application of blood-based biomarkers in pancreatic cancer surveillance, and the use of artificial intelligence to improve our imaging modalities. We also hope to gain a better understanding of the tumor biology in carriers of CDKN2A PVs and the high risk of second PDACs.

Read the study here and expert commentary about it here.