Outcomes of surveillance in patients with intraductal papillary mucinous neoplasms (IPMNs) who tested negative for high-risk mutations (HRMs) in next-generation sequencing (NGS).
Authors: Kannan Amudhan , Murimwa Gilbert Zvikomborero , Mansour John C. , Ellis Daniel , Sawas Tarek , Vanderveldt Hendrikus Dutch , Foley Samantha Blake , Coleman Veronica , Rajamohan Naveen , Khatri Gaurav , Fleming Jason B. , Zeh Herbert J. , Kubiliun Nisa , Polanco Patricio M. 
Published: January 2025

704

Background:
HRMs in NGS have demonstrated high sensitivity and specificity for predicting advanced neoplasia in patients with IPMNs. However, the outcomes of surveillance in patients who tested negative for these HRMs have not been investigated in prior studies. This study aimed to identify the predictors of progression in patients with negative NGS results for HRMs.
Methods:
We conducted a retrospective review of prospectively collected data from patients who underwent NGS testing between 2016 and 2023 in our pancreatic cancer prevention program. Patients without IPMNs (i.e., negative for KRAS/GNAS), with HRMs, and those without at least one follow-up imaging post-NGS were excluded from the study. Progression was defined as the development of new or additional worrisome features or high-risk stigmata (per Kyoto guidelines), or advanced neoplasia (HGD/PDAC) following NGS testing. A Cox proportional hazards regression model was used to identify predictors of progression.
Results:
A total of 543 patients underwent NGS testing during the study period, of which 210 patients met the inclusion criteria. The median follow-up duration was 22 months (IQR = 12-36). Of these, 72 patients developed progression following NGS testing. A total of 11 patients underwent surgical resection, and 5 of them had HGD. Factors predictive of progression included a history of smoking (HR = 1.74; 95% CI = 1.06 - 2.86), larger cyst size (HR = 1.09; 95% CI = 1.03 - 1.16), and the presence of a dilated main pancreatic duct (MPD) (HR = 2.56; 95% CI = 1.5 - 4.4) prior to NGS testing. The median time to progression for patients with worrisome features was 33 months, compared to 59 months for those without worrisome features at baseline. Similarly, the median time to progression for patients with cysts ≥ 2 cm was 38 months, compared to 57 months for those with cysts < 2 cm.
Conclusions:
Patients who test negative for high-risk mutations in NGS are not exempt from the risk of progression. Any smoking history and presence of any worrisome features before NGS testing showed to be independent predictors of disease progression. For patients with smoking history, worrisome features or cysts ≥ 2 cm, frequent surveillance should be recommended following NGS testing.

Results of Cox proportional hazards regression model for identifying the predictors of progression.

Variables
Hazards ratio (HR)
95% Confidence Interval
P-value

Age
0.99
0.96 – 1.01
0.257

Male sex
1.02
0.62 – 1.7
0.93

White race
1.07
0.63 – 0.83
0.8

Family history of pancreatic cancer
0.6
0.26 – 1.36
0.22

Personal history of other cancers
0.95
0.56 – 1.62
0.86

Diabetes
1.22
0.72 – 2.05
0.46

Any history of smoking
1.74
1.06 – 2.86

0.03*

Pre-NGS cyst size (cm)
1.09
1.03 – 1.16

0.006*

Pre-NGS dilated main pancreatic duct (≥5mm)
2.56
1.5 – 4.4

0.001*

Pre-NGS presence of mural nodules
0.32
0.04 – 2.37
0.26

*Significant p-value.