Pancreatic NETs Subtypes Could Signal Risk of Recurrence

Article

Two distinct subtypes of nonfunctional pancreatic neuroendocrine tumors could help prognosticate risk of recurrence following surgery.

Ramesh Shivdasani, MD, PhD, a medical oncologist at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School

Ramesh Shivdasani, MD, PhD, a medical oncologist at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School

Ramesh Shivdasani, MD, PhD

Two distinct subtypes of nonfunctional pancreatic neuroendocrine tumors (pNETs) could help prognosticate risk of recurrence following surgery, according to results of a study published in Nature.1,2

Among 103 pNET tumor specimens evaluated, the majority of distant relapses occurred in tumors that expressed the regulatory protein ARX (type A) compared with only 3 reports of distant metastasis in tumors that expressed PDX1 (type B), suggesting the favorable prognosis of PDX1-expressing pNETs. These findings translated to a ≥35% risk of recurrence among ARX-expressing cells versus a ≤5% risk of recurrence among PDX1-expressing cells.

“This finding moves us closer to being able to identify patients with a high risk for metastasis at diagnosis and initial treatment,” said study investigator Ramesh Shivdasani, MD, PhD, a medical oncologist at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, said in a press release. “These patients can be monitored vigilantly for recurrent cancers, which may be treatable if detected early, while patients with the less aggressive kind of pNET can be advised that their prognosis is excellent.”

Despite surgery, approximately half of all patients with nonfunctional pNETs will progress, and there is no method of tracing why or when the disease might recur apart from tumor size. Although alternative lengthening of telomeres (ALT) has been associated with increased risk of recurrence, it is not available for routine clinical testing.

As part of the study, 77 Dutch pNET specimens were collected, 61 (79%) of which harbored a germline MEN1 mutation. Overall, the tumor samples were classified as either ARX-expressing (n = 34), PDX1-expressing (n = 31), or double positive (DP)/double negative (n = 12; DN) with immunohistochemistry (IHC). Among the 61 MEN1-mutant cases, ARX-expressing and PDX1-expressing pNETs (n = 47) were comparable with regard to tumor size and grade. At a median follow-up of 24 months, the only relapses that had been reported occurred in the liver of ARX-expressing or DN samples. No recurrences were reported in the PDX1-expressing or DP samples.

Additionally, 67 unselected pNET specimens revealed, through IHC, approximately the same amount of ARX-expressing and PDX1-expressing cases, with a slightly higher proportion of DN tumors than in the Dutch cohort. At a median follow-up of 66 months, all relapses occurred at distant sites, the majority of which were ARX-expressing or DN (P = .02). Only 1 PDX1-expressing and 2 DP tumors relapsed.

Using telomere-specific fluorescence in situ hybridization to determine ALT status, investigators tested 50 Dutch MEN1-related and 62 American sporadic pNET samples. Among 27 sporadic ARX-expressing and DN tumors, 48.1% of tumors reflected ALT versus 14.3% of 35 PDX1-

expressing and DP tumors (P <.005, Fisher’s exact test). Assessed collectively, every ARX-expressing/ALT-expressing tumor relapsed, 9% of ARX-expressing/ALT−negative tumors relapsed, and 1 PDX1-positive/ALT-negative tumor relapsed.

“This robust molecular stratification provides insight into cell lineage correlates of nonfunctional pNETs, accurately predicts disease course, and can inform postoperative clinical decisions,” the authors wrote.

Among the study cases, 83 had evaluable data on the subtype, size, and World Health Organization grade of the tumor. Notably, ARX-expressing or DN tumors had a higher likelihood of relapse (odds ratio [OR], 14.45; 95% CI, 1.79-116.61) compared with tumors that were 2 cm (OR, 1.14; 95% CI, 0.12-11.07) or 3 cm in size (OR, 8.47; 95% CI, 2.11-34.02).

In an attempt to control for potentially confounding factors, investigators removed DN or DP samples from the analysis. Again, ARX-expressing tumors (n = 64) displayed the greatest likelihood of relapse (OR, 10.31; 95% CI 1.25-84.73) compared with tumors >2 cm (OR, 8.13; 95% CI, 0.99-66.97) or >3 cm in size (OR, 9.6; 95% CI, 1.94-47.44).

All relapses occurred in patients with grade 1 pNETs. However, this was not found to be an independent risk factor—, as only ALT and lack of PDX1 expression were found to be independent risk factors for relapse.

“Now you can tell patients with [the] type B [subtype] that your recurrence risk after surgery is very small,” Shivdasani said in the press release. “Knowing that is very comforting.”

In conclusion, co-investigator Bradley Bernstein, MD, PhD, Bernard and Mildred Kayden Endowed MGH Research Institute Chair, professor of pathology of Harvard Medical School, and pathologist of Massachusetts General Hospital stated in the press release that, “Even with metastatic disease, people can live more than 5 years, in some cases even 10 years or longer.”

References

  1. Discovery of Pancreatic Neuroendocrine Subtypes Could Help Predict Likelihood of Recurrence. Dana-Farber Cancer Institute. Published July 2, 2019. https://bit.ly/2NWY11w. Accessed 27 Aug. 2019.
  2. Cejas P, Drier Y, Dreijerink K, et al. Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. Nature. 2019;25:1260-1265. doi: 10.1038/s41591-019-0493-4.
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