Vital Molecular Differences Found in Neuroendocrine Tumor Subtypes

Manuel Hidalgo, MD, PhD

A genomic analysis of poorly differentiated neuroendocrine tumors (NETs) from primary lung and gastrointestinal sites underscores the diversity of these tumors and the evolving need to move toward precision medicine when it comes to treating patients with these malignancies, according to recent research.^1,2

The analysis, presented in a poster at the 2016 ASCO Annual Meeting, opens the door to consideration of therapies tailored to the molecular profile of particular NETs, said Manuel Hidalgo, MD, PhD, who served as discussant on the research.²

“When you compare the most frequently mutated genes across the different locations, it is very clear that the [tumors] are different,” said Hidalgo, director of the Leon V. & Marilyn L. Rosenberg Clinical Cancer Center and chief of the Division of Hematology-Oncology at Beth Israel Deaconess Medical Center in Boston. “I think this is a new message.”

Hidalgo noted that neuroendocrine tumors can be classified by body site location, functionality, and histology. The histology is further characterized by whether the tumor is well or poorly differentiated and by grade. Poorly differentiated tumors generally correlate with a higher mitotic index and proliferative rate, Hidalgo said.

“The classification of neuroendocrine tumors is complex and it’s a moving target,” Hidalgo said. “It’s really a diverse group of tumors arising in many different locations with similar but distinct histological subtypes.”

Genomic Differences in Subtypes Revealed

Nevertheless, NETs currently are all managed with platinum-based chemotherapy as if they were SCLC, according to Hidalgo. SCLC is the most common poorly differentiated NET subtype.¹In order to obtain a more detailed picture of NETs, investigators searched a database from Foundation Medicine, a molecular analytics company based in Cambridge, Massachusetts, for GEP-NET and SCLC samples collected from February 2012 through November 2015.

Genomic profiling was performed on 867 NETs, comprising 593 SCLC samples and 274 GEP-NET specimens. In the GEPNET category, the samples consisted of pancreatic cancers (n = 123); colon cancers including colorectal and anal (n = 92); and other gastrointestinal cancers (n = 59), made up of esophageal, stomach, and small intestine malignancies.

In all, 192 genes were analyzed on 2 different platforms. All classes of genomic alterations were identified, including copy number alterations, amplifications, rearrangements, and short variant mutations.

The analysis found 10 genes with alterations in >15% of tumors in any group. Although the tumor categories harbored similar mutations for many of the genes, only TP53 crossed the 15% threshold in every group.

When comparing the most frequently mutated genes across the different locations, it became quite clear just how different they all were. For example, SCLC has frequently mutated TP53 and RB1 genes, yet these alterations are not quite as common in other sites, like the pancreas or other gastrointestinal locations.

Researchers further divided the GEP-NET samples into 2 groups; the first included samples (n = 274) with a confirmed NET component reviewed by a pathologist and the second consisted of samples (n = 159) vetted by a different pathologist using stricter criteria.

Treatment Implications in Findings

Specimens from the second group of samples were further analyzed for actionable mutations by disease site, histological subtype, and type of alteration. In 52 out of 142 pancreas samples, there were mutations in these categories: mTOR pathway (23%); RAS-MAPK pathway (13%); mismatch repair genes (6%); and other DNA repair genes (10%).As it stands now, there are more available options for treating patients with well-differentiated as opposed to poorly differentiated neuroendocrine tumors, according to a recent OncLive Peer Exchange panel discussion.³

In the well-differentiated population, targeted therapies that inhibit VEGF or mTOR inhibitors are employed along with cytotoxic therapies based on primary tumor site. But for poorly differentiated tumors, systemic chemotherapy is typically used. Hidalgo said the analysis presented at ASCO shows the potential to use targeted therapy approaches for NETs but “that doesn’t mean the mutations in these particular tumors behave like mutations in other tumors.”

He said the organ of origin for NETs must still be considered. “The context is very important but [the study] provides therapeutic opportunities,” said Hidalgo, noting that studies with small groups of patients in basket trials would be desirable.

References

1. Bergsland EK, Roy R, Stephens P, et al. Genomic profiling to distinguish poorly differentiated neuroendocrine carcinomas arising in different sites. J Clin Oncol. 2016;34 (suppl;abstr 4020).
2. Hidalgo M. Pancreatic and neuroendocrine tumors: can we practice precision medicine? Presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL.
3. Petersen T. Neuroendocrine tumor treatment options are growing. OncLive.com. http://goo.gl/2DyKf0. Published March 25, 2016. Accessed September 5, 2016.

Investigators from the UCSF Helen Diller Family Comprehensive Cancer Center found that genomic alterations differed according to primary site for gastroenteropancreatic NETs (GEP-NETs) and small cell lung cancer (SCLC) NETs (Figure).¹ Notably, 36.6% of a more closely analyzed subset of the GEPNET samples had an actionable gene mutation in at least 1 of 4 categories.¹