Molecular alterations of extrapulmonary neuroendocrine carcinomas differ by tumor site

CHICAGO — The occurrence of genetic alterations appeared to differ in extrapulmonary neuroendocrine carcinoma arising in the gastrointestinal tract and pancreas based on specific tumor site, according to study results presented at the ASCO Annual Meeting.

These findings may have implications for choosing the best therapy for patients, researchers said.

Optimal treatment for extrapulmonary poorly differentiated (small and large cell) gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) has yet to be defined. “Traditionally, poorly differentiated neuroendocrine carcinomas arising outside the lung are treated like small cell lung cancer; yet, overall, they are associated with a poor prognosis and new therapies are needed,” Emily K. Bergsland, MD, professor of clinical medicine at University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, told HemOnc Today.

Bergsland and colleagues analyzed results of genomic profiling on patients with neuroendocrine carcinoma, which included 274 patients with neuroendocrine carcinoma arising in the gastrointestinal tract and pancreas, compared to 593 patients with small cell lung cancer. Of the GEP-NECs, 123 occurred in the pancreas, 92 in the colon and 59 in “other gastrointestinal” sites. Ten genetic alterations that occurred in more than 15% of tumors in any group included TP53, RB1, CDKN2A, MEN1, CDKN2B, DAXX, APC, KRAS and CCNE1.

The only molecular alteration that appeared in more than 15% of every dataset was TP53.

MEN1 (33%) and DAXX (20%) appeared in more than 15% of neuroendocrine carcinomas specific to the pancreas, whereas APC (47%) and KRAS (37%) were specific to the colon and CCNE1 (17%) was specific to other gastrointestinal tract sites. Overall, the GEP-NEC group demonstrated lower rates of alterations for TP53 and RB1 compared with small cell lung cancer. Pooled data from pancreas and colorectal NEC with small cell histology specifically, confirmed a lower rate of TP53 and Rb alteration and higher frequency of APC, RAS, MEN1 and DAXX alteration compared to SCLC.

“The data suggest that the genomic alterations vary between organ sites within the gastroenteropancreatic organ system, as well as between GEP-NECs and small cell lung cancer,” Bergsland said. “Taken together, the results raise the possibility that optimal therapy for poorly differentiated neuroendocrine carcinomas depends on site of origin.”

The researchers acknowledged the study was limited by its lack of outcomes data, potential selection bias, limited size of certain subgroups and lack of access to original tumor samples for pathology review (although digital images of pathology slides were examined).

Bergsland and colleagues intend to evaluate the correlation between genomic alterations in different histopathologic subtypes. “Also of interest is that potentially ‘actionable mutations’ were identified in GEP-NEC, raising the possibility of future therapeutic approaches based on specific genomic alterations as opposed to site of origin and/or histology,” Bergsland said.

– by Kristie L. Kahl

Reference: Bergsland EK, et al. Abstract 4020. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclosures: Bergsland reports consultant roles with Celgene, Genentech/Roche, Lexicon and Novartis; research funding from Genentech/Roche, Lexicon, Novartis and Sanofi; and travel and accommodation expenses from Lexicon. Please see the abstract for a list of all other researchers’ relevant financial disclosures.