GLOBAL COLLABORATION PROVIDES INSIGHT ON RARE NEUROENDOCRINE TUMORS

 Researchers in Madrid recently wrapped up the largest-yet genomic study of rare neuroendocrine tumors, known as pheochromocytomas and paragangliomas (PPGLs), which identified a seemingly perfect panel of metastatic disease markers as well as a group of patients who could potentially benefit from immunotherapy. The objective here is a better means to predict, at the time of diagnosis of the primary tumor, whether patients will be immediately affected by cancer spread, according to Bruna Calsina, a researcher at the Spanish National Cancer Research Center (CNIO). 

Surgical removal of the primary tumor is standard practice, with physicians relying on clinical characteristics of the tumor and patient symptoms in the absence of reliable molecular markers of metastatic potential, she says. The central problem is that PPGLs are exceedingly rare. Samples from more than 100 patients with metastatic disease were analyzed in the latest study, published in Nature Communications, out of a pool of 100 million patients served by 16 collaborating centers across six countries.  

Neuroendocrine neoplasms (NENs) represent a diverse group of tumors which most commonly arise from gastroenteropancreatic (GEP) structures. Though most NENs are neuroendocrine tumors (NETs) and possess an indolent disease biology, 10–20% of NENs are neuroendocrine carcinomas (NECs) which are highly proliferative tumors characterized by rapid disease progression. NET epidemiologic studies have been more commonly reported whereas NEC epidemiologic studies, largely due to issues pertaining to appropriate classification and disease rarity, have been reported much more infrequently. The incidence and prevalence of NETs continues to rise globally, with the greatest rates of increase in nations such as the USA, Canada, and Norway. In the USA alone, the incidence of NETs has increased more than 6-fold over the last 4 decades, with a predominant rise in localized tumors rather than metastatic tumors; current disease prevalence of NETs in the USA approximates 170,000 patients. GEP NETs represent the most common NET subtype, comprising 55–70% of all NETs. Herein, we discuss the incidence and prevalence of GEP NETs as reported in national registries and survey studies from countries around the world, to assess whether global differences in epidemiology may exist. We also highlight the many pitfalls present when comparing epidemiologic data for GEP NET patients across eras and regions. 

Epidemiology of GEP NECs

Few dedicated studies have solely explored the epidemiology of GEP NECs. One such study was an exploration of the Surveillance, Epidemiology and End Results (SEER) database from the National Cancer Institute where investigators assessed incidence rates of these tumors. Between 1973 and 2012, 6291 GEP NEC cases were identified. Of these cases, 38% of NECs originated in the colon, rectum, or anus while 23% originated in the pancreas. The incidence rates of GEP NECs increased consistently from 1.5 cases per 1,000,000 in 1973 to 4.6 cases per 1,000,000 in 2012. By histology, 34% of cases were small cell carcinomas. Certain primary tumor sites such as the anus and esophagus were more predominantly small cell histology. The presence of metastatic disease at diagnosis ranged from 40 to 76%, with pancreatic NECs most likely to present with metastatic disease.

Two underlying themes are relevant to contextualizing the described GEP NET epidemiologic data. First, comparing epidemiologic data between populations from different eras is fraught with limitations. With the advent and widespread adoption of improved somatostatin receptor-based functional imaging, and more ready availability of cross-sectional imaging, detecting occult NETs has improved significantly. Health care utilization and access must be considered a significant influence when comparing GEP NET epidemiology between current and prior eras. Second, classifying GEP NET cases, even from shared databases, carries a degree of inherent subjectivity. Studies utilizing the same GEP NET national database (e.g., SEER) were not always consistent with one another, suggesting the difficulty and imprecise nature of using ICD codes or other deidentified means to identify true NET cases.

VIEW TO THE RESEARCHERS

The fact that the study was unable to find a single marker that could discriminate all patients whose tumors would spread suggests other components, including non-genetic ones, may be linked to the development of metastasis. The research team is nonetheless “super happy to see that only four marker events were classifying all of the metastatic patients,” Calsina says. Efforts are already underway to validate that finding in a prospective series of tumors collected from a new and possibly smaller cohort of patients. 

A four-marker biomarker panel could be developed easily enough, she says. For their study, researchers did genomic profiling using whole-exome sequencing and RNA sequencing, which is both less time- and resource-intensive than whole-genome sequencing and thus more readily deployable in clinical settings.  

Given results of the analysis, investigation of the potential of CDK1-specific inhibitors for treatment of metastatic PPGLs may be warranted, says Calsina. Interestingly, in MAML3 tumors, the study also found comparatively higher PD-L1 positivity, higher TMB and neoantigen load, and CD8+ T cell infiltration—all traits associated with improved responses to immunotherapy using PD-1/PD-L1 inhibitors.  

The CNIO research team is now seeking collaborators with clinical trials ongoing to see if they can get the tumors of patients with metastatic disease that have responded to this type of treatment, she adds. They could thereby learn if those patients have the identified alterations.  

The cohort study was made possible by a large consortium, including reference centers for the study of this disease located in Europe and the U.S. providing metastatic samples over the years. It was co-led by Mercedes Robledo, who has been studying pheochromocytomas since 1996 and leads the CNIO’s Hereditary Endocrine Cancer Group that has identified five of the 22 genes associated with these rare tumors. 

CONCLUSION

Uniformly conducted population-based epidemiologic studies are needed in each country to assess the true healthcare burden of GEP NETs. Standardized data collection methods utilizing an up-to-date pathologic grading system (e.g., 2019 WHO NET grading criteria) and common data collection tools and analysis metrics (e.g., crude incidence rate, age-adjusted incidence rate) are necessary to draw meaningful conclusions. Insights from these data may lead to the identification of the forces which contribute to the observed regional differences between GEP NETs globally.