Global Collaboration Enables Headway On Rare Neuroendocrine Tumors
By Deborah Borfitz
April 6, 2023 | 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 (DOI: 10.1038/s41467-023-36769-6), out of a pool of 100 million patients served by 16 collaborating centers across six countries.
PPGLs have no accepted post-surgical treatment, so clinicians proceed “by trial and error,” says Calsina, which means no robust treatment response data exists on large cohorts of patients. The options include different chemotherapies, together with some targeted therapies under investigation.
Calsina and her colleagues were looking at the molecular patterns in patients that hadn’t yet been treated medically, based on tumor samples research collaborators have been contributing over the past decade. This was correlated with known characteristics in other types of tumors where patients responded to immunotherapy, including high expression of PD-L1 and high tumor mutational burden (TMB).
Genomic profiling of the metastatic tumors identified four best events for classifying metastatic risk: ATRX (α thalassemia/mental retardation syndrome X-linked) mutations, high microsatellite instability score, high CDK1 (cyclin-dependent kinase 1) expression, and MAML3 (mastermind like transcriptional coactivator 3)-fusions. Together, they showed 100% sensitivity in predicting metastatic PPGL.
PPGLs are mostly hereditary tumors, with approximately 40% of patients carrying mutations in one of the 22 implicated genes, says Calsina. Another 30% of tumors carry somatic mutations in the same set of genes, but the identified mutations don’t necessarily correlate with the prognosis of patients.
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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.
Metastatic pheochromocytomas account for 20% of all such cancer cases, Robledo says, and the odds of survival range from 20% to 60% after five years. While most patients who develop metastasis do so one or two years after the diagnosis of the disease, for others it can take up to 20 years. The hope is that the new molecular markers will help clinicians know which patients they need to follow more closely.