Despite a spate of therapeutic advances in recent years, neuroendocrine (NET) tumors remain a poorly investigated collection of cancers whose rarity has limited clinical trial enrollment. Now, genome sequencing studies are providing clues for therapeutic avenues of inquiry for the most common types of NETs but are raising as many questions as they answer.
What has emerged thus far is a picture of a group of molecularly heterogeneous malignancies, with a paucity of readily targetable, classic oncogenic drivers. Although clinical applications are a long way off, important insights have been gained that suggest the need for distinct treatment strategies.
The Treatment Landscape
NETs arise from neuroendocrine cells of the endocrine and nervous systems. Although they are most commonly found in the gastrointestinal (GI) tract, they can arise throughout the body.
In addition to being classified by their anatomical location, NETs are divided according to whether they are functional or nonfunctional— that is, whether or not they secrete hormones such as insulinoma, gastrinoma, or glucagonoma— and by how well differentiated they are.
Surgery is currently the only potentially curative treatment option, but tumors frequently return and metastasize. Chemotherapy is considered the standard of care for patients with poorly differentiated tumors, which tend to be highly aggressive, but the options have been expanding for well-differentiated, relatively indolent tumors.
Somatostatin receptors are highly expressed on the surface of many NETs and receptor analogs have a central place in the treatment of NETs. In December 2014, the FDA approved the somatostatin analog lanreotide (Somatuline Depot) for patients with unresectable, well- or moderately differentiated locally advanced or mestastatic gastroenteropancreatic NETS after clinical trial data demonstrated an improvement in progression-free survival (PFS).
The identification of alterations in the mammalian target of rapamycin (mTOR) pathway, as well as aberrant expression of proangiogenic molecules including vascular endothelial growth factor (VEGF) and the highly vascularized nature of NETs, has driven the development of two alternative therapeutic strategies.
Several mTOR and VEGF receptor inhibitors have shown clinical activity in NETs. In 2011, the FDA approved sunitinib (Sutent), which inhibits VEGF receptor and other angiogenic kinases, and everolimus (Afinitor), which targets mTOR, for the treatment of patients with pancreatic NETs (pNETs).
The indication for everolimus was expanded to include nonfunctional gastrointestinal and lung NETs earlier this year, based on data from the phase III RADIANT-4 trial in which everolimus reduced the risk of progression by 52% (HR = 0.48; P
<0.001) compared with placebo and increased median PFS by 7.1 months as assessed by central radiology review (11.0 months vs 3.9 months, respectively; P
A Clinical Challenge
Despite such notable advances, these drugs are not effective in many patients, and there is a pressing need for new therapeutic options. NETs present a significant clinical challenge, and survival rates have remained stubbornly unchanged for decades, for the most part because these rare tumors are difficult to study.
While they may look identical under the microscope, these tumors often respond very differently to treatment and have varied prognoses. Relatively few genome sequencing studies have been performed to date, but they have begun to reveal important molecular distinctions between the different types of NETs.
On the whole, the mutation rate of NETs is significantly lower than for other types of cancer from the same primary location, suggesting they are more genetically stable. In general, NETs have a paucity of somatic mutations, though the frequency of mutations has been shown to increase with higher tumor grade, which may partly explain why poorly differentiated tumors tend to be more aggressive in clinical course than well-differentiated ones.
The classical tumor suppressors and oncogenes implicated in the development of other tumors do not seem to play a significant role in the pathogenesis of NETs. Even within groups of NETs from the same primary site, there are genomic distinctions. A picture has begun to emerge of biologically unique entities that may require very different treatment strategies.
Distinct Tumor Types Revealed
Most sequencing studies to date have been performed in patients with pNET and small intestine NETs (SI-NET).
Small Intestine NETs
In addition to being the most common malignancy of the small intestine, SI-NETs make up the largest group of NETs by primary site. These tumors have been analyzed in two separate genome sequencing studies.