RET mutations in neuroendocrine tumors: Including small-cell lung cancer

The RET oncogene is becoming a target of increasingly broad interest in thoracic malignancies, from papillary thyroid carcinomas to medullary thyroid cancers, to lung adenocarcinomas, and now to small cell lung cancers. In this issue of the Journal of Thoracic Oncology, Dabir and colleagues identify an activating somatic mutation in the RET oncogene in a small cell lung cancer, and demonstrate that overexpression of either wild-type or mutant RET in small cell lung cancer cell lines increases cell proliferation, activates mitogenic pathways, and confers increased reactivity to RET tyrosine kinase inhibitors. While these several thoracic tumor types may share an oncogene in common, the mechanisms resulting in oncogenic activation and the implications for therapy may be quite distinct. RET oncogene rearrangement in papillary thyroid cancer was the first recurrent tyrosine kinase gene fusion identified in a solid tumor.1 Oncogenic RET gene rearrangements, including inversions, intrachromosomal rearrangements and interchromosomal translocations, occur in about 20% of sporadic papillary thyroid cancers and 60-80% of papillary thyroid cancers induced by radiation exposure. These mutations result in growth promotion through constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Biologically and clinically, of course, papillary thyroid cancers are a world away from small cell lung cancers: the former being indolent and frequently localized tumors with an overall 5-year survival rate of 97-98%;2, 3 the latter being exceptionally aggressive and rapidly metastatic cancers with a 5-year survival rate of 1-2%. Major interest in the role of RET as a driver oncogene in lung cancer derived from the identification and characterization of RET-containing fusion oncogenes in approximately 2% of lung adenocarcinomas, a discovery made concurrently by four independent research groups.4-7 RET fusion-positive lung adenocarcinoma is a striking example of our current potential for exceptionally rapid translation between novel target discovery (2012) and dramatic clinical validation (2013).8 The RET tyrosine kinase receptor is required for normal neuroendocrine development. Among other neural crest defects, RET-deficient mice demonstrate a failure of maturation throughout the sympathetic nervous system.9 In humans, germline missense mutations in RET are associated with the multiple endocrine neoplasia type 2 (MEN2) syndromes, MEN2A, MEN2B, and familial MTC.10 The MEN2 syndromes are familial clusters of tumors of neuroendocrine cancers including medullary thyroid carcinoma and pheochromocytoma. In MEN2A, these tumors are found together with parathyroid hyperplasia or adenoma; in MEN2B additional tumors include mucosal and gastrointestinal ganglioneuromas. The MEN2 syndromes can be associated with a variety of other neuroendocrine cancers, including both pulmonary and extrapulmonary carcinoids. Dabir and colleagues extend the spectrum of RET mutant tumors to include another neuroendocrine tumor type, small cell lung cancer, identifying a RET M918T mutation in a metastatic small cell lung cancer. M918T is the mutation most strongly associated with MEN2B syndrome, and is also found in about 50% of sporadic medullary thyroid carcinomas. Notably, the M918T mutation is one of the most highly transforming RET mutations in vitro and leads to a more severe clinical MEN2B phenotype than the next most common mutation, A883F.11 It is interesting that the M918T was identified in what is arguably the most aggressive neuroendocrine tumor type, small cell lung cancer. This report is not the first demonstration of RET mutations in small cell lung cancers. Futami and colleagues identified mutations in exon 11 of RET in two small cell lung cancer cell lines, and demonstrated that these were not present in germline DNA of the patients from whom these were derived.12 Overall, however, RET mutations in small cell lung cancer are clearly rare. Mulligan and colleagues looked specifically for RET mutations in a panel of 54 small cell lung cancers and found none.13 Two recent relatively comprehensive small cell lung cancer genomic analyses, including a total of over 100 cancers, revealed only three examples of RET mutations, and at least two of these are of questionable significance.14, 15 Neither of these studies identified RET as a statistically significantly mutated gene in small cell lung cancer. That these mutations are rare does not detract from the potential importance of finding such a targetable driver for the patient with that particular cancer. The genome studies of small cell lung cancer to date have been biologically informative, but somewhat disappointing from a therapeutic perspective in that the most commonly identified genetic alterations in this tumor type are loss of function mutations or deletions in tumor suppressor genes, including nearly universal inactivation of TP53 and RB.14, 15 Loss of function genetic alterations do not provide the clear opportunity for rapid clinical translation offered by an activating mutation in a known receptor tyrosine kinase. It would be of great interest to treat the rare patient with a RET-mutant small cell lung cancer with a targeted inhibitor of RET. A consequence of extensive genomic characterization of major tumor types has been the fragmentation of these tumor types into many distinct subsets defined by mutant drivers that may be present at low frequencies across widely disparate tumor histologies. Detailed genomic studies have revealed oncogenic RET gene mutations in multiple tumor types, typically at very low frequency (Figure). Our cancer center among several others has approached this problem by launching a unified comprehensive next generation sequencing platform covering a few hundred genes implicated in cancer, applied as a clinical test across all tumor types. This approach supports the conduct of “basket trials,” early phase studies of novel targeted therapies specifically in the patients whose tumors harbor the putative oncogenic target. One goal is to facilitate rapid drug development by focusing on the patient populations most likely to benefit from these novel agents. Figure Reported frequencies of gene alterations in RET across multiple common solid tumor types The relative paucity of tumor material for molecular and genetic analysis constitutes a primary barrier to progress in small cell lung cancer research. This disease has been typically diagnosed by fine needle aspirate, and primary tumors are only rarely surgically resected. The genomic studies performed to date have been small in scale relative to those of the tumor types analyzed by the Cancer Genome Atlas consortium – too small to dependably identify recurrent genetic alterations in small cell lung cancer with a frequency of less than 5%. Some of the exciting recent progress in targeted therapy for lung adenocarcinoma has been directed at oncogenic drivers (BRAF, ROS1, RET, even ALK) well below this threshold. These observations underscore the need for substantially broader and deeper characterization of potentially targetable genomic alterations in small cell lung cancer. There may be more gold in them hills, but it's going to take some digging.