OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Matthew H. Kulke, MD, MMSc, has been a leader in the development of new therapies and clinical management strategies for patients with neuroendocrine tumors (NETs).

: What are NETs and how are they currently treated?

Kulke is director of the Program in Neuroendocrine and Carcinoid-Tumors at Dana-Farber/ Brigham and Women’s Cancer Center and an associate professor of Medicine at Harvard Medical School. In an interview with 

, he described the clues obtained from genome sequencing studies in this tumor type and the pressing need for further research.

: NETs tend to be divided into two main groups: one group are pancreatic NETs and the second group are carcinoid tumors. The treatment options differ to some extent for the two tumor types but there are also some parallels. Really, for both tumor types right now, most people will start treatment with a somatostatin analog and these have been shown to both improve symptoms related to hormone secretion and also slow down tumor growth.

What are the key molecular drivers of NETs?

For pancreatic NETs, there are several system ic treatment options. These include treatment with an mTOR inhibitor, everolimus; treatment with a VEGFR-targeted tyrosine kinase inhibitor, sunitinib; and treatment with chemotherapy, usually with alkylating agents like temozolomide. Then, for the carcinoid tumors, beyond somatostatin analogs, treatment with everolimus has recently been shown to be effective in a clinical trial and was approved by the FDA. There’s also early data showing that treatment with radiolabeled somatostatin analogs is effective.

In terms of the molecular drivers, I would say that much remains unknown. What we know in pancreatic NETs is that there are common mutations in three genes and those are 

. Those genes are really tumor suppressor genes, so they have a different function from the oncogenes that are commonly targeted in other malignancies. The function of those three genes at this point is not fully understood.

What have genome sequencing studies taught us about NETs?

Rarely, in pancreatic NETs there are mutations in genes in the mTOR pathway and right now whether mutations in those genes are associated with response to mTOR inhibitors is an area of active investigation.

The main study in pancreatic NETs was a study by Jiao and colleagues published in Science a few years ago and that was a whole-genome sequencing study. In carcinoid tumors, there have been two studies that performed whole-genome sequencing in small bowel carcinoid tumors. One was a study by Francis and colleagues, published in 

 and then there was a second study by Michaela Banck.

Those studies found that, in a small proportion of small bowel carcinoid tumors, there are mutations in a gene called 

, also known as p27, a cyclin-dependent kinase inhibitor. But those mutations were identified in less than 10% of the samples, so in the majority of small bowel carcinoid tumors we really don’t know the molecular drivers. I think there are a few common themes. One is that for the most part we are not identifying classic oncogene driver mutations in NETs, and that suggests that there are likely other mechanisms that are driving these tumors.

What are the major limitations in translating this information into clinical care?

One area of very active investigation is whether there may be epigenetic changes that are contributing to growth in these tumors and that may well be a targetable event. But at the present time, given the mutational profile, for the most part these are not tumors—at least right now&mdash;where we can just look at a sequence and select a drug. The story is a little different from other cancers where that is the case.

Right now, sequencing these tumors does not directly inform clinical care, but the sequencing studies that have been done at least are suggesting a direction to look. One of those directions may well be epigenetic changes that are important and are really the oncogenic change, if you will, in these tumors and that potentially may be targetable. So, it’s pointing us in a direction, but we don’t yet have the answer. The major limitation here is that we still don’t fully understand the molecular drivers of these tumors. We have some clues but we don’t yet have a complete understanding.

In a recent milestone, Kulke presented phase III clinical trial data at the 2015 European Cancer Congress indicating that telotristat etiprate, a novel tryptophan hydroxylase inhibitor, improves diarrhea control in combination with a somatostatin analog for patients with metastatic NETs and inadequately controlled carcinoid syndrome. In the clinical arena, Kulke serves as co-chair for the National Comprehensive Cancer Network guidelines panel on NETs and also is an active member of medical society advisory boards and task forces related to NETs.

Articles

Matthew H. Kulke, MD, MMSc, discusses the clues obtained from genome sequencing studies in neuroendocrine tumors and the pressing need for further research.

NET Oncogene Patterns Don't Fit the Classic Mold

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.

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&mdash; 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; 

<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; 

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.

Most sequencing studies to date have been performed in patients with pNET and small intestine NETs (SI-NET).

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.

In the first, an analysis of mutations and copy number changes in 48 tumors was performed. The rate of somatic mutations was low and although a number of genes were mutated, none were recurrently altered. Both the frequency and type of mutations differed significantly from other GI cancers as well as other types of NETs.

Although no recurrently mutated genes were observed, many clustered into the same pathway. Almost half of the tumor samples had mutated or deleted 

 genes, which encode proteins involved in the transforming growth factor beta (TGFβ) pathway, suggesting it may be an important regulator of SI-NET growth.

Drugs targeting this pathway might be an effective treatment option in SI-NET and some are in clinical development for other tumor types. The study authors also suggested that patients with 

 mutations may be less likely to respond to 5-fluorouracil, as has previously been observed in patients with colorectal cancer.

Genes involved in the phosphatidylinositol- 3-kinase (PI3K)/Akt/mTOR pathway, a key regulator of numerous hallmark cellular processes involved in the development of cancer, were mutated in around a third of tumors, particularly amplification of the AKT1 or AKT2 genes, which were mutually exclusive events.

Amplification of the SRC gene was also frequently observed in SI-NET. SRC encodes a nonreceptor tyrosine kinase, and a number of multitargeted tyrosine kinases include Src among their targets. Src also has been shown to activate mTOR activity in neuroendocrine cells, offering the possibility of synergistic activity between mTOR and Src-targeting therapies.

In the second study, 55 tumors were profiled with whole-exome and whole-genome sequencing. Again, the vast majority of mutations were found in only a single patient. Statistically significant mutations were observed in a single gene, 

, in 10% of patients. This gene encodes a cyclin-dependent kinase inhibitor p27, which regulates the cell cycle.

pNETs are the second most common NET after SI-NETs. The first whole-exome sequencing study of pNET was published in 2011 and analyzed 58 tumor samples. In addition to being distinct from SI-NET, the pNETs had a mutation profile that was distinct from other types of pancreatic cancer; the genes most frequently mutated in pancreatic ductal adenocarcinoma were rarely altered in pNET.

 mutations, observed in 43% of cases collectively, were mutually exclusive, but were found in combination with 

 mutations in around one-fifth of tumors. MEN1, found in 44% of cases, encodes a nuclear protein called menin that interacts with a complex of other proteins that remodel chromatin by methylating histone proteins, ultimately regulating gene expression.

In particular, menin seems to be involved in the activation of genes involved in the cell cycle and the repair of damaged DNA. Thus, MEN1 acts as a tumor suppressor and its loss may serve a dual blow in pNET cells, promoting excessive cell growth and genome instability. What the 

 genes do and how they lead to pNET is much less clear.

Like menin, both are nuclear proteins. ATRX is a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, and both it and DAXX are involved in chromatin remodeling. It is suggested that they might play an important role in a process called alternative lengthening of telomeres (ALT).

Telomeres are specialized structures that form a protective cap on the end of the chromosomes. They are progressively eroded over time and this limits the replicative potential of a cell. In order to become immortal, cancer cells have to overcome telomere shortening and they usually achieve this goal by reactivating the telomerase enzyme, which lengthens telomeres. However, in a minority of cases they can use an alternative mechanism—ALT&mdash;which is much more poorly understood. ALT was noted in 60% of cases of pNET and these correlated with mutations in 

Genes involved in the mTOR pathway, including tuberous sclerosis gene (TSC2) and phosphatase and tensin homolog gene (

), were also mutated (8.8% and 7.3%, respectively). Both regulate the activity of mTOR, perhaps explaining why mTOR inhibitors have proved so successful in pNET in particular.

A second study of pNETs also identified mutations in 

, which were infrequently mutated in the previous study. It was suggested that differences in the mutational profiles may have resulted from the different patient populations, which were 85% Caucasian in the former and 100% Chinese in the latter.

In a separate study, researchers specifically focused on poorly differentiated neuroendocrine carcinomas of the pancreas (PNEC), which have a particularly poor prognosis and are highly aggressive. This group includes small cell and large cell histologies and is generally very rare. The molecular alterations found in these tumors was distinct from other, well-differentiated pNETs.

 and abnormal immunolabeling of these two proteins by immunohistochemistry was also almost universal. 

 mutations are rare, by contrast, in well-differentiated pNETs; however, they may be inactivated by other mechanisms, such as extra copies of p53- and pRb-related genes including 

Finally, a small sequencing study of insulinomas, the most common type of functional NET, was also performed in 10 tumor samples and matched normal pairs. The most notable mutations were in the YY1 transcription factor (30%). Mutations in other potential cancer-related genes included 

Around a quarter of lung tumors are neuroendocrine in nature, with small cell lung cancer (SCLC) being the most common and the most malignant type. A limited number of sequencing studies have been performed and have mostly focused on carcinoid tumors.

Altered genes involved in chromatin remodeling were frequently identified in this tumor type, including those encoding proteins involved in histone modification (in 40% of tumors), such as 

, and in the SWI/SNF complex (in 22%) such as the 

Another study sequenced 70 pulmonary NETs, including typical carcinoids, atypical carcinoids, large cell neuroendocrine carcinomas (LCNECs) and SCLCs. Mutations in 

 were altered in atypical carcinoids and 

 was found in typical carcinoids. The frequency of mutations observed overall increased as the malignancy of the subtype increased.

The most frequently mutated gene in pulmonary NETs overall was 

 (22%), but this mutation was not found in carcinoids and was most prevalent in SCLC, highlighting the genomic diversity among different subtypes. Mutations common to all pulmonary NET subtypes included RET and EGFR, though the latter are not the usual activating mutations observed in other tumor types.

There are numerous other types of less common NETs. Among prostate cancers, true NETs are rare, but often prostate adenocarcinoma can evolve a neuroendocrine phenotype. A growing body of evidence suggests that the evolution of the neuroendocrine phenotype in castrationresistant prostate cancer (CRPC) is one of leading causes of resistance to androgen receptor (AR)-targeted therapies.

A recent study published in Nature Medicine suggested that the selective pressure of AR-targeted therapy causes genomic aberrations in CRPC that drive clonal evolution of AR-positive CRPC adenocarcinoma into an AR-negative CRPC NET. The study further concluded that these genomic alterations were most likely epigenetic rather than genetic in nature.

Medullary thyroid cancers (MTC) are also a form of NET. Whole-exome sequencing of 17 tumors found that 90% tumors had mutually exclusive mutations in 

There were relatively few other mutations and no common recurrent mutations. RET is a proto-oncogene that encodes a receptor tyrosine kinase. Mutations and gene rearrangements in RET have been recognized in MTC for more than a decade, and drugs that inhibit RET including vandetanib (Caprelsa) and cabozantinib (Cometriq) have been successfully developed for its treatment.

It is clear from genome sequencing studies that somatic mutations are rare in NETs compared with other tumor types, and those that are present are often not recurrently altered and many may represent passenger mutations rather than oncogenic drivers. What makes the management of NETs more challenging still is that most recurrently mutated genes encode tumor suppressor proteins that are particularly difficult to target therapeutically.

Epigenetic changes, which impact gene expression without affecting the DNA sequence, have also been evaluated in genome-wide studies and are much more common. In addition, when genes are mutated in NETs they are often epigenetic modifiers involved in processes like chromatin remodeling. This has led many researchers to suggest that epigenetic regulation may play a more important role in the development of NETs than the acquisition of mutations.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in New Haven, Connecticut.

Agrawal N, Jiao Y, Sausen M, et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS.

Banck MS, Kanwar R, Kulkarni AA, et al. The genomic landscape of small intestine neuroendocrine tumors. 

Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. 

Capdevila J, Meeker A, García-Carbonero R, et al. Molecular biology of neuroendocrine tumors: from pathways to biomarkers and targets. 

Feldman R, Astsaturov I, Millis S, et al. Molecular profiling in small cell lung cancer and lung neuroendocrine tumors. 

Francis JM, Kiezun A, Ramos AH, et al. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. 

Fernandez-Cuesta L, Peifer M, Lu X, et al. Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids. 

Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1 and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. 

Karpathakis A, Dibra H, Thirlwell C. Neuroendocrine tumors: cracking the epigenetic code. 

Vollbrecht C, Werner R, Walter RFH, et al. Mutational analysis of pulmonary tumors with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumor group. 

Yachida S, Vakiani E, White CM, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. 

Genome sequencing studies are providing clues for therapeutic avenues of inquiry for the most common types of neuroendocrine tumors but are raising as many questions as they answer.

Genomic Diversity Clouds Outlook for Neuroendocrine Tumors

Value-based care is becoming a new catch phrase in American medicine, especially in the oncology arena. But seldom do we see as clear and compelling an explanation of what that might mean in oncology as we did recently at the 1st Annual School of Gastrointestinal Oncology that Physicians’ Education Resource (PER) hosted in New York City on April 23.

In his opening address, Georgetown University’s John L. Marshall, MD, detailed some of the “inconvenient truths” nagging at the oncology field today. Although progress is certainly being made, drug approvals still take 17 years from concept to approval and rising costs are out of proportion to the improvement in outcomes.

Notably, most patients today are being treated according to guidelines—which means they are not receiving the promising new therapies in development and their experiences are not helping to move cancer care forward.

As the established consumption model of cancer care changes, Marshall believes oncology specialists will have to start analyzing therapies based on the clinical value they would deliver in terms of measurable outcome balanced against the costs of that drug.

More significantly, however, Marshall discussed the importance of truly establishing precision medicine as a method of operation in delivering cancer care at more affordable prices. He gave a glimpse of what this might look like in practice in a diagram reproduced as part of our coverage of his presentation in this issue of 

, entitled “A Call to Action in GI Cancers.”

The model of profiling tumors for molecular biomarkers and then using that information to evaluate potential new therapies should apply not only to laboratory research but also to clinical practice, Marshall maintained.

“This is how I want to be treated,” he said. “…And I think if you asked all of our cancer patients, this is how they want to be treated. They’re ready for it and we need to build an infrastructure that enables this.”

Marshall’s vision is an inspiring one. Change is surely coming in this most dynamic of healthcare fields, and we who care about the quality of cancer care must join leaders such as Marshall in examining and supporting new ways to deliver that care.

Please let us know your thoughts on these matters and, as always, thank you for reading.

Value-based care is becoming a
new catch phrase in American
medicine, especially in the
oncology arena.

Something’s Gotta Give

Obesity increases cancer risk by anywhere from 10% to 300% depending on the type of cancer.

 Obesity is also often associated with a poor prognosis, including higher risk of recurrence. For example, obesity (BMI >30) increases mortality in prostate cancer by about 25%

 Similarly, in colon cancer, the very obese (with a BMI >35) face a 38% greater chance that their cancer will return after treatment.

Given the current obesity epidemic and an aging population susceptible to cancer, significant efforts are being undertaken to understand the foundations of the obesity-cancer link. Today, we have an emerging picture of how obesity creates a tumorigenic environment through inflammation, altered adipokines, metabolic changes, and reshaping the microbiome.

Obesity increases the abundance of proinflammatory macrophages in adipose tissue, which release cytokines including TNF, IL-6, and IL-1β. These signaling molecules promote a number of cell events that promote tumorigenesis, including survival, proliferation, DNA damage, angiogenesis, and invasiveness. This multitude of procancer effects has led to recognition of inflammation as a fuel that feeds the flame of cancer progression.

Large amounts of adipose tissue lead to high levels of the hormone leptin, which directly enhances angiogenesis and activates a gene expression program that supports cell proliferation, survival, and invasiveness. Obesity also decreases levels of adiponectin, a hormone with significant antiangiogenic and tumor growth-limiting properties.

The metabolic changes that follow increased adiposity include hyperinsulinemia and hyperglycemia, both of which favor cancer development. Insulin intrinsically promotes cell growth and inhibits apoptosis. Hyperglycemia enhances glycolysis, increasing energy supplies in tumor cells, and activates a pathway that enables survival despite hypoxia.

Finally, in many obese patients, the consumption of a high fat, low fiber diet alters the gut microbiota, which may worsen metabolic imbalances and enhance inflammation. Studies in mice suggest that these changes affect host gene expression to increase fat storage and intestinal permeability, which exacerbates inflammation by enhancing absorption of endotoxins.

Our laboratory has had a long-term interest in the protein p62. Since our initial discovery of the ubiquitously expressed protein, we have shown that p62 is an adapter that creates protein-protein complexes to produce key cellular signals. Our research so far, summarized here, suggests that p62 may represent a link connecting obesity, inflammation, and progression of certain cancers. By studying p62, we aim to delineate how various signaling pathways are altered in these conditions, which could lead to interventions that break the link and limit cancer risk.

p62 plays a key role in controlling metabolism, limiting adiposity and maintaining normal responses to glucose. Loss of p62 leads to enhanced activity of the kinase ERK1, promoting insulin resistance and decreasing metabolic rate.

 The latter effect results from an increase in the ratio of white to brown adipose tissue, favoring fat storage over energy consumption.

Inactivation of this gene also supports inflammation in adipose tissue via decreased interaction of another kinase, PKCζ, with its targets.

 Adipose inflammation, in turn, further contributes to insulin resistance. These results both highlight the complexity of p62’s function and the overlap of signaling pathways between metabolic disease and cancer; ERK is often overactive in cancer, and PKCζ is a tumor suppressor.

In the tumor stroma, p62 suppresses tumorigenesis by modulating metabolism.

 We have shown that p62 levels are reduced in the stroma of several tumors, including prostate, breast, and colon. Further, loss of p62 in the tumor microenvironment or stromal fibroblasts results in increased tumor formation by epithelial prostate cancer cells. The mechanism involves regulation of cellular metabolism through mTORC1, resulting in increased production of inflammatory cytokines, which are required for tumor promotion.

It should be noted that p62 deficiency in cancer cells limits cancer progression. Nonetheless, given its multiple synergistic protumor effects in the stroma, preventing the downregulation of p62 in the stroma may represent a promising therapeutic target for obesity-related cancers.

In some cases, p62 may link obesity to cancer even more directly. Periprostatic fat correlates with tumor aggressiveness in patients with prostate cancer (PCa),

 suggesting that adipocytes may have local proinflammatory effects. Presently, we are examining the role of p62 in promoting inflammation in the PCa tumor microenvironment, as well as in adipocyte-PCa cell interactions.

This is just one example of research on the obesity-cancer link. Other critical areas of investigation are focused on the mechanisms whereby obesity-associated changes in insulin signaling, estrogen (in the case of breast and endometrial cancers), and the gut microbiome contribute to cancer progression. As mechanisms vary with tumor site and driving mutations, it may be years before we can apply insights from these studies to the clinic. Nonetheless, deciphering the underlying mechanisms will undoubtedly lead to better tailoring of cancer treatments to each patient.

			Polednak AP, Estimating the number of U.S. incident cancers attributable to obesity and the impact on temporal trends in incidence rates for obesity-related cancers. 

			Rodriguez C, Patel AV, Calle EE, et al. Body mass index, height, and prostate cancer mortality in two large cohorts of adult men in the United States. 

			Chan DS, Vieira AR, Aune D, et al. Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. 

			Dignam JJ, Polite BN, Yothers G, et al. Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J Natl Cancer Inst. 2006;98:1647—1654.

			Moscat J, Diaz-Meco M. Feedback on fat: p62-mTORC1-autophagy connections. 

			Müller TD1, Lee SJ, Jastroch M et al. p62 links β-adrenergic input to mitochondrial function and thermogenesis. 

			Valencia T, Kim JY, Abu-Baker S, et al. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.

			van Roermund JG, Hinnen KA, Tolman CJ, et al. Periprostatic fat correlates with tumour aggressiveness in prostate cancer patients. 

Researchers of Sanford Burnham Prebys Medical Discovery Institute indicates that p62 may represent a link connecting obesity, inflammation, and progression of certain cancers. 

Novel Protein Research May Help Unravel Obesity-Cancer Link

After a decade of advances in the diagnosis and treatment of patients with adenocarcinoma non—small cell lung cancer (NSCLC), the prospect for further progress remains bright, according to experts who participated in a recent 

There are now first- and second-line targeted therapies for both 

-mutant disease. Immunotherapies have been moving closer to the front line, an important development in that most patients with NSCLC do not harbor a currently actionable mutation. And, advances in plasma genotyping give hope that eventually there will be routine clinical use of a predictive molecular proxy of tumor biology derived from a noninvasive test.

The take-home message from the roundtable, entitled “Treating Adenocarcinoma of the Lung,” is that many studies are underway to further define how best to use targeted therapies and immunotherapies with personalized approaches.

Adenocarcinomas represent 40% of all lung cancers and constitute the most dominant histological subgroup in the NSCLC category, according to the American Cancer Society. Accurately diagnosing adenocarcinomas has become more complex, panelists noted.

“In 2016, an accurate diagnosis means you understand the histology well and you have molecular testing done for that tumor because all these things drive what patients are going to get in terms of treatment,” said Gregory J. Riely, MD, PhD. “A fine-needle aspirate, simple one pass needle biopsy is not enough in 2016. We need either multiple passes with a fine needle, multiple passes with a core needle, or even surgical biopsy.”

Riely said it is critical that individual patients are tested for 

 mutations, ALK status, and ROS1 rearrangements; this testing should be completed within 7 to 10 days. “Randomized clinical trial data has said platinum-based chemotherapy is inferior to targeted therapy for those patients, so we need to know [mutation status] up front,” he said.

 mutations and MET exon 14 skipping mutations, Riely said.

To go beyond the standard FDA-approved tests is to look for ways to make patients eligible for trials and to consider using drugs approved for other indications. Larger gene panel tests may yield information about mutations with no relevance to lung cancer but would make efficient use of tissue samples if priced in the range of single-mutation assays. The panel agreed strongly that once a biopsy has been obtained, testing for markers should be reflexively ordered.

The need to obtain sufficient tissue to conduct molecular testing has been a growing topic of discussion, noted John W. Longshore, PhD.

However, he said, “it’s not really the quantity of tissue that’s important but it’s the quantity of tumor that is important. Making sure we get a good biopsy that has sufficient tumor content really is what drives the biomarker testing landscape.” It is essential that clinicians and pathologists communicate well, noted Mark A. Socinski, MD, who served as moderator for the Peer Exchange panel. Oncologists should give the pathologist a tentative diagnosis, so he does not conduct stains to rule out a pancreatic or colon primary tumor.

Communication is particularly important in the community setting where physicians do not have the ready access to tumor boards, Longshore said. This includes communicating with radiologists and pulmonologists. Even in the community setting, multidisciplinary tumor conferences can be conducted via Skype or another platform.

A major change in practice now emerging involves rebiopsying at progression, Longshore said. This is particularly important because of new therapies directed at the EGFR T790M resistance mutation and the need to learn a patient’s PD-L1 expression level. These markers can change over time.

“This is a huge paradigm shift for us because we never rebiopsied. We were always happy with the first biopsy. But I think we have to rebiopsy.,” said Socinski, adding that some of his patients have had four or five biopsies over time. Plasma-based testing for biomarkers, often called a liquid biopsy, already is approved in Europe and hopefully will be introduced soon in the United States, noted Longshore. Such tests are not quite as sensitive or specific as a tissue-based diagnostic but institutions are using plasma-based testing for circulating DNA for initial screening and, if a negative result appears, perhaps going to a tissue biopsy.

However, that entails a delay, Thomas E. Stinchcombe, MD, pointed out. Liquid biopsies are clearly the way of the future but relatively little validation has been completed and there is poor standardization among the several available platforms, panelists said.

Chemotherapy remains an important therapeutic tool in the treatment of NSCLC. It is the first-line option for patients without mutations and even patients with targetable mutations will receive chemotherapy at some point.

For patients without mutations, Stinchcombe first looks at performance status and comorbidities and then talks extensively with the patient about preferences and care goals. He typically starts patients with performance status scores of 0-1 with either carboplatin/pemetrexed or carboplatin/ paclitaxel and bevacizumab.

He gives the bevacizumab component to approximately 20% of patients, however. Carboplatin/ pemetrexed is very easy to give and there is not the degree of concern about hypertension or hemoptysis, he said. Notably, there was some disagreement among panel members about the relative efficacy and toxicity profiles of these regimens.

After looking at performance status, patient preferences, and comorbidities, Benjamin Levy, MD, tries to put every patient who reaches second-line therapy or who has progressed on platinum chemotherapy into a clinical trial.

Outside of a clinical trial, his default second-line therapy would be a PD-1 checkpoint inhibitor, with nivolumab (Opdivo) as his leading choice. He also will look to docetaxel or docetaxel plus the angiogenesis inhibitor ramucirumab (Cyramza) for very fit patients.

For third-line therapy, there is no excellent evidence.

For Jared Weiss, MD, avoiding docetaxel is a central concern, as he sees docetaxel as being one of the most toxic cytotoxic agents in current use. Riely noted that once he has decided to give docetaxel and accept the toxicity profile, however, he will frequently include ramucirumab, as its toxicity profile is modest.

The three approved EGFR tyrosine kinase inhibitors (TKI)—gefitinib (Iressa), erlotinib (Tarceva), afatinib (Gilotrif)&mdash;have similar mechanisms of action and side-effect profiles, and all have demonstrated improved outcomes compared with chemotherapy, Riely said. At the FDA-approved dose, there is a modest difference in the side-effect profile of the three drugs, however. Gefitinib has a more moderate side-effect profile with lower rates of rash and diarrhea, afatinib the least moderate.

However, the LUX-Lung-7 study demonstrated a statistically and clinically significant difference in progression-free survival (PFS) among 319 patients with EGFR-mutated advanced NSCLC randomized to receive afatinib versus gefitinib as first-line therapy, particularly after approximately 6 months.

As a result, Riely is now considering the possibility that afatinib has a greater efficacy than gefitinib in this setting. He also noted that a large analysis of multiple trials demonstrated that patients who had EGFR exon 19 deletions had a better overall survival with afatinib compared with chemotherapy.

Regardless of which EGFR TKI is chosen as frontline therapy, approximately 50% to 60% of patients will develop a second-site EGFR mutation in T790M, said Benjamin Levy, MD. In November 2015, the FDA approved osimertinib (Tagrisso) for this population.

In a phase I study, osimertinib demonstrated a 61% response rate among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response.

 The median PFS achieved by mutation- positive patients was 9.6 months, while adverse events (AEs) were very manageable. Osimertinib does not bring the rash and diarrhea seen with first-generation TKIs. As to the use of osimertinib as a first-line agent, Riely said there is insufficient data.

Rociletinib, another highly anticipated third-generation drug aimed at the resistance mutation, faltered in a phase III trial, prompting the company developing the drug to terminate all studies in early May.

For patients with ALK-positive disease, crizotinib (Xalkori) has demonstrated better outcomes compared with both first- and second-line standard chemotherapy, Socinski said. Although crizotinib is an extraordinarily useful drug, emerging agents have proved superior as second-line therapy, Riely said. Ceritinib (Zykadia) and alectinib (Alecensa) both achieve very high response rates with durable PFS rates. Yet, how to sequence these agents, which have somewhat different spectrums of activity against particular resistance changes, is unknown, Weiss said. Alectinib seems to be the better tolerated drug, Levy said. Importantly, both agents have CNS activity, and ALK-positive disease frequently involves brain metastases, said Stinchcombe.

The PD-1 inhibitors nivolumab and pembrolizumab (Keytruda) are approved for second-line treatment of patients with nonsquamous NSCLC, which includes adenocarcinoma. Nivolumab was approved based on an improvement in overall survival versus docetaxel (12.2 months vs 9.4 months), while pembrolizumab gained approval based on a 41% objective response rate among patients with PD-L1 expression on ≥50% of tumor cells.

Stinchcombe said the efficacy and the toxicity profiles of the two drugs are similar. Nivolumab is administered every 2 weeks, while pembrolizumab is given every 3 weeks. Additionally, PD-L1 testing is currently required with pembrolizumab although that might not necessarily be the case going forward. This class of drugs obviously brings tremendous excitement, but they also bring a challenging AE profile for some patients, Levy said.

Endocrinopathies, thyroid problems, pneumonitis, colitis, and hepatitis may be relevant, and are forcing oncologists to consult pulmonologists, gastroenterologists, and other physicians. Other immune checkpoint blockade agents in development in NSCLC include the PD-L1 inhibitors atezolizumab and durvalumab and the CTLA-4 inhibitor tremelimumab. Although more immunotherapy agents are on the horizon, Riely believes the near-term goal is determining whether the existing agents should move into the first line of therapy. As data about comparative first-line trials are reported, “it’s really going to be exciting because it’s going to transform how we think about first line, if any of them are positive,” said Riely.

Weiss stressed the need for continued gains through clinical trials. “I’ve been dazzled by the acceleration of progress that we’ve had in our clinical trials and how much more promising our clinical trials are than they were even just 5 years ago,” he said. “And so I’ll make a pitch that we should lower our threshold to put patients on clinical trials, including even in first-line for the most promising of these agents.”

			Park K, Tan E, Zhang L, et al. Afatinib (A) vs gefinitib (G) as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations: results of the global, randomized, open-label phase IIb trial LUX-Lung 7 (LL7). Presented at: 2015 ESMO Asia Symposium; December 18-21, 2015; Singapore.

			Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor—resistant non-small-cell lung cancer. 

After a decade of advances in the diagnosis
and treatment of patients with adenocarcinoma
non-small cell lung cancer,
the prospect for further progress remains bright.

More Advances Anticipated in Fast-Moving Lung Adenocarcinoma Field

The simply stunning advances in our understanding of the molecular basis of human disease are providing revolutionary changes in the management of multiple illnesses. It is well recognized that cancer has been at the leading edge of this paradigm change through the demonstration of the clinical utility associated with knowledge of the unique genomic profile present within an individual patient’s malignancy.

Not surprisingly, the past and current major focus of using molecular testing has been in the treatment of an established malignancy, and in examining for the presence of particular mutations, rearrangements, or amplifications of specific genes that may suggest the delivery of a particular antineoplastic agent targeted to that abnormality. Patients with cancer and their oncology teams are witness to increasingly relevant advances in this arena in multiple clinical settings.

Another critically important and highly clinically relevant issue—one that is less frequently discussed among oncologists&mdash;concerns the implications of knowing the germline genetic background for individuals with known cancer or who are at a higher risk for developing a malignancy.

Cancers of the colon, breast, and ovary are excellent examples where germline testing has been shown to be of value and where prophylactic interventions in specific clinical settings have been documented to be of substantial utility.

However, there is a particular issue when a search is undertaken to discover unique normal polymorphisms or actual mutations that may be present in the germline—versus a sole focus on molecular abnormalities within the cancer itself&mdash;that requires particularly careful consideration and discussion. When cancer is present, what is specifically being explored are differences between the individual’s germline versus the cancer, with the goal of finding a target for therapy. In essence, the germline itself is purposefully ignored since there is no intent to target the normal genome.

But when the normal germline is examined to define cancer risk, evaluate genetically influenced probability of treatment-related toxicity, or for other purposes such as assisting in the determination of prognosis, there is the realistic potential that what might be found would include incidental genetically relevant markers associated with illnesses completely unrelated to the intent of the specific search.

For example, it has been reported that the presence of unique normal polymorphisms of apolipoprotein E suggest an increased risk for the development of Alzheimer disease. Should such “incidental” information simply be routinely provided to individuals if it is found? Should individuals undergoing genomic testing be asked if they would like to receive this information if it is discovered? This request could be made prior to obtaining the testing or after the results are available and a laboratory reports the presence of such incidental information.

This is a complex and controversial issue, with considerable ongoing debate. Included in the discussion are questions of whether the individual or her/his family would be able to take any action following notification of the results that may lead to a decreased risk of a suggested negative outcome, or conversely whether the information would solely be anxiety-provoking with no current potential to be actionable.

Unfortunately, for example, knowledge of a heightened risk of Alzheimer disease would currently fall into the second category of the impact associated with providing genetically based information.

A related question is the impact of specific germline information being obtained for one indication which may have direct relevance (pleomorphic effect) for a second, unrelated indication. And, for one indication the genomic information may be actionable while that is not currently the case in the second condition.

An interesting report outside the cancer arena begins to address this question. Asymptomatic individuals (N = 257) undergoing testing to determine their genetic risk for Alzheimer disease were randomized to either receive this information alone or the Alzheimer disease risk data plus that associated with coronary artery disease risk.

Previous research had revealed similar genetic data could influence risk in both disease settings. Of considerable interest, among the individuals found to be carriers of the apolipoprotein allele associated with a heightened risk of Alzheimer disease, there was a lower incidence of distress and more changes in health behavior associated with providing genomic for both conditions versus Alzheimer disease risk alone.

Although this highly provocative study does not directly address the issue of malignancy-associated incidental genetic data or pleomorphic germline effects, there are important lessons here that might easily be applied in the cancer domain. The clinical utility associated with the discovery of a statistically significant heightened risk of cancer in a setting where there is no evidence this information is actionable such as with Alzheimer disease may lead to heightened distress in the absence of an individual being able to take any action known to favorably impact that outcome. This conclusion may have relevance for an individual undergoing germline testing for cancer or as an incidental finding for an unrelated condition or a pleomorphic effect of a single gene.

Hopefully, as the cancer research community develops effective screening strategies to discover early-stage cancers such as CT scanning for lung cancer and prophylactic approaches to prevent the development of malignant disease as is the case with bilateral salpingo-oophorectomy for ovarian cancer in the presence of a BRCA mutation, the conclusion that nothing actionable is possible will become an increasingly rare statement.

Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie. markman@ctca-hope.com.

			Christensen KD, Roberts JS, Whitehouse PJ, et al. Disclosing pleiotropic effects during genetic risk assessment for Alzheimer disease: a randomized trial. 

If germline testing for a cancer-associated purpose reveals the risk of an unrelated
illness like Alzheimer disease, should patients routinely be toldâ€”even if thereâ€™s nothing
that can be done about that â€œincidentalâ€ finding?

Vol. 17/No. 10 | Oncology Live®

NET Oncogene Patterns Don't Fit the Classic Mold

Genomic Diversity Clouds Outlook for Neuroendocrine Tumors

Something’s Gotta Give

Novel Protein Research May Help Unravel Obesity-Cancer Link

More Advances Anticipated in Fast-Moving Lung Adenocarcinoma Field

Germline Genetic Testing Raises Thorny Ethical Questions