This article reviews two newly described cancer syndromes: DICER1 and BAP1 tumor predisposition syndrome, and four uncommon syndromes: Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, Cowden syndrome (CS), and von Hippel Lindau (VHL) disease which can be under-recognized in an oncology practice. Clinical features and indications for testing are reviewed to help oncologists identify patients appropriate for genetic evaluation. Medical management recommendations and notable counseling points, such as potential for pediatric risk are detailed to highlight the importance of testing for patients and families.

Over 200 hereditary cancer syndromes have been described, with the majority being rare or uncommon. These syndromes are almost certainly under-reported given the broad range and variable expressivity of the associated features. The advent of next generation sequencing has enabled greater access to testing and has led to the discovery that at least some of these syndromes are more common than previously thought.

The major benefit of cancer genetic testing is that it can lead to personalized treatment, screening, and risk reducing strategies for patients and their families. Oncologists are often the first-line providers in helping to recognize patients with inherited cancer syndromes and are increasingly integrating genetic test results in the care of their patients. While referrals to cancer genetics are diverse in nature, some indications include: patients with rare tumor types, patients diagnosed with cancer at younger than typical ages, patients diagnosed with multiple primary cancers, patients who do not have cancer, but do have at least one relative with a rare tumor or at least two relatives with related cancers or multiple primaries, and/or patients who have a known gene mutation in the family.

In this review, we discuss the clinical features, gene function, and medical management recommendations for six hereditary cancer syndromes. This includes two newly described syndromes: DICER1 and BAP1 tumor predisposition syndrome, and four under-recognized syndromes: Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, Cowden syndrome (CS), and von Hippel Lindau (VHL) disease.

DICER1 syndrome is an autosomal dominant hereditary cancer syndrome.

 The most common features of DICER1 syndrome are pleuropulmonary blastomas (PPB), cystic nephromas, and ovarian sex-cord stromal tumors, especially Sertoli Leydig

. Other associated tumors include embryonal rhabdomyosarcomas of the uterine cervix and other sites, nasal chondromesenchymal hamartomas, cerebral and ciliary body medulloepitheliomas, pituitary blastoma, Wilms’ tumor, bladder cancer, and thyroid cancer.

 Juvenile hamartomatous intestinal polyps, multinodular goiter, and thyroid, lung, and kidney cysts are also seen.

The cancer risk is highest in early childhood, in large part due to the PPB risk with the majority of DICER1-associated tumors occurring before age 40.

 DICER1 syndrome is newly described and information about associated cancer risks is still emerging. The DICER1-related lifetime tumor risk seems to be 50% for females and 20% for males.

 Individuals who have personal and/or family histories of PPB, cystic nephroma, ovarian sex-cord stromal tumor, nasal chondromesenchymal hamartoma, medulloepitheliomas, pituitary blastoma, and/or embryonal rhabdomyosarcoma of the uterine cervix should be offered DICER1 genetic testing.

DICER1 is a ribonuclease responsible for producing short-interfering RNA and microRNA (miRNA) that regulate post-translational gene expression.

 Aberrant DICER1 function results in oncogenic miRNA, which does not require loss of the wild-type allele or a second-hit for disease development.

Management for infants and children with DICER1 syndrome includes complete physical exams, chest CT scans, chest x-rays, and renal ultrasound exams. Older children and adults with DICER1 syndrome should have clinical thyroid exams and possibly thyroid ultrasound scans.

BAP1 (BRCA1 associated protein-1) tumor predisposition syndrome is an autosomal dominant inherited cancer syndrome. Germline BAP1 mutations are associated with an increased risk for atypical melanocytic tumors, cutaneous and uveal melanoma, mesothelioma, and renal cell carcinomas,

. The atypical melanocytic lesions resemble Spitz nevi and have been characterized as “atypical Spitz tumors” (ASTs), although they have a unique histology and exhibit both BRAF and BAP1 mutations.

One study found 8% of patients with metastatic uveal melanoma to carry a germline BAP1 mutation.

 The exact spectrum of BAP1 associated malignancies and the extent of risk to develop these malignancies continues to evolve. A referral to genetics should be considered for individuals with a personal or family history of: metastatic uveal melanoma; non-metastatic uveal melanoma and cutaneous melanoma; cutaneous melanoma and mesothelioma; >1 mesothelioma diagnoses.

BAP1 is a deubiquitinating enzyme associated with the BRCA1 protein complex and it is involved in many cellular processes including regulation of the cell cycle and signaling pathways. Somatic BAP1 mutations have been seen frequently in malignant melanomas, uveal melanomas, and renal cell carcinomas. One study found inactivating BAP1 mutations in 47% of uveal melanomas.

Patients with a germline BAP1 mutation can be followed with annual eye exams and frequent skin checks.

 Low-dose computed tomography (CT) scan, magnetic resonance imaging (MRI), and ultrasound have been proposed as possible screening measures for lung and renal carcinomas however no consensus guidelines have been established.

Familial Atypical Multiple Mole Melanoma Syndrome

Familial Atypical Multiple Mole Melanoma (FAMMM) is a dominant condition thought to account for 40% of familial melanoma,

 1% of single primary melanomas, and 3% of multiple primary melanomas (MPM).

 Features of FAMMM include numerous (usually > 50) atypical nevi and familial melanoma often at early ages of onset.

 The risk for melanoma varies based on geography and exposure to the sun with estimates ranging from 50% to over 90%.

 The lifetime risk for pancreatic cancer in individuals with FAMMM is increased,

 but can vary tremendously from 10% to over 60%.

 Individuals with numerous dysplastic nevi, MPM, or melanoma in the context of family history of melanoma and/or pancreatic cancer should be referred for testing. 

FAMMM is caused by mutations in the CDKN2A gene, which disrupts the function of the p16 (INK4) isoform of the protein.

 This can lead to unregulated cell cycle progression from G1 to S phase and subsequent genomic instability that is critical in the pathogenesis of melanoma and pancreatic cancer.

Management of individuals with FAMMM has historically focused on patient education

 to limit sun exposure, quarterly dermatological exams often with digital dermoscopy, and vitamin D supplementation. Although pancreatic cancer screening has not demonstrated efficacy, surveillance options are available through both research studies and cancer centers that employ a combination of imaging and endoscopic ultrasound.

 The risk for pediatric melanoma and the opportunity to reduce risk by stringent sun protection should prompt assessment and testing of children in affected families.

Hereditary Leiomyomatosis and Renal Cell Cancer

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant syndrome caused by mutations in the FH (fumarate hydratase) gene. HLRCC is characterized by cutaneous and uterine leiomyomas and renal tumors.

 Most individuals with HLRCC have >1 cutaneous leiomyoma, typically on their trunk and/or extremities. Uterine leiomyomas (fibroids) are present in virtually all women with HLRCC.

While many women have uterine fibroids, HLRCC-associated leiomyomas are numerous, large, and on pathology show prominent nuclei or large orangeophilic nucleoli surrounded by a perinucleolar halo.

 HLRCC confers approximately a 15% lifetime risk of renal carcinoma, typically aggressive Type 2 papillary renal cell carcinomas, which often present as unilateral and solitary tumors.

 Cutaneous and uterine leiomyosarcoma have been reported but this risk is low. Individuals with multiple cutaneous leiomyomas (one histologically confirmed), individuals with Type 2 papillary renal cell carcinoma, and individuals with a single cutaneous leiomyoma with a family history of kidney cancers and/or uterine leiomyomas should be referred to genetics.

FH is a mitochondrial tumor suppressor gene that produces fumarase, the enzyme responsible for converting fumarate into malate in the citric acid cycle. Build up of fumarate impairs the degradation of hypoxia inducible factor HIF-1a resulting in a pseudo-hypoxic state that contributes to tumor development.

Individuals found to carry a mutation can be followed with frequent dermatologic examinations as well as annual abdominal MRIs in children and adults. Women are followed with annual gynecological exams and may need myomectomy or hysterectomy for symptom management.

 Individuals with HLRCC are at risk to have a child with Fumarate Hydratase Deficiency (FHD) if their partner also carries an FH mutation. FHD is a severe autosomal recessive inborn error of metabolism.

Cowden Syndrome (CS) is an autosomal dominant hereditary cancer syndrome that predisposes to multi-organ hamartomas and cancers.

 The most common cancers to develop in CS are hormone receptor positive breast cancers, follicular thyroid cancer, and endometrial cancers. Other CS-associated cancers are renal cell carcinomas and colorectal cancers.

 Benign features such as macrocephaly, biopsy proven tricholemmomas, gastrointestinal harmartomas/ganglioneuromas, and neurodevelopment issues are also features of CS.

 Testing for CS is indicated when individuals meet a number of criteria which entail a combination of benign, often pathognomonic features, and/or have component tumors of the disease.

PTEN gene mutations only account for 25% of individuals who meet CS clinical criteria.

 The PTEN protein functions both in the nucleus and cytoplasm to downregulate MAPK and PI3K/Akt.

CS cases without an identifiable PTEN mutation may be explained by methylation of KLLN, 

The National Comprehensive Cancer Network Comprehensive (NCCN) has published recommendations for management of CS including: annual thyroid ultrasounds, breast MRIs and mammograms, as well as early and frequent colonoscopies.

Dermatological follow-up is often indicated and renal imaging has been proposed. Patients should be counseled regarding reproductive risks, which include risk for pediatric cancers in offspring as well as developmental delay and autism.

von Hippel Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that is associated with a variety of tumors and cysts. The most common features of VHL syndrome are retinal angiomas, central nervous system (CNS) hemangioblastomas, and clear cell renal cell carcinomas (RCC).

 The lifetime risk of a CNS hemangioblastoma is 60% to 80% and the risk of RCC is 70%.

 Other features include pheochromocytomas and paragangliomas, pancreatic islet cells, endolymphatic sac tumors, epididymal cystadenomas, polycythemia (erythrocytosis), and cystadenomas of the broad ligaments of the uterus.

 Cysts, adenomas, and angiomas can also occur in the kidney, liver, pancreas, spleen and adrenal gland.

Individuals who have a personal and/or family history of clear cell kidney cancer, pheochromocytoma and/or paraganglioma, cerebellar hemangioblastoma, or retinal angioma should be offered VHL genetic testing.

 About 90% of individuals with VHL syndrome develop at least one manifestation; however, there is wide variable expressivity.

 The tumors can occur in childhood or adulthood.Â 

VHL is a multifunctional gene with a strong gatekeeper role, especially in the kidney. When the VHL gene is mutated, the absence of HIF degradation results in abnormal accumulation of VEGF and other hypoxia-inducible mRNA leading to tumor and cyst development.

Management for children and adults with VHL disease includes: annual physical exam, dilated eye exam, kidney evaluation with ultrasound, MRI exams of the brain, spine, and abdomen, including thin-slice MRI with contrast of the internal auditory canal, biochemical screening for pheochromocytomas, and annual audiology testing.46,48,49 Pregnant women with VHL need to be monitored closely due to the potential rapid growth of vascular tumors.

DICER1 syndrome, BAP1 tumor predisposition syndrome, FAMMM, HLRCC, Cowden syndrome, and VHL are complex disorders with reduced penetrance and pleiotropic effects. It remains important for patients and providers to recognize the evolving nature of these syndromes and the inherent limitations in predicting age-specific risk of component cancers. As several of these syndromes are newly described and others exceedingly rare, management guidelines are often based on expert consensus rather than evidence-based outcome measures. Greater recognition of individuals with these syndromes and comprehensive, long-term follow-up studies are needed to determine the efficacy of various screening modalities and establish best practices.

The skills of a diverse set of medical providers including oncologists, pathologists, dermatologists, genetics professionals, and others are required for proper diagnosis and age appropriate risk management. Genetic counseling and testing can serve to provide an explanation for the development of cancers in a family and define risk for unaffected family members. Astute oncologists, through close collaboration with their genetics colleagues, are instrumental in identifying individuals with rare cancer syndromes to ensure that these patients–and their families–receive optimal care tailored to their specific genetic predispositions.

Affiliations: Carmelina E. Heydrich, MS, LGC, Dana-Farber Cancer Institute; Katherine A. Schneider, MPH, LGC, Dana-Farber Cancer Institute; Huma Q. Rana, MD, Clinical Director, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute.

Huma Q. Rana, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115; phone: 617-632-6292; email: HumaQ_Rana@dfci.harvard.edu.

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Articles

Experts discuss the clinical features, gene function, and medical management recommendations for six hereditary cancer syndromes. 

When to Consider Referral to a Genetic Counselor for Lesser Known Cancer Syndromes

The paradigm of observation alone following 4-6 cycles of frontline platinum-based combination chemotherapy has become obsolete for patients with nonsquamous non-small cell lung cancer (NSCLC), while no clinically significant breakthroughs in “continuation,” or “maintenance,” therapy have occurred to date for patients with squamous NSCLC.

Agents that have been shown to improve survival when administered as maintenance therapy include bevacizumab and pemetrexed, although questions have been raised regarding the design of the randomized trials that led to their approval in this setting. Doublet maintenance has not been proved to be superior to single-agent therapy, although this question is currently being addressed in a large randomized trial.

Quality of life and cost considerations clearly become important for patients receiving prolonged intravenous therapy for durations ranging from months to years; therefore optimization of drug and patient selection for maintenance therapies will continue to be a research focus in today’s environment of value-based care.

Despite the discovery of oncogenic driver mutations and corresponding targeted agents with clinical activity in a small percentage of non-small cell lung cancers (NSCLCs), the majority of patients with advanced disease will receive cytotoxic agents as frontline therapy, most commonly in the form of a platinum-based doublet.

 Traditional treatment paradigms with platinum combinations consisted of 6 cycles of therapy in patients with response/disease stability followed by observation, with consideration of second-line therapy initiation at the time of disease progression.

Unfortunately, the typical survival time for an advanced NSCLC patient only approached 10 months with this strategy.

Continuation, or “maintenance,” therapy in advanced NSCLC is not a new concept; however early tests of the hypothesis have proved disappointing. Socinski and colleagues found that 6 cycles of paclitaxel plus carboplatin produced the similar response rate, survival benefit, and quality of life as continuation of combination therapy past 4 cycles, with greater neurotoxicity occurring in the continuation arm.

Proceeding with single-agent maintenance therapy as an alternative to the continuation of more toxic doublet therapy also failed to show survival benefit in multiple trials of agents including gemcitabine and docetaxel (Table 1).

 A subsequent meta-analysis published in 2009 revealed that continuation therapy produced significant improvement in PFS, however, overall survival was only slightly improved (HR, 0.92; 

These findings did not generate further enthusiasm in the thoracic oncology community for maintenance therapy with the cytotoxic agents evaluated in the trials included in the meta-analysis (with the exception of pemetrexed), especially given the reported increase in associated adverse events.

The landmark ECOG 4599 trial established the continuation of bevacizumab until progression following 6 cycles of combination bevacizumab plus paclitaxel/carboplatin as a new standard of care for patients with nonsquamous disease who were otherwise candidates for bevacizumab, making bevacizumab the first agent to garner such an indication.

Patients receiving bevacizumab survived a median of 12.3 months, significantly improved by 2 months over chemotherapy alone, as were response rates (35% vs 15%) and PFS (6.2 vs 4.5 months).

Of note is that a third arm of bevacizumab plus chemotherapy without bevacizumab maintenance was not included in this trial, raising questions that persist to this day regarding the contribution of continuation therapy to the overall survival improvement.

The restriction of the approval of bevacizumab to nonsquamous patients because of an increased incidence of fatal hemoptysis in those with squamous histology, as well as the initial exclusion of patients with hemoptysis, brain metastases, or those receiving anticoagulation limited the initial use of bevacizumab in the clinic for NSCLC patients, as did concerns about rare but life-threatening toxicities. While bevacizumab has since been shown to be safe in patients with treated brain metastases and can as well be given concurrent with anticoagulants, subsequent retrospective analyses have called into question the efficacy of bevacizumab in elderly NSCLC patients (older than 65 years in 1 study) as well as its cost-effectiveness.

The initial finding of the effectiveness and tolerability of pemetrexed in the second-line setting for advanced NSCLC patients led investigators to study its use earlier in the disease course as “switch” maintenance following platinum doublet therapy.

Ciuleanu and colleagues showed that immediate pemetrexed following 4 cycles of a platinum plus paclitaxel, docetaxel, or gemcitabine improved overall survival by nearly 3 months over placebo (13.4 v 10.6 months; 

 = .012) in a randomized trial of 663 patients.

 The survival benefit was noted despite the fact that 67% of patients in the placebo arm went on to receive subsequent systemic therapy (pemetrexed in 18%).

Coincident with this report, Scagliotti et al, showed that the combination of first-line pemetrexed/cisplatin produced significant improvement in overall survival versus gemcitabine/cisplatin in a randomized trial of over 1700 patients.

However, this improvement was only noted for patients with nonsquamous histology, while gemcitabine/cisplatin had superior efficacy in squamous histology. Therefore the maintenance indication for pemetrexed was limited to nonsquamous patients only. Given positive randomized trials of pemetrexed in the frontline as well as the switch maintenance settings, the next most relevant question pertained to the use of maintenance pemetrexed following frontline pemetrexed/platinum therapy.

trial of maintenance pemetrexed vs placebo following 4 cycles of induction pemetrexed/cisplatin showed significant improvement in PFS (4.1 vs 2.8 months) and OS (13.9 vs 11.0 months) remarkably similar to the Ciuleanu et al trial. Thus pemetrexed continuation maintenance has been validated after frontline pemetrexed/platinum doublet therapy.

The use of bevacizumab and pemetrexed as single agents in the maintenance setting has not surprisingly led to the investigation of doublet maintenance therapy, especially as these drugs are administered as short infusions and in general have non-overlapping toxicities (Table 2). Trials of doublet maintenance have taken different forms. In the wake of promising phase II results of combination bevacizumab/pemetrexed maintenance following 6 cycles of bevacizumab plus pemetrexed/carboplatin, this strategy was compared to standard bevacizumab alone after bevacizumab plus paclitaxel/carboplatin in the phase III PointBreak trial of over 900 patients.

No difference in overall survival with doublet maintenance was noted (12.6 vs 13.4 months, HR, 1.00; 

Results from the 253 patient phase III AVAPERL trial also indicated no survival benefit (19.8 versus 15.9 months, HR, 0.88, 

 = 0.32) to bevacizumab/pemetrexed maintenance over bevacizumab alone following 4 cycles of bevacizumab plus pemetrexed/cisplatin, despite significant improvement in PFS noted at the time the trial was initially reported.

One criticism of these studies is that they did not include maintenance pemetrexed alone as a treatment arm. A large randomized trial (ECOG 5508) of maintenance bevacizumab versus pemetrexed versus bevacizumab/pemetrexed following frontline bevacizumab/paclitaxel/carboplatin is currently open across cooperative groups and should provide useful evidence regarding optimal maintenance therapy following bevacizumab-containing frontline treatment.

The role of bevacizumab in induction and maintenance when pemetrexed is used is also a question of interest. Overall survival times from randomized trials of frontline pemetrexed plus cisplatin as described above are comparable to trials of platinum combinations plus bevacizumab. Zinner and colleagues recently published the results of a 361 patient randomized trial (PRONOUNCE) of 4 cycles of pemetrexed/carboplatin followed by maintenance pemetrexed versus 4 cycles of bevacizumab plus paclitaxel/carboplatin with maintenance bevacizumab.

 Overall survival was noted to be similar in both arms (10.5 versus 11.7 months, HR, 1.07; 

Significantly less hematologic and neurologic toxicity was noted in the patients receiving pemetrexed, as well as less grade 2 alopecia. This has led some to favor the use of pemetrexed-based induction and maintenance therapy without bevacizumab in nonsquamous patients; there are also favorable cost-effectiveness data to support the use of pemetrexed plus platinum in this setting.

The third agent to have an indication for maintenance therapy is erlotinib, which was approved based on the large, randomized SATURN trial of erlotinib versus placebo following 4 cycles of frontline platinum-based therapy in 889 NSCLC patients of any histology.

Erlotinib produced significant improvement in overall survival (12.0 versus 11.0 months, HR, 0.81; 

 = .0088) that was also evident in patients without epidermal growth factor receptor (EGFR)-mutated tumors (HR, 0.77; 

 = .0243), although testing was completed only on approximately half of the randomized patients and there was no pre-specified stratification based on this marker.

Other investigations of EGFR tyrosine kinase inhibitors (TKIs) as maintenance therapy in unselected NSCLC patients following frontline platinum-based treatment have not duplicated these results. Four trials employing this strategy (2 with erlotinib, 2 with gefitinib) showed no statistically significant improvement in survival with maintenance EGFR TKI therapy.

 Therefore, despite the approval of erlotinib as a maintenance therapy for NSCLC, it has not been widely employed in the clinic in such a fashion.

Another EGFR targeted agent to be studied in the maintenance setting is the monoclonal antibody cetuximab. Two large randomized trials of continuation cetuximab following the addition of cetuximab to frontline platinum-based therapy have been reported. The FLEX trial involved cetuximab added to vinorelbine plus cisplatin followed by maintenance cetuximab versus vinorelbine plus cisplatin alone in 1125 patients with EGFR immunohistochemistry (IHC) positive NSCLC.

These data were not considered robust enough to elicit FDA approval for an NSCLC indication, and this decision was perhaps informed by the negative result of the second randomized trial, reported by Lynch and colleagues.

 In that study of 676 unselected NSCLC patients, cetuximab produced no improvement in PFS or OS when added to up to 6 cycles of frontline paclitaxel/carboplatin and then continued as a single agent.

As noted here, the results of maintenance trials in NSCLC as well as other malignancies underscore the need to better define the clinical meaningfulness of significantly improved survival endpoints: these costly therapies may be continued for months to years in patients who do not progress. In the current value-based medical environment, survival improvement benchmarks and cost-effectiveness analyses will play an increasing role in approvals by regulatory agencies, acceptance by payers, and the day-to-day decisions of individual practitioners.

 Trials showing marginal benefit in unselected histologic or genomic tumor subtypes are unlikely to find their way to the clinic or the patient.

Continuation maintenance therapy with either pemetrexed or bevacizumab has become a widely accepted standard of care, and this strategy has significantly impacted the prognosis for nonsquamous NSCLC patients, although questions remain regarding the use of bevacizumab in the elderly, and there is an unmet need in patients with squamous histology. There are currently no compelling data to support the use of these drugs in combination, although a large ongoing randomized trial (ECOG 5508) examines this and is expected to complete accrual in late 2015.

It otherwise appears unlikely that further refinement and improvements in maintenance treatment following frontline platinum-based chemotherapy will come from available cytotoxic agents. The promise of immunotherapy has become real for patients with malignant melanoma, and agents that target the PD-1 receptor, including nivolumab and pembrolizumab, have shown hopeful and sometimes striking results in pretreated nonsquamous and squamous NSCLC patients.

The CheckMate (nivolumab) and KEYNOTE (pembrolizumab) series of ongoing clinical trials involve the use of these agents in different manners as frontline and maintenance therapies: alone versus platinum chemotherapy, or in combination with platinum doublets and then continued as monotherapy in patients showing benefit. Positive results from trials such as these could dramatically change the landscape of current initial treatment paradigms for patients with advanced NSCLC.

James P. Stevenson, MD, Cleveland Clinic Foundation — Taussig Cancer Institute, 9500 Euclid Ave, R-35, Cleveland, OH 44195, phone: 216-636-6888, fax: 216-636-2498. E-mail: stevenj5@ccf.org.

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James P. Stevenson, MD, discusses optimization of drug and patient selection for maintenance therapies in NSCLC, and how it will continue to be a research focus in today's environment of value-based care.

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