Annual Review of Medicine - Volume 66, 2015

Despite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also examine the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups.

Patients with diabetes mellitus are at increased risk of cancer development. Metformin is a well-established, effective agent for the management of type 2 diabetes mellitus. Epidemiological studies have identified an association between metformin use and a beneficial effect on cancer prevention and treatment, which has led to increasing interest in the potential use of metformin as an anticancer agent. Basic science has provided a better understanding of the mechanism of action of metformin and the potential for metformin to modulate molecular pathways involved in cancer cell signaling and metabolism. This article outlines the link between metformin and cancer, the potential for metformin in oncology, and limitations of currently available evidence.

Neoadjuvant treatment of breast cancer refers to the use of different treatment modalities prior to surgical excision of the tumor. It has been accepted as a treatment option for patients with nonmetastatic disease, because it renders inoperable tumors operable and increases the rates of breast-conserving surgery, while achieving similar long-term clinical outcomes as adjuvant treatment. The neoadjuvant setting is being increasingly perceived as a research platform, where the biologic effects of traditional anticancer agents can be delineated, prognostic and predictive biomarkers can be identified, and the development of targeted agents can be expedited. Surrogate endpoints that can predict long-term clinical outcome and are evaluable early on, such as the pathologic complete response, offer valuable opportunities for rapid assessment of anticancer agents. Additionally, efforts for molecular profiling of the post-neoadjuvant residual disease hold the potential to lead to personalized therapy for breast cancer patients with early-stage high-risk disease.

Neuroblastoma is a developmental tumor of young children arising from the embryonic sympathoadrenal lineage of the neural crest. Neuroblastoma is the primary cause of death from pediatric cancer for children between the ages of one and five years and accounts for ∼13% of all pediatric cancer mortality. Its clinical impact and unique biology have made this aggressive malignancy the focus of a large concerted translational research effort. New insights into tumor biology are driving the development of new classification schemas. Novel targeted therapeutic approaches include small-molecule inhibitors as well as epigenetic, noncoding-RNA, and cell-based immunologic therapies. In this review, recent insights regarding the pathogenesis and biology of neuroblastoma are placed in context with the current understanding of tumor biology and tumor/host interactions. Systematic classification of patients coupled with therapeutic advances point to a future of improved clinical outcomes for this biologically distinct and highly aggressive pediatric malignancy.

The variability in treatment outcomes among patients receiving the same therapy for seemingly similar tumors can be attributed in part to genetics. The tumor's (somatic) genome largely dictates the effectiveness of the therapy, and the patient's (germline) genome influences drug exposure and the patient's sensitivity to toxicity. Many potentially clinically useful associations have been discovered between common germline genetic polymorphisms and outcomes of cancer treatment. This review highlights the germline pharmacogenetic associations that are currently being used to guide cancer treatment decisions, those that are most likely to someday be clinically useful, and associations that are well known but their roles in clinical management are not yet certain. In the future, germline genetic information will likely be available from tumor genetic analyses, creating an efficient opportunity to integrate the two genomes to optimize treatment outcomes for each individual cancer patient.

Metastatic colorectal cancer is a prevalent disease for which novel targeted therapies and biologically based combinations are under development. Cytotoxic chemotherapy doublets (FOLFOX, FOLFIRI) and triplets (FOLFOXIRI) in combination with biologics are standard regimens, and efforts are ongoing to delineate the optimal sequence for each patient based on unique underlying tumor biology. Molecular profiling of metastatic colorectal cancer (including mutational analysis for KRAS, NRAS, BRAF, PIK3CA, and others) has become increasingly important for identification of prognostic and predictive biomarkers, as well as for insights into the biology that drives the tumor. Large comprehensive analyses such as that of The Cancer Genome Atlas have provided important clues into carcinogenesis and discerned potentially druggable targets for metastatic colorectal cancer. Novel therapeutic agents currently under investigation for subtypes of this disease include immunotherapies such as anti–programmed cell death receptor antibody, cancer stem cell inhibitors, targeted combinations such as BRAF and PI3K inhibitors, and the anti-RAS reovirus Reolysin®.

Accumulation of pathologically activated immature myeloid cells with potent immune-suppressive activity is one of the major immunological hallmarks of cancer. In recent years, it became clear that in addition to their immune-suppressive activity, myeloid-derived suppressor cells (MDSCs) influence tumor progression in a variety of ways. They are directly implicated in the promotion of tumor metastases by participating in the formation of premetastatic niches, promoting angiogenesis and tumor cell invasion. In this review, we discuss recent data describing various roles of MDSCs in the formation of tumor metastases.

HER2 (ErbB2), a member of the HER family of tyrosine kinase receptors (HER1–4), is a major driver of tumor growth in 20% of breast cancers. Treatment with the anti-HER2 monoclonal antibody trastuzumab has revolutionized the outcome of patients with this aggressive breast cancer subtype, but intrinsic and acquired resistance is common. Growing understanding of the biology and complexity of the HER2 signaling network and of potential resistance mechanisms has guided the development of new HER2-targeted agents. Combinations of these drugs to more completely inhibit the HER receptor layer, or combining HER2-targeted agents with agents that target downstream signaling, alternative pathways, or components of the host immune system, are being vigorously investigated in the preclinical and clinical settings. As a result, the list of more effective and well tolerated FDA-approved new regimens for patients with HER2+ tumors is constantly growing.

Cellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of molecular pathways governing DNA damage signaling and DNA repair in response to different types of DNA lesions allows for a better understanding of the effects of radiation and chemotherapy on normal and tumor cells. Although dysregulation of the DNA damage response (DDR) is associated with predisposition to cancer development, it can also result in hypersensitivity or resistance of tumors to therapy and can be exploited for improvement of cancer treatment. We highlight the DDR pathways that are activated after treatment with radiation and different classes of chemotherapeutic drugs and describe mechanisms determining tumor sensitivity and resistance to these agents. Further, we discuss approaches to enhance tumor sensitivity to radiation and chemotherapy by modulating the DDR with a goal of enhancing the effectiveness of cancer therapies.

Macrophage activation syndrome (MAS) is an acute episode of overwhelming inflammation characterized by activation and expansion of T lymphocytes and hemophagocytic macrophages. In rheumatology, it occurs most frequently in patients with systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus. The main clinical manifestations include cytopenias, liver dysfunction, coagulopathy resembling disseminated intravascular coagulation, and extreme hyperferritinemia. Clinically and pathologically, MAS bears strong similarity to hemophagocytic lymphohistiocytosis (HLH), and some authors prefer the term secondary HLH to describe it. Central to its pathogenesis is a cytokine storm, with markedly increased levels of numerous proinflammatory cytokines including IL-1, IL-6, IL-18, TNFα, and IFNγ. Although there is evidence that IFNγ may play a central role in the pathogenesis of MAS, the role of other cytokines is still not clear. There are several reports of SJIA-associated MAS dramatically benefiting from anakinra, a recombinant IL-1 receptor antagonist, but the utility of other biologics in MAS is not clear. The mainstay of treatment remains corticosteroids; other medications, including cyclosporine, are used in patients who fail to respond.

Treatment advances have increased survival in children with cancer, but subclinical, progressive, irreversible, and sometimes fatal treatment-related cardiovascular effects may appear years later. Cardio-oncologists have identified promising preventive and treatment strategies. Dexrazoxane provides long-term cardioprotection from doxorubicin-associated cardiotoxicity without compromising the efficacy of anticancer treatment. Continuous infusion of doxorubicin is as effective as bolus administration in leukemia treatment, but no evidence has indicated that it provides long-term cardioprotection; continuous infusions should be eliminated from pediatric cancer treatment. Angiotensin-converting enzyme inhibitors can delay the progression of subclinical and clinical cardiotoxicity. All survivors, regardless of whether they were treated with anthracyclines or radiation, should be monitored for systemic inflammation and the risk of premature cardiovascular disease. Echocardiographic screening must be supplemented with screening for biomarkers of cardiotoxicity and perhaps by identification of genetic susceptibilities to cardiovascular diseases; optimal strategies need to be identified. The health burden related to cancer treatment will increase as this population expands and ages.

Nanoparticle imaging agents for vascular pathologies are in development, and some agents are already in clinical trials. Untargeted agents, with long circulation, are excellent blood-pool agents, but molecularly targeted agents have significant advantages due to the signal enhancement possible with nanoparticle presentation of the contrast agent molecules. Molecular targets that are accessible directly from the vasculature are optimal for such agents. Targets that are removed from the vasculature, such as those on tumor cell surfaces, have limited accessibility owing to the enhanced permeation and retention effect. Yet, efforts at molecular targeting have tested small molecules, peptides, antibodies, and most recently aptamers as possible targeting ligands. The future is bright for nanoparticle-based imaging of vascular pathologies.

The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization.

Pathogenesis of thrombotic thrombocytopenic purpura (TTP) was a mystery for over half a century until the discovery of ADAMTS13. ADAMTS13 is primarily synthesized in the liver, and its main function is to cleave von Willebrand factor (VWF) anchored on the endothelial surface, in circulation, and at the sites of vascular injury. Deficiency of plasma ADAMTS13 activity (<10%) resulting from mutations of the ADAMTS13 gene or autoantibodies against ADAMTS13 causes hereditary or acquired (idiopathic) TTP. ADAMTS13 activity is usually normal or modestly reduced (>20%) in other forms of thrombotic microangiopathy secondary to hematopoietic progenitor cell transplantation, infection, and disseminated malignancy or in hemolytic uremic syndrome. Plasma infusion or exchange remains the initial treatment of choice to date, but novel therapeutics such as recombinant ADAMTS13 and gene therapy are under development. Moreover, ADAMTS13 deficiency has been shown to be a risk factor for the development of myocardial infarction, stroke, cerebral malaria, and preeclampsia.

The ANCA-associated vasculitides, granulomatosis with polyangiitis (GPA, formerly Wegener's), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss), are a group of multisystem autoimmune diseases characterized by necrotizing small- to medium-vessel vasculitis and the presence of anti-neutrophil cytoplasmic antibodies. Current therapeutic strategies consist of glucocorticoids in conjunction with either conventional or biologic agents for both induction of remission and remission maintenance. Treatment goals include reducing toxicity of induction therapy, preventing disease relapse, and limiting overall accrual of both disease-related damage and treatment-related morbidity. Future research directions include investigation of the optimal duration and frequency of maintenance therapy as well as development of targeted therapeutic agents, which is enhanced by emerging insights into disease pathogenesis.

The target-specific oral anticoagulants are a class of agents that inhibit factor Xa or thrombin. They are effective and safe compared to warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation and for the treatment of venous thromboembolism, and they are comparable to low-molecular-weight heparin for thromboprophylaxis after hip or knee arthroplasty. For other indications, however, such as the prevention of stroke in patients with mechanical heart valves, initial studies have been unfavorable for the newer agents, leaving warfarin the anticoagulant of choice. Further studies are needed before the target-specific anticoagulants can be recommended for patients with cancer-associated thrombosis or heparin-induced thrombocytopenia. Concerns also persist about difficulties with the laboratory assessment of anticoagulant effect and the lack of a specific reversal agent. For these reasons, we anticipate that the vitamin K antagonists will continue to be important anticoagulants for years to come.

The kidneys in normoglycemic humans filter 160–180 g of glucose per day (∼30% of daily calorie intake), which is reabsorbed and returned to the systemic circulation by the proximal tubule. Hyperglycemia increases the filtered and reabsorbed glucose up to two- to three-fold. The sodium glucose cotransporter SGLT2 in the early proximal tubule is the major pathway for renal glucose reabsorption. Inhibition of SGLT2 increases urinary glucose and calorie excretion, thereby reducing plasma glucose levels and body weight. The first SGLT2 inhibitors have been approved as a new class of antidiabetic drugs in type 2 diabetes mellitus, and studies are under way to investigate their use in type 1 diabetes mellitus. These compounds work independent of insulin, improve glycemic control in all stages of diabetes mellitus in the absence of clinically relevant hypoglycemia, and can be combined with other antidiabetic agents. By lowering blood pressure and diabetic glomerular hyperfiltration, SGLT2 inhibitors may induce protective effects on the kidney and cardiovascular system beyond blood glucose control.

Steroid hormones are produced throughout the phylogenetic tree, from plants to mammals. In the past 40 years, steroid receptors localized to the nucleus have been recognized as being important to mediating steroid action in many organs. This action mainly arises from the regulation of key genes that are important for organ development and function. These include but are not limited to genes influencing the reproductive tract, mammary glands, bone, brain, fat differentiation, pituitary hormone regulation, and metabolic effects in many organs. Unfortunately, steroids also promote the development of hormone-responsive cancers, including breast, uterus, and prostate cancer. It has also been shown that steroid receptors exist outside the nucleus in many organs and cells, with unclear impact for normal development, health, and disease. This review describes the evidence from many laboratories that these receptors exist and function with nuclear receptors to provide the full impact of all steroid hormones.

There is growing appreciation that the current obesity epidemic is associated with increases in cancer incidence at a population level and may lead to poor cancer outcomes; concurrent decreases in cancer mortality at a population level may represent a paradox, i.e., they may also reflect improvements in the diagnosis and treatment of cancer that mask obesity effects. An association of obesity with cancer is biologically plausible because adipose tissue is biologically active, secreting estrogens, adipokines, and cytokines. In obesity, adipose tissue reprogramming may lead to insulin resistance, with or without diabetes, and it may contribute to cancer growth and progression locally or through systemic effects. Obesity-associated changes impact cancer in a complex fashion, potentially acting directly on cells through pathways, such as the phosphoinositide 3-kinase (PI3K) and Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathways, or indirectly via changes in the tumor microenvironment. Approaches to obesity management are discussed, and the potential for pharmacologic interventions that target the obesity–cancer link is addressed.

Obesity is a leading modifiable risk factor for the development of several epithelial malignancies. In addition to increasing risk, obesity also confers worse prognosis for many cancers. Obesity represents an overall state of energy imbalance frequently associated with systemic effects including insulin resistance, altered hormone signaling, and high circulating levels of proinflammatory mediators. In addition to its systemic effects, obesity causes subclinical white adipose inflammation including increased tissue levels of proinflammatory mediators. Both local and systemic effects are likely to contribute to the development and progression of cancer. An understanding of the interplay between local and systemic alterations involved in the obesity–cancer link provides the basis for developing interventions aimed at mitigating the protumorigenic effects.