New Therapies

Altered cell metabolism has long been recognized as a distinctive feature of malignant cells but, until recently, research efforts had focused on a single aspect. It has become increasingly evident that many metabolic pathways are altered in cancer cells. Improved understanding has yielded the first regulatory approval in this new class of drugs. Here, we discuss the latest developments in the therapeutic targeting of the cancer metabolism hallmark.

A cancer cell’s sweet tooth

The metabolism of cancer cells differs from that of normal cells, an observation that has spawned a dedicated field of research and new targeted drug development. The German physiologist Otto Warburg is credited as the father of the field with his observations about the way in which cancer cells derive energy from glucose.¹

In normal cells, glucose is converted into pyruvate in the cytoplasm, which is then, most often, fed to the mitochondria that use oxidative phosphorylation to produce energy in the form of adenosine triphosphate (ATP). Cancer cells seem instead to favor using the pyruvate to produce lactate through glycolysis (Figure 1).

Targeting glycolysis and glucose uptake

According to one study, glucose transporters and glycolytic enzymes are overexpressed in 24 different types of cancer, representing more than 70% of all cancer cases.⁷ This enables cancer cells to respond metabolically as though they are experiencing hypoxia, even when oxygen is plentiful and, indeed, when hypoxia is a concern, to mount a faster response. It also provides a tempting avenue for anticancer drug design by exploiting the dependency of cancer cells on glycolysis to survive and thrive.

Inhibitors of HKII, LDH, PFK, PDK, and GLUT-1 have been and continue to be developed. For example, 2-deoxy-D-glucose is a glucose molecule in which the 2-hydroxyl group has been replaced by hydrogen, preventing further glycolysis; it acts as a competitive inhibitor of HKII. Dichloroacetate (DCA) activates the pyruvate dehydrogenase complex and inhibits the actions of the PDKs. Although development of DCA itself was unsuccessful, DCA derivatives continue to be pursued. WZB117 and STF-31 are novel small-molecule inhibitors of GLUT-1-mediated glucose transport. To date, where inhibitors of glycolysis have progressed into clinical trials, they have not proved successful, often limited by off-target effects and low potency.^8-11

A variety of cell signaling pathways are implicated in metabolism by tightly regulating the ability of cells to gain access to and use nutrients. Through aberrations in these pathways, cancer cells can essentially go rogue, ignoring regulatory signals and taking up nutrients in an autonomous manner. One of the most frequently altered signaling pathways in human cancer, the PI3K-Akt-mTOR pathway, is also an important regulator of metabolism, coordinating the uptake of multiple nutrients, including glucose.

Akt in particular is thought to have a critical role in glucose metabolism and increased Akt pathway signaling has been shown to correlate with increased rates of glycolysis in cancer cells. Thus, Akt inhibitors could double as glycolytic or glucose transport inhibitors.^12,13

A number of Akt inhibitors are being evaluated in clinical trials (Table) and results from the phase 2 LOTUS trial of ipatasertib (GDC-0068) were recently published.

The Warburg paradox

Although the molecular mechanisms underlying the Warburg effect have been revealed to some extent, why cancer cells would choose to use such an energy-inefficient process when they have such high energy demands, remains something of a paradox. It’s still not entirely clear, but several explanations that are not necessarily mutually exclusive have been proposed and relate to the inherent benefits of glycolysis and might explain why cancer cells favor this pathway despite its poor energy yield. First, ATP is produced much more rapidly through glycolysis than oxidative phosphorylation, up to 100 times faster. Thus, using glycolysis is a trade-off, between making less energy and making it more quickly.

Second, cancer cells require more than just ATP to meet their metabolic demands. They need amino acids for protein synthesis; nucleotides for DNA replication; lipids for cell membrane synthesis; nicotinamide adenine dinucleotide phosphate (NADPH), which helps the cancer cell deal with oxidative stress; and various other metabolites. Glycolysis branches off into other metabolic pathways that generate many of these metabolites. Among these branched pathways is the pentose phosphate pathway (PPP), which is required for the generation of ribonucleotides and is a major source for NADPH. Cancer cells have been shown to upregulate the flux of glucose into the PPP to meet their anabolic demands and counter oxidative stress.

Third, the lactic acid produced through glycolysis is actively exported from tumor cells by monocarboxylate transporters (MCTs). This creates a highly acidic tumor microenvironment, which can promote several cancer-related processes and also plays a role in tumor-induced immunosuppression, by inhibiting the activity of tumor-infiltrating T cells, reducing dendritic cell maturation, and promoting the transformation of macrophages to a protumorigenic form.^2,4,6
 

Beyond the Warburg effect

Although the focus has been on glucose metabolism and glycolysis, it has been increasingly recognized that many different metabolic pathways are altered. Fundamental changes to the metabolism of all 4 major classes of macromolecules – carbohydrates, lipids, proteins, and nucleic acids – have been observed, encompassing all aspects of cellular metabolism and enabling cancer cells to meet their complete metabolic requirements. There is also evidence that cancer cells are able to switch between different metabolic pathways depending on the availability of oxygen, their energetic needs, environmental stresses, and many other factors. Certainly, there is significant heterogeneity in the metabolic changes that occur in tumors, which vary from tumor to tumor and even within the same tumor and across the lifespan of a tumor as it progresses from an early stage to more advanced or metastatic disease.

The notion of the Warburg effect as a universal phenomenon in cancer cells is now being widely disregarded. Many tumors continue to use oxidative phosphorylation, particularly slower growing tumors, to meet their energy needs. More recently a “reverse” Warburg effect was described, whereby cancer cells are thought to influence the metabolism of the surrounding stromal fibroblasts and essentially outsource aerobic glycolysis to these cells, while performing energy-efficient oxidative phosphorylation themselves (Figure 2).^5,15,16

IDH inhibitors first to market

A number of new metabolically-targeted treatment strategies are being developed. Most promising are small molecule inhibitors of the isocitrate dehydrogenase (IDH) enzymes. These enzymes play an essential role in the TCA cycle, catalyzing the conversion of isocitrate to alpha-ketoglutarate, generating carbon dioxide and NADPH. Recurrent mutations in the IDH1 and IDH2 genes have been observed in several different types of cancer, including glioma, acute myeloid leukemia (AML), and cholangiocarcinoma.

IDH mutations are known as neomorphic mutations because they confer a new function on the altered gene product. In this case, the mutant IDH enzyme converts alpha-ketoglutarate further into D-2-hydroxyglutarate (D-2HG). This molecule has a number of different effects that promote tumorigenesis, including fostering defective DNA repair (Figure 3).^20,21

Pursuing alternative targets and repurposing drugs

Other metabolic targets that are being pursued include glutaminase, given the observation of significantly enhanced glutamine uptake in cancer cells. CB-839 is a glutaminase inhibitor that is currently being evaluated in phase 1 and 2 clinical trials. Updated clinical trial data from a phase 1 trial of CB-839 in combination with paclitaxel in patients with advanced/metastatic TNBC were presented at the San Antonio Breast Cancer Symposium last year.²⁶

As of October 2017, 49 patients had been treated with 400 mg, 600 mg, or 800 mg CB-839 twice daily in combination with 80 mg/m² intravenous paclitaxel weekly. Among the 44 patients evaluable for response, the rate of PR was 22% and of disease control, 59%. The one DLT was grade 3 neutropenia at the 400 mg dose. Overall AEs were mostly low grade and reversible.

In recent years, lactate has emerged as more than just a by-product of altered cancer cell metabolism. It is responsible, at least in part, for the highly acidic tumor microenvironment that fosters many of the other hallmarks of cancer. In addition, lactate promotes angiogenesis by upregulating HIF-1α in endothelial cells. Depriving tumor cells of the ability to export lactate is a potentially promising therapeutic strategy. An MCT-1 inhibitor, AZD3965, is being evaluated in early stage clinical trials.

Finally, several drugs that are renowned for their use in other disease settings are being repurposed for cancer therapy because of their potential effects on cancer cell metabolism. Ritonavir, an antiretroviral drug used in the treatment of HIV, is an inhibitor of GLUT-1 and is being evaluated in phase 1 and 2 clinical trials. Meanwhile, long-term studies of metformin, a drug that has revolutionized the treatment of diabetes, have revealed a reduction in the emergence of new cancers in diabetic patients treated who are treated with it, and the drug has been shown to improve breast cancer survival rates. Its precise anticancer effects are somewhat unclear, but it is thought to act in part by inhibiting oxidative phosphorylation. Numerous clinical trials of metformin in different types of cancer are ongoing.^27,2

Altered cell metabolism has long been recognized as a distinctive feature of malignant cells but, until recently, research efforts had focused on a single aspect. It has become increasingly evident that many metabolic pathways are altered in cancer cells. Improved understanding has yielded the first regulatory approval in this new class of drugs. Here, we discuss the latest developments in the therapeutic targeting of the cancer metabolism hallmark.

A cancer cell’s sweet tooth

The metabolism of cancer cells differs from that of normal cells, an observation that has spawned a dedicated field of research and new targeted drug development. The German physiologist Otto Warburg is credited as the father of the field with his observations about the way in which cancer cells derive energy from glucose.¹

In normal cells, glucose is converted into pyruvate in the cytoplasm, which is then, most often, fed to the mitochondria that use oxidative phosphorylation to produce energy in the form of adenosine triphosphate (ATP). Cancer cells seem instead to favor using the pyruvate to produce lactate through glycolysis (Figure 1).

Targeting glycolysis and glucose uptake

According to one study, glucose transporters and glycolytic enzymes are overexpressed in 24 different types of cancer, representing more than 70% of all cancer cases.⁷ This enables cancer cells to respond metabolically as though they are experiencing hypoxia, even when oxygen is plentiful and, indeed, when hypoxia is a concern, to mount a faster response. It also provides a tempting avenue for anticancer drug design by exploiting the dependency of cancer cells on glycolysis to survive and thrive.

Inhibitors of HKII, LDH, PFK, PDK, and GLUT-1 have been and continue to be developed. For example, 2-deoxy-D-glucose is a glucose molecule in which the 2-hydroxyl group has been replaced by hydrogen, preventing further glycolysis; it acts as a competitive inhibitor of HKII. Dichloroacetate (DCA) activates the pyruvate dehydrogenase complex and inhibits the actions of the PDKs. Although development of DCA itself was unsuccessful, DCA derivatives continue to be pursued. WZB117 and STF-31 are novel small-molecule inhibitors of GLUT-1-mediated glucose transport. To date, where inhibitors of glycolysis have progressed into clinical trials, they have not proved successful, often limited by off-target effects and low potency.^8-11

A variety of cell signaling pathways are implicated in metabolism by tightly regulating the ability of cells to gain access to and use nutrients. Through aberrations in these pathways, cancer cells can essentially go rogue, ignoring regulatory signals and taking up nutrients in an autonomous manner. One of the most frequently altered signaling pathways in human cancer, the PI3K-Akt-mTOR pathway, is also an important regulator of metabolism, coordinating the uptake of multiple nutrients, including glucose.

Akt in particular is thought to have a critical role in glucose metabolism and increased Akt pathway signaling has been shown to correlate with increased rates of glycolysis in cancer cells. Thus, Akt inhibitors could double as glycolytic or glucose transport inhibitors.^12,13

A number of Akt inhibitors are being evaluated in clinical trials (Table) and results from the phase 2 LOTUS trial of ipatasertib (GDC-0068) were recently published.

The Warburg paradox

Although the molecular mechanisms underlying the Warburg effect have been revealed to some extent, why cancer cells would choose to use such an energy-inefficient process when they have such high energy demands, remains something of a paradox. It’s still not entirely clear, but several explanations that are not necessarily mutually exclusive have been proposed and relate to the inherent benefits of glycolysis and might explain why cancer cells favor this pathway despite its poor energy yield. First, ATP is produced much more rapidly through glycolysis than oxidative phosphorylation, up to 100 times faster. Thus, using glycolysis is a trade-off, between making less energy and making it more quickly.

Second, cancer cells require more than just ATP to meet their metabolic demands. They need amino acids for protein synthesis; nucleotides for DNA replication; lipids for cell membrane synthesis; nicotinamide adenine dinucleotide phosphate (NADPH), which helps the cancer cell deal with oxidative stress; and various other metabolites. Glycolysis branches off into other metabolic pathways that generate many of these metabolites. Among these branched pathways is the pentose phosphate pathway (PPP), which is required for the generation of ribonucleotides and is a major source for NADPH. Cancer cells have been shown to upregulate the flux of glucose into the PPP to meet their anabolic demands and counter oxidative stress.

Third, the lactic acid produced through glycolysis is actively exported from tumor cells by monocarboxylate transporters (MCTs). This creates a highly acidic tumor microenvironment, which can promote several cancer-related processes and also plays a role in tumor-induced immunosuppression, by inhibiting the activity of tumor-infiltrating T cells, reducing dendritic cell maturation, and promoting the transformation of macrophages to a protumorigenic form.^2,4,6
 

Beyond the Warburg effect

Although the focus has been on glucose metabolism and glycolysis, it has been increasingly recognized that many different metabolic pathways are altered. Fundamental changes to the metabolism of all 4 major classes of macromolecules – carbohydrates, lipids, proteins, and nucleic acids – have been observed, encompassing all aspects of cellular metabolism and enabling cancer cells to meet their complete metabolic requirements. There is also evidence that cancer cells are able to switch between different metabolic pathways depending on the availability of oxygen, their energetic needs, environmental stresses, and many other factors. Certainly, there is significant heterogeneity in the metabolic changes that occur in tumors, which vary from tumor to tumor and even within the same tumor and across the lifespan of a tumor as it progresses from an early stage to more advanced or metastatic disease.

The notion of the Warburg effect as a universal phenomenon in cancer cells is now being widely disregarded. Many tumors continue to use oxidative phosphorylation, particularly slower growing tumors, to meet their energy needs. More recently a “reverse” Warburg effect was described, whereby cancer cells are thought to influence the metabolism of the surrounding stromal fibroblasts and essentially outsource aerobic glycolysis to these cells, while performing energy-efficient oxidative phosphorylation themselves (Figure 2).^5,15,16

IDH inhibitors first to market

A number of new metabolically-targeted treatment strategies are being developed. Most promising are small molecule inhibitors of the isocitrate dehydrogenase (IDH) enzymes. These enzymes play an essential role in the TCA cycle, catalyzing the conversion of isocitrate to alpha-ketoglutarate, generating carbon dioxide and NADPH. Recurrent mutations in the IDH1 and IDH2 genes have been observed in several different types of cancer, including glioma, acute myeloid leukemia (AML), and cholangiocarcinoma.

IDH mutations are known as neomorphic mutations because they confer a new function on the altered gene product. In this case, the mutant IDH enzyme converts alpha-ketoglutarate further into D-2-hydroxyglutarate (D-2HG). This molecule has a number of different effects that promote tumorigenesis, including fostering defective DNA repair (Figure 3).^20,21

Pursuing alternative targets and repurposing drugs

Other metabolic targets that are being pursued include glutaminase, given the observation of significantly enhanced glutamine uptake in cancer cells. CB-839 is a glutaminase inhibitor that is currently being evaluated in phase 1 and 2 clinical trials. Updated clinical trial data from a phase 1 trial of CB-839 in combination with paclitaxel in patients with advanced/metastatic TNBC were presented at the San Antonio Breast Cancer Symposium last year.²⁶

As of October 2017, 49 patients had been treated with 400 mg, 600 mg, or 800 mg CB-839 twice daily in combination with 80 mg/m² intravenous paclitaxel weekly. Among the 44 patients evaluable for response, the rate of PR was 22% and of disease control, 59%. The one DLT was grade 3 neutropenia at the 400 mg dose. Overall AEs were mostly low grade and reversible.

In recent years, lactate has emerged as more than just a by-product of altered cancer cell metabolism. It is responsible, at least in part, for the highly acidic tumor microenvironment that fosters many of the other hallmarks of cancer. In addition, lactate promotes angiogenesis by upregulating HIF-1α in endothelial cells. Depriving tumor cells of the ability to export lactate is a potentially promising therapeutic strategy. An MCT-1 inhibitor, AZD3965, is being evaluated in early stage clinical trials.

Finally, several drugs that are renowned for their use in other disease settings are being repurposed for cancer therapy because of their potential effects on cancer cell metabolism. Ritonavir, an antiretroviral drug used in the treatment of HIV, is an inhibitor of GLUT-1 and is being evaluated in phase 1 and 2 clinical trials. Meanwhile, long-term studies of metformin, a drug that has revolutionized the treatment of diabetes, have revealed a reduction in the emergence of new cancers in diabetic patients treated who are treated with it, and the drug has been shown to improve breast cancer survival rates. Its precise anticancer effects are somewhat unclear, but it is thought to act in part by inhibiting oxidative phosphorylation. Numerous clinical trials of metformin in different types of cancer are ongoing.^27,2

Altered cell metabolism has long been recognized as a distinctive feature of malignant cells but, until recently, research efforts had focused on a single aspect. It has become increasingly evident that many metabolic pathways are altered in cancer cells. Improved understanding has yielded the first regulatory approval in this new class of drugs. Here, we discuss the latest developments in the therapeutic targeting of the cancer metabolism hallmark.

A cancer cell’s sweet tooth

The metabolism of cancer cells differs from that of normal cells, an observation that has spawned a dedicated field of research and new targeted drug development. The German physiologist Otto Warburg is credited as the father of the field with his observations about the way in which cancer cells derive energy from glucose.¹

In normal cells, glucose is converted into pyruvate in the cytoplasm, which is then, most often, fed to the mitochondria that use oxidative phosphorylation to produce energy in the form of adenosine triphosphate (ATP). Cancer cells seem instead to favor using the pyruvate to produce lactate through glycolysis (Figure 1).

Targeting glycolysis and glucose uptake

According to one study, glucose transporters and glycolytic enzymes are overexpressed in 24 different types of cancer, representing more than 70% of all cancer cases.⁷ This enables cancer cells to respond metabolically as though they are experiencing hypoxia, even when oxygen is plentiful and, indeed, when hypoxia is a concern, to mount a faster response. It also provides a tempting avenue for anticancer drug design by exploiting the dependency of cancer cells on glycolysis to survive and thrive.

Inhibitors of HKII, LDH, PFK, PDK, and GLUT-1 have been and continue to be developed. For example, 2-deoxy-D-glucose is a glucose molecule in which the 2-hydroxyl group has been replaced by hydrogen, preventing further glycolysis; it acts as a competitive inhibitor of HKII. Dichloroacetate (DCA) activates the pyruvate dehydrogenase complex and inhibits the actions of the PDKs. Although development of DCA itself was unsuccessful, DCA derivatives continue to be pursued. WZB117 and STF-31 are novel small-molecule inhibitors of GLUT-1-mediated glucose transport. To date, where inhibitors of glycolysis have progressed into clinical trials, they have not proved successful, often limited by off-target effects and low potency.^8-11

A variety of cell signaling pathways are implicated in metabolism by tightly regulating the ability of cells to gain access to and use nutrients. Through aberrations in these pathways, cancer cells can essentially go rogue, ignoring regulatory signals and taking up nutrients in an autonomous manner. One of the most frequently altered signaling pathways in human cancer, the PI3K-Akt-mTOR pathway, is also an important regulator of metabolism, coordinating the uptake of multiple nutrients, including glucose.

Akt in particular is thought to have a critical role in glucose metabolism and increased Akt pathway signaling has been shown to correlate with increased rates of glycolysis in cancer cells. Thus, Akt inhibitors could double as glycolytic or glucose transport inhibitors.^12,13

A number of Akt inhibitors are being evaluated in clinical trials (Table) and results from the phase 2 LOTUS trial of ipatasertib (GDC-0068) were recently published.

The Warburg paradox

Although the molecular mechanisms underlying the Warburg effect have been revealed to some extent, why cancer cells would choose to use such an energy-inefficient process when they have such high energy demands, remains something of a paradox. It’s still not entirely clear, but several explanations that are not necessarily mutually exclusive have been proposed and relate to the inherent benefits of glycolysis and might explain why cancer cells favor this pathway despite its poor energy yield. First, ATP is produced much more rapidly through glycolysis than oxidative phosphorylation, up to 100 times faster. Thus, using glycolysis is a trade-off, between making less energy and making it more quickly.

Second, cancer cells require more than just ATP to meet their metabolic demands. They need amino acids for protein synthesis; nucleotides for DNA replication; lipids for cell membrane synthesis; nicotinamide adenine dinucleotide phosphate (NADPH), which helps the cancer cell deal with oxidative stress; and various other metabolites. Glycolysis branches off into other metabolic pathways that generate many of these metabolites. Among these branched pathways is the pentose phosphate pathway (PPP), which is required for the generation of ribonucleotides and is a major source for NADPH. Cancer cells have been shown to upregulate the flux of glucose into the PPP to meet their anabolic demands and counter oxidative stress.

Third, the lactic acid produced through glycolysis is actively exported from tumor cells by monocarboxylate transporters (MCTs). This creates a highly acidic tumor microenvironment, which can promote several cancer-related processes and also plays a role in tumor-induced immunosuppression, by inhibiting the activity of tumor-infiltrating T cells, reducing dendritic cell maturation, and promoting the transformation of macrophages to a protumorigenic form.^2,4,6
 

Beyond the Warburg effect

Although the focus has been on glucose metabolism and glycolysis, it has been increasingly recognized that many different metabolic pathways are altered. Fundamental changes to the metabolism of all 4 major classes of macromolecules – carbohydrates, lipids, proteins, and nucleic acids – have been observed, encompassing all aspects of cellular metabolism and enabling cancer cells to meet their complete metabolic requirements. There is also evidence that cancer cells are able to switch between different metabolic pathways depending on the availability of oxygen, their energetic needs, environmental stresses, and many other factors. Certainly, there is significant heterogeneity in the metabolic changes that occur in tumors, which vary from tumor to tumor and even within the same tumor and across the lifespan of a tumor as it progresses from an early stage to more advanced or metastatic disease.

The notion of the Warburg effect as a universal phenomenon in cancer cells is now being widely disregarded. Many tumors continue to use oxidative phosphorylation, particularly slower growing tumors, to meet their energy needs. More recently a “reverse” Warburg effect was described, whereby cancer cells are thought to influence the metabolism of the surrounding stromal fibroblasts and essentially outsource aerobic glycolysis to these cells, while performing energy-efficient oxidative phosphorylation themselves (Figure 2).^5,15,16

IDH inhibitors first to market

A number of new metabolically-targeted treatment strategies are being developed. Most promising are small molecule inhibitors of the isocitrate dehydrogenase (IDH) enzymes. These enzymes play an essential role in the TCA cycle, catalyzing the conversion of isocitrate to alpha-ketoglutarate, generating carbon dioxide and NADPH. Recurrent mutations in the IDH1 and IDH2 genes have been observed in several different types of cancer, including glioma, acute myeloid leukemia (AML), and cholangiocarcinoma.

IDH mutations are known as neomorphic mutations because they confer a new function on the altered gene product. In this case, the mutant IDH enzyme converts alpha-ketoglutarate further into D-2-hydroxyglutarate (D-2HG). This molecule has a number of different effects that promote tumorigenesis, including fostering defective DNA repair (Figure 3).^20,21

Pursuing alternative targets and repurposing drugs

Other metabolic targets that are being pursued include glutaminase, given the observation of significantly enhanced glutamine uptake in cancer cells. CB-839 is a glutaminase inhibitor that is currently being evaluated in phase 1 and 2 clinical trials. Updated clinical trial data from a phase 1 trial of CB-839 in combination with paclitaxel in patients with advanced/metastatic TNBC were presented at the San Antonio Breast Cancer Symposium last year.²⁶

As of October 2017, 49 patients had been treated with 400 mg, 600 mg, or 800 mg CB-839 twice daily in combination with 80 mg/m² intravenous paclitaxel weekly. Among the 44 patients evaluable for response, the rate of PR was 22% and of disease control, 59%. The one DLT was grade 3 neutropenia at the 400 mg dose. Overall AEs were mostly low grade and reversible.

In recent years, lactate has emerged as more than just a by-product of altered cancer cell metabolism. It is responsible, at least in part, for the highly acidic tumor microenvironment that fosters many of the other hallmarks of cancer. In addition, lactate promotes angiogenesis by upregulating HIF-1α in endothelial cells. Depriving tumor cells of the ability to export lactate is a potentially promising therapeutic strategy. An MCT-1 inhibitor, AZD3965, is being evaluated in early stage clinical trials.

Finally, several drugs that are renowned for their use in other disease settings are being repurposed for cancer therapy because of their potential effects on cancer cell metabolism. Ritonavir, an antiretroviral drug used in the treatment of HIV, is an inhibitor of GLUT-1 and is being evaluated in phase 1 and 2 clinical trials. Meanwhile, long-term studies of metformin, a drug that has revolutionized the treatment of diabetes, have revealed a reduction in the emergence of new cancers in diabetic patients treated who are treated with it, and the drug has been shown to improve breast cancer survival rates. Its precise anticancer effects are somewhat unclear, but it is thought to act in part by inhibiting oxidative phosphorylation. Numerous clinical trials of metformin in different types of cancer are ongoing.^27,2

As our understanding of the biology of breast cancer has improved, treatment has become increasingly personalized. Targeted therapies continue to significantly improve patient outcomes in multiple subtypes, with several recent drug approvals. Here, we discuss some of these latest developments.

A disease of many faces

Clinically speaking, breast cancers can be divided into at least 5 subtypes on the basis of the genes they express (Figure 1). The luminal subtypes make up the largest proportion and are characterized by the expression of hormone receptor (HR) genes. Luminal A tumors are negative for human epidermal growth factor receptor 2 (HER2; HER2-negative), whereas luminal B tumors often co-express the HER2 genes.¹

The remainder of HER2-positive patients fall into the HER2-enriched category, in which HER2 expression is the defining characteristic. Basal-like tumors, meanwhile, represent the most heterogeneous subtype, overlapping to a large extent with tumors dubbed “triple-negative” because of their lack of either HER2 or ESR1 and PGR gene expression. The fifth subtype is known as normal breast-like and remains poorly characterized.

In recent years, there have been significant advancements in the genomic characterization of breast cancer that have begun to provide a more comprehensive understanding of the driver molecular mechanisms, which has helped to explain some of the limitations of current targeted approaches and to reveal new possible treatments, with a shift toward increasingly personalized strategies.²
 

HER2: what’s neu?

An estimated 18%-20% of breast tumors are HER2 positive, displaying amplification of the HER2/neu gene or overexpression of its protein product.³ Historically, HER2 positivity correlated with a highly aggressive and metastatic form of disease, conferring poor prognosis.^4,5 The HER2-targeted monoclonal antibody (mAb), trastuzumab serves as a prime example of the power of personalized medicine. Evidence suggests that trastuzumab has altered the natural history of HER2-positive breast cancer, such that trastuzumab-treated patients with HER2-positive breast cancer now have a better prognosis than do patients with HER2-negative disease.^6,7

Several additional HER2-targeted drugs have joined trastuzumab on the market, including other mAbs, small molecule tyrosine kinase inhibitors (TKIs), and an antibody–drug conjugate that combines the specificity of a mAb with the anti-tumor potency of a cytotoxic drug. These drugs have further improved patient outcomes in both early and advanced disease settings (Table 1).

Tucatinib (ONT-380) has shown significant promise in this respect. In a phase 1 trial, ONT-380 had significant efficacy in patients with and without central nervous system metastases; the overall response rate (ORR) in the CNS was 36%. ONT-380 is also notable for its specificity for HER2, without significant inhibition of HER1 and EGFR, which could translate into a better toxicity profile.¹²
 

Doubling down on resistant tumors

Since the success of HER2-targeted therapy is limited by the development of resistance, there has been significant interest in assessing the potential of dual HER2 blockade, exploiting the unique mechanisms of action of different drugs in combination therapy, and ensuring more complete inhibition of the HER2 pathway. Although numerous different combinations have been tested, a double antibody combination has proved most effective.

In fact, dual HER2 targeting with trastuzumab and pertuzumab in combination with chemotherapy has replaced a trastuzumab-chemotherapy regimen as the new standard of care in the metastatic setting. A 6-month improvement in progression-free survival (PFS) sealed FDA approval for the combination and in a recently published final analysis of the trial overall survival (OS) was also improved to a level unprecedented in the first-line setting.^13,14The double antibody combination has also been successful in the neoadjuvant setting. Approval followed the results of the phase 2 NeoSphere trial, in which the combination was associated with a significant improvement in pathologic complete response (pCR) rate, a measure that acts as a surrogate for improved survival in the neoadjuvant setting. In a 5-year analysis of the NeoSphere trial, improved pCR did indeed translate into improved PFS and DFS.^15,16

The results of the phase 3 APHINITY trial evaluating this combination in the adjuvant setting have been hotly anticipated. In a presentation at the 2017 American Society of Clinical Oncology (ASCO) meeting in June, the study authors reported that in 4,085 patients with operable HER2-positive disease, it significantly reduced the risk of disease recurrence or death compared with trastuzumab and chemotherapy alone.¹⁷

There is an ongoing effort to determine if it is possible to de-escalate treatment by removing the chemotherapy component. At least in the neoadjuvant setting, pCR rates in the chemotherapy-free arms of several studies suggest that a proportion of patients might benefit from this strategy^15,18,19 and the challenge now is to identify them. To that end, the phase 2 PAMELA trial identified the HER2-enriched subtype as a strong predictor of response to neoadjuvant dual blockade (lapatinib and trastuzumab) without chemotherapy. The pCR rate was 40.6% for the combination in patients with the HER2-enriched subtype of breast cancer and only 10% in patients with non–HER2-enriched tumors.²⁰

Targeting resistance to endocrine therapy

Another coup for personalized medicine in breast cancer is the treatment of hormone receptor–positive cases with endocrine therapy, which has become the cornerstone of treatment in the metastatic and adjuvant settings. Those drugs are designed to block the growth-stimulating effects of the estrogen and progesterone hormones on tumor cells. They include the selective estrogen receptor (ER) modulator tamoxifen, aromatase inhibitors (AIs) such as letrozole, anastrozole, and exemestane, which work by blocking the activity of the aromatase enzyme that converts androgens into estrogens, and the selective estrogen-receptor down-regulator fulvestrant.

As with HER2-targeted therapy, patients treated with endocrine therapy often develop resistance. Activation of alternate signaling cascades, such as the P13K–Akt–mTOR (phosphatidylinositol-3-kinase–Akt–mammalian target of rapamycin) pathway, or downstream targets of ER signaling, including the cyclin-dependent kinases, CDK4 and CDK6, have emerged as important mechanisms of resistance.^21,22

Drugs directed against these secondary targets, aimed to enhance the efficacy of endocrine therapies, have shown significant promise (Table 2). The mTOR inhibitor everolimus received FDA approval in 2012 in combination with exemestane for the treatment of advanced HR-positive, HER2-negative breast cancer.²³ More recently, everolimus has also proven effective in combination with either fulvestrant or letrozole, according to the phase 2 PrECOG 0102 and BOLERO-4 studies, both doubling PFS compared with endocrine therapy alone.^24,25

Teasing out ‘HER2-positive’ subtypes

Until recently, “HER2-positive” and “HR-positive” tumors have been treated as separate subtypes, despite the fact that about half of HER2-positive tumors fall into the luminal A subtype and are also HR-positive. Patients were typically treated with HER2-targeted therapy regardless of their endocrine status because of the aggressive nature of HER2-positive disease.

Increasingly, researchers are reconsidering this view, especially as several studies have shown differential response rates to HER2-targeted therapy in HR-positive compared with HR-negative patients and accumulating evidence suggests that there is significant crosstalk between the HER2 and HR pathways, which may be responsible for the development of resistance with both treatment paradigms.

Findings from several studies have shown a benefit to combining HER2-targeted and hormonal therapies in patients with luminal (HR-positive), HER2-positive disease. In the metastatic setting, the results of the phase 2 PERTAIN study, presented at the 2017 ASCO annual meeting suggest that dual HER2 blockade could prove even more effective. The addition of pertuzumab to a combination of trastuzumab and an AI improved PFS by more than 3 months (median PFS, 19.89 vs 15.8 months; HR, 0.65; P = .007).³³

The clinical application of these combinations may be limited by the additional cost – several studies have suggested that they are not cost effective – and toxicity, but have served to drive the development of new clinical trial designs as the importance of considering luminal and nonluminal HER2-positive tumors has become increasingly apparent.
 

PARP inhibitors make a dent in BRCA1/2-mutated cancers

The most renowned breast cancer genes, BRCA1 and BRCA2 are present in about 5%-10% of all breast cancers. They play a central role in the homologous recombination pathway that fixes double-strand breaks in the DNA. Genome sequencing studies have revealed that the presence of the BRCA1/2 genes and other DNA repair defects is highest among patients with the basal-like subtype of breast cancer, in particular those who have triple-negative disease.^34,35

This type of breast cancer has proved stubbornly resistant to efforts to improve patient outcomes with targeted therapies. BRCA1/2 mutations and other DNA repair defects that confer a so-called BRCAness phenotype, render tumor cells dependent on other pathways for DNA repair and there has been considerable interest in therapeutically exploiting this through the development of inhibitors of the poly(ADP-ribose) polymerase (PARP) enzyme, which is involved in the repair of single-strand breaks in the DNA. The double damage to DNA repair mechanisms through PARP inhibition in patients with BRCA1/2-mutant tumors proves overwhelming to cancerous cells.

Despite more than a decade of investigation in breast cancer, PARP inhibitors have yet to yield any FDA-approved treatment options. That may be set to change imminently, following the success of olaparib (Table 3). In the first randomized phase 3 trial of a PARP inhibitor in breast cancer (OlympiAD), olaparib was compared with standard chemotherapy in patients with BRCA1/2-mutated MBC who had received up to 2 previous lines of chemotherapy. Olaparib reduced the risk of disease progression by 42% compared with standard chemotherapy and was well tolerated.³⁶

As our understanding of the biology of breast cancer has improved, treatment has become increasingly personalized. Targeted therapies continue to significantly improve patient outcomes in multiple subtypes, with several recent drug approvals. Here, we discuss some of these latest developments.

A disease of many faces

Clinically speaking, breast cancers can be divided into at least 5 subtypes on the basis of the genes they express (Figure 1). The luminal subtypes make up the largest proportion and are characterized by the expression of hormone receptor (HR) genes. Luminal A tumors are negative for human epidermal growth factor receptor 2 (HER2; HER2-negative), whereas luminal B tumors often co-express the HER2 genes.¹

The remainder of HER2-positive patients fall into the HER2-enriched category, in which HER2 expression is the defining characteristic. Basal-like tumors, meanwhile, represent the most heterogeneous subtype, overlapping to a large extent with tumors dubbed “triple-negative” because of their lack of either HER2 or ESR1 and PGR gene expression. The fifth subtype is known as normal breast-like and remains poorly characterized.

In recent years, there have been significant advancements in the genomic characterization of breast cancer that have begun to provide a more comprehensive understanding of the driver molecular mechanisms, which has helped to explain some of the limitations of current targeted approaches and to reveal new possible treatments, with a shift toward increasingly personalized strategies.²
 

HER2: what’s neu?

An estimated 18%-20% of breast tumors are HER2 positive, displaying amplification of the HER2/neu gene or overexpression of its protein product.³ Historically, HER2 positivity correlated with a highly aggressive and metastatic form of disease, conferring poor prognosis.^4,5 The HER2-targeted monoclonal antibody (mAb), trastuzumab serves as a prime example of the power of personalized medicine. Evidence suggests that trastuzumab has altered the natural history of HER2-positive breast cancer, such that trastuzumab-treated patients with HER2-positive breast cancer now have a better prognosis than do patients with HER2-negative disease.^6,7

Several additional HER2-targeted drugs have joined trastuzumab on the market, including other mAbs, small molecule tyrosine kinase inhibitors (TKIs), and an antibody–drug conjugate that combines the specificity of a mAb with the anti-tumor potency of a cytotoxic drug. These drugs have further improved patient outcomes in both early and advanced disease settings (Table 1).

Tucatinib (ONT-380) has shown significant promise in this respect. In a phase 1 trial, ONT-380 had significant efficacy in patients with and without central nervous system metastases; the overall response rate (ORR) in the CNS was 36%. ONT-380 is also notable for its specificity for HER2, without significant inhibition of HER1 and EGFR, which could translate into a better toxicity profile.¹²
 

Doubling down on resistant tumors

Since the success of HER2-targeted therapy is limited by the development of resistance, there has been significant interest in assessing the potential of dual HER2 blockade, exploiting the unique mechanisms of action of different drugs in combination therapy, and ensuring more complete inhibition of the HER2 pathway. Although numerous different combinations have been tested, a double antibody combination has proved most effective.

In fact, dual HER2 targeting with trastuzumab and pertuzumab in combination with chemotherapy has replaced a trastuzumab-chemotherapy regimen as the new standard of care in the metastatic setting. A 6-month improvement in progression-free survival (PFS) sealed FDA approval for the combination and in a recently published final analysis of the trial overall survival (OS) was also improved to a level unprecedented in the first-line setting.^13,14The double antibody combination has also been successful in the neoadjuvant setting. Approval followed the results of the phase 2 NeoSphere trial, in which the combination was associated with a significant improvement in pathologic complete response (pCR) rate, a measure that acts as a surrogate for improved survival in the neoadjuvant setting. In a 5-year analysis of the NeoSphere trial, improved pCR did indeed translate into improved PFS and DFS.^15,16

The results of the phase 3 APHINITY trial evaluating this combination in the adjuvant setting have been hotly anticipated. In a presentation at the 2017 American Society of Clinical Oncology (ASCO) meeting in June, the study authors reported that in 4,085 patients with operable HER2-positive disease, it significantly reduced the risk of disease recurrence or death compared with trastuzumab and chemotherapy alone.¹⁷

There is an ongoing effort to determine if it is possible to de-escalate treatment by removing the chemotherapy component. At least in the neoadjuvant setting, pCR rates in the chemotherapy-free arms of several studies suggest that a proportion of patients might benefit from this strategy^15,18,19 and the challenge now is to identify them. To that end, the phase 2 PAMELA trial identified the HER2-enriched subtype as a strong predictor of response to neoadjuvant dual blockade (lapatinib and trastuzumab) without chemotherapy. The pCR rate was 40.6% for the combination in patients with the HER2-enriched subtype of breast cancer and only 10% in patients with non–HER2-enriched tumors.²⁰

Targeting resistance to endocrine therapy

Another coup for personalized medicine in breast cancer is the treatment of hormone receptor–positive cases with endocrine therapy, which has become the cornerstone of treatment in the metastatic and adjuvant settings. Those drugs are designed to block the growth-stimulating effects of the estrogen and progesterone hormones on tumor cells. They include the selective estrogen receptor (ER) modulator tamoxifen, aromatase inhibitors (AIs) such as letrozole, anastrozole, and exemestane, which work by blocking the activity of the aromatase enzyme that converts androgens into estrogens, and the selective estrogen-receptor down-regulator fulvestrant.

As with HER2-targeted therapy, patients treated with endocrine therapy often develop resistance. Activation of alternate signaling cascades, such as the P13K–Akt–mTOR (phosphatidylinositol-3-kinase–Akt–mammalian target of rapamycin) pathway, or downstream targets of ER signaling, including the cyclin-dependent kinases, CDK4 and CDK6, have emerged as important mechanisms of resistance.^21,22

Drugs directed against these secondary targets, aimed to enhance the efficacy of endocrine therapies, have shown significant promise (Table 2). The mTOR inhibitor everolimus received FDA approval in 2012 in combination with exemestane for the treatment of advanced HR-positive, HER2-negative breast cancer.²³ More recently, everolimus has also proven effective in combination with either fulvestrant or letrozole, according to the phase 2 PrECOG 0102 and BOLERO-4 studies, both doubling PFS compared with endocrine therapy alone.^24,25

Teasing out ‘HER2-positive’ subtypes

Until recently, “HER2-positive” and “HR-positive” tumors have been treated as separate subtypes, despite the fact that about half of HER2-positive tumors fall into the luminal A subtype and are also HR-positive. Patients were typically treated with HER2-targeted therapy regardless of their endocrine status because of the aggressive nature of HER2-positive disease.

Increasingly, researchers are reconsidering this view, especially as several studies have shown differential response rates to HER2-targeted therapy in HR-positive compared with HR-negative patients and accumulating evidence suggests that there is significant crosstalk between the HER2 and HR pathways, which may be responsible for the development of resistance with both treatment paradigms.

Findings from several studies have shown a benefit to combining HER2-targeted and hormonal therapies in patients with luminal (HR-positive), HER2-positive disease. In the metastatic setting, the results of the phase 2 PERTAIN study, presented at the 2017 ASCO annual meeting suggest that dual HER2 blockade could prove even more effective. The addition of pertuzumab to a combination of trastuzumab and an AI improved PFS by more than 3 months (median PFS, 19.89 vs 15.8 months; HR, 0.65; P = .007).³³

The clinical application of these combinations may be limited by the additional cost – several studies have suggested that they are not cost effective – and toxicity, but have served to drive the development of new clinical trial designs as the importance of considering luminal and nonluminal HER2-positive tumors has become increasingly apparent.
 

PARP inhibitors make a dent in BRCA1/2-mutated cancers

The most renowned breast cancer genes, BRCA1 and BRCA2 are present in about 5%-10% of all breast cancers. They play a central role in the homologous recombination pathway that fixes double-strand breaks in the DNA. Genome sequencing studies have revealed that the presence of the BRCA1/2 genes and other DNA repair defects is highest among patients with the basal-like subtype of breast cancer, in particular those who have triple-negative disease.^34,35

This type of breast cancer has proved stubbornly resistant to efforts to improve patient outcomes with targeted therapies. BRCA1/2 mutations and other DNA repair defects that confer a so-called BRCAness phenotype, render tumor cells dependent on other pathways for DNA repair and there has been considerable interest in therapeutically exploiting this through the development of inhibitors of the poly(ADP-ribose) polymerase (PARP) enzyme, which is involved in the repair of single-strand breaks in the DNA. The double damage to DNA repair mechanisms through PARP inhibition in patients with BRCA1/2-mutant tumors proves overwhelming to cancerous cells.

Despite more than a decade of investigation in breast cancer, PARP inhibitors have yet to yield any FDA-approved treatment options. That may be set to change imminently, following the success of olaparib (Table 3). In the first randomized phase 3 trial of a PARP inhibitor in breast cancer (OlympiAD), olaparib was compared with standard chemotherapy in patients with BRCA1/2-mutated MBC who had received up to 2 previous lines of chemotherapy. Olaparib reduced the risk of disease progression by 42% compared with standard chemotherapy and was well tolerated.³⁶

As our understanding of the biology of breast cancer has improved, treatment has become increasingly personalized. Targeted therapies continue to significantly improve patient outcomes in multiple subtypes, with several recent drug approvals. Here, we discuss some of these latest developments.

A disease of many faces

Clinically speaking, breast cancers can be divided into at least 5 subtypes on the basis of the genes they express (Figure 1). The luminal subtypes make up the largest proportion and are characterized by the expression of hormone receptor (HR) genes. Luminal A tumors are negative for human epidermal growth factor receptor 2 (HER2; HER2-negative), whereas luminal B tumors often co-express the HER2 genes.¹

The remainder of HER2-positive patients fall into the HER2-enriched category, in which HER2 expression is the defining characteristic. Basal-like tumors, meanwhile, represent the most heterogeneous subtype, overlapping to a large extent with tumors dubbed “triple-negative” because of their lack of either HER2 or ESR1 and PGR gene expression. The fifth subtype is known as normal breast-like and remains poorly characterized.

In recent years, there have been significant advancements in the genomic characterization of breast cancer that have begun to provide a more comprehensive understanding of the driver molecular mechanisms, which has helped to explain some of the limitations of current targeted approaches and to reveal new possible treatments, with a shift toward increasingly personalized strategies.²
 

HER2: what’s neu?

An estimated 18%-20% of breast tumors are HER2 positive, displaying amplification of the HER2/neu gene or overexpression of its protein product.³ Historically, HER2 positivity correlated with a highly aggressive and metastatic form of disease, conferring poor prognosis.^4,5 The HER2-targeted monoclonal antibody (mAb), trastuzumab serves as a prime example of the power of personalized medicine. Evidence suggests that trastuzumab has altered the natural history of HER2-positive breast cancer, such that trastuzumab-treated patients with HER2-positive breast cancer now have a better prognosis than do patients with HER2-negative disease.^6,7

Several additional HER2-targeted drugs have joined trastuzumab on the market, including other mAbs, small molecule tyrosine kinase inhibitors (TKIs), and an antibody–drug conjugate that combines the specificity of a mAb with the anti-tumor potency of a cytotoxic drug. These drugs have further improved patient outcomes in both early and advanced disease settings (Table 1).

Tucatinib (ONT-380) has shown significant promise in this respect. In a phase 1 trial, ONT-380 had significant efficacy in patients with and without central nervous system metastases; the overall response rate (ORR) in the CNS was 36%. ONT-380 is also notable for its specificity for HER2, without significant inhibition of HER1 and EGFR, which could translate into a better toxicity profile.¹²
 

Doubling down on resistant tumors

Since the success of HER2-targeted therapy is limited by the development of resistance, there has been significant interest in assessing the potential of dual HER2 blockade, exploiting the unique mechanisms of action of different drugs in combination therapy, and ensuring more complete inhibition of the HER2 pathway. Although numerous different combinations have been tested, a double antibody combination has proved most effective.

In fact, dual HER2 targeting with trastuzumab and pertuzumab in combination with chemotherapy has replaced a trastuzumab-chemotherapy regimen as the new standard of care in the metastatic setting. A 6-month improvement in progression-free survival (PFS) sealed FDA approval for the combination and in a recently published final analysis of the trial overall survival (OS) was also improved to a level unprecedented in the first-line setting.^13,14The double antibody combination has also been successful in the neoadjuvant setting. Approval followed the results of the phase 2 NeoSphere trial, in which the combination was associated with a significant improvement in pathologic complete response (pCR) rate, a measure that acts as a surrogate for improved survival in the neoadjuvant setting. In a 5-year analysis of the NeoSphere trial, improved pCR did indeed translate into improved PFS and DFS.^15,16

The results of the phase 3 APHINITY trial evaluating this combination in the adjuvant setting have been hotly anticipated. In a presentation at the 2017 American Society of Clinical Oncology (ASCO) meeting in June, the study authors reported that in 4,085 patients with operable HER2-positive disease, it significantly reduced the risk of disease recurrence or death compared with trastuzumab and chemotherapy alone.¹⁷

There is an ongoing effort to determine if it is possible to de-escalate treatment by removing the chemotherapy component. At least in the neoadjuvant setting, pCR rates in the chemotherapy-free arms of several studies suggest that a proportion of patients might benefit from this strategy^15,18,19 and the challenge now is to identify them. To that end, the phase 2 PAMELA trial identified the HER2-enriched subtype as a strong predictor of response to neoadjuvant dual blockade (lapatinib and trastuzumab) without chemotherapy. The pCR rate was 40.6% for the combination in patients with the HER2-enriched subtype of breast cancer and only 10% in patients with non–HER2-enriched tumors.²⁰

Targeting resistance to endocrine therapy

Another coup for personalized medicine in breast cancer is the treatment of hormone receptor–positive cases with endocrine therapy, which has become the cornerstone of treatment in the metastatic and adjuvant settings. Those drugs are designed to block the growth-stimulating effects of the estrogen and progesterone hormones on tumor cells. They include the selective estrogen receptor (ER) modulator tamoxifen, aromatase inhibitors (AIs) such as letrozole, anastrozole, and exemestane, which work by blocking the activity of the aromatase enzyme that converts androgens into estrogens, and the selective estrogen-receptor down-regulator fulvestrant.

As with HER2-targeted therapy, patients treated with endocrine therapy often develop resistance. Activation of alternate signaling cascades, such as the P13K–Akt–mTOR (phosphatidylinositol-3-kinase–Akt–mammalian target of rapamycin) pathway, or downstream targets of ER signaling, including the cyclin-dependent kinases, CDK4 and CDK6, have emerged as important mechanisms of resistance.^21,22

Drugs directed against these secondary targets, aimed to enhance the efficacy of endocrine therapies, have shown significant promise (Table 2). The mTOR inhibitor everolimus received FDA approval in 2012 in combination with exemestane for the treatment of advanced HR-positive, HER2-negative breast cancer.²³ More recently, everolimus has also proven effective in combination with either fulvestrant or letrozole, according to the phase 2 PrECOG 0102 and BOLERO-4 studies, both doubling PFS compared with endocrine therapy alone.^24,25

Teasing out ‘HER2-positive’ subtypes

Until recently, “HER2-positive” and “HR-positive” tumors have been treated as separate subtypes, despite the fact that about half of HER2-positive tumors fall into the luminal A subtype and are also HR-positive. Patients were typically treated with HER2-targeted therapy regardless of their endocrine status because of the aggressive nature of HER2-positive disease.

Increasingly, researchers are reconsidering this view, especially as several studies have shown differential response rates to HER2-targeted therapy in HR-positive compared with HR-negative patients and accumulating evidence suggests that there is significant crosstalk between the HER2 and HR pathways, which may be responsible for the development of resistance with both treatment paradigms.

Findings from several studies have shown a benefit to combining HER2-targeted and hormonal therapies in patients with luminal (HR-positive), HER2-positive disease. In the metastatic setting, the results of the phase 2 PERTAIN study, presented at the 2017 ASCO annual meeting suggest that dual HER2 blockade could prove even more effective. The addition of pertuzumab to a combination of trastuzumab and an AI improved PFS by more than 3 months (median PFS, 19.89 vs 15.8 months; HR, 0.65; P = .007).³³

The clinical application of these combinations may be limited by the additional cost – several studies have suggested that they are not cost effective – and toxicity, but have served to drive the development of new clinical trial designs as the importance of considering luminal and nonluminal HER2-positive tumors has become increasingly apparent.
 

PARP inhibitors make a dent in BRCA1/2-mutated cancers

The most renowned breast cancer genes, BRCA1 and BRCA2 are present in about 5%-10% of all breast cancers. They play a central role in the homologous recombination pathway that fixes double-strand breaks in the DNA. Genome sequencing studies have revealed that the presence of the BRCA1/2 genes and other DNA repair defects is highest among patients with the basal-like subtype of breast cancer, in particular those who have triple-negative disease.^34,35

This type of breast cancer has proved stubbornly resistant to efforts to improve patient outcomes with targeted therapies. BRCA1/2 mutations and other DNA repair defects that confer a so-called BRCAness phenotype, render tumor cells dependent on other pathways for DNA repair and there has been considerable interest in therapeutically exploiting this through the development of inhibitors of the poly(ADP-ribose) polymerase (PARP) enzyme, which is involved in the repair of single-strand breaks in the DNA. The double damage to DNA repair mechanisms through PARP inhibition in patients with BRCA1/2-mutant tumors proves overwhelming to cancerous cells.

Despite more than a decade of investigation in breast cancer, PARP inhibitors have yet to yield any FDA-approved treatment options. That may be set to change imminently, following the success of olaparib (Table 3). In the first randomized phase 3 trial of a PARP inhibitor in breast cancer (OlympiAD), olaparib was compared with standard chemotherapy in patients with BRCA1/2-mutated MBC who had received up to 2 previous lines of chemotherapy. Olaparib reduced the risk of disease progression by 42% compared with standard chemotherapy and was well tolerated.³⁶

What’s the right duration of dual antiplatelet therapy (DAPT) for patients who have had drug-eluting stents implanted? According to researchers from Sungkyunkwan University in Seoul, Korea, long-term clinical outcomes are similar whether patients receive therapy for less than or longer than 12 months.

The researchers conducted a retrospective study of 512 patients who had undergone percutaneous coronary intervention (PCI) for coronary chronic total occlusion (CTO) and were event free at 12 months. They separated the patients into 2 groups: 199 received aspirin and clopidogrel for ≤ 12 months, and 313 for > 12 months. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) during follow-up. Median follow-up was 64 months.

Related: Statins for the Physically Fit: Do They Help or Hurt?

No significant differences were seen between the groups in the incidence of MACCE: 21.6% of the patients in the ≤ 12-month group and 17.6% of the patients in the > 12-month group developed MACCE. After propensity matching, moderate or severe bleeding rates were also similar (1.6% in the shorter duration group and 2.2% in the longer duration group).

The researchers note that previously published data showed that longer duration DAPT was not associated with improved clinical outcomes in patients with CTO, although other subsets of complex PCI, such as longer stent length, bifurcation stenting, or multiple stents showed better clinical outcomes. To the best of their knowledge, the researchers add, theirs is the first study to directly compare DAPT durations in patients with CTO-PCI.

Related: A Heart Failure Management Program Using Shared Medical Appointments

Source:
Lee SH, Yang JH, Choi SH, et al. PLoS One. 2017;12(5):e0176737.
doi: 10.1371/journal.pone.0176737.

What’s the right duration of dual antiplatelet therapy (DAPT) for patients who have had drug-eluting stents implanted? According to researchers from Sungkyunkwan University in Seoul, Korea, long-term clinical outcomes are similar whether patients receive therapy for less than or longer than 12 months.

The researchers conducted a retrospective study of 512 patients who had undergone percutaneous coronary intervention (PCI) for coronary chronic total occlusion (CTO) and were event free at 12 months. They separated the patients into 2 groups: 199 received aspirin and clopidogrel for ≤ 12 months, and 313 for > 12 months. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) during follow-up. Median follow-up was 64 months.

Related: Statins for the Physically Fit: Do They Help or Hurt?

No significant differences were seen between the groups in the incidence of MACCE: 21.6% of the patients in the ≤ 12-month group and 17.6% of the patients in the > 12-month group developed MACCE. After propensity matching, moderate or severe bleeding rates were also similar (1.6% in the shorter duration group and 2.2% in the longer duration group).

The researchers note that previously published data showed that longer duration DAPT was not associated with improved clinical outcomes in patients with CTO, although other subsets of complex PCI, such as longer stent length, bifurcation stenting, or multiple stents showed better clinical outcomes. To the best of their knowledge, the researchers add, theirs is the first study to directly compare DAPT durations in patients with CTO-PCI.

Related: A Heart Failure Management Program Using Shared Medical Appointments

Source:
Lee SH, Yang JH, Choi SH, et al. PLoS One. 2017;12(5):e0176737.
doi: 10.1371/journal.pone.0176737.

What’s the right duration of dual antiplatelet therapy (DAPT) for patients who have had drug-eluting stents implanted? According to researchers from Sungkyunkwan University in Seoul, Korea, long-term clinical outcomes are similar whether patients receive therapy for less than or longer than 12 months.

The researchers conducted a retrospective study of 512 patients who had undergone percutaneous coronary intervention (PCI) for coronary chronic total occlusion (CTO) and were event free at 12 months. They separated the patients into 2 groups: 199 received aspirin and clopidogrel for ≤ 12 months, and 313 for > 12 months. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) during follow-up. Median follow-up was 64 months.

Related: Statins for the Physically Fit: Do They Help or Hurt?

No significant differences were seen between the groups in the incidence of MACCE: 21.6% of the patients in the ≤ 12-month group and 17.6% of the patients in the > 12-month group developed MACCE. After propensity matching, moderate or severe bleeding rates were also similar (1.6% in the shorter duration group and 2.2% in the longer duration group).

The researchers note that previously published data showed that longer duration DAPT was not associated with improved clinical outcomes in patients with CTO, although other subsets of complex PCI, such as longer stent length, bifurcation stenting, or multiple stents showed better clinical outcomes. To the best of their knowledge, the researchers add, theirs is the first study to directly compare DAPT durations in patients with CTO-PCI.

Related: A Heart Failure Management Program Using Shared Medical Appointments

Source:
Lee SH, Yang JH, Choi SH, et al. PLoS One. 2017;12(5):e0176737.
doi: 10.1371/journal.pone.0176737.

Arthritis aches and pains are not a normal part of aging. Nonetheless, approximately 54 million American adults who took the CDC’s National Health Survey said their doctor had diagnosed them with arthritis. That’s about 1 in 4 US adults, the majority of whom are of working age.

Related: Taking Steps to Reduce Arthritis Pain

Arthritis can make it hard to lift a cup, let alone a bag of groceries or a heavy briefcase. The percentage of adults with arthritis who have activity limitations grew from 35.9% in 2002 to 42.8% in 2014, a 20% increase independent of the aging of the population.

Research has shown that engaging in physical activity can reduce arthritis symptoms by up to 40%. But one third of adults with arthritis say they don’t engage in physical activity during leisure time. And, while they also can reduce their symptoms by participating in disease management education programs, only 1 in 10 has taken part in such programs.

Related: Lessons Learned From the RACAT Trial: A Comparison of Rheumatoid Arthritis Therapies

“It’s extremely important for primary care providers to encourage their patients with arthritis to be physically active,” says CDC epidemiologist Kamil Barbour, PhD. But Barbour adds that it’s just as important to motivate patients to attend education programs. The CDC says adults with arthritis are significantly more likely to attend an education program when a health care provider has recommended it.

Arthritis aches and pains are not a normal part of aging. Nonetheless, approximately 54 million American adults who took the CDC’s National Health Survey said their doctor had diagnosed them with arthritis. That’s about 1 in 4 US adults, the majority of whom are of working age.

Related: Taking Steps to Reduce Arthritis Pain

Arthritis can make it hard to lift a cup, let alone a bag of groceries or a heavy briefcase. The percentage of adults with arthritis who have activity limitations grew from 35.9% in 2002 to 42.8% in 2014, a 20% increase independent of the aging of the population.

Research has shown that engaging in physical activity can reduce arthritis symptoms by up to 40%. But one third of adults with arthritis say they don’t engage in physical activity during leisure time. And, while they also can reduce their symptoms by participating in disease management education programs, only 1 in 10 has taken part in such programs.

Related: Lessons Learned From the RACAT Trial: A Comparison of Rheumatoid Arthritis Therapies

“It’s extremely important for primary care providers to encourage their patients with arthritis to be physically active,” says CDC epidemiologist Kamil Barbour, PhD. But Barbour adds that it’s just as important to motivate patients to attend education programs. The CDC says adults with arthritis are significantly more likely to attend an education program when a health care provider has recommended it.

Arthritis aches and pains are not a normal part of aging. Nonetheless, approximately 54 million American adults who took the CDC’s National Health Survey said their doctor had diagnosed them with arthritis. That’s about 1 in 4 US adults, the majority of whom are of working age.

Related: Taking Steps to Reduce Arthritis Pain

Arthritis can make it hard to lift a cup, let alone a bag of groceries or a heavy briefcase. The percentage of adults with arthritis who have activity limitations grew from 35.9% in 2002 to 42.8% in 2014, a 20% increase independent of the aging of the population.

Research has shown that engaging in physical activity can reduce arthritis symptoms by up to 40%. But one third of adults with arthritis say they don’t engage in physical activity during leisure time. And, while they also can reduce their symptoms by participating in disease management education programs, only 1 in 10 has taken part in such programs.

Related: Lessons Learned From the RACAT Trial: A Comparison of Rheumatoid Arthritis Therapies

“It’s extremely important for primary care providers to encourage their patients with arthritis to be physically active,” says CDC epidemiologist Kamil Barbour, PhD. But Barbour adds that it’s just as important to motivate patients to attend education programs. The CDC says adults with arthritis are significantly more likely to attend an education program when a health care provider has recommended it.

“Mixed results,” is the current status report on the Testosterone Trials (“T Trials”). In older men with low testosterone, 1 year of testosterone treatment not only improved bone density and corrected anemia, but also increased the volume of coronary artery plaque.

The T Trials were designed to determine whether testosterone treatment could alleviate problems, such as impaired cognition, anemia, cardiovascular disease, diminished sexual function, decreased mobility, and fatigue. The trials were conducted at 12 sites nationwide in 790 men aged ≥ 65 years. Participants were randomly assigned to apply testosterone gel or placebo to the skin daily. Serum testosterone was measured at 1, 2, 3,6, 9, and 12 months. The men were closely monitored for prostate and cardiovascular problems.

Related: Testosterone Replacement Therapy: Playing Catch-up With Patients

After 1 year of testosterone treatment, 54% of men with unexplained anemia and 52% of men with anemia from known causes had clinically significant increases in hemoglobin, compared with 15% and 12% of men in the placebo group. Older men with low testosterone had significantly increased volumetric bone density and estimated bone strength compared with the controls.

However, the testosterone-treated group also had significantly higher levels of coronary artery plaque, although only 170 men had coronary computed tomograph arteriography. The researchers found no significant differences between the 2 groups in cognition in older men with age-associated memory impairment.

Related: Restoring Testosterone Levels May Improve Sexual Function

The results illustrate the need for individualized decisions about testosterone treatment, said Evan Hadley, MD, director of National Institute on Aging’s Division of Geriatrics and Clinical Gerontology. The “diverse outcomes,” he notes, indicate the potential trade-offs between benefits and risks of testosterone treatment in older men. Clarifying the effects of testosterone will take longer, larger scale trials.

“Mixed results,” is the current status report on the Testosterone Trials (“T Trials”). In older men with low testosterone, 1 year of testosterone treatment not only improved bone density and corrected anemia, but also increased the volume of coronary artery plaque.

The T Trials were designed to determine whether testosterone treatment could alleviate problems, such as impaired cognition, anemia, cardiovascular disease, diminished sexual function, decreased mobility, and fatigue. The trials were conducted at 12 sites nationwide in 790 men aged ≥ 65 years. Participants were randomly assigned to apply testosterone gel or placebo to the skin daily. Serum testosterone was measured at 1, 2, 3,6, 9, and 12 months. The men were closely monitored for prostate and cardiovascular problems.

Related: Testosterone Replacement Therapy: Playing Catch-up With Patients

After 1 year of testosterone treatment, 54% of men with unexplained anemia and 52% of men with anemia from known causes had clinically significant increases in hemoglobin, compared with 15% and 12% of men in the placebo group. Older men with low testosterone had significantly increased volumetric bone density and estimated bone strength compared with the controls.

However, the testosterone-treated group also had significantly higher levels of coronary artery plaque, although only 170 men had coronary computed tomograph arteriography. The researchers found no significant differences between the 2 groups in cognition in older men with age-associated memory impairment.

Related: Restoring Testosterone Levels May Improve Sexual Function

The results illustrate the need for individualized decisions about testosterone treatment, said Evan Hadley, MD, director of National Institute on Aging’s Division of Geriatrics and Clinical Gerontology. The “diverse outcomes,” he notes, indicate the potential trade-offs between benefits and risks of testosterone treatment in older men. Clarifying the effects of testosterone will take longer, larger scale trials.

“Mixed results,” is the current status report on the Testosterone Trials (“T Trials”). In older men with low testosterone, 1 year of testosterone treatment not only improved bone density and corrected anemia, but also increased the volume of coronary artery plaque.

The T Trials were designed to determine whether testosterone treatment could alleviate problems, such as impaired cognition, anemia, cardiovascular disease, diminished sexual function, decreased mobility, and fatigue. The trials were conducted at 12 sites nationwide in 790 men aged ≥ 65 years. Participants were randomly assigned to apply testosterone gel or placebo to the skin daily. Serum testosterone was measured at 1, 2, 3,6, 9, and 12 months. The men were closely monitored for prostate and cardiovascular problems.

Related: Testosterone Replacement Therapy: Playing Catch-up With Patients

After 1 year of testosterone treatment, 54% of men with unexplained anemia and 52% of men with anemia from known causes had clinically significant increases in hemoglobin, compared with 15% and 12% of men in the placebo group. Older men with low testosterone had significantly increased volumetric bone density and estimated bone strength compared with the controls.

However, the testosterone-treated group also had significantly higher levels of coronary artery plaque, although only 170 men had coronary computed tomograph arteriography. The researchers found no significant differences between the 2 groups in cognition in older men with age-associated memory impairment.

Related: Restoring Testosterone Levels May Improve Sexual Function

The results illustrate the need for individualized decisions about testosterone treatment, said Evan Hadley, MD, director of National Institute on Aging’s Division of Geriatrics and Clinical Gerontology. The “diverse outcomes,” he notes, indicate the potential trade-offs between benefits and risks of testosterone treatment in older men. Clarifying the effects of testosterone will take longer, larger scale trials.

High-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) has had “highly promising” results for patients with relapsing-remitting multiple sclerosis (MS), according to researchers from the HALT-MS trial. In the 5-year study, 69% of 24 participants survived without progression of disability, relapse, or new brain lesions, despite not taking MS medications.

Findings published at the 3-year mark were encouraging. The event-free survival rate was 78%. The extended findings suggest that “onetime treatment with HDIT/HCT may be substantially more effective than long-term treatment with the best available medications” for these patients, said NIAID Director Anthony Fauci, MD.

The treatment “resets” the immune system, the researchers say. First, doctors collect the patient’s blood-forming stem cells, then give the patient chemotherapy to deplete the immune system. Finally, the doctors return the patient’s stem cells to rebuild the immune system.

Adverse events were consistent with those routinely observed after HDIT/HCT. Adverse effects recorded at 4 and 5 years were not related to the transplant and were not considered severe. Three patients died, but their deaths were not related to the study treatments.

Five years later, most trial participants remained in remission and stabilized, and some showed improvements, such as recovering mobility.

High-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) has had “highly promising” results for patients with relapsing-remitting multiple sclerosis (MS), according to researchers from the HALT-MS trial. In the 5-year study, 69% of 24 participants survived without progression of disability, relapse, or new brain lesions, despite not taking MS medications.

Findings published at the 3-year mark were encouraging. The event-free survival rate was 78%. The extended findings suggest that “onetime treatment with HDIT/HCT may be substantially more effective than long-term treatment with the best available medications” for these patients, said NIAID Director Anthony Fauci, MD.

The treatment “resets” the immune system, the researchers say. First, doctors collect the patient’s blood-forming stem cells, then give the patient chemotherapy to deplete the immune system. Finally, the doctors return the patient’s stem cells to rebuild the immune system.

Adverse events were consistent with those routinely observed after HDIT/HCT. Adverse effects recorded at 4 and 5 years were not related to the transplant and were not considered severe. Three patients died, but their deaths were not related to the study treatments.

Five years later, most trial participants remained in remission and stabilized, and some showed improvements, such as recovering mobility.

High-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) has had “highly promising” results for patients with relapsing-remitting multiple sclerosis (MS), according to researchers from the HALT-MS trial. In the 5-year study, 69% of 24 participants survived without progression of disability, relapse, or new brain lesions, despite not taking MS medications.

Findings published at the 3-year mark were encouraging. The event-free survival rate was 78%. The extended findings suggest that “onetime treatment with HDIT/HCT may be substantially more effective than long-term treatment with the best available medications” for these patients, said NIAID Director Anthony Fauci, MD.

The treatment “resets” the immune system, the researchers say. First, doctors collect the patient’s blood-forming stem cells, then give the patient chemotherapy to deplete the immune system. Finally, the doctors return the patient’s stem cells to rebuild the immune system.

Adverse events were consistent with those routinely observed after HDIT/HCT. Adverse effects recorded at 4 and 5 years were not related to the transplant and were not considered severe. Three patients died, but their deaths were not related to the study treatments.

Five years later, most trial participants remained in remission and stabilized, and some showed improvements, such as recovering mobility.

Roughly 25% of veterans have diabetes mellitus (DM) as opposed to 9% of the general public. A small percentage of veterans have type 1 DM, which according to research, can be caused by both physical and mental trauma that affects the pancreas.

“Managing type 1 diabetes currently requires a constant juggling act between checking bloodglucose levels frequently and delivering just the right amount of insulin while taking into account meals, physical activity, and other aspects of daily life, where a missed or wrong delivery could lead to potential complications,” said Dr. Andrew Bremer, of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). But that may change soon as we draw near to a functional “artificial pancreas,” a fully automated system that will sense rising glucose levels and adjust insulin automatically.

 The FDA approved a hybrid model of an artificial pancreas in 2016, which still required users to adjust insulin intake. Now, 4 separate projects are designed to be the “potential last steps” toward requesting regulatory approval for permanent use of a fully automated system, according to NIDDK. The research studies beginning this year will look at safety, efficacy, user-friendliness, physical and emotional health of participants, and cost. The participants will live at home and monitor themselves with remote monitoring by study staff.

“Nearly 100 years since the discovery of insulin,” said NIDDK Director Dr. Griffin P. Rodgers, “a successful artificial pancreas would mark another huge step toward better health for people with type 1 diabetes.”

Roughly 25% of veterans have diabetes mellitus (DM) as opposed to 9% of the general public. A small percentage of veterans have type 1 DM, which according to research, can be caused by both physical and mental trauma that affects the pancreas.

“Managing type 1 diabetes currently requires a constant juggling act between checking bloodglucose levels frequently and delivering just the right amount of insulin while taking into account meals, physical activity, and other aspects of daily life, where a missed or wrong delivery could lead to potential complications,” said Dr. Andrew Bremer, of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). But that may change soon as we draw near to a functional “artificial pancreas,” a fully automated system that will sense rising glucose levels and adjust insulin automatically.

 The FDA approved a hybrid model of an artificial pancreas in 2016, which still required users to adjust insulin intake. Now, 4 separate projects are designed to be the “potential last steps” toward requesting regulatory approval for permanent use of a fully automated system, according to NIDDK. The research studies beginning this year will look at safety, efficacy, user-friendliness, physical and emotional health of participants, and cost. The participants will live at home and monitor themselves with remote monitoring by study staff.

“Nearly 100 years since the discovery of insulin,” said NIDDK Director Dr. Griffin P. Rodgers, “a successful artificial pancreas would mark another huge step toward better health for people with type 1 diabetes.”

Roughly 25% of veterans have diabetes mellitus (DM) as opposed to 9% of the general public. A small percentage of veterans have type 1 DM, which according to research, can be caused by both physical and mental trauma that affects the pancreas.

“Managing type 1 diabetes currently requires a constant juggling act between checking bloodglucose levels frequently and delivering just the right amount of insulin while taking into account meals, physical activity, and other aspects of daily life, where a missed or wrong delivery could lead to potential complications,” said Dr. Andrew Bremer, of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). But that may change soon as we draw near to a functional “artificial pancreas,” a fully automated system that will sense rising glucose levels and adjust insulin automatically.

 The FDA approved a hybrid model of an artificial pancreas in 2016, which still required users to adjust insulin intake. Now, 4 separate projects are designed to be the “potential last steps” toward requesting regulatory approval for permanent use of a fully automated system, according to NIDDK. The research studies beginning this year will look at safety, efficacy, user-friendliness, physical and emotional health of participants, and cost. The participants will live at home and monitor themselves with remote monitoring by study staff.

“Nearly 100 years since the discovery of insulin,” said NIDDK Director Dr. Griffin P. Rodgers, “a successful artificial pancreas would mark another huge step toward better health for people with type 1 diabetes.”

Mindfulness practices, such as meditation, yoga, tai chi, and qigong, are on the rise in the workplace, as more studies show how they can improve health and reduce the costs of stress.

Researchers who analyzed data on 85,004 respondents to the National Health Interview Survey say that their findings are “encouraging”; about 1 in 7 workers report engaging in some form of mindfulness-based activity. From 2002 to 2012, the number of yoga practitioners nearly doubled from 6% to 11%. From 2002 to 2007, the number of people who began meditating increased from 8% to 9.9%.

Related: Mindfulness to Reduce Stress

The rise in activity was seen across different groups of workers. In 2002, 2.2% of farm workers reported engaging in at least 1 of the practices studied, as did 18.2% of white-collar workers in 2007. Mindfulness found a foothold among 9% to 12% of the unemployed as well.

Still the trend is mostly seen among white-collar workers, attributable mainly to differences in household income and education level, the researchers say. After they controlled for those 2 factors, blue-collar workers were still less likely to engage in meditation or yoga, and farm workers were less likely to engage in any of the 4 practices.

Related: Preventing Burnout With Cognitive Empathy

But the lack of engagement among blue-collar and farm workers can’t be explained by sociodemographic factors alone, the researchers say. White-collar workers may have more time, access, and opportunity to practice mindfulness and might have different beliefs about the value of these practices.

Lack of engagement could be ameliorated in part by developing interventions to target those occupational groups, the researchers suggest. They found no studies that focused on blue-collar or farm workers—the low prevalence of mindfulness practices in those groups indicates a “pressing need” for interventions, even though those workplace settings may present “unique implementation challenges.”

Related: Mindfulness as a Tool for Patients With Cancer

Mindfulness practices, such as meditation, yoga, tai chi, and qigong, are on the rise in the workplace, as more studies show how they can improve health and reduce the costs of stress.

Researchers who analyzed data on 85,004 respondents to the National Health Interview Survey say that their findings are “encouraging”; about 1 in 7 workers report engaging in some form of mindfulness-based activity. From 2002 to 2012, the number of yoga practitioners nearly doubled from 6% to 11%. From 2002 to 2007, the number of people who began meditating increased from 8% to 9.9%.

Related: Mindfulness to Reduce Stress

The rise in activity was seen across different groups of workers. In 2002, 2.2% of farm workers reported engaging in at least 1 of the practices studied, as did 18.2% of white-collar workers in 2007. Mindfulness found a foothold among 9% to 12% of the unemployed as well.

Still the trend is mostly seen among white-collar workers, attributable mainly to differences in household income and education level, the researchers say. After they controlled for those 2 factors, blue-collar workers were still less likely to engage in meditation or yoga, and farm workers were less likely to engage in any of the 4 practices.

Related: Preventing Burnout With Cognitive Empathy

But the lack of engagement among blue-collar and farm workers can’t be explained by sociodemographic factors alone, the researchers say. White-collar workers may have more time, access, and opportunity to practice mindfulness and might have different beliefs about the value of these practices.

Lack of engagement could be ameliorated in part by developing interventions to target those occupational groups, the researchers suggest. They found no studies that focused on blue-collar or farm workers—the low prevalence of mindfulness practices in those groups indicates a “pressing need” for interventions, even though those workplace settings may present “unique implementation challenges.”

Related: Mindfulness as a Tool for Patients With Cancer

Mindfulness practices, such as meditation, yoga, tai chi, and qigong, are on the rise in the workplace, as more studies show how they can improve health and reduce the costs of stress.

Researchers who analyzed data on 85,004 respondents to the National Health Interview Survey say that their findings are “encouraging”; about 1 in 7 workers report engaging in some form of mindfulness-based activity. From 2002 to 2012, the number of yoga practitioners nearly doubled from 6% to 11%. From 2002 to 2007, the number of people who began meditating increased from 8% to 9.9%.

Related: Mindfulness to Reduce Stress

The rise in activity was seen across different groups of workers. In 2002, 2.2% of farm workers reported engaging in at least 1 of the practices studied, as did 18.2% of white-collar workers in 2007. Mindfulness found a foothold among 9% to 12% of the unemployed as well.

Still the trend is mostly seen among white-collar workers, attributable mainly to differences in household income and education level, the researchers say. After they controlled for those 2 factors, blue-collar workers were still less likely to engage in meditation or yoga, and farm workers were less likely to engage in any of the 4 practices.

Related: Preventing Burnout With Cognitive Empathy

But the lack of engagement among blue-collar and farm workers can’t be explained by sociodemographic factors alone, the researchers say. White-collar workers may have more time, access, and opportunity to practice mindfulness and might have different beliefs about the value of these practices.

Lack of engagement could be ameliorated in part by developing interventions to target those occupational groups, the researchers suggest. They found no studies that focused on blue-collar or farm workers—the low prevalence of mindfulness practices in those groups indicates a “pressing need” for interventions, even though those workplace settings may present “unique implementation challenges.”

Related: Mindfulness as a Tool for Patients With Cancer

Ginsenosides are pharmacologically active components of ginseng, which often is used to relieve coughs and colds. They also have been found to have antineoplastic, antioxidant, antimicrobial, and antifungal properties; other studies suggest neuroprotective properties as well. Ginsenosides may act against coxsackievirus B3, enterovirus 71, human rhinovirus 3, and hemagglutinating virus of Japan (HVJ) infection. But do they have an antiviral effect on influenza?

Related: A New Kind of Flu Drug

Researchers from University Health Network & Shantou University Medical College and Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, both in China, and University of Toronto in Canada conducted a study in mice of the anti-influenza properties of ginseng and ginseng-derived compounds both in vitro and in vivo. They found that ginsenosides exerted “strong antiviral activity” to 2009 pandemic H1N1 virus. Ginsenoside protected the animals from infection and lowered viral titers in their lungs.

Sugars were the key to the effectiveness of the ginsenosides, which are composed of a steroid skeleton with various sugar groups attached. The researchers note that previous studies have shown that ginsenosides’ anticancer activity and antioxidant activity are related to the type and position of sugar moieties.

Related: How Common is Flu Without Fever?

The pilot experiment did not have negative or toxic effects on the animals or in cell proliferation in vitro, thus “defining the nontoxic nature and therapeutic value of these compounds,” the researchers say. They also point out that in phase 2 randomized clinical trials in children, oral consumption of ginseng extract as an alternative influenza treatment did not result in severe adverse effects. They suggest that their findings could spur other research into a novel antiviral drug for influenza.

Source:

Dong W, Farooqui A, Leon AJ, Kelvin DJ. PloS One. 2017;12(2):e0171936.
doi: 10.1371/journal.pone.0171936.

Ginsenosides are pharmacologically active components of ginseng, which often is used to relieve coughs and colds. They also have been found to have antineoplastic, antioxidant, antimicrobial, and antifungal properties; other studies suggest neuroprotective properties as well. Ginsenosides may act against coxsackievirus B3, enterovirus 71, human rhinovirus 3, and hemagglutinating virus of Japan (HVJ) infection. But do they have an antiviral effect on influenza?

Related: A New Kind of Flu Drug

Researchers from University Health Network & Shantou University Medical College and Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, both in China, and University of Toronto in Canada conducted a study in mice of the anti-influenza properties of ginseng and ginseng-derived compounds both in vitro and in vivo. They found that ginsenosides exerted “strong antiviral activity” to 2009 pandemic H1N1 virus. Ginsenoside protected the animals from infection and lowered viral titers in their lungs.

Sugars were the key to the effectiveness of the ginsenosides, which are composed of a steroid skeleton with various sugar groups attached. The researchers note that previous studies have shown that ginsenosides’ anticancer activity and antioxidant activity are related to the type and position of sugar moieties.

Related: How Common is Flu Without Fever?

The pilot experiment did not have negative or toxic effects on the animals or in cell proliferation in vitro, thus “defining the nontoxic nature and therapeutic value of these compounds,” the researchers say. They also point out that in phase 2 randomized clinical trials in children, oral consumption of ginseng extract as an alternative influenza treatment did not result in severe adverse effects. They suggest that their findings could spur other research into a novel antiviral drug for influenza.

Source:

Dong W, Farooqui A, Leon AJ, Kelvin DJ. PloS One. 2017;12(2):e0171936.
doi: 10.1371/journal.pone.0171936.

Ginsenosides are pharmacologically active components of ginseng, which often is used to relieve coughs and colds. They also have been found to have antineoplastic, antioxidant, antimicrobial, and antifungal properties; other studies suggest neuroprotective properties as well. Ginsenosides may act against coxsackievirus B3, enterovirus 71, human rhinovirus 3, and hemagglutinating virus of Japan (HVJ) infection. But do they have an antiviral effect on influenza?

Related: A New Kind of Flu Drug

Researchers from University Health Network & Shantou University Medical College and Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, both in China, and University of Toronto in Canada conducted a study in mice of the anti-influenza properties of ginseng and ginseng-derived compounds both in vitro and in vivo. They found that ginsenosides exerted “strong antiviral activity” to 2009 pandemic H1N1 virus. Ginsenoside protected the animals from infection and lowered viral titers in their lungs.

Sugars were the key to the effectiveness of the ginsenosides, which are composed of a steroid skeleton with various sugar groups attached. The researchers note that previous studies have shown that ginsenosides’ anticancer activity and antioxidant activity are related to the type and position of sugar moieties.

Related: How Common is Flu Without Fever?

The pilot experiment did not have negative or toxic effects on the animals or in cell proliferation in vitro, thus “defining the nontoxic nature and therapeutic value of these compounds,” the researchers say. They also point out that in phase 2 randomized clinical trials in children, oral consumption of ginseng extract as an alternative influenza treatment did not result in severe adverse effects. They suggest that their findings could spur other research into a novel antiviral drug for influenza.

Source:

Dong W, Farooqui A, Leon AJ, Kelvin DJ. PloS One. 2017;12(2):e0171936.
doi: 10.1371/journal.pone.0171936.