Bruce Jancin

LOS ANGELES – Oral vitamin D₃ may have a future as adjunctive therapy in patients with heart failure, according to Dr. Rebecca S. Boxer.

Six months of oral vitamin D₃ therapy at 50,000 IU/wk resulted in a 37% decrease in serum aldosterone level in a randomized, double-blind, placebo-controlled trial conducted in vitamin D–deficient patients with heart failure.

Moreover, parathyroid hormone levels, which were elevated at baseline, fell by 41% in the active treatment arm, she reported at the annual scientific sessions of the American Heart Association.

The study involved 64 patients with New York Heart Association class II-IV heart failure, all having a baseline serum vitamin D level below 20 ng/mL. All participants were on maximum tolerated doses of standard heart failure medications. The patients were randomized to oral vitamin D₃ at 50,000 IU/wk plus 400 mg of calcium citrate twice daily for 6 months or to calcium plus placebo.

Mean serum vitamin D levels climbed from 19 ng/mL to 60 ng/mL in treated patients while remaining unchanged over time in controls.

Serum aldosterone levels fell from 10.0 ng/mL to 6.3 ng/dL in the active treatment group and remained static in controls. The mean serum parathyroid hormone level dropped from 62.3 pg/mL to 37.1 pg/mL with vitamin D therapy but stayed steady in controls, said Dr. Boxer of Case Western Reserve University, Cleveland.

The primary endpoint in this randomized trial was change in aerobic capacity; vitamin D supplementation had no effect on this endpoint. Nor did it have any significant impact on heart failure symptoms, echocardiographic findings, body weight, blood pressure, serum renin, or C-reactive protein levels in this relatively small study.

Nonetheless, the finding of a moderate reduction in serum aldosterone level indicates that the effects of vitamin D₃ on the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure warrants further study, including assessment of possible long-term clinical benefit.

Dr. Boxer pointed out that serum aldosterone level in patients with heart failure predicts mortality. And aldosterone blockade with an aldosterone antagonist has been shown to improve clinical outcomes in heart failure patients with a depressed left ventricular ejection fraction in RALES, the Randomized Aldactone Evaluation Study (N. Engl. J. Med. 1999;341:709-17) and EPHESUS, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (N. Engl. J. Med. 2003;348:1309-21). Aldosterone blockade is also actively under study in heart failure patients with preserved systolic function in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) study, due to report results next year.

"There may be certain patient groups that could greatly benefit from vitamin D₃ therapy, particularly patients who may not be able to tolerate RAAS blockade or those who have aldosterone escape," she said.

The mechanism by which oral vitamin D₃ reduces serum aldosterone is unknown. The mechanism is clearly non–renin-dependent, given that serum renin level remained unchanged. In vitro studies suggest that vitamin D might act through a direct effect on steroidogenesis in adrenal cortical cells, Dr. Boxer said.

The study was funded by the American Heart Association. Dr. Boxer reported having no relevant financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – Oral vitamin D₃ may have a future as adjunctive therapy in patients with heart failure, according to Dr. Rebecca S. Boxer.

Six months of oral vitamin D₃ therapy at 50,000 IU/wk resulted in a 37% decrease in serum aldosterone level in a randomized, double-blind, placebo-controlled trial conducted in vitamin D–deficient patients with heart failure.

Moreover, parathyroid hormone levels, which were elevated at baseline, fell by 41% in the active treatment arm, she reported at the annual scientific sessions of the American Heart Association.

The study involved 64 patients with New York Heart Association class II-IV heart failure, all having a baseline serum vitamin D level below 20 ng/mL. All participants were on maximum tolerated doses of standard heart failure medications. The patients were randomized to oral vitamin D₃ at 50,000 IU/wk plus 400 mg of calcium citrate twice daily for 6 months or to calcium plus placebo.

Mean serum vitamin D levels climbed from 19 ng/mL to 60 ng/mL in treated patients while remaining unchanged over time in controls.

Serum aldosterone levels fell from 10.0 ng/mL to 6.3 ng/dL in the active treatment group and remained static in controls. The mean serum parathyroid hormone level dropped from 62.3 pg/mL to 37.1 pg/mL with vitamin D therapy but stayed steady in controls, said Dr. Boxer of Case Western Reserve University, Cleveland.

The primary endpoint in this randomized trial was change in aerobic capacity; vitamin D supplementation had no effect on this endpoint. Nor did it have any significant impact on heart failure symptoms, echocardiographic findings, body weight, blood pressure, serum renin, or C-reactive protein levels in this relatively small study.

Nonetheless, the finding of a moderate reduction in serum aldosterone level indicates that the effects of vitamin D₃ on the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure warrants further study, including assessment of possible long-term clinical benefit.

Dr. Boxer pointed out that serum aldosterone level in patients with heart failure predicts mortality. And aldosterone blockade with an aldosterone antagonist has been shown to improve clinical outcomes in heart failure patients with a depressed left ventricular ejection fraction in RALES, the Randomized Aldactone Evaluation Study (N. Engl. J. Med. 1999;341:709-17) and EPHESUS, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (N. Engl. J. Med. 2003;348:1309-21). Aldosterone blockade is also actively under study in heart failure patients with preserved systolic function in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) study, due to report results next year.

"There may be certain patient groups that could greatly benefit from vitamin D₃ therapy, particularly patients who may not be able to tolerate RAAS blockade or those who have aldosterone escape," she said.

The mechanism by which oral vitamin D₃ reduces serum aldosterone is unknown. The mechanism is clearly non–renin-dependent, given that serum renin level remained unchanged. In vitro studies suggest that vitamin D might act through a direct effect on steroidogenesis in adrenal cortical cells, Dr. Boxer said.

The study was funded by the American Heart Association. Dr. Boxer reported having no relevant financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – Oral vitamin D₃ may have a future as adjunctive therapy in patients with heart failure, according to Dr. Rebecca S. Boxer.

Six months of oral vitamin D₃ therapy at 50,000 IU/wk resulted in a 37% decrease in serum aldosterone level in a randomized, double-blind, placebo-controlled trial conducted in vitamin D–deficient patients with heart failure.

Moreover, parathyroid hormone levels, which were elevated at baseline, fell by 41% in the active treatment arm, she reported at the annual scientific sessions of the American Heart Association.

The study involved 64 patients with New York Heart Association class II-IV heart failure, all having a baseline serum vitamin D level below 20 ng/mL. All participants were on maximum tolerated doses of standard heart failure medications. The patients were randomized to oral vitamin D₃ at 50,000 IU/wk plus 400 mg of calcium citrate twice daily for 6 months or to calcium plus placebo.

Mean serum vitamin D levels climbed from 19 ng/mL to 60 ng/mL in treated patients while remaining unchanged over time in controls.

Serum aldosterone levels fell from 10.0 ng/mL to 6.3 ng/dL in the active treatment group and remained static in controls. The mean serum parathyroid hormone level dropped from 62.3 pg/mL to 37.1 pg/mL with vitamin D therapy but stayed steady in controls, said Dr. Boxer of Case Western Reserve University, Cleveland.

The primary endpoint in this randomized trial was change in aerobic capacity; vitamin D supplementation had no effect on this endpoint. Nor did it have any significant impact on heart failure symptoms, echocardiographic findings, body weight, blood pressure, serum renin, or C-reactive protein levels in this relatively small study.

Nonetheless, the finding of a moderate reduction in serum aldosterone level indicates that the effects of vitamin D₃ on the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure warrants further study, including assessment of possible long-term clinical benefit.

Dr. Boxer pointed out that serum aldosterone level in patients with heart failure predicts mortality. And aldosterone blockade with an aldosterone antagonist has been shown to improve clinical outcomes in heart failure patients with a depressed left ventricular ejection fraction in RALES, the Randomized Aldactone Evaluation Study (N. Engl. J. Med. 1999;341:709-17) and EPHESUS, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (N. Engl. J. Med. 2003;348:1309-21). Aldosterone blockade is also actively under study in heart failure patients with preserved systolic function in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) study, due to report results next year.

"There may be certain patient groups that could greatly benefit from vitamin D₃ therapy, particularly patients who may not be able to tolerate RAAS blockade or those who have aldosterone escape," she said.

The mechanism by which oral vitamin D₃ reduces serum aldosterone is unknown. The mechanism is clearly non–renin-dependent, given that serum renin level remained unchanged. In vitro studies suggest that vitamin D might act through a direct effect on steroidogenesis in adrenal cortical cells, Dr. Boxer said.

The study was funded by the American Heart Association. Dr. Boxer reported having no relevant financial conflicts.

b.jancin@elsevier.com

PRAGUE  – Low-dose thalidomide for refractory cutaneous lupus erythematosus is best used together with hydroxychloroquine or another antimalarial agent rather than as monotherapy, Dr. Victoria P. Werth asserted at the annual congress of the European Academy of Dermatology and Venereology.

When prescribing thalidomide for a patient with refractory cutaneous lupus erythematosus (CLE), many physicians discontinue antimalarial therapy, reasoning that since the patient wasn’t responsive to monotherapy, there’s no point in continued exposure to the potential risks. But that’s probably a mistake. Combination therapy acting through different mechanisms may boost the likelihood of a good response; plus, the antiplatelet action of hydroxychloroquine or another antimalarial agent will help counteract thalidomide’s prothrombotic effects, said Dr. Werth, professor of dermatology at the University of Pennsylvania, Philadelphia.

Thalidomide is unquestionably an effective therapy in patients with refractory CLE. But it’s also a drug with big problems, including perhaps an increased stroke risk, as highlighted in a recent Spanish study, she noted.

The Spanish study included 60 consecutive patients with refractory CLE who were treated with thalidomide at 100 mg/day and followed for up to 8 years. One dropped out due to side effects. Fifty-eight of the remaining 59 experienced significant clinical improvement, including 49 (85%) with a complete response as defined by a CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) activity score of 0.

Relapse occurred in most patients, usually about 5 months after thalidomide dose reduction or withdrawal. Patients with subacute CLE were 30-fold more likely to remain in remission after drug discontinuation; those with discoid LE were at increased risk for relapse (Br. J. Dermatol. 2012;166:616-23).

Of particular concern to Dr. Werth was the finding that two patients had a stroke while on the drug. Neither had antiphospholipid antibodies, and one was quite young to have had a stroke, although both were heavy smokers.

Prescribing a drug such as thalidomide that promotes a hypercoagulable state to patients with refractory CLE is problematic because they often already have multiple risk factors for thrombosis. For one thing, treatment-refractory CLE patients tend to be smokers. Many of them are women on oral contraceptives. And there is an increased prevalence of antiphospholipid antibodies in patients with CLE, according to Dr. Werth.

Neuropathy is another major issue with thalidomide. In the Spanish study, 11 of 60 patients (18%) developed paresthesias; nerve conduction studies confirmed sensory polyneuropathy in 5 of the 11. Fortunately, the neurologic symptoms resolved in an average of 12 months after drug withdrawal.

Of course, thalidomide is a notorious teratogen. It can also cause premature ovarian failure, although this is usually reversible upon drug discontinuation.

"Obviously we need better therapies than thalidomide," Dr. Werth concluded.

Toward that end, interest is growing in thalidomide analogues as a novel potential therapy for refractory CLE. These analogues are up to 50,000 times more active than thalidomide, and are potentially less neurotoxic. One of them, lenalidomide (Revlimid), is marketed as a treatment for multiple myeloma and myelodysplastic syndrome. Others are in the development pipeline.

Several small observational studies have recently reported favorable results with lenalidomide in patients with refractory CLE. For example, investigators at Vall d’Hebron University Hospital in Barcelona reported on 15 patients treated open label with lenalidomide at 5-10 mg/day, with a follow-up of 15 months. One patient dropped out early due to side effects, but the other 14 saw clinical improvement within the first 2 weeks. Twelve patients, or 86%, achieved a CLASI score of 0. However, 9 of 12 complete responders experienced clinical relapse, usually 2-8 weeks after the drug was tapered and discontinued. Side effects were mild and infrequent, with no thrombosis or polyneuropathy (Arthritis Res. Ther. 2012;14:R265).

In another series, 4 of 5 lenalidomide-treated patients showed significant skin improvement, although one eventually developed symptoms of SLE (J. Am. Acad. Dermatol. 2012;66:571-82).

Based upon these and other promising reports, Celgene, which markets lenalidomide, recently launched the first-ever phase II study of a thalidomide analogue for the treatment of CLE.

Dr. Werth reported having no financial conflicts.

PRAGUE  – Low-dose thalidomide for refractory cutaneous lupus erythematosus is best used together with hydroxychloroquine or another antimalarial agent rather than as monotherapy, Dr. Victoria P. Werth asserted at the annual congress of the European Academy of Dermatology and Venereology.

When prescribing thalidomide for a patient with refractory cutaneous lupus erythematosus (CLE), many physicians discontinue antimalarial therapy, reasoning that since the patient wasn’t responsive to monotherapy, there’s no point in continued exposure to the potential risks. But that’s probably a mistake. Combination therapy acting through different mechanisms may boost the likelihood of a good response; plus, the antiplatelet action of hydroxychloroquine or another antimalarial agent will help counteract thalidomide’s prothrombotic effects, said Dr. Werth, professor of dermatology at the University of Pennsylvania, Philadelphia.

Thalidomide is unquestionably an effective therapy in patients with refractory CLE. But it’s also a drug with big problems, including perhaps an increased stroke risk, as highlighted in a recent Spanish study, she noted.

The Spanish study included 60 consecutive patients with refractory CLE who were treated with thalidomide at 100 mg/day and followed for up to 8 years. One dropped out due to side effects. Fifty-eight of the remaining 59 experienced significant clinical improvement, including 49 (85%) with a complete response as defined by a CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) activity score of 0.

Relapse occurred in most patients, usually about 5 months after thalidomide dose reduction or withdrawal. Patients with subacute CLE were 30-fold more likely to remain in remission after drug discontinuation; those with discoid LE were at increased risk for relapse (Br. J. Dermatol. 2012;166:616-23).

Of particular concern to Dr. Werth was the finding that two patients had a stroke while on the drug. Neither had antiphospholipid antibodies, and one was quite young to have had a stroke, although both were heavy smokers.

Prescribing a drug such as thalidomide that promotes a hypercoagulable state to patients with refractory CLE is problematic because they often already have multiple risk factors for thrombosis. For one thing, treatment-refractory CLE patients tend to be smokers. Many of them are women on oral contraceptives. And there is an increased prevalence of antiphospholipid antibodies in patients with CLE, according to Dr. Werth.

Neuropathy is another major issue with thalidomide. In the Spanish study, 11 of 60 patients (18%) developed paresthesias; nerve conduction studies confirmed sensory polyneuropathy in 5 of the 11. Fortunately, the neurologic symptoms resolved in an average of 12 months after drug withdrawal.

Of course, thalidomide is a notorious teratogen. It can also cause premature ovarian failure, although this is usually reversible upon drug discontinuation.

"Obviously we need better therapies than thalidomide," Dr. Werth concluded.

Toward that end, interest is growing in thalidomide analogues as a novel potential therapy for refractory CLE. These analogues are up to 50,000 times more active than thalidomide, and are potentially less neurotoxic. One of them, lenalidomide (Revlimid), is marketed as a treatment for multiple myeloma and myelodysplastic syndrome. Others are in the development pipeline.

Several small observational studies have recently reported favorable results with lenalidomide in patients with refractory CLE. For example, investigators at Vall d’Hebron University Hospital in Barcelona reported on 15 patients treated open label with lenalidomide at 5-10 mg/day, with a follow-up of 15 months. One patient dropped out early due to side effects, but the other 14 saw clinical improvement within the first 2 weeks. Twelve patients, or 86%, achieved a CLASI score of 0. However, 9 of 12 complete responders experienced clinical relapse, usually 2-8 weeks after the drug was tapered and discontinued. Side effects were mild and infrequent, with no thrombosis or polyneuropathy (Arthritis Res. Ther. 2012;14:R265).

In another series, 4 of 5 lenalidomide-treated patients showed significant skin improvement, although one eventually developed symptoms of SLE (J. Am. Acad. Dermatol. 2012;66:571-82).

Based upon these and other promising reports, Celgene, which markets lenalidomide, recently launched the first-ever phase II study of a thalidomide analogue for the treatment of CLE.

Dr. Werth reported having no financial conflicts.

PRAGUE  – Low-dose thalidomide for refractory cutaneous lupus erythematosus is best used together with hydroxychloroquine or another antimalarial agent rather than as monotherapy, Dr. Victoria P. Werth asserted at the annual congress of the European Academy of Dermatology and Venereology.

When prescribing thalidomide for a patient with refractory cutaneous lupus erythematosus (CLE), many physicians discontinue antimalarial therapy, reasoning that since the patient wasn’t responsive to monotherapy, there’s no point in continued exposure to the potential risks. But that’s probably a mistake. Combination therapy acting through different mechanisms may boost the likelihood of a good response; plus, the antiplatelet action of hydroxychloroquine or another antimalarial agent will help counteract thalidomide’s prothrombotic effects, said Dr. Werth, professor of dermatology at the University of Pennsylvania, Philadelphia.

Thalidomide is unquestionably an effective therapy in patients with refractory CLE. But it’s also a drug with big problems, including perhaps an increased stroke risk, as highlighted in a recent Spanish study, she noted.

The Spanish study included 60 consecutive patients with refractory CLE who were treated with thalidomide at 100 mg/day and followed for up to 8 years. One dropped out due to side effects. Fifty-eight of the remaining 59 experienced significant clinical improvement, including 49 (85%) with a complete response as defined by a CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) activity score of 0.

Relapse occurred in most patients, usually about 5 months after thalidomide dose reduction or withdrawal. Patients with subacute CLE were 30-fold more likely to remain in remission after drug discontinuation; those with discoid LE were at increased risk for relapse (Br. J. Dermatol. 2012;166:616-23).

Of particular concern to Dr. Werth was the finding that two patients had a stroke while on the drug. Neither had antiphospholipid antibodies, and one was quite young to have had a stroke, although both were heavy smokers.

Prescribing a drug such as thalidomide that promotes a hypercoagulable state to patients with refractory CLE is problematic because they often already have multiple risk factors for thrombosis. For one thing, treatment-refractory CLE patients tend to be smokers. Many of them are women on oral contraceptives. And there is an increased prevalence of antiphospholipid antibodies in patients with CLE, according to Dr. Werth.

Neuropathy is another major issue with thalidomide. In the Spanish study, 11 of 60 patients (18%) developed paresthesias; nerve conduction studies confirmed sensory polyneuropathy in 5 of the 11. Fortunately, the neurologic symptoms resolved in an average of 12 months after drug withdrawal.

Of course, thalidomide is a notorious teratogen. It can also cause premature ovarian failure, although this is usually reversible upon drug discontinuation.

"Obviously we need better therapies than thalidomide," Dr. Werth concluded.

Toward that end, interest is growing in thalidomide analogues as a novel potential therapy for refractory CLE. These analogues are up to 50,000 times more active than thalidomide, and are potentially less neurotoxic. One of them, lenalidomide (Revlimid), is marketed as a treatment for multiple myeloma and myelodysplastic syndrome. Others are in the development pipeline.

Several small observational studies have recently reported favorable results with lenalidomide in patients with refractory CLE. For example, investigators at Vall d’Hebron University Hospital in Barcelona reported on 15 patients treated open label with lenalidomide at 5-10 mg/day, with a follow-up of 15 months. One patient dropped out early due to side effects, but the other 14 saw clinical improvement within the first 2 weeks. Twelve patients, or 86%, achieved a CLASI score of 0. However, 9 of 12 complete responders experienced clinical relapse, usually 2-8 weeks after the drug was tapered and discontinued. Side effects were mild and infrequent, with no thrombosis or polyneuropathy (Arthritis Res. Ther. 2012;14:R265).

In another series, 4 of 5 lenalidomide-treated patients showed significant skin improvement, although one eventually developed symptoms of SLE (J. Am. Acad. Dermatol. 2012;66:571-82).

Based upon these and other promising reports, Celgene, which markets lenalidomide, recently launched the first-ever phase II study of a thalidomide analogue for the treatment of CLE.

Dr. Werth reported having no financial conflicts.

SAN ANTONIO – Researchers have taken a first stride toward the goal of developing a gene test that predicts a breast cancer patient’s likelihood of a favorable clinical outcome in response to adjuvant trastuzumab.

A massive gene expression profiling analysis of baseline pretreatment tumor specimens obtained from 372 breast cancer patients identified 32 genes that correlated strongly with 5-year relapse-free survival, each with a P value less than .001, Dr. Edith A. Perez reported at the San Antonio Breast Cancer Symposium.

The ideal thing would be to find a gene that, if highly expressed, predicts for benefit or not of Herceptin [trastuzumab]. We are on our way to developing a predictive test that can define the right treatment for individual patients, and that is very exciting," declared Dr. Perez, deputy director at large of the Mayo Clinic Comprehensive Cancer Center and director of the breast cancer translational genomics program at the Mayo Clinic in Jacksonville, Fla.

In all, 27 of the genes were associated with good outcome, while the other 5 correlated with poor outcome. The major functional categories these genes are involved in have been identified: cell receptor signaling, chromatin structure and transcription, control of cell death, cell cycle, Wnt/beta-catenin signaling, and lipid signaling. It’s not yet known whether these 32 genes are expressed in the epithelial or the stromal component of the tumors, and it will be challenging to figure that out, she said.

All 372 specimens in this analysis came from women randomized to adjuvant chemotherapy plus concurrent trastuzumab in the previously reported North Central Cancer Treatment Group N9831 trial. The N9831 trial was one of the pivotal studies that led to adjuvant trastuzumab plus chemotherapy becoming established as the standard of care in treating HER2-positive breast cancer

Dr. Perez and her coinvestigators have also just completed a gene expression profiling analysis of baseline tumor samples from an additional 910 women in the N9831 trial who were randomized to either chemotherapy alone or chemotherapy followed sequentially by trastuzumab. The plan is to identify similarities and differences in the patterns of gene expression in the chemotherapy-only and the two chemotherapy-plus-trastuzumab groups in order to home in more specifically on genes associated with the outcome of trastuzumab therapy. Those data weren’t ready for presentation at the symposium.

The study used the DNA-mediated DASL (annealing, extension, selection, and ligation) assay marketed by Illumina to scrutinize the activity of more than 29,000 genes in tumor specimens from 1,262 N9831 trial participants.

In addition, Dr. Perez and her coworkers are collaborating with other investigators around the world who also conducted adjuvant trastuzumab trials with collections of tumor samples, including the HERA (Herceptin Adjuvant) and FinHer studies, in order to carry out a validation study.

Discussant Dr. Dennis C. Sgroi called this work tremendously exciting. He noted that trastuzumab is a very expensive drug, and roughly 25% of treated patients relapse within 5 years. Trastuzumab also carries a risk of cardiotoxicity, and he was intrigued by Dr. Perez’ suggestion that the investigators believe they may have identified baseline tumor gene activity signatures predisposing to symptomatic cardiomyopathy and transient asymptomatic drops in left ventricular ejection fraction.

A noteworthy aspect of this study is that many of the 32 predictive genomic markers that were identified function in domains other than proliferation. Genes that figure in proliferation are the predominant drivers of the prognostic performance of Genomic Health’s Oncotype DX and all the other molecular biomarker assays developed to date. So the work of Dr. Perez and her coinvestigators is definitely next-generation in the molecular profiling arena, said Dr. Sgroi of Massachusetts General Hospital, Boston.

This study was funded by the National Cancer Institute, the Breast Cancer Research Foundation, and the 26.2 with Donna Foundation. Dr. Perez reported no financial conflicts.

SAN ANTONIO – Researchers have taken a first stride toward the goal of developing a gene test that predicts a breast cancer patient’s likelihood of a favorable clinical outcome in response to adjuvant trastuzumab.

A massive gene expression profiling analysis of baseline pretreatment tumor specimens obtained from 372 breast cancer patients identified 32 genes that correlated strongly with 5-year relapse-free survival, each with a P value less than .001, Dr. Edith A. Perez reported at the San Antonio Breast Cancer Symposium.

The ideal thing would be to find a gene that, if highly expressed, predicts for benefit or not of Herceptin [trastuzumab]. We are on our way to developing a predictive test that can define the right treatment for individual patients, and that is very exciting," declared Dr. Perez, deputy director at large of the Mayo Clinic Comprehensive Cancer Center and director of the breast cancer translational genomics program at the Mayo Clinic in Jacksonville, Fla.

In all, 27 of the genes were associated with good outcome, while the other 5 correlated with poor outcome. The major functional categories these genes are involved in have been identified: cell receptor signaling, chromatin structure and transcription, control of cell death, cell cycle, Wnt/beta-catenin signaling, and lipid signaling. It’s not yet known whether these 32 genes are expressed in the epithelial or the stromal component of the tumors, and it will be challenging to figure that out, she said.

All 372 specimens in this analysis came from women randomized to adjuvant chemotherapy plus concurrent trastuzumab in the previously reported North Central Cancer Treatment Group N9831 trial. The N9831 trial was one of the pivotal studies that led to adjuvant trastuzumab plus chemotherapy becoming established as the standard of care in treating HER2-positive breast cancer

Dr. Perez and her coinvestigators have also just completed a gene expression profiling analysis of baseline tumor samples from an additional 910 women in the N9831 trial who were randomized to either chemotherapy alone or chemotherapy followed sequentially by trastuzumab. The plan is to identify similarities and differences in the patterns of gene expression in the chemotherapy-only and the two chemotherapy-plus-trastuzumab groups in order to home in more specifically on genes associated with the outcome of trastuzumab therapy. Those data weren’t ready for presentation at the symposium.

The study used the DNA-mediated DASL (annealing, extension, selection, and ligation) assay marketed by Illumina to scrutinize the activity of more than 29,000 genes in tumor specimens from 1,262 N9831 trial participants.

In addition, Dr. Perez and her coworkers are collaborating with other investigators around the world who also conducted adjuvant trastuzumab trials with collections of tumor samples, including the HERA (Herceptin Adjuvant) and FinHer studies, in order to carry out a validation study.

Discussant Dr. Dennis C. Sgroi called this work tremendously exciting. He noted that trastuzumab is a very expensive drug, and roughly 25% of treated patients relapse within 5 years. Trastuzumab also carries a risk of cardiotoxicity, and he was intrigued by Dr. Perez’ suggestion that the investigators believe they may have identified baseline tumor gene activity signatures predisposing to symptomatic cardiomyopathy and transient asymptomatic drops in left ventricular ejection fraction.

A noteworthy aspect of this study is that many of the 32 predictive genomic markers that were identified function in domains other than proliferation. Genes that figure in proliferation are the predominant drivers of the prognostic performance of Genomic Health’s Oncotype DX and all the other molecular biomarker assays developed to date. So the work of Dr. Perez and her coinvestigators is definitely next-generation in the molecular profiling arena, said Dr. Sgroi of Massachusetts General Hospital, Boston.

This study was funded by the National Cancer Institute, the Breast Cancer Research Foundation, and the 26.2 with Donna Foundation. Dr. Perez reported no financial conflicts.

SAN ANTONIO – Researchers have taken a first stride toward the goal of developing a gene test that predicts a breast cancer patient’s likelihood of a favorable clinical outcome in response to adjuvant trastuzumab.

A massive gene expression profiling analysis of baseline pretreatment tumor specimens obtained from 372 breast cancer patients identified 32 genes that correlated strongly with 5-year relapse-free survival, each with a P value less than .001, Dr. Edith A. Perez reported at the San Antonio Breast Cancer Symposium.

The ideal thing would be to find a gene that, if highly expressed, predicts for benefit or not of Herceptin [trastuzumab]. We are on our way to developing a predictive test that can define the right treatment for individual patients, and that is very exciting," declared Dr. Perez, deputy director at large of the Mayo Clinic Comprehensive Cancer Center and director of the breast cancer translational genomics program at the Mayo Clinic in Jacksonville, Fla.

In all, 27 of the genes were associated with good outcome, while the other 5 correlated with poor outcome. The major functional categories these genes are involved in have been identified: cell receptor signaling, chromatin structure and transcription, control of cell death, cell cycle, Wnt/beta-catenin signaling, and lipid signaling. It’s not yet known whether these 32 genes are expressed in the epithelial or the stromal component of the tumors, and it will be challenging to figure that out, she said.

All 372 specimens in this analysis came from women randomized to adjuvant chemotherapy plus concurrent trastuzumab in the previously reported North Central Cancer Treatment Group N9831 trial. The N9831 trial was one of the pivotal studies that led to adjuvant trastuzumab plus chemotherapy becoming established as the standard of care in treating HER2-positive breast cancer

Dr. Perez and her coinvestigators have also just completed a gene expression profiling analysis of baseline tumor samples from an additional 910 women in the N9831 trial who were randomized to either chemotherapy alone or chemotherapy followed sequentially by trastuzumab. The plan is to identify similarities and differences in the patterns of gene expression in the chemotherapy-only and the two chemotherapy-plus-trastuzumab groups in order to home in more specifically on genes associated with the outcome of trastuzumab therapy. Those data weren’t ready for presentation at the symposium.

The study used the DNA-mediated DASL (annealing, extension, selection, and ligation) assay marketed by Illumina to scrutinize the activity of more than 29,000 genes in tumor specimens from 1,262 N9831 trial participants.

In addition, Dr. Perez and her coworkers are collaborating with other investigators around the world who also conducted adjuvant trastuzumab trials with collections of tumor samples, including the HERA (Herceptin Adjuvant) and FinHer studies, in order to carry out a validation study.

Discussant Dr. Dennis C. Sgroi called this work tremendously exciting. He noted that trastuzumab is a very expensive drug, and roughly 25% of treated patients relapse within 5 years. Trastuzumab also carries a risk of cardiotoxicity, and he was intrigued by Dr. Perez’ suggestion that the investigators believe they may have identified baseline tumor gene activity signatures predisposing to symptomatic cardiomyopathy and transient asymptomatic drops in left ventricular ejection fraction.

A noteworthy aspect of this study is that many of the 32 predictive genomic markers that were identified function in domains other than proliferation. Genes that figure in proliferation are the predominant drivers of the prognostic performance of Genomic Health’s Oncotype DX and all the other molecular biomarker assays developed to date. So the work of Dr. Perez and her coinvestigators is definitely next-generation in the molecular profiling arena, said Dr. Sgroi of Massachusetts General Hospital, Boston.

This study was funded by the National Cancer Institute, the Breast Cancer Research Foundation, and the 26.2 with Donna Foundation. Dr. Perez reported no financial conflicts.

LONDON – A simple, straightforward protocol for management of medication-overuse headache has established its clinical utility in the large joint European/Latin American COMOESTAS study.

"These findings confirm the efficacy, the usability worldwide, and the low economic cost of detoxifying patients with medication-overuse headache," Dr. Cristina Tassorelli said in presenting the COMOESTAS data at the European Headache and Migraine Trust International Congress.

The protocol utilized in COMOESTAS (continuous monitoring of medication-overuse headache in Europe and Latin America: development and standardization of an alert and decision support system) consists of abrupt detoxification, patient education, early initiation of individualized prophylactic therapy, and regular scheduled follow-up by one dedicated physician guided by electronic support. Patients maintain an electronic medical diary which automatically signals their physician if they begin to slide down the slope toward relapse, explained Dr. Tassorelli, a neurologist at the University of Pavia (Italy).

Medication-overuse headache (MOH) is a common and disabling condition. It affects 1%-3% of the general population and 20%-60% of patients in specialized headache clinics. It occurs when patients with chronic headache, most often migraine without aura, experience a worsening of their headaches and respond by using more and more acute medication – triptans and/or NSAIDs – which in turn paradoxically exacerbates their headache pattern. MOH is defined by the occurrence of headache on at least 15 days/month coupled with use of triptans on 10 or more days/month or NSAIDs on at least 15 days/month.

MOH is treatable via detoxification but typically has a relapse rate of 30%-40% within the following 6 months. The COMOESTAS protocol, in contrast, had a 6-month relapse rate of 10%.

The COMOESTAS protocol for MOH was devised by expert consensus. It is designed as a first-line intervention for MOH patients who are detoxification-naive.

"Three-quarters of first timers will do well with this approach. It’s a good tool for stratifying patients: If they relapse, then they need a more intensive multidisciplinary approach," Dr. Tassorelli explained.

In a separate presentation, COMOESTAS coinvestigator Dr. Lars Bendsten reported that the management protocol proved successful not only in terms of the primary outcome measures of reduced headache frequency and fewer days per month of acute medication use but also from the standpoint of reduced depression, anxiety, and disability along with improved quality of life.

Among 519 COMOESTAS participants who completed 6 months of follow-up at centers in Spain, Italy, Denmark, Germany, Argentina, and Chile, the mean number of headache days per month fell from 23.6 at baseline to 9.8. Days of acute drug therapy dropped in sync.

Moreover, quality of life as assessed using the MIDAS (Migraine Disability Assessment Score) scale improved from 59.8 to 25.5. The mean HADS (Hospital Anxiety and Depression Scale) depression score fell from 6.6 at baseline to 4.1, while the HADS anxiety score dropped from 9.3 to 7.1. All of these differences were statistically significant and clinically meaningful, commented Dr. Bendsten of the University of Copenhagen.

Dr. Tassorelli noted that detoxification in the COMOESTAS study could be carried out on either an inpatient or outpatient basis, depending upon local practice. The 6-month results were closely similar regardless of the detoxification setting, meaning that outpatient detoxification, which is vastly less expensive, is clearly the winning strategy.

The COMOESTAS protocol began with a day 1 detailed explanation of the vicious cycle of MOH and advice to the patient to abruptly stop the overused medication. Rescue medication could be employed on days 1-7 to combat withdrawal headaches, with the drug, dose, and route of administration to be chosen from a menu based upon the patient’s medical history and headache characteristics. Options included a variety of antiemetics, acetaminophen, and naproxen.

Preventive therapy was started within the first 7 days. The options were propranolol, atenolol, metoprolol, valproic acid, topiramate, candesartan, flunarizine, or amitriptyline. The selection was based upon comorbid conditions, patient preference, and side effect profiles.

Acute headache medication was permitted beginning on day 8 for a maximum of 2 days per week. The inviolable rule was that patients could not use the same drug that was previously overused.

Elsewhere at the conference, European Headache Federation president and COMOESTAS coinvestigator Dr. Rigmor Højland Jensen diverged from providing an update on the therapeutic pipeline for migraine to draw special attention to the importance of detoxifying patients with MOH.

"This is something we can do starting Monday morning. We don’t have to have a bag full of new drugs. We can do a lot for these patients now," said Dr. Jensen, professor of neurology at the University of Copenhagen.

The COMOESTAS project is funded by the European Commission. The investigators reported having no financial conflicts.

b.jancin@elsevier.com

LONDON – A simple, straightforward protocol for management of medication-overuse headache has established its clinical utility in the large joint European/Latin American COMOESTAS study.

"These findings confirm the efficacy, the usability worldwide, and the low economic cost of detoxifying patients with medication-overuse headache," Dr. Cristina Tassorelli said in presenting the COMOESTAS data at the European Headache and Migraine Trust International Congress.

The protocol utilized in COMOESTAS (continuous monitoring of medication-overuse headache in Europe and Latin America: development and standardization of an alert and decision support system) consists of abrupt detoxification, patient education, early initiation of individualized prophylactic therapy, and regular scheduled follow-up by one dedicated physician guided by electronic support. Patients maintain an electronic medical diary which automatically signals their physician if they begin to slide down the slope toward relapse, explained Dr. Tassorelli, a neurologist at the University of Pavia (Italy).

Medication-overuse headache (MOH) is a common and disabling condition. It affects 1%-3% of the general population and 20%-60% of patients in specialized headache clinics. It occurs when patients with chronic headache, most often migraine without aura, experience a worsening of their headaches and respond by using more and more acute medication – triptans and/or NSAIDs – which in turn paradoxically exacerbates their headache pattern. MOH is defined by the occurrence of headache on at least 15 days/month coupled with use of triptans on 10 or more days/month or NSAIDs on at least 15 days/month.

MOH is treatable via detoxification but typically has a relapse rate of 30%-40% within the following 6 months. The COMOESTAS protocol, in contrast, had a 6-month relapse rate of 10%.

The COMOESTAS protocol for MOH was devised by expert consensus. It is designed as a first-line intervention for MOH patients who are detoxification-naive.

"Three-quarters of first timers will do well with this approach. It’s a good tool for stratifying patients: If they relapse, then they need a more intensive multidisciplinary approach," Dr. Tassorelli explained.

In a separate presentation, COMOESTAS coinvestigator Dr. Lars Bendsten reported that the management protocol proved successful not only in terms of the primary outcome measures of reduced headache frequency and fewer days per month of acute medication use but also from the standpoint of reduced depression, anxiety, and disability along with improved quality of life.

Among 519 COMOESTAS participants who completed 6 months of follow-up at centers in Spain, Italy, Denmark, Germany, Argentina, and Chile, the mean number of headache days per month fell from 23.6 at baseline to 9.8. Days of acute drug therapy dropped in sync.

Moreover, quality of life as assessed using the MIDAS (Migraine Disability Assessment Score) scale improved from 59.8 to 25.5. The mean HADS (Hospital Anxiety and Depression Scale) depression score fell from 6.6 at baseline to 4.1, while the HADS anxiety score dropped from 9.3 to 7.1. All of these differences were statistically significant and clinically meaningful, commented Dr. Bendsten of the University of Copenhagen.

Dr. Tassorelli noted that detoxification in the COMOESTAS study could be carried out on either an inpatient or outpatient basis, depending upon local practice. The 6-month results were closely similar regardless of the detoxification setting, meaning that outpatient detoxification, which is vastly less expensive, is clearly the winning strategy.

The COMOESTAS protocol began with a day 1 detailed explanation of the vicious cycle of MOH and advice to the patient to abruptly stop the overused medication. Rescue medication could be employed on days 1-7 to combat withdrawal headaches, with the drug, dose, and route of administration to be chosen from a menu based upon the patient’s medical history and headache characteristics. Options included a variety of antiemetics, acetaminophen, and naproxen.

Preventive therapy was started within the first 7 days. The options were propranolol, atenolol, metoprolol, valproic acid, topiramate, candesartan, flunarizine, or amitriptyline. The selection was based upon comorbid conditions, patient preference, and side effect profiles.

Acute headache medication was permitted beginning on day 8 for a maximum of 2 days per week. The inviolable rule was that patients could not use the same drug that was previously overused.

Elsewhere at the conference, European Headache Federation president and COMOESTAS coinvestigator Dr. Rigmor Højland Jensen diverged from providing an update on the therapeutic pipeline for migraine to draw special attention to the importance of detoxifying patients with MOH.

"This is something we can do starting Monday morning. We don’t have to have a bag full of new drugs. We can do a lot for these patients now," said Dr. Jensen, professor of neurology at the University of Copenhagen.

The COMOESTAS project is funded by the European Commission. The investigators reported having no financial conflicts.

b.jancin@elsevier.com

LONDON – A simple, straightforward protocol for management of medication-overuse headache has established its clinical utility in the large joint European/Latin American COMOESTAS study.

"These findings confirm the efficacy, the usability worldwide, and the low economic cost of detoxifying patients with medication-overuse headache," Dr. Cristina Tassorelli said in presenting the COMOESTAS data at the European Headache and Migraine Trust International Congress.

The protocol utilized in COMOESTAS (continuous monitoring of medication-overuse headache in Europe and Latin America: development and standardization of an alert and decision support system) consists of abrupt detoxification, patient education, early initiation of individualized prophylactic therapy, and regular scheduled follow-up by one dedicated physician guided by electronic support. Patients maintain an electronic medical diary which automatically signals their physician if they begin to slide down the slope toward relapse, explained Dr. Tassorelli, a neurologist at the University of Pavia (Italy).

Medication-overuse headache (MOH) is a common and disabling condition. It affects 1%-3% of the general population and 20%-60% of patients in specialized headache clinics. It occurs when patients with chronic headache, most often migraine without aura, experience a worsening of their headaches and respond by using more and more acute medication – triptans and/or NSAIDs – which in turn paradoxically exacerbates their headache pattern. MOH is defined by the occurrence of headache on at least 15 days/month coupled with use of triptans on 10 or more days/month or NSAIDs on at least 15 days/month.

MOH is treatable via detoxification but typically has a relapse rate of 30%-40% within the following 6 months. The COMOESTAS protocol, in contrast, had a 6-month relapse rate of 10%.

The COMOESTAS protocol for MOH was devised by expert consensus. It is designed as a first-line intervention for MOH patients who are detoxification-naive.

"Three-quarters of first timers will do well with this approach. It’s a good tool for stratifying patients: If they relapse, then they need a more intensive multidisciplinary approach," Dr. Tassorelli explained.

In a separate presentation, COMOESTAS coinvestigator Dr. Lars Bendsten reported that the management protocol proved successful not only in terms of the primary outcome measures of reduced headache frequency and fewer days per month of acute medication use but also from the standpoint of reduced depression, anxiety, and disability along with improved quality of life.

Among 519 COMOESTAS participants who completed 6 months of follow-up at centers in Spain, Italy, Denmark, Germany, Argentina, and Chile, the mean number of headache days per month fell from 23.6 at baseline to 9.8. Days of acute drug therapy dropped in sync.

Moreover, quality of life as assessed using the MIDAS (Migraine Disability Assessment Score) scale improved from 59.8 to 25.5. The mean HADS (Hospital Anxiety and Depression Scale) depression score fell from 6.6 at baseline to 4.1, while the HADS anxiety score dropped from 9.3 to 7.1. All of these differences were statistically significant and clinically meaningful, commented Dr. Bendsten of the University of Copenhagen.

Dr. Tassorelli noted that detoxification in the COMOESTAS study could be carried out on either an inpatient or outpatient basis, depending upon local practice. The 6-month results were closely similar regardless of the detoxification setting, meaning that outpatient detoxification, which is vastly less expensive, is clearly the winning strategy.

The COMOESTAS protocol began with a day 1 detailed explanation of the vicious cycle of MOH and advice to the patient to abruptly stop the overused medication. Rescue medication could be employed on days 1-7 to combat withdrawal headaches, with the drug, dose, and route of administration to be chosen from a menu based upon the patient’s medical history and headache characteristics. Options included a variety of antiemetics, acetaminophen, and naproxen.

Preventive therapy was started within the first 7 days. The options were propranolol, atenolol, metoprolol, valproic acid, topiramate, candesartan, flunarizine, or amitriptyline. The selection was based upon comorbid conditions, patient preference, and side effect profiles.

Acute headache medication was permitted beginning on day 8 for a maximum of 2 days per week. The inviolable rule was that patients could not use the same drug that was previously overused.

Elsewhere at the conference, European Headache Federation president and COMOESTAS coinvestigator Dr. Rigmor Højland Jensen diverged from providing an update on the therapeutic pipeline for migraine to draw special attention to the importance of detoxifying patients with MOH.

"This is something we can do starting Monday morning. We don’t have to have a bag full of new drugs. We can do a lot for these patients now," said Dr. Jensen, professor of neurology at the University of Copenhagen.

The COMOESTAS project is funded by the European Commission. The investigators reported having no financial conflicts.

b.jancin@elsevier.com

LONDON – The recent discovery of the first four genetic susceptibility loci for migraine without aura has zero clinical relevance today for migraine patients or their physicians, according to experts on migraine genetics.

"Whenever there is a new genetic study, you can easily become almost convinced that now we have the gene and we can treat migraine better. No! Currently there is no indication to test migraine patients for specific genes. It wouldn’t help you at all in terms of treatment or prognosis," Dr. Tobias Kurth emphasized at the European Headache and Migraine Trust International Congress.

"Make no mistake: We have achieved a lot over the last years, and many groups continue to do extraordinary work. However, we all have to realize that we still don’t know the precise mechanisms involved in genetic markers of migraine. We haven’t really shown that having these genes is a predictive tool that can tell patients that they will get migraine, or if they have it what their disease course will be," added Dr. Kurth, director of research at the French National Institute of Health and Medical Research, Bordeaux.

Dr. Arn M.J.M. van den Maagdenberg, a coauthor of the recently published genomewide association study that identified the first four susceptibility loci for migraine without aura (Nat. Gen. 2012;44:777-82), presented highlights of the ambitious study, which was carried out by the International Headache Genetics Consortium. The study involved testing 2,326 headache clinic patients with migraine without aura and 4,580 matched controls for roughly 500,000 genetic variants. The investigators then confirmed their results in a separate replication cohort composed of 2,508 patients with migraine without aura and 2,652 controls.

Dr. van den Maagdenberg was quick to agree that the results aren’t clinically relevant, in part because the four genes explain only a small portion of the genetic variance in migraine. However, the findings do implicate specific pathways of importance in the disease process, he noted.

"You can plot these four genes in three different pathways: neuronal, vascular, and pain. You may think you already knew that these pathways are important in migraine, but now we have molecular proof that migraine patients do indeed have genes that predispose them to migraine based on these pathways. Of course, we’ll need to do a lot of further studies of different kinds in order to identify the mechanisms involved," said Dr. van den Maagdenberg of Leiden (the Netherlands) University.

Of the four novel migraine genes, three – MEF2D, ASTN2, and PHACTR1 – are involved in the neuronal pathway. PHACTR1 also figures in the vascular pathway of migraine. And TGFBR2 plays roles in both the vascular and pain pathways, according to the neurologist.

Dr. Kurth has personal experience in fielding overreaction to genetic study findings, both by the public and by health professionals. He was a coinvestigator in a much-publicized report from the Women’s Genome Health Study that identified five single nucleotide polymorphisms (SNPs), or susceptibility loci, that may be associated with increased risk of cardiovascular events in women with migraine.

This was a genomewide association study of 5,122 women with migraine who were followed for 12 years as part of the National Institutes of Health–sponsored Women’s Health Study. One susceptibility locus was associated with a statistically significant and sky-high 12.3-fold risk of cardiovascular death during follow-up. Two others were linked to impressive-sounding 5- and 6.4-fold increased risks of ischemic stroke in women with migraine with aura (PLoS One 2011;6:e22106). But neither Dr. Kurth nor his coworkers really believe those numbers.

"Those odds ratios look quite high, but the number of outcome events is extraordinarily small here: 164 cardiovascular events in 12 years. So despite the statistical significance, these odds ratios are completely meaningless. We have to be extremely careful not to say that these genes are actually the cause of women with migraine getting cardiovascular disease. This is a hypothesis-generating study," Dr. Kurth explained.

Dr. Kurth and Dr. van den Maagdenberg reported having no financial conflicts.

LONDON – The recent discovery of the first four genetic susceptibility loci for migraine without aura has zero clinical relevance today for migraine patients or their physicians, according to experts on migraine genetics.

"Whenever there is a new genetic study, you can easily become almost convinced that now we have the gene and we can treat migraine better. No! Currently there is no indication to test migraine patients for specific genes. It wouldn’t help you at all in terms of treatment or prognosis," Dr. Tobias Kurth emphasized at the European Headache and Migraine Trust International Congress.

"Make no mistake: We have achieved a lot over the last years, and many groups continue to do extraordinary work. However, we all have to realize that we still don’t know the precise mechanisms involved in genetic markers of migraine. We haven’t really shown that having these genes is a predictive tool that can tell patients that they will get migraine, or if they have it what their disease course will be," added Dr. Kurth, director of research at the French National Institute of Health and Medical Research, Bordeaux.

Dr. Arn M.J.M. van den Maagdenberg, a coauthor of the recently published genomewide association study that identified the first four susceptibility loci for migraine without aura (Nat. Gen. 2012;44:777-82), presented highlights of the ambitious study, which was carried out by the International Headache Genetics Consortium. The study involved testing 2,326 headache clinic patients with migraine without aura and 4,580 matched controls for roughly 500,000 genetic variants. The investigators then confirmed their results in a separate replication cohort composed of 2,508 patients with migraine without aura and 2,652 controls.

Dr. van den Maagdenberg was quick to agree that the results aren’t clinically relevant, in part because the four genes explain only a small portion of the genetic variance in migraine. However, the findings do implicate specific pathways of importance in the disease process, he noted.

"You can plot these four genes in three different pathways: neuronal, vascular, and pain. You may think you already knew that these pathways are important in migraine, but now we have molecular proof that migraine patients do indeed have genes that predispose them to migraine based on these pathways. Of course, we’ll need to do a lot of further studies of different kinds in order to identify the mechanisms involved," said Dr. van den Maagdenberg of Leiden (the Netherlands) University.

Of the four novel migraine genes, three – MEF2D, ASTN2, and PHACTR1 – are involved in the neuronal pathway. PHACTR1 also figures in the vascular pathway of migraine. And TGFBR2 plays roles in both the vascular and pain pathways, according to the neurologist.

Dr. Kurth has personal experience in fielding overreaction to genetic study findings, both by the public and by health professionals. He was a coinvestigator in a much-publicized report from the Women’s Genome Health Study that identified five single nucleotide polymorphisms (SNPs), or susceptibility loci, that may be associated with increased risk of cardiovascular events in women with migraine.

This was a genomewide association study of 5,122 women with migraine who were followed for 12 years as part of the National Institutes of Health–sponsored Women’s Health Study. One susceptibility locus was associated with a statistically significant and sky-high 12.3-fold risk of cardiovascular death during follow-up. Two others were linked to impressive-sounding 5- and 6.4-fold increased risks of ischemic stroke in women with migraine with aura (PLoS One 2011;6:e22106). But neither Dr. Kurth nor his coworkers really believe those numbers.

"Those odds ratios look quite high, but the number of outcome events is extraordinarily small here: 164 cardiovascular events in 12 years. So despite the statistical significance, these odds ratios are completely meaningless. We have to be extremely careful not to say that these genes are actually the cause of women with migraine getting cardiovascular disease. This is a hypothesis-generating study," Dr. Kurth explained.

Dr. Kurth and Dr. van den Maagdenberg reported having no financial conflicts.

LONDON – The recent discovery of the first four genetic susceptibility loci for migraine without aura has zero clinical relevance today for migraine patients or their physicians, according to experts on migraine genetics.

"Whenever there is a new genetic study, you can easily become almost convinced that now we have the gene and we can treat migraine better. No! Currently there is no indication to test migraine patients for specific genes. It wouldn’t help you at all in terms of treatment or prognosis," Dr. Tobias Kurth emphasized at the European Headache and Migraine Trust International Congress.

"Make no mistake: We have achieved a lot over the last years, and many groups continue to do extraordinary work. However, we all have to realize that we still don’t know the precise mechanisms involved in genetic markers of migraine. We haven’t really shown that having these genes is a predictive tool that can tell patients that they will get migraine, or if they have it what their disease course will be," added Dr. Kurth, director of research at the French National Institute of Health and Medical Research, Bordeaux.

Dr. Arn M.J.M. van den Maagdenberg, a coauthor of the recently published genomewide association study that identified the first four susceptibility loci for migraine without aura (Nat. Gen. 2012;44:777-82), presented highlights of the ambitious study, which was carried out by the International Headache Genetics Consortium. The study involved testing 2,326 headache clinic patients with migraine without aura and 4,580 matched controls for roughly 500,000 genetic variants. The investigators then confirmed their results in a separate replication cohort composed of 2,508 patients with migraine without aura and 2,652 controls.

Dr. van den Maagdenberg was quick to agree that the results aren’t clinically relevant, in part because the four genes explain only a small portion of the genetic variance in migraine. However, the findings do implicate specific pathways of importance in the disease process, he noted.

"You can plot these four genes in three different pathways: neuronal, vascular, and pain. You may think you already knew that these pathways are important in migraine, but now we have molecular proof that migraine patients do indeed have genes that predispose them to migraine based on these pathways. Of course, we’ll need to do a lot of further studies of different kinds in order to identify the mechanisms involved," said Dr. van den Maagdenberg of Leiden (the Netherlands) University.

Of the four novel migraine genes, three – MEF2D, ASTN2, and PHACTR1 – are involved in the neuronal pathway. PHACTR1 also figures in the vascular pathway of migraine. And TGFBR2 plays roles in both the vascular and pain pathways, according to the neurologist.

Dr. Kurth has personal experience in fielding overreaction to genetic study findings, both by the public and by health professionals. He was a coinvestigator in a much-publicized report from the Women’s Genome Health Study that identified five single nucleotide polymorphisms (SNPs), or susceptibility loci, that may be associated with increased risk of cardiovascular events in women with migraine.

This was a genomewide association study of 5,122 women with migraine who were followed for 12 years as part of the National Institutes of Health–sponsored Women’s Health Study. One susceptibility locus was associated with a statistically significant and sky-high 12.3-fold risk of cardiovascular death during follow-up. Two others were linked to impressive-sounding 5- and 6.4-fold increased risks of ischemic stroke in women with migraine with aura (PLoS One 2011;6:e22106). But neither Dr. Kurth nor his coworkers really believe those numbers.

"Those odds ratios look quite high, but the number of outcome events is extraordinarily small here: 164 cardiovascular events in 12 years. So despite the statistical significance, these odds ratios are completely meaningless. We have to be extremely careful not to say that these genes are actually the cause of women with migraine getting cardiovascular disease. This is a hypothesis-generating study," Dr. Kurth explained.

Dr. Kurth and Dr. van den Maagdenberg reported having no financial conflicts.

LONDON – The drug development pipeline for migraine holds numerous promising new classes of medications addressing novel therapeutic targets – and that’s welcome news because recent surveys indicate a substantial proportion of migraineurs aren’t satisfied with their current options for acute treatment and prophylaxis.

However, most of the novel agents are in only phase II studies. And snares abound on the path ahead to the marketplace, as recent history demonstrates.

The pharmaceutical industry seems less enthusiastic overall about developing new drugs for headache now than it was 15 years ago. It’s a shame because an enormous underserved market exists for new agents that can offer the triad of efficacy, convenience, and tolerability, Dr. Rigmor Højland Jensen said at the European Headache and Migraine Trust International Congress.

A chill was cast over the field of headache treatment development last year when Merck abruptly announced a halt to further development of telcagepant, a previously highly promising, first-in-class calcitonin gene-related peptide (CGRP) antagonist, after elevated liver enzymes emerged as a concern in analysis of a completed phase III randomized clinical trial, she said.

CGRP plays a key role in neurovasoconstriction. The promise of the CGRP antagonists for short-term treatment of migraine is that they will provide the cerebral vasodilatory efficacy of the triptans without the cardiovascular side effects. However, the future post-telcagepant remains uncertain for other agents in this class, including Boehringer Ingelheim’s olcegepant as well as other CGRP antagonists in phase II studies being developed by Bristol-Myers Squibb, Eli Lilly, and Merck, noted Dr. Jensen, president of the European Headache Federation and professor of neurology at the University of Copenhagen.

Meanwhile, the development of highly selective antibodies to CGRP looks very promising, although these agents are still in the preclinical stage.

Dr. Jensen said surveys indicate roughly 40% of patients with migraine are unhappy with the triptans and simple analgesics used as first-line short-term therapy, either because of lack of efficacy or side effects. Moreover, the current options for migraine prophylaxis leave much to be desired.

"We don’t know how prophylaxis works. It’s nonspecific, often ineffective, and has side effects. We really need good prophylactics without side effects," Dr. Jensen said.

The drug furthest along in development for acute migraine is oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor antagonist with no vascular effects. Lasmiditan, being developed by CoLucid Pharmaceuticals, is currently in phase III trials.

"This one is just around the corner," according to the neurologist.

In a recent phase II study, lasmiditan showed an excellent response rate 2 hours after administration, with no vasoconstriction (Lancet Neurol. 2012;11:405-13).

Nitric oxide synthase (NOS) has emerged as a promising new nonvascular target for acute migraine therapy. NeurAxon, a Canadian company, has developed a first-in-class selective inhibitor of the neuronal form of NOS, which modulates the central and peripheral response to pain and neuronal sensitization.

In a recent randomized, placebo-controlled phase II study of 179 patients with migraine without aura, this agent, known for now as NXN-188, produced prolonged pain relief that became significant beginning 3 hours after administration and remained so for 24 hours even though rescue medication wasn’t permitted. The side effect profile was reassuringly benign.

Other companies have developed selective inhibitors of the inducible form of NOS, which is released by macrophages. Inducible NOS participates in the immune response to stress and inflammation, making it another attractive target for acute migraine therapy, Dr. Jensen continued.

Turning to emerging agents for migraine prophylaxis, she highlighted several novel drugs now in phase II studies: DP-VPA, a valproic acid prodrug being developed by the Israeli company D-Pharm; a botanically sourced compound, MGX-008, that comes from the bark of the Monterey pine and is under development by Migco; an oral leukotriene D₄ receptor antagonist backed by Lilly; and lacosamide, also known as BGG492, an AMPA/kainate glutamate receptor antagonist under development by Novartis.

In addition, a couple of very familiar drugs – the angiotensin receptor blocker candesartan and the muscle relaxant cyclobenzaprine – are now in phase III trials for migraine prevention.

Dr. Jensen reported serving on the advisory boards for ATI, Medotech, Neurocore, and Linde Gas and on the speakers bureaus for Pfizer, Merck, and NorPharma.

LONDON – The drug development pipeline for migraine holds numerous promising new classes of medications addressing novel therapeutic targets – and that’s welcome news because recent surveys indicate a substantial proportion of migraineurs aren’t satisfied with their current options for acute treatment and prophylaxis.

However, most of the novel agents are in only phase II studies. And snares abound on the path ahead to the marketplace, as recent history demonstrates.

The pharmaceutical industry seems less enthusiastic overall about developing new drugs for headache now than it was 15 years ago. It’s a shame because an enormous underserved market exists for new agents that can offer the triad of efficacy, convenience, and tolerability, Dr. Rigmor Højland Jensen said at the European Headache and Migraine Trust International Congress.

A chill was cast over the field of headache treatment development last year when Merck abruptly announced a halt to further development of telcagepant, a previously highly promising, first-in-class calcitonin gene-related peptide (CGRP) antagonist, after elevated liver enzymes emerged as a concern in analysis of a completed phase III randomized clinical trial, she said.

CGRP plays a key role in neurovasoconstriction. The promise of the CGRP antagonists for short-term treatment of migraine is that they will provide the cerebral vasodilatory efficacy of the triptans without the cardiovascular side effects. However, the future post-telcagepant remains uncertain for other agents in this class, including Boehringer Ingelheim’s olcegepant as well as other CGRP antagonists in phase II studies being developed by Bristol-Myers Squibb, Eli Lilly, and Merck, noted Dr. Jensen, president of the European Headache Federation and professor of neurology at the University of Copenhagen.

Meanwhile, the development of highly selective antibodies to CGRP looks very promising, although these agents are still in the preclinical stage.

Dr. Jensen said surveys indicate roughly 40% of patients with migraine are unhappy with the triptans and simple analgesics used as first-line short-term therapy, either because of lack of efficacy or side effects. Moreover, the current options for migraine prophylaxis leave much to be desired.

"We don’t know how prophylaxis works. It’s nonspecific, often ineffective, and has side effects. We really need good prophylactics without side effects," Dr. Jensen said.

The drug furthest along in development for acute migraine is oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor antagonist with no vascular effects. Lasmiditan, being developed by CoLucid Pharmaceuticals, is currently in phase III trials.

"This one is just around the corner," according to the neurologist.

In a recent phase II study, lasmiditan showed an excellent response rate 2 hours after administration, with no vasoconstriction (Lancet Neurol. 2012;11:405-13).

Nitric oxide synthase (NOS) has emerged as a promising new nonvascular target for acute migraine therapy. NeurAxon, a Canadian company, has developed a first-in-class selective inhibitor of the neuronal form of NOS, which modulates the central and peripheral response to pain and neuronal sensitization.

In a recent randomized, placebo-controlled phase II study of 179 patients with migraine without aura, this agent, known for now as NXN-188, produced prolonged pain relief that became significant beginning 3 hours after administration and remained so for 24 hours even though rescue medication wasn’t permitted. The side effect profile was reassuringly benign.

Other companies have developed selective inhibitors of the inducible form of NOS, which is released by macrophages. Inducible NOS participates in the immune response to stress and inflammation, making it another attractive target for acute migraine therapy, Dr. Jensen continued.

Turning to emerging agents for migraine prophylaxis, she highlighted several novel drugs now in phase II studies: DP-VPA, a valproic acid prodrug being developed by the Israeli company D-Pharm; a botanically sourced compound, MGX-008, that comes from the bark of the Monterey pine and is under development by Migco; an oral leukotriene D₄ receptor antagonist backed by Lilly; and lacosamide, also known as BGG492, an AMPA/kainate glutamate receptor antagonist under development by Novartis.

In addition, a couple of very familiar drugs – the angiotensin receptor blocker candesartan and the muscle relaxant cyclobenzaprine – are now in phase III trials for migraine prevention.

Dr. Jensen reported serving on the advisory boards for ATI, Medotech, Neurocore, and Linde Gas and on the speakers bureaus for Pfizer, Merck, and NorPharma.

LONDON – The drug development pipeline for migraine holds numerous promising new classes of medications addressing novel therapeutic targets – and that’s welcome news because recent surveys indicate a substantial proportion of migraineurs aren’t satisfied with their current options for acute treatment and prophylaxis.

However, most of the novel agents are in only phase II studies. And snares abound on the path ahead to the marketplace, as recent history demonstrates.

The pharmaceutical industry seems less enthusiastic overall about developing new drugs for headache now than it was 15 years ago. It’s a shame because an enormous underserved market exists for new agents that can offer the triad of efficacy, convenience, and tolerability, Dr. Rigmor Højland Jensen said at the European Headache and Migraine Trust International Congress.

A chill was cast over the field of headache treatment development last year when Merck abruptly announced a halt to further development of telcagepant, a previously highly promising, first-in-class calcitonin gene-related peptide (CGRP) antagonist, after elevated liver enzymes emerged as a concern in analysis of a completed phase III randomized clinical trial, she said.

CGRP plays a key role in neurovasoconstriction. The promise of the CGRP antagonists for short-term treatment of migraine is that they will provide the cerebral vasodilatory efficacy of the triptans without the cardiovascular side effects. However, the future post-telcagepant remains uncertain for other agents in this class, including Boehringer Ingelheim’s olcegepant as well as other CGRP antagonists in phase II studies being developed by Bristol-Myers Squibb, Eli Lilly, and Merck, noted Dr. Jensen, president of the European Headache Federation and professor of neurology at the University of Copenhagen.

Meanwhile, the development of highly selective antibodies to CGRP looks very promising, although these agents are still in the preclinical stage.

Dr. Jensen said surveys indicate roughly 40% of patients with migraine are unhappy with the triptans and simple analgesics used as first-line short-term therapy, either because of lack of efficacy or side effects. Moreover, the current options for migraine prophylaxis leave much to be desired.

"We don’t know how prophylaxis works. It’s nonspecific, often ineffective, and has side effects. We really need good prophylactics without side effects," Dr. Jensen said.

The drug furthest along in development for acute migraine is oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor antagonist with no vascular effects. Lasmiditan, being developed by CoLucid Pharmaceuticals, is currently in phase III trials.

"This one is just around the corner," according to the neurologist.

In a recent phase II study, lasmiditan showed an excellent response rate 2 hours after administration, with no vasoconstriction (Lancet Neurol. 2012;11:405-13).

Nitric oxide synthase (NOS) has emerged as a promising new nonvascular target for acute migraine therapy. NeurAxon, a Canadian company, has developed a first-in-class selective inhibitor of the neuronal form of NOS, which modulates the central and peripheral response to pain and neuronal sensitization.

In a recent randomized, placebo-controlled phase II study of 179 patients with migraine without aura, this agent, known for now as NXN-188, produced prolonged pain relief that became significant beginning 3 hours after administration and remained so for 24 hours even though rescue medication wasn’t permitted. The side effect profile was reassuringly benign.

Other companies have developed selective inhibitors of the inducible form of NOS, which is released by macrophages. Inducible NOS participates in the immune response to stress and inflammation, making it another attractive target for acute migraine therapy, Dr. Jensen continued.

Turning to emerging agents for migraine prophylaxis, she highlighted several novel drugs now in phase II studies: DP-VPA, a valproic acid prodrug being developed by the Israeli company D-Pharm; a botanically sourced compound, MGX-008, that comes from the bark of the Monterey pine and is under development by Migco; an oral leukotriene D₄ receptor antagonist backed by Lilly; and lacosamide, also known as BGG492, an AMPA/kainate glutamate receptor antagonist under development by Novartis.

In addition, a couple of very familiar drugs – the angiotensin receptor blocker candesartan and the muscle relaxant cyclobenzaprine – are now in phase III trials for migraine prevention.

Dr. Jensen reported serving on the advisory boards for ATI, Medotech, Neurocore, and Linde Gas and on the speakers bureaus for Pfizer, Merck, and NorPharma.

LONDON – Funding for headache research and therapy gets the short end of the stick in European neurology.

Two ambitious recent studies tell the tale. One, carried out by the European Brain Council, estimated the annual costs for 19 categories of brain disorders, both neurologic and psychiatric, in 30 European countries. The other study focused specifically on the direct and indirect monetary costs of the major headache disorders, including migraine, tension-type headache, and medication-overuse headache.

Dr. Rigmor Højland Jensen referenced both studies in her address as incoming president of the European Headache Federation at the European Headache and Migraine Trust International Congress.

"Headache is competing with other diseases for funding. These are very important studies we have to include in our arguments all the time," said Dr. Jensen, professor of neurology at the University of Copenhagen.

The European Brain Council study (Eur. J. Neurol. 2012;19:155-62) employed sophisticated modeling techniques to estimate the total cost of brain disorders in Europe in 2010 at 798 billion euros. That’s an average of 1,550 euros per inhabitant.

The average cost per European with a headache disorder in 2010 was 285 euros, a figure that pales in comparison to the 30,000 euros per patient with a neuromuscular disorder. Because headache disorders are so common, though, the total annual cost for headache disorders was calculated at a hefty 43.5 billion euros.

In contrast, the annual total cost for neuromuscular disorders was 7.7 billion euros; for epilepsy, 13.8 billion euros; multiple sclerosis, 14.6 billion euros; Parkinson’s disease, 13.9 billion euros; and traumatic brain injury, 33 billion euros.

"Headaches cost more than epilepsy, multiple sclerosis, and Parkinson’s disease together. And yet how much more research in your department and how many more resources are dedicated to treating these three disorders, compared with headache?" Dr. Jensen asked.

For 2010, the costliest brain disorders in Europe included dementia at 105.2 billion euros, stroke at 64.1 billion euros, and several psychiatric disorders: psychotic disorders came in at 93.9 billion euros, mood disorders at 113.4 billion euros, anxiety disorders at 74.4 billion euros, and addiction disorders at 65.7 billion euros. In addition, the cost of personality disorders was estimated at 27.3 billion euros and somatoform disorders at 21.2 billion euros.

The headache cost study, known as the Eurolight Project, involved extrapolation from a detailed cross-sectional survey conducted in 8,412 individuals in eight countries representing 55% of the adult European Union population.

The investigators calculated the annual cost of headache among 18- to 65-year-olds in the European Union at 173 billion euros. That’s considerably more than the 43.5 billion euros figure cited in the European Brain Council study because, in figuring the estimated indirect costs associated with headache, the Eurolight Project investigators included not only work absenteeism but also reduced productivity while at work.

Sixty-four percent of the estimated annual cost of headache among European adults was apportioned to migraine, 21% to medication-overuse headache, 12% to tension-type headache, and the remainder to other headaches (Eur. J. Neurol. 2012;19:703-11).

Dr. Jensen reported financial relationships with ATI, Medotech, Merck, Neurocore, NorPharma, and Pfizer.

B.Jancin@elsevier.com

LONDON – Funding for headache research and therapy gets the short end of the stick in European neurology.

Two ambitious recent studies tell the tale. One, carried out by the European Brain Council, estimated the annual costs for 19 categories of brain disorders, both neurologic and psychiatric, in 30 European countries. The other study focused specifically on the direct and indirect monetary costs of the major headache disorders, including migraine, tension-type headache, and medication-overuse headache.

Dr. Rigmor Højland Jensen referenced both studies in her address as incoming president of the European Headache Federation at the European Headache and Migraine Trust International Congress.

"Headache is competing with other diseases for funding. These are very important studies we have to include in our arguments all the time," said Dr. Jensen, professor of neurology at the University of Copenhagen.

The European Brain Council study (Eur. J. Neurol. 2012;19:155-62) employed sophisticated modeling techniques to estimate the total cost of brain disorders in Europe in 2010 at 798 billion euros. That’s an average of 1,550 euros per inhabitant.

The average cost per European with a headache disorder in 2010 was 285 euros, a figure that pales in comparison to the 30,000 euros per patient with a neuromuscular disorder. Because headache disorders are so common, though, the total annual cost for headache disorders was calculated at a hefty 43.5 billion euros.

In contrast, the annual total cost for neuromuscular disorders was 7.7 billion euros; for epilepsy, 13.8 billion euros; multiple sclerosis, 14.6 billion euros; Parkinson’s disease, 13.9 billion euros; and traumatic brain injury, 33 billion euros.

"Headaches cost more than epilepsy, multiple sclerosis, and Parkinson’s disease together. And yet how much more research in your department and how many more resources are dedicated to treating these three disorders, compared with headache?" Dr. Jensen asked.

For 2010, the costliest brain disorders in Europe included dementia at 105.2 billion euros, stroke at 64.1 billion euros, and several psychiatric disorders: psychotic disorders came in at 93.9 billion euros, mood disorders at 113.4 billion euros, anxiety disorders at 74.4 billion euros, and addiction disorders at 65.7 billion euros. In addition, the cost of personality disorders was estimated at 27.3 billion euros and somatoform disorders at 21.2 billion euros.

The headache cost study, known as the Eurolight Project, involved extrapolation from a detailed cross-sectional survey conducted in 8,412 individuals in eight countries representing 55% of the adult European Union population.

The investigators calculated the annual cost of headache among 18- to 65-year-olds in the European Union at 173 billion euros. That’s considerably more than the 43.5 billion euros figure cited in the European Brain Council study because, in figuring the estimated indirect costs associated with headache, the Eurolight Project investigators included not only work absenteeism but also reduced productivity while at work.

Sixty-four percent of the estimated annual cost of headache among European adults was apportioned to migraine, 21% to medication-overuse headache, 12% to tension-type headache, and the remainder to other headaches (Eur. J. Neurol. 2012;19:703-11).

Dr. Jensen reported financial relationships with ATI, Medotech, Merck, Neurocore, NorPharma, and Pfizer.

B.Jancin@elsevier.com

LONDON – Funding for headache research and therapy gets the short end of the stick in European neurology.

Two ambitious recent studies tell the tale. One, carried out by the European Brain Council, estimated the annual costs for 19 categories of brain disorders, both neurologic and psychiatric, in 30 European countries. The other study focused specifically on the direct and indirect monetary costs of the major headache disorders, including migraine, tension-type headache, and medication-overuse headache.

Dr. Rigmor Højland Jensen referenced both studies in her address as incoming president of the European Headache Federation at the European Headache and Migraine Trust International Congress.

"Headache is competing with other diseases for funding. These are very important studies we have to include in our arguments all the time," said Dr. Jensen, professor of neurology at the University of Copenhagen.

The European Brain Council study (Eur. J. Neurol. 2012;19:155-62) employed sophisticated modeling techniques to estimate the total cost of brain disorders in Europe in 2010 at 798 billion euros. That’s an average of 1,550 euros per inhabitant.

The average cost per European with a headache disorder in 2010 was 285 euros, a figure that pales in comparison to the 30,000 euros per patient with a neuromuscular disorder. Because headache disorders are so common, though, the total annual cost for headache disorders was calculated at a hefty 43.5 billion euros.

In contrast, the annual total cost for neuromuscular disorders was 7.7 billion euros; for epilepsy, 13.8 billion euros; multiple sclerosis, 14.6 billion euros; Parkinson’s disease, 13.9 billion euros; and traumatic brain injury, 33 billion euros.

"Headaches cost more than epilepsy, multiple sclerosis, and Parkinson’s disease together. And yet how much more research in your department and how many more resources are dedicated to treating these three disorders, compared with headache?" Dr. Jensen asked.

For 2010, the costliest brain disorders in Europe included dementia at 105.2 billion euros, stroke at 64.1 billion euros, and several psychiatric disorders: psychotic disorders came in at 93.9 billion euros, mood disorders at 113.4 billion euros, anxiety disorders at 74.4 billion euros, and addiction disorders at 65.7 billion euros. In addition, the cost of personality disorders was estimated at 27.3 billion euros and somatoform disorders at 21.2 billion euros.

The headache cost study, known as the Eurolight Project, involved extrapolation from a detailed cross-sectional survey conducted in 8,412 individuals in eight countries representing 55% of the adult European Union population.

The investigators calculated the annual cost of headache among 18- to 65-year-olds in the European Union at 173 billion euros. That’s considerably more than the 43.5 billion euros figure cited in the European Brain Council study because, in figuring the estimated indirect costs associated with headache, the Eurolight Project investigators included not only work absenteeism but also reduced productivity while at work.

Sixty-four percent of the estimated annual cost of headache among European adults was apportioned to migraine, 21% to medication-overuse headache, 12% to tension-type headache, and the remainder to other headaches (Eur. J. Neurol. 2012;19:703-11).

Dr. Jensen reported financial relationships with ATI, Medotech, Merck, Neurocore, NorPharma, and Pfizer.

B.Jancin@elsevier.com

LONDON – Enthusiasm is mounting among headache specialists for noninvasive device therapy for acute migraine.

"Normally I’m quite a cynical person, but I think within 10 years time half of my people in the headache clinic won’t be using any medications for their headaches. They’ll have an electronic device of some kind. You get your migraine sorted out, you put your device back in your pants pocket, and you carry on," Dr. Fayyaz Ahmed said at the European Headache and Migraine Trust International Congress.

"I think in about 10 years time you’ll have SIM cards for these neurostimulatory devices, you’ll put the card in an ATM-like machine – perhaps in a supermarket – and you’ll top it up and recharge it," predicted Dr. Ahmed, a consultant neurologist in Hull, England, and chair of the British Association for the Study of Headache.

The noninvasive neurostimulatory therapy most discussed at the congress was the Spring TMS single-pulse transcranial magnetic stimulation device, which since 2011 has been approved in Europe for the acute treatment of migraine. The Spring TMS device is manufactured by U.S.-based eNeura Therapeutics, which is seeking marketing approval from the Food and Drug Administration.

The international congress also saw the presentation of the first multicenter, randomized, sham-controlled study of the noninvasive Cefaly device for prevention of migraine via supraorbital transcutaneous neurostimulation.

"It’s not a revolutionary therapy. The effect size is moderate and inferior to that of the most effective preventive drugs. Its great advantage is that it’s devoid of side effects. I think the Cefaly device is another tool we can use for preventing migraine," Dr. Jean Schoenen concluded in presenting the study data.

Dr. Ahmed said physician and patient interest in noninvasive device therapy is being driven by the sizable proportion of migraine patients who don’t respond adequately to drug therapy, can’t tolerate it, or have contraindications to its use. Plus, some patients would just rather be drug free.

Neurostimulatory therapy for headache has followed an evolutionary process, progressing from highly invasive to minimally invasive and now to noninvasive devices, the neurologist observed.

First came deep brain stimulation of the subthalamic nucleus via implanted electrodes, which proved useful in treating Parkinson’s disease.

In the field of headache, there are 14 published studies of deep brain stimulation of the ventroposterior hypothalamus for treatment of intractable chronic cluster headache in a collective total of 64 patients. Two-thirds responded with at least a 50% decrease in pain. But this highly invasive form of therapy is not effective as acute therapy, only for prevention, and it entails a 3% rate of intracranial bleeding.

Next came minimally invasive systems for occipital nerve stimulation. Response rates have been variable in 10 published studies totaling roughly 500 patients treated for chronic migraine. In addition, the devices are quite expensive and are susceptible to lead migration or breakage and battery depletion.

"Only a couple of centers in the U.K. are doing occipital nerve stimulation now," according to Dr. Ahmed.

Yet there is still commercial interest in developing minimally invasive neurostimulatory therapy for headache. During the London headache congress, St. Jude Medical announced that its Eon family of neurostimulators had just received European regulatory approval for treatment of intractable chronic migraine. Among the newly approved devices is the Eon Mini, which weighs about an ounce and has a 10-mm profile.

The recently published 12-week, double-blind, multicenter pivotal study sponsored by St. Jude Medical involved 157 patients with chronic migraine randomized 2:1 to peripheral nerve stimulation or sham control. Of patients on active therapy, 35% achieved at least a 30% reduction in pain, a rate more than twice that in controls. The active treatment group also had a mean 6.1-day reduction in headache days per month from a baseline of 22 days, compared with a 3-day reduction in controls (Cephalalgia 2012 Oct. 3 [doi: 10.1177/0333102412462642]).

A company spokesperson said St. Jude Medical definitely plans to seek U.S. marketing approval for its Eon neurostimulators.

The best-studied noninvasive neurostimulatory device therapy for migraine is the single-pulse transcranial magnetic stimulation Spring TMS device. It delivers a complete treatment in less than a minute at the first sign of migraine pain and has a side effect profile similar to that of sham therapy in clinical trials, according to Dr. Kevin G. Shields, a neurologist at the National Hospital for Neurology and Neurosurgery in London.

Single-pulse transcranial magnetic stimulation has been in clinical use for 30 years, first diagnostically, then as therapy. The mechanism of benefit has been mapped out. The treatment’s safety is very well established; indeed, the FDA has classified it as a nonsignificant risk technology, he noted.

The major technical advance that’s occurred in single-pulse transcranial magnetic stimulation has been a radical reduction in capacitor size. The equipment has shrunk from refrigerator-size in the therapy’s early development, which took place in London, to the highly portable Spring TMS device that patients can stick in a briefcase and utilize unobtrusively at work, Dr. Shields observed.

The contraindications to use of the device are a history of epilepsy; the presence of metal objects in the head, neck, or upper body; and pacemakers or other cardiac devices.

The evidence base supporting the safety and efficacy of the Spring TMS device includes a published randomized, double-blind, sham-controlled clinical trial conducted in patients with migraine with aura (Lancet Neurol. 2010;9:373-80).

In addition, at the international congress Dr. Mark W. Weatherall of the University of Edinburgh, Scotland, presented the first results of an ongoing multicenter U.K. postmarketing study of the single-pulse transcranial magnetic stimulation device as used in clinical practice. The study population consisted of 13 patients with migraine without aura and 24 having migraine with aura who had been using the device for at least 3 months and collectively had treated 777 attacks.

Efficacy reports were:

• 73% of patients said the device showed good to excellent efficacy, reducing or even alleviating migraine pain. Sixty-three percent pronounced the therapy effective in diminishing other migraine symptoms.

• 55% reported a reduction in the number of headache days per month.

The mean attack duration was 2.46 days before transcranial magnetic stimulation therapy and 0.77 days after subjects started using the device. The benefits were reproducible over the 3-month study period and beyond, and no adverse events were reported, he said.

Dr. Jean Schoenen presented the first randomized trial data on the Cefaly device. The supraorbital transcutaneous neurostimulation device has been available in Europe for 5 years, but until now it had no supporting data from controlled trials.

The device consists of a thin silver band that looks like something out of Star Trek. It is hooked over the ears and worn across the forehead like futuristic sunglasses. Patients don it once daily for 20 minutes. The investigators set the programmable device to deliver a square pulse at 60 Hz, 300 microseconds, and a maximum of 14.99 mA.

The 3-month, multicenter, double-blind, sham-controlled Belgian study involved 67 patients with episodic migraine. The mean number of headache-days per month dropped significantly, from 6.9 at baseline to 4.9 at 3 months in the Cefaly group but was unchanged in controls. Thirty-eight percent of patients using the active device experienced at least a 50% reduction in their number of headache-days per month, compared with 12% of controls. Monthly consumption of triptans for acute therapy was reduced by 36% in the Cefaly-treated patients as a whole and by 75% in the Cefaly responders, reported Dr. Schoenen of the University of Liege, Belgium.

To get a crude idea of how supraorbital transcutaneous neurostimulation stacks up against standard prophylactic drug therapy, Dr. Schoenen turned to the extensive published randomized trial literature on topiramate. While the 50% or greater responder rate in the Cefaly trial was 38%, in the pooled topiramate data it’s 45%. Moreover, topiramate was associated with an impressive average 48% reduction in the number of migraine attacks per month, compared with a 19% decrease with the Cefaly device.

On the other hand, one in four patients assigned to topiramate in the randomized trials dropped out due to side effects. No one experienced any adverse effects from the device therapy, he noted.

This was an investigator-initiated study carried out by the Belgian Headache Society and sponsored by STX-Med, which markets the Cefaly device in Europe. Dr. Schoenen is on the advisory boards of St. Jude Medical, Allergan, and ATI. Dr. Ahmed, Dr. Shields, and Dr. Weatherall are on the speakers bureau for eNeura Therapeutics.

LONDON – Enthusiasm is mounting among headache specialists for noninvasive device therapy for acute migraine.

"Normally I’m quite a cynical person, but I think within 10 years time half of my people in the headache clinic won’t be using any medications for their headaches. They’ll have an electronic device of some kind. You get your migraine sorted out, you put your device back in your pants pocket, and you carry on," Dr. Fayyaz Ahmed said at the European Headache and Migraine Trust International Congress.

"I think in about 10 years time you’ll have SIM cards for these neurostimulatory devices, you’ll put the card in an ATM-like machine – perhaps in a supermarket – and you’ll top it up and recharge it," predicted Dr. Ahmed, a consultant neurologist in Hull, England, and chair of the British Association for the Study of Headache.

The noninvasive neurostimulatory therapy most discussed at the congress was the Spring TMS single-pulse transcranial magnetic stimulation device, which since 2011 has been approved in Europe for the acute treatment of migraine. The Spring TMS device is manufactured by U.S.-based eNeura Therapeutics, which is seeking marketing approval from the Food and Drug Administration.

The international congress also saw the presentation of the first multicenter, randomized, sham-controlled study of the noninvasive Cefaly device for prevention of migraine via supraorbital transcutaneous neurostimulation.

"It’s not a revolutionary therapy. The effect size is moderate and inferior to that of the most effective preventive drugs. Its great advantage is that it’s devoid of side effects. I think the Cefaly device is another tool we can use for preventing migraine," Dr. Jean Schoenen concluded in presenting the study data.

Dr. Ahmed said physician and patient interest in noninvasive device therapy is being driven by the sizable proportion of migraine patients who don’t respond adequately to drug therapy, can’t tolerate it, or have contraindications to its use. Plus, some patients would just rather be drug free.

Neurostimulatory therapy for headache has followed an evolutionary process, progressing from highly invasive to minimally invasive and now to noninvasive devices, the neurologist observed.

First came deep brain stimulation of the subthalamic nucleus via implanted electrodes, which proved useful in treating Parkinson’s disease.

In the field of headache, there are 14 published studies of deep brain stimulation of the ventroposterior hypothalamus for treatment of intractable chronic cluster headache in a collective total of 64 patients. Two-thirds responded with at least a 50% decrease in pain. But this highly invasive form of therapy is not effective as acute therapy, only for prevention, and it entails a 3% rate of intracranial bleeding.

Next came minimally invasive systems for occipital nerve stimulation. Response rates have been variable in 10 published studies totaling roughly 500 patients treated for chronic migraine. In addition, the devices are quite expensive and are susceptible to lead migration or breakage and battery depletion.

"Only a couple of centers in the U.K. are doing occipital nerve stimulation now," according to Dr. Ahmed.

Yet there is still commercial interest in developing minimally invasive neurostimulatory therapy for headache. During the London headache congress, St. Jude Medical announced that its Eon family of neurostimulators had just received European regulatory approval for treatment of intractable chronic migraine. Among the newly approved devices is the Eon Mini, which weighs about an ounce and has a 10-mm profile.

The recently published 12-week, double-blind, multicenter pivotal study sponsored by St. Jude Medical involved 157 patients with chronic migraine randomized 2:1 to peripheral nerve stimulation or sham control. Of patients on active therapy, 35% achieved at least a 30% reduction in pain, a rate more than twice that in controls. The active treatment group also had a mean 6.1-day reduction in headache days per month from a baseline of 22 days, compared with a 3-day reduction in controls (Cephalalgia 2012 Oct. 3 [doi: 10.1177/0333102412462642]).

A company spokesperson said St. Jude Medical definitely plans to seek U.S. marketing approval for its Eon neurostimulators.

The best-studied noninvasive neurostimulatory device therapy for migraine is the single-pulse transcranial magnetic stimulation Spring TMS device. It delivers a complete treatment in less than a minute at the first sign of migraine pain and has a side effect profile similar to that of sham therapy in clinical trials, according to Dr. Kevin G. Shields, a neurologist at the National Hospital for Neurology and Neurosurgery in London.

Single-pulse transcranial magnetic stimulation has been in clinical use for 30 years, first diagnostically, then as therapy. The mechanism of benefit has been mapped out. The treatment’s safety is very well established; indeed, the FDA has classified it as a nonsignificant risk technology, he noted.

The major technical advance that’s occurred in single-pulse transcranial magnetic stimulation has been a radical reduction in capacitor size. The equipment has shrunk from refrigerator-size in the therapy’s early development, which took place in London, to the highly portable Spring TMS device that patients can stick in a briefcase and utilize unobtrusively at work, Dr. Shields observed.

The contraindications to use of the device are a history of epilepsy; the presence of metal objects in the head, neck, or upper body; and pacemakers or other cardiac devices.

The evidence base supporting the safety and efficacy of the Spring TMS device includes a published randomized, double-blind, sham-controlled clinical trial conducted in patients with migraine with aura (Lancet Neurol. 2010;9:373-80).

In addition, at the international congress Dr. Mark W. Weatherall of the University of Edinburgh, Scotland, presented the first results of an ongoing multicenter U.K. postmarketing study of the single-pulse transcranial magnetic stimulation device as used in clinical practice. The study population consisted of 13 patients with migraine without aura and 24 having migraine with aura who had been using the device for at least 3 months and collectively had treated 777 attacks.

Efficacy reports were:

• 73% of patients said the device showed good to excellent efficacy, reducing or even alleviating migraine pain. Sixty-three percent pronounced the therapy effective in diminishing other migraine symptoms.

• 55% reported a reduction in the number of headache days per month.

The mean attack duration was 2.46 days before transcranial magnetic stimulation therapy and 0.77 days after subjects started using the device. The benefits were reproducible over the 3-month study period and beyond, and no adverse events were reported, he said.

Dr. Jean Schoenen presented the first randomized trial data on the Cefaly device. The supraorbital transcutaneous neurostimulation device has been available in Europe for 5 years, but until now it had no supporting data from controlled trials.

The device consists of a thin silver band that looks like something out of Star Trek. It is hooked over the ears and worn across the forehead like futuristic sunglasses. Patients don it once daily for 20 minutes. The investigators set the programmable device to deliver a square pulse at 60 Hz, 300 microseconds, and a maximum of 14.99 mA.

The 3-month, multicenter, double-blind, sham-controlled Belgian study involved 67 patients with episodic migraine. The mean number of headache-days per month dropped significantly, from 6.9 at baseline to 4.9 at 3 months in the Cefaly group but was unchanged in controls. Thirty-eight percent of patients using the active device experienced at least a 50% reduction in their number of headache-days per month, compared with 12% of controls. Monthly consumption of triptans for acute therapy was reduced by 36% in the Cefaly-treated patients as a whole and by 75% in the Cefaly responders, reported Dr. Schoenen of the University of Liege, Belgium.

To get a crude idea of how supraorbital transcutaneous neurostimulation stacks up against standard prophylactic drug therapy, Dr. Schoenen turned to the extensive published randomized trial literature on topiramate. While the 50% or greater responder rate in the Cefaly trial was 38%, in the pooled topiramate data it’s 45%. Moreover, topiramate was associated with an impressive average 48% reduction in the number of migraine attacks per month, compared with a 19% decrease with the Cefaly device.

On the other hand, one in four patients assigned to topiramate in the randomized trials dropped out due to side effects. No one experienced any adverse effects from the device therapy, he noted.

This was an investigator-initiated study carried out by the Belgian Headache Society and sponsored by STX-Med, which markets the Cefaly device in Europe. Dr. Schoenen is on the advisory boards of St. Jude Medical, Allergan, and ATI. Dr. Ahmed, Dr. Shields, and Dr. Weatherall are on the speakers bureau for eNeura Therapeutics.

LONDON – Enthusiasm is mounting among headache specialists for noninvasive device therapy for acute migraine.

"Normally I’m quite a cynical person, but I think within 10 years time half of my people in the headache clinic won’t be using any medications for their headaches. They’ll have an electronic device of some kind. You get your migraine sorted out, you put your device back in your pants pocket, and you carry on," Dr. Fayyaz Ahmed said at the European Headache and Migraine Trust International Congress.

"I think in about 10 years time you’ll have SIM cards for these neurostimulatory devices, you’ll put the card in an ATM-like machine – perhaps in a supermarket – and you’ll top it up and recharge it," predicted Dr. Ahmed, a consultant neurologist in Hull, England, and chair of the British Association for the Study of Headache.

The noninvasive neurostimulatory therapy most discussed at the congress was the Spring TMS single-pulse transcranial magnetic stimulation device, which since 2011 has been approved in Europe for the acute treatment of migraine. The Spring TMS device is manufactured by U.S.-based eNeura Therapeutics, which is seeking marketing approval from the Food and Drug Administration.

The international congress also saw the presentation of the first multicenter, randomized, sham-controlled study of the noninvasive Cefaly device for prevention of migraine via supraorbital transcutaneous neurostimulation.

"It’s not a revolutionary therapy. The effect size is moderate and inferior to that of the most effective preventive drugs. Its great advantage is that it’s devoid of side effects. I think the Cefaly device is another tool we can use for preventing migraine," Dr. Jean Schoenen concluded in presenting the study data.

Dr. Ahmed said physician and patient interest in noninvasive device therapy is being driven by the sizable proportion of migraine patients who don’t respond adequately to drug therapy, can’t tolerate it, or have contraindications to its use. Plus, some patients would just rather be drug free.

Neurostimulatory therapy for headache has followed an evolutionary process, progressing from highly invasive to minimally invasive and now to noninvasive devices, the neurologist observed.

First came deep brain stimulation of the subthalamic nucleus via implanted electrodes, which proved useful in treating Parkinson’s disease.

In the field of headache, there are 14 published studies of deep brain stimulation of the ventroposterior hypothalamus for treatment of intractable chronic cluster headache in a collective total of 64 patients. Two-thirds responded with at least a 50% decrease in pain. But this highly invasive form of therapy is not effective as acute therapy, only for prevention, and it entails a 3% rate of intracranial bleeding.

Next came minimally invasive systems for occipital nerve stimulation. Response rates have been variable in 10 published studies totaling roughly 500 patients treated for chronic migraine. In addition, the devices are quite expensive and are susceptible to lead migration or breakage and battery depletion.

"Only a couple of centers in the U.K. are doing occipital nerve stimulation now," according to Dr. Ahmed.

Yet there is still commercial interest in developing minimally invasive neurostimulatory therapy for headache. During the London headache congress, St. Jude Medical announced that its Eon family of neurostimulators had just received European regulatory approval for treatment of intractable chronic migraine. Among the newly approved devices is the Eon Mini, which weighs about an ounce and has a 10-mm profile.

The recently published 12-week, double-blind, multicenter pivotal study sponsored by St. Jude Medical involved 157 patients with chronic migraine randomized 2:1 to peripheral nerve stimulation or sham control. Of patients on active therapy, 35% achieved at least a 30% reduction in pain, a rate more than twice that in controls. The active treatment group also had a mean 6.1-day reduction in headache days per month from a baseline of 22 days, compared with a 3-day reduction in controls (Cephalalgia 2012 Oct. 3 [doi: 10.1177/0333102412462642]).

A company spokesperson said St. Jude Medical definitely plans to seek U.S. marketing approval for its Eon neurostimulators.

The best-studied noninvasive neurostimulatory device therapy for migraine is the single-pulse transcranial magnetic stimulation Spring TMS device. It delivers a complete treatment in less than a minute at the first sign of migraine pain and has a side effect profile similar to that of sham therapy in clinical trials, according to Dr. Kevin G. Shields, a neurologist at the National Hospital for Neurology and Neurosurgery in London.

Single-pulse transcranial magnetic stimulation has been in clinical use for 30 years, first diagnostically, then as therapy. The mechanism of benefit has been mapped out. The treatment’s safety is very well established; indeed, the FDA has classified it as a nonsignificant risk technology, he noted.

The major technical advance that’s occurred in single-pulse transcranial magnetic stimulation has been a radical reduction in capacitor size. The equipment has shrunk from refrigerator-size in the therapy’s early development, which took place in London, to the highly portable Spring TMS device that patients can stick in a briefcase and utilize unobtrusively at work, Dr. Shields observed.

The contraindications to use of the device are a history of epilepsy; the presence of metal objects in the head, neck, or upper body; and pacemakers or other cardiac devices.

The evidence base supporting the safety and efficacy of the Spring TMS device includes a published randomized, double-blind, sham-controlled clinical trial conducted in patients with migraine with aura (Lancet Neurol. 2010;9:373-80).

In addition, at the international congress Dr. Mark W. Weatherall of the University of Edinburgh, Scotland, presented the first results of an ongoing multicenter U.K. postmarketing study of the single-pulse transcranial magnetic stimulation device as used in clinical practice. The study population consisted of 13 patients with migraine without aura and 24 having migraine with aura who had been using the device for at least 3 months and collectively had treated 777 attacks.

Efficacy reports were:

• 73% of patients said the device showed good to excellent efficacy, reducing or even alleviating migraine pain. Sixty-three percent pronounced the therapy effective in diminishing other migraine symptoms.

• 55% reported a reduction in the number of headache days per month.

The mean attack duration was 2.46 days before transcranial magnetic stimulation therapy and 0.77 days after subjects started using the device. The benefits were reproducible over the 3-month study period and beyond, and no adverse events were reported, he said.

Dr. Jean Schoenen presented the first randomized trial data on the Cefaly device. The supraorbital transcutaneous neurostimulation device has been available in Europe for 5 years, but until now it had no supporting data from controlled trials.

The device consists of a thin silver band that looks like something out of Star Trek. It is hooked over the ears and worn across the forehead like futuristic sunglasses. Patients don it once daily for 20 minutes. The investigators set the programmable device to deliver a square pulse at 60 Hz, 300 microseconds, and a maximum of 14.99 mA.

The 3-month, multicenter, double-blind, sham-controlled Belgian study involved 67 patients with episodic migraine. The mean number of headache-days per month dropped significantly, from 6.9 at baseline to 4.9 at 3 months in the Cefaly group but was unchanged in controls. Thirty-eight percent of patients using the active device experienced at least a 50% reduction in their number of headache-days per month, compared with 12% of controls. Monthly consumption of triptans for acute therapy was reduced by 36% in the Cefaly-treated patients as a whole and by 75% in the Cefaly responders, reported Dr. Schoenen of the University of Liege, Belgium.

To get a crude idea of how supraorbital transcutaneous neurostimulation stacks up against standard prophylactic drug therapy, Dr. Schoenen turned to the extensive published randomized trial literature on topiramate. While the 50% or greater responder rate in the Cefaly trial was 38%, in the pooled topiramate data it’s 45%. Moreover, topiramate was associated with an impressive average 48% reduction in the number of migraine attacks per month, compared with a 19% decrease with the Cefaly device.

On the other hand, one in four patients assigned to topiramate in the randomized trials dropped out due to side effects. No one experienced any adverse effects from the device therapy, he noted.

This was an investigator-initiated study carried out by the Belgian Headache Society and sponsored by STX-Med, which markets the Cefaly device in Europe. Dr. Schoenen is on the advisory boards of St. Jude Medical, Allergan, and ATI. Dr. Ahmed, Dr. Shields, and Dr. Weatherall are on the speakers bureau for eNeura Therapeutics.

SAN ANTONIO – Diabetes is independently associated with a 27% increased risk of breast cancer, but this elevated risk is confined to postmenopausal type 2 diabetic patients, a large meta-analysis has shown.

The meta-analysis, which included 40 published studies and 56,111 women with breast cancer, found no association between risk of the malignancy and circulating serum insulin level, insulin growth factor–1 level, fasting blood glucose level, or C-peptide concentration.

These findings suggest that the hyperinsulinemic theory of the pathogenesis of breast cancer may need to be reevaluated in order to account for the increased risk being confined to postmenopausal patients and unrelated to indices of metabolic control, Dr. Peter Boyle said at the annual San Antonio Breast Cancer Symposium.

The key risk factors for breast cancer that emerged from the meta-analysis were adiposity and lack of physical activity. Both are also well established as risk factors for diabetes.

Based on the findings from this meta-analysis, efforts to avoid overweight and increase physical activity should form the basis of a common public health strategy simultaneously aimed at preventing diabetes and breast cancer, according to Dr. Boyle of the International Prevention Research Institute in Lyon, France.

High levels of physical activity, whether occupational or recreational, were independently associated with a 17% reduction in the relative risk of being diagnosed with breast cancer in premenopausal women and a 12% decrease in the postmenopausal population.

The relationship between adiposity and breast cancer was less straightforward. Premenopausal women who were overweight or obese had a significantly lower breast cancer risk than did leaner women, while breast cancer risk was increased in adipose postmenopausal women. More specifically, a 5-U increase in body mass index – equivalent to an extra 14.5 kg in a woman 1.7 m tall – was associated with an 11% increased risk of breast cancer in postmenopausal women but a 10% reduction in risk in premenopausal women.

Dr. Boyle and coworkers also presented a related meta-analysis looking at breast cancer risk in women using insulin glargine (Lantus). The study was prompted by recent evidence linking pioglitazone to a possible increase in bladder cancer, liraglutide and pancreatic cancer, insulin use and lung cancer, and exenatide and pancreatic cancer.

This meta-analysis included 18 epidemiologic studies published within the past 3 years. Collectively the studies involved 4,080 cases of breast cancer in 903,675 patients followed for 2.7 million person-years.

The meta-analysis demonstrated no increase in breast cancer risk in insulin glargine users, compared with users of other insulins. Indeed, the risk of all forms of cancer was 9% lower in insulin glargine users, a statistically significant reduction. This was driven by a 14% reduction in the relative risk of colorectal cancer.

Another reassuring finding was that breast cancer risk did not increase with longer use of insulin glargine, as would be expected if a causal relationship existed, he added.

Both meta-analyses were funded by Sanofi-Aventis, which markets glargine. Dr. Boyle reported having no relevant financial conflicts, although several of his coinvestigators have served on advisory boards for Sanofi-Aventis and other insulin manufacturers.

SAN ANTONIO – Diabetes is independently associated with a 27% increased risk of breast cancer, but this elevated risk is confined to postmenopausal type 2 diabetic patients, a large meta-analysis has shown.

The meta-analysis, which included 40 published studies and 56,111 women with breast cancer, found no association between risk of the malignancy and circulating serum insulin level, insulin growth factor–1 level, fasting blood glucose level, or C-peptide concentration.

These findings suggest that the hyperinsulinemic theory of the pathogenesis of breast cancer may need to be reevaluated in order to account for the increased risk being confined to postmenopausal patients and unrelated to indices of metabolic control, Dr. Peter Boyle said at the annual San Antonio Breast Cancer Symposium.

The key risk factors for breast cancer that emerged from the meta-analysis were adiposity and lack of physical activity. Both are also well established as risk factors for diabetes.

Based on the findings from this meta-analysis, efforts to avoid overweight and increase physical activity should form the basis of a common public health strategy simultaneously aimed at preventing diabetes and breast cancer, according to Dr. Boyle of the International Prevention Research Institute in Lyon, France.

High levels of physical activity, whether occupational or recreational, were independently associated with a 17% reduction in the relative risk of being diagnosed with breast cancer in premenopausal women and a 12% decrease in the postmenopausal population.

The relationship between adiposity and breast cancer was less straightforward. Premenopausal women who were overweight or obese had a significantly lower breast cancer risk than did leaner women, while breast cancer risk was increased in adipose postmenopausal women. More specifically, a 5-U increase in body mass index – equivalent to an extra 14.5 kg in a woman 1.7 m tall – was associated with an 11% increased risk of breast cancer in postmenopausal women but a 10% reduction in risk in premenopausal women.

Dr. Boyle and coworkers also presented a related meta-analysis looking at breast cancer risk in women using insulin glargine (Lantus). The study was prompted by recent evidence linking pioglitazone to a possible increase in bladder cancer, liraglutide and pancreatic cancer, insulin use and lung cancer, and exenatide and pancreatic cancer.

This meta-analysis included 18 epidemiologic studies published within the past 3 years. Collectively the studies involved 4,080 cases of breast cancer in 903,675 patients followed for 2.7 million person-years.

The meta-analysis demonstrated no increase in breast cancer risk in insulin glargine users, compared with users of other insulins. Indeed, the risk of all forms of cancer was 9% lower in insulin glargine users, a statistically significant reduction. This was driven by a 14% reduction in the relative risk of colorectal cancer.

Another reassuring finding was that breast cancer risk did not increase with longer use of insulin glargine, as would be expected if a causal relationship existed, he added.

Both meta-analyses were funded by Sanofi-Aventis, which markets glargine. Dr. Boyle reported having no relevant financial conflicts, although several of his coinvestigators have served on advisory boards for Sanofi-Aventis and other insulin manufacturers.

SAN ANTONIO – Diabetes is independently associated with a 27% increased risk of breast cancer, but this elevated risk is confined to postmenopausal type 2 diabetic patients, a large meta-analysis has shown.

The meta-analysis, which included 40 published studies and 56,111 women with breast cancer, found no association between risk of the malignancy and circulating serum insulin level, insulin growth factor–1 level, fasting blood glucose level, or C-peptide concentration.

These findings suggest that the hyperinsulinemic theory of the pathogenesis of breast cancer may need to be reevaluated in order to account for the increased risk being confined to postmenopausal patients and unrelated to indices of metabolic control, Dr. Peter Boyle said at the annual San Antonio Breast Cancer Symposium.

The key risk factors for breast cancer that emerged from the meta-analysis were adiposity and lack of physical activity. Both are also well established as risk factors for diabetes.

Based on the findings from this meta-analysis, efforts to avoid overweight and increase physical activity should form the basis of a common public health strategy simultaneously aimed at preventing diabetes and breast cancer, according to Dr. Boyle of the International Prevention Research Institute in Lyon, France.

High levels of physical activity, whether occupational or recreational, were independently associated with a 17% reduction in the relative risk of being diagnosed with breast cancer in premenopausal women and a 12% decrease in the postmenopausal population.

The relationship between adiposity and breast cancer was less straightforward. Premenopausal women who were overweight or obese had a significantly lower breast cancer risk than did leaner women, while breast cancer risk was increased in adipose postmenopausal women. More specifically, a 5-U increase in body mass index – equivalent to an extra 14.5 kg in a woman 1.7 m tall – was associated with an 11% increased risk of breast cancer in postmenopausal women but a 10% reduction in risk in premenopausal women.

Dr. Boyle and coworkers also presented a related meta-analysis looking at breast cancer risk in women using insulin glargine (Lantus). The study was prompted by recent evidence linking pioglitazone to a possible increase in bladder cancer, liraglutide and pancreatic cancer, insulin use and lung cancer, and exenatide and pancreatic cancer.

This meta-analysis included 18 epidemiologic studies published within the past 3 years. Collectively the studies involved 4,080 cases of breast cancer in 903,675 patients followed for 2.7 million person-years.

The meta-analysis demonstrated no increase in breast cancer risk in insulin glargine users, compared with users of other insulins. Indeed, the risk of all forms of cancer was 9% lower in insulin glargine users, a statistically significant reduction. This was driven by a 14% reduction in the relative risk of colorectal cancer.

Another reassuring finding was that breast cancer risk did not increase with longer use of insulin glargine, as would be expected if a causal relationship existed, he added.

Both meta-analyses were funded by Sanofi-Aventis, which markets glargine. Dr. Boyle reported having no relevant financial conflicts, although several of his coinvestigators have served on advisory boards for Sanofi-Aventis and other insulin manufacturers.

SAN ANTONIO – A lower-dose, briefer radiotherapy regimen than is standard for early-stage breast cancer in the U.S. demonstrated comparable efficacy with fewer side effects at 10 years of follow-up in a pair of landmark U.K. studies.

"Long-term follow-up confirms that a lower total dose of radiation in fewer, slightly larger fractions delivered over a shorter treatment time is at least as safe and effective as standard 5-week schedules of curative radiotherapy in women with early breast cancer," Dr. John R. Yarnold declared in presenting the latest data from the U.K. START (Standardization of Breast Radiotherapy) trials at the annual San Antonio Breast Cancer Symposium.

The historical standard of care for radiotherapy in patients with surgically excised early breast cancer is 50 Gy delivered in 25 fractions of 2.0 Gy each over the course of 5 weeks. That’s still standard practice in the United States.

In the United Kingdom, however, the standard nationwide is 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Radiologists term this "hypofractionation": delivering a lower total dose of radiation using fewer but larger fractions. Hypofractionation has standard practice in the United Kingdom since the National Institute for Health and Clinical Excellence–issued guidelines to that effect in 2009. Those guidelines were based in large part on the earlier, highly favorable 5-year outcomes of START A (Lancet Oncology 2008;9:331-41) and START B (Lancet 2008;371:1098-107).

The START investigators deemed it essential to conduct the new 10-year analysis because adverse effects of radiotherapy given for breast cancer can arise after the 5-year mark. Also, it was important to learn whether the early antitumor effects of hypofractionated radiotherapy persisted, explained Dr. Yarnold, professor of clinical oncology at the Institute of Cancer Research, London.

The two key findings at the 10-year mark of START are, first, that both breast cancer and the dose-limiting normal tissues respond similarly to fraction size, so there’s no advantage in continuing the 2 Gy fractions that have historically been the international standard; and, second, that a 15-fraction/3-week schedule is gentler on normal tissues and comparable in antitumor efficacy to a 25-fraction/5-week regimen.

The clinical implications are clear, Dr. Yarnold emphasized: "Patients can safely be treated to a lower total dose with fewer fractions than the historical standard of 50 Gy and 25 fractions. There are no detrimental effects of hypofractionation noted in any of the subgroups studied."

The 10-year rate of moderate to marked adverse treatment effects on normal tissues in START A survivors who received 39 Gy in 13 fractions over 5 weeks was 43.9% compared with 50.4% in those randomized to 50 Gy in 25 fractions over 5 weeks. The resultant 20% relative risk reduction with a lower total radiation dose delivered in fewer fractions was statistically significant. In contrast, the 10-year locoregional tumor relapse rates in the two groups were similarly low.

At 10 years in START B, patients who received 40 Gy in 15 fractions over 3 weeks had a 37.9% rate of moderate-to-marked adverse effects on normal tissues, compared with a 45.3% rate in those who got 50 Gy in 25 fractions over 5 weeks, for a highly significant 23% risk reduction. The relapse rate was 4.3% after 40 Gy and 5.5% after 50 Gy, a nonsignificant difference.

In both trials, all types of side effects involving normal tissues were significantly less common in the lower-total-dose, fewer-fraction groups. That includes brachial plexus injury, which has been a concern expressed by supporters of the historical standard regimen, Dr. Yarnold added.

Radiologists and surgeons in the audience called the 10-year START results "very, very important" and likely to be practice changing.

Canada has already switched from the historical standard to 42.5 Gy delivered in 16 fractions over the course of 22 days. Asked if he thinks U.S. radiologists, too, should change their practice in light of the START findings, Dr. Yarnold was diplomatic. "I foresee no scientific reasons why they should not consider that very carefully," he replied.

Follow-up will continue in the START trials, which are funded by the Institute for Cancer Research, Cancer Research UK, the Medical Research Council, and the National Cancer Research Institute. Dr. Yarnold reported having no financial conflicts.

b.jancin@elsevier.com

SAN ANTONIO – A lower-dose, briefer radiotherapy regimen than is standard for early-stage breast cancer in the U.S. demonstrated comparable efficacy with fewer side effects at 10 years of follow-up in a pair of landmark U.K. studies.

"Long-term follow-up confirms that a lower total dose of radiation in fewer, slightly larger fractions delivered over a shorter treatment time is at least as safe and effective as standard 5-week schedules of curative radiotherapy in women with early breast cancer," Dr. John R. Yarnold declared in presenting the latest data from the U.K. START (Standardization of Breast Radiotherapy) trials at the annual San Antonio Breast Cancer Symposium.

The historical standard of care for radiotherapy in patients with surgically excised early breast cancer is 50 Gy delivered in 25 fractions of 2.0 Gy each over the course of 5 weeks. That’s still standard practice in the United States.

In the United Kingdom, however, the standard nationwide is 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Radiologists term this "hypofractionation": delivering a lower total dose of radiation using fewer but larger fractions. Hypofractionation has standard practice in the United Kingdom since the National Institute for Health and Clinical Excellence–issued guidelines to that effect in 2009. Those guidelines were based in large part on the earlier, highly favorable 5-year outcomes of START A (Lancet Oncology 2008;9:331-41) and START B (Lancet 2008;371:1098-107).

The START investigators deemed it essential to conduct the new 10-year analysis because adverse effects of radiotherapy given for breast cancer can arise after the 5-year mark. Also, it was important to learn whether the early antitumor effects of hypofractionated radiotherapy persisted, explained Dr. Yarnold, professor of clinical oncology at the Institute of Cancer Research, London.

The two key findings at the 10-year mark of START are, first, that both breast cancer and the dose-limiting normal tissues respond similarly to fraction size, so there’s no advantage in continuing the 2 Gy fractions that have historically been the international standard; and, second, that a 15-fraction/3-week schedule is gentler on normal tissues and comparable in antitumor efficacy to a 25-fraction/5-week regimen.

The clinical implications are clear, Dr. Yarnold emphasized: "Patients can safely be treated to a lower total dose with fewer fractions than the historical standard of 50 Gy and 25 fractions. There are no detrimental effects of hypofractionation noted in any of the subgroups studied."

The 10-year rate of moderate to marked adverse treatment effects on normal tissues in START A survivors who received 39 Gy in 13 fractions over 5 weeks was 43.9% compared with 50.4% in those randomized to 50 Gy in 25 fractions over 5 weeks. The resultant 20% relative risk reduction with a lower total radiation dose delivered in fewer fractions was statistically significant. In contrast, the 10-year locoregional tumor relapse rates in the two groups were similarly low.

At 10 years in START B, patients who received 40 Gy in 15 fractions over 3 weeks had a 37.9% rate of moderate-to-marked adverse effects on normal tissues, compared with a 45.3% rate in those who got 50 Gy in 25 fractions over 5 weeks, for a highly significant 23% risk reduction. The relapse rate was 4.3% after 40 Gy and 5.5% after 50 Gy, a nonsignificant difference.

In both trials, all types of side effects involving normal tissues were significantly less common in the lower-total-dose, fewer-fraction groups. That includes brachial plexus injury, which has been a concern expressed by supporters of the historical standard regimen, Dr. Yarnold added.

Radiologists and surgeons in the audience called the 10-year START results "very, very important" and likely to be practice changing.

Canada has already switched from the historical standard to 42.5 Gy delivered in 16 fractions over the course of 22 days. Asked if he thinks U.S. radiologists, too, should change their practice in light of the START findings, Dr. Yarnold was diplomatic. "I foresee no scientific reasons why they should not consider that very carefully," he replied.

Follow-up will continue in the START trials, which are funded by the Institute for Cancer Research, Cancer Research UK, the Medical Research Council, and the National Cancer Research Institute. Dr. Yarnold reported having no financial conflicts.

b.jancin@elsevier.com

SAN ANTONIO – A lower-dose, briefer radiotherapy regimen than is standard for early-stage breast cancer in the U.S. demonstrated comparable efficacy with fewer side effects at 10 years of follow-up in a pair of landmark U.K. studies.

"Long-term follow-up confirms that a lower total dose of radiation in fewer, slightly larger fractions delivered over a shorter treatment time is at least as safe and effective as standard 5-week schedules of curative radiotherapy in women with early breast cancer," Dr. John R. Yarnold declared in presenting the latest data from the U.K. START (Standardization of Breast Radiotherapy) trials at the annual San Antonio Breast Cancer Symposium.

The historical standard of care for radiotherapy in patients with surgically excised early breast cancer is 50 Gy delivered in 25 fractions of 2.0 Gy each over the course of 5 weeks. That’s still standard practice in the United States.

In the United Kingdom, however, the standard nationwide is 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Radiologists term this "hypofractionation": delivering a lower total dose of radiation using fewer but larger fractions. Hypofractionation has standard practice in the United Kingdom since the National Institute for Health and Clinical Excellence–issued guidelines to that effect in 2009. Those guidelines were based in large part on the earlier, highly favorable 5-year outcomes of START A (Lancet Oncology 2008;9:331-41) and START B (Lancet 2008;371:1098-107).

The START investigators deemed it essential to conduct the new 10-year analysis because adverse effects of radiotherapy given for breast cancer can arise after the 5-year mark. Also, it was important to learn whether the early antitumor effects of hypofractionated radiotherapy persisted, explained Dr. Yarnold, professor of clinical oncology at the Institute of Cancer Research, London.

The two key findings at the 10-year mark of START are, first, that both breast cancer and the dose-limiting normal tissues respond similarly to fraction size, so there’s no advantage in continuing the 2 Gy fractions that have historically been the international standard; and, second, that a 15-fraction/3-week schedule is gentler on normal tissues and comparable in antitumor efficacy to a 25-fraction/5-week regimen.

The clinical implications are clear, Dr. Yarnold emphasized: "Patients can safely be treated to a lower total dose with fewer fractions than the historical standard of 50 Gy and 25 fractions. There are no detrimental effects of hypofractionation noted in any of the subgroups studied."

The 10-year rate of moderate to marked adverse treatment effects on normal tissues in START A survivors who received 39 Gy in 13 fractions over 5 weeks was 43.9% compared with 50.4% in those randomized to 50 Gy in 25 fractions over 5 weeks. The resultant 20% relative risk reduction with a lower total radiation dose delivered in fewer fractions was statistically significant. In contrast, the 10-year locoregional tumor relapse rates in the two groups were similarly low.

At 10 years in START B, patients who received 40 Gy in 15 fractions over 3 weeks had a 37.9% rate of moderate-to-marked adverse effects on normal tissues, compared with a 45.3% rate in those who got 50 Gy in 25 fractions over 5 weeks, for a highly significant 23% risk reduction. The relapse rate was 4.3% after 40 Gy and 5.5% after 50 Gy, a nonsignificant difference.

In both trials, all types of side effects involving normal tissues were significantly less common in the lower-total-dose, fewer-fraction groups. That includes brachial plexus injury, which has been a concern expressed by supporters of the historical standard regimen, Dr. Yarnold added.

Radiologists and surgeons in the audience called the 10-year START results "very, very important" and likely to be practice changing.

Canada has already switched from the historical standard to 42.5 Gy delivered in 16 fractions over the course of 22 days. Asked if he thinks U.S. radiologists, too, should change their practice in light of the START findings, Dr. Yarnold was diplomatic. "I foresee no scientific reasons why they should not consider that very carefully," he replied.

Follow-up will continue in the START trials, which are funded by the Institute for Cancer Research, Cancer Research UK, the Medical Research Council, and the National Cancer Research Institute. Dr. Yarnold reported having no financial conflicts.

b.jancin@elsevier.com