Breast Cancer ICYMI

Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

Biologically active pituitary adenylate cyclase-activating polypeptide (PACAP) is released by mast cells: a finding that may provide an explanation for the association between allergy and migraine. “In the investigation of the role of mast cells in migraine pathology, we found that human mast cells contain PACAP in their cytoplasmic granules. Bioactive PACAP can be released from mast cells by inducing degranulation,” said lead author Angela J. Okragly, Senior Research Scientist at Eli Lilly and Company in Indianapolis, and colleagues. “This finding provides a potential explanation linking mast cell activation to migraine through the release of PACAP.” Their study was published in the August issue of Cephalalgia.

The relationship between allergy and migraine has long been noted. Many patients with migraines have allergies, and vice versa. In 1983, researchers hypothesized that mast cells, which are effectors of allergies, play a role in the pathophysiology of migraines. To investigate the relationship between mast cell activation and known neurogenic peptides related to migraine, researchers from Eli Lilly and Company assayed cultured human mast cells for the presence of neuropeptides and their receptors at the RNA and protein levels. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. The investigators also performed mast cell degranulation assays and measured PACAP activity with bioassay.

The team of Lilly researchers found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. In addition, the researchers confirmed existing evidence that several neurogenic peptides also can induce mast cell degranulation, which results in PACAP release.

“Since it has been demonstrated that PACAP infusion can trigger migraines, we propose that [our] finding provides a potential mechanistic explanation of how mast cell degranulation could contribute to migraines,” the authors said.

Migraine remains a complex disorder with multiple causes, the researchers noted. “Recent clinical trial results demonstrate a role for the calcitonin gene-related peptide (CGRP) pathway, since its blockade resulted in a high degree of efficacy in significant groups of patients. In our study, we found no direct relationship between mast cells and CGRP, suggesting that migraines involving mast cell activation, either via classical IgE or pseudoallergic pathways, involve a different pathophysiologic mechanism,” the authors said.

—Glenn S. Williams

Suggested Reading

Okragly AJ, Morin SM, DeRosa D, et al. Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP). Cephalalgia. 2018;38(9):1564-1574.

Self-management of epilepsy using a group-format, remote intervention improves mood, quality of life, and health functioning in high-risk individuals, according to a randomized, controlled trial published in the September issue of Epilepsia.

In the six-month trial, 120 individuals with epilepsy who had experienced at least one epilepsy-related negative health event in the previous six months were randomized to a wait-list control group or a novel self‐management intervention.

The eight-session intervention, known as SMART, focused on modifiable factors that can be addressed with self-management, such as stress, substance abuse, routine, nutrition, and social support. It was delivered remotely during eight to 10 weeks, either by telephone or online, after an initial in-person session.

“SMART combines the portability and low cost of a Web‐based intervention with the personally salient components of behavior modeling obtained by interacting with individuals who have walked the walk in living with epilepsy,” said Martha Sajatovic, MD, Professor of Psychiatry at Case Western Reserve University in Cleveland, and her colleagues.

—Bianca Nogrady

Suggested Reading

Sajatovic M, Colon-Zimmermann K, Kahriman M, et al. A 6-month prospective randomized controlled trial of remotely delivered group format epilepsy self-management versus waitlist control for high-risk people with epilepsy. Epilepsia. 2018;59(9):1684-1695.

Self-management of epilepsy using a group-format, remote intervention improves mood, quality of life, and health functioning in high-risk individuals, according to a randomized, controlled trial published in the September issue of Epilepsia.

In the six-month trial, 120 individuals with epilepsy who had experienced at least one epilepsy-related negative health event in the previous six months were randomized to a wait-list control group or a novel self‐management intervention.

The eight-session intervention, known as SMART, focused on modifiable factors that can be addressed with self-management, such as stress, substance abuse, routine, nutrition, and social support. It was delivered remotely during eight to 10 weeks, either by telephone or online, after an initial in-person session.

“SMART combines the portability and low cost of a Web‐based intervention with the personally salient components of behavior modeling obtained by interacting with individuals who have walked the walk in living with epilepsy,” said Martha Sajatovic, MD, Professor of Psychiatry at Case Western Reserve University in Cleveland, and her colleagues.

—Bianca Nogrady

Suggested Reading

Sajatovic M, Colon-Zimmermann K, Kahriman M, et al. A 6-month prospective randomized controlled trial of remotely delivered group format epilepsy self-management versus waitlist control for high-risk people with epilepsy. Epilepsia. 2018;59(9):1684-1695.

Self-management of epilepsy using a group-format, remote intervention improves mood, quality of life, and health functioning in high-risk individuals, according to a randomized, controlled trial published in the September issue of Epilepsia.

In the six-month trial, 120 individuals with epilepsy who had experienced at least one epilepsy-related negative health event in the previous six months were randomized to a wait-list control group or a novel self‐management intervention.

The eight-session intervention, known as SMART, focused on modifiable factors that can be addressed with self-management, such as stress, substance abuse, routine, nutrition, and social support. It was delivered remotely during eight to 10 weeks, either by telephone or online, after an initial in-person session.

“SMART combines the portability and low cost of a Web‐based intervention with the personally salient components of behavior modeling obtained by interacting with individuals who have walked the walk in living with epilepsy,” said Martha Sajatovic, MD, Professor of Psychiatry at Case Western Reserve University in Cleveland, and her colleagues.

—Bianca Nogrady

Suggested Reading

Sajatovic M, Colon-Zimmermann K, Kahriman M, et al. A 6-month prospective randomized controlled trial of remotely delivered group format epilepsy self-management versus waitlist control for high-risk people with epilepsy. Epilepsia. 2018;59(9):1684-1695.

An estimated 3% of patients with multiple sclerosis (MS) have a benign course of disease, according to findings from a population-based UK study published online ahead of print September 3 in Journal of Neurology, Neurosurgery & Psychiatry. The term “benign MS” remains problematic, however.

“The study of the individuals with extremely favorable outcomes may uncover insights about disease pathogenesis or repair. However, the insensitivity of Expanded Disability Status Scale [EDSS]–based definitions of benign MS and the discrepancy between patient and clinician perception of benign MS undermine use of the term ‘benign’ in the clinical setting,” said Emma Clare Tallantyre, BMBS, PhD, Clinical Senior Lecturer in Neurosciences at Cardiff University in the UK, and her colleagues.

The investigators found that of 1,049 patients with a disease duration of longer than 15 years, 200 had a recent EDSS score of less than 4.0. Of those patients, 60 were clinically assessed, and nine (15%) had benign MS, which was defined as an EDSS score less than 3.0 and lack of significant fatigue, mood disturbance, cognitive impairment, and disruption to employment in the absence of disease-modifying therapy at at least 15 years after symptom onset.

Extrapolating these data, the investigators estimated that 30 patients in the study population of 1,049 had benign MS, yielding a prevalence of 2.9%. Of the 60 patients who were clinically assessed, 39 thought they had benign MS, based on the following definition: “When referring to illness, ‘benign’ usually means a condition which has little or no harmful effects on a person. There are no complications, and there is a good outcome or prognosis.”

Patients who self-reported benign MS had significantly lower EDSS scores, fewer depressive symptoms, lower fatigue severity, and lower reported MS impact than did patients who did not report benign MS. “Self-reported benign MS status showed poor agreement with our composite definition of benign MS status and only fair agreement with EDSS-based definitions of benign MS status,” said the investigators.

—Jeff Evans

Suggested Reading

Tallantyre EC, Major PC, Atherton MJ, et al. How common is truly benign MS in a UK population? J Neurol Neurosurg Psychiatry. 2018 Sep 3 [Epub ahead of print].

An estimated 3% of patients with multiple sclerosis (MS) have a benign course of disease, according to findings from a population-based UK study published online ahead of print September 3 in Journal of Neurology, Neurosurgery & Psychiatry. The term “benign MS” remains problematic, however.

“The study of the individuals with extremely favorable outcomes may uncover insights about disease pathogenesis or repair. However, the insensitivity of Expanded Disability Status Scale [EDSS]–based definitions of benign MS and the discrepancy between patient and clinician perception of benign MS undermine use of the term ‘benign’ in the clinical setting,” said Emma Clare Tallantyre, BMBS, PhD, Clinical Senior Lecturer in Neurosciences at Cardiff University in the UK, and her colleagues.

The investigators found that of 1,049 patients with a disease duration of longer than 15 years, 200 had a recent EDSS score of less than 4.0. Of those patients, 60 were clinically assessed, and nine (15%) had benign MS, which was defined as an EDSS score less than 3.0 and lack of significant fatigue, mood disturbance, cognitive impairment, and disruption to employment in the absence of disease-modifying therapy at at least 15 years after symptom onset.

Extrapolating these data, the investigators estimated that 30 patients in the study population of 1,049 had benign MS, yielding a prevalence of 2.9%. Of the 60 patients who were clinically assessed, 39 thought they had benign MS, based on the following definition: “When referring to illness, ‘benign’ usually means a condition which has little or no harmful effects on a person. There are no complications, and there is a good outcome or prognosis.”

Patients who self-reported benign MS had significantly lower EDSS scores, fewer depressive symptoms, lower fatigue severity, and lower reported MS impact than did patients who did not report benign MS. “Self-reported benign MS status showed poor agreement with our composite definition of benign MS status and only fair agreement with EDSS-based definitions of benign MS status,” said the investigators.

—Jeff Evans

Suggested Reading

Tallantyre EC, Major PC, Atherton MJ, et al. How common is truly benign MS in a UK population? J Neurol Neurosurg Psychiatry. 2018 Sep 3 [Epub ahead of print].

An estimated 3% of patients with multiple sclerosis (MS) have a benign course of disease, according to findings from a population-based UK study published online ahead of print September 3 in Journal of Neurology, Neurosurgery & Psychiatry. The term “benign MS” remains problematic, however.

“The study of the individuals with extremely favorable outcomes may uncover insights about disease pathogenesis or repair. However, the insensitivity of Expanded Disability Status Scale [EDSS]–based definitions of benign MS and the discrepancy between patient and clinician perception of benign MS undermine use of the term ‘benign’ in the clinical setting,” said Emma Clare Tallantyre, BMBS, PhD, Clinical Senior Lecturer in Neurosciences at Cardiff University in the UK, and her colleagues.

The investigators found that of 1,049 patients with a disease duration of longer than 15 years, 200 had a recent EDSS score of less than 4.0. Of those patients, 60 were clinically assessed, and nine (15%) had benign MS, which was defined as an EDSS score less than 3.0 and lack of significant fatigue, mood disturbance, cognitive impairment, and disruption to employment in the absence of disease-modifying therapy at at least 15 years after symptom onset.

Extrapolating these data, the investigators estimated that 30 patients in the study population of 1,049 had benign MS, yielding a prevalence of 2.9%. Of the 60 patients who were clinically assessed, 39 thought they had benign MS, based on the following definition: “When referring to illness, ‘benign’ usually means a condition which has little or no harmful effects on a person. There are no complications, and there is a good outcome or prognosis.”

Patients who self-reported benign MS had significantly lower EDSS scores, fewer depressive symptoms, lower fatigue severity, and lower reported MS impact than did patients who did not report benign MS. “Self-reported benign MS status showed poor agreement with our composite definition of benign MS status and only fair agreement with EDSS-based definitions of benign MS status,” said the investigators.

—Jeff Evans

Suggested Reading

Tallantyre EC, Major PC, Atherton MJ, et al. How common is truly benign MS in a UK population? J Neurol Neurosurg Psychiatry. 2018 Sep 3 [Epub ahead of print].

Teva Pharmaceutical Industries Ltd. announced that the FDA approved Ajovy (fremanezumab-vfrm) injection for the preventive treatment of migraine in adults. Ajovy, a humanized monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor, is the first and only anti-CGRP treatment for the prevention of migraine with quarterly (675 mg) and monthly (225 mg) dosing options.

“Migraine is a disabling neurological disease that affects more than 36 million people in the United States,” said Stephen Silberstein, MD, Director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, and lead investigator of the Phase III clinical trial program for Ajovy. “About 40% of people living with migraine may be appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days.”

Ajovy was evaluated in two Phase III, placebo-controlled clinical trials that enrolled patients with disabling migraine and was studied as both a stand-alone preventive treatment and in combination with oral preventive treatments. In these trials, patients experienced a reduction in monthly migraine days during a 12-week period. The most common adverse reactions (≥ 5% and greater than placebo) were injection site reactions.

Teva Pharmaceutical Industries Ltd. announced that the FDA approved Ajovy (fremanezumab-vfrm) injection for the preventive treatment of migraine in adults. Ajovy, a humanized monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor, is the first and only anti-CGRP treatment for the prevention of migraine with quarterly (675 mg) and monthly (225 mg) dosing options.

“Migraine is a disabling neurological disease that affects more than 36 million people in the United States,” said Stephen Silberstein, MD, Director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, and lead investigator of the Phase III clinical trial program for Ajovy. “About 40% of people living with migraine may be appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days.”

Ajovy was evaluated in two Phase III, placebo-controlled clinical trials that enrolled patients with disabling migraine and was studied as both a stand-alone preventive treatment and in combination with oral preventive treatments. In these trials, patients experienced a reduction in monthly migraine days during a 12-week period. The most common adverse reactions (≥ 5% and greater than placebo) were injection site reactions.

Teva Pharmaceutical Industries Ltd. announced that the FDA approved Ajovy (fremanezumab-vfrm) injection for the preventive treatment of migraine in adults. Ajovy, a humanized monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor, is the first and only anti-CGRP treatment for the prevention of migraine with quarterly (675 mg) and monthly (225 mg) dosing options.

“Migraine is a disabling neurological disease that affects more than 36 million people in the United States,” said Stephen Silberstein, MD, Director of the Jefferson Headache Center at Thomas Jefferson University Hospital in Philadelphia, and lead investigator of the Phase III clinical trial program for Ajovy. “About 40% of people living with migraine may be appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days.”

Ajovy was evaluated in two Phase III, placebo-controlled clinical trials that enrolled patients with disabling migraine and was studied as both a stand-alone preventive treatment and in combination with oral preventive treatments. In these trials, patients experienced a reduction in monthly migraine days during a 12-week period. The most common adverse reactions (≥ 5% and greater than placebo) were injection site reactions.

The immune microenvironment of metastatic breast cancer lesions is relatively inert and depleted versus primary tumors, results of a recent study suggest.

“These results predict that immune therapy may be more successful in early stage breast cancers rather than in metastatic disease,” Lajos Pusztai, MD, and study coinvestigators reported in Annals of Oncology.

However, metastatic breast cancers showed high expression levels of some targetable molecules that may provide a “foundation for rational immunotherapy combination strategies,” wrote Dr. Pusztai, director of breast cancer translational research at Yale Cancer Center, New Haven, Conn., and his coinvestigators.

The investigators looked at tumor PD-L1 protein expression, tumor infiltrating lymphocyte (TIL) count, and mRNA expression for 730 immune-related genes in both primary and metastatic cancer samples obtained from pathologists at Yale.

The study included one cohort with full sections of paired metastatic and primary tumors from 45 patients, and a second cohort of tissue microarrays from 55 other patients.

Compared with primary lesions, metastatic lesions had substantially lower levels of PD-L1 expression and TIL counts, the investigators found.

Staining of PD-L1 was primarily seen in stromal immune cells, rather than tumor cells, according to investigators. The median stromal PD-L1 positivity was 14% for metastases and 52% for primary tumors in the first cohort (P = .0004), and 7% for metastases and 22% for primary tumors in the second cohort (P = .03).

They also reported significant decreased TIL counts in metastatic lesions for both the first (P = .026) and second (P = .089) cohorts, the report shows.

Immune gene expression profiling results, similarly, showed that most immune cell types and functions were “depleted” in the metastatic lesions, including a decreased mRNA expression of CTLA4, Dr. Pusztai and his colleagues reported.

The “lesser immunogenicity” of metastatic breast cancer cells was shown by decreased expression of immune proteasome and MHC class I genes, along with increased expression of HLA-E, which has been shown to suppress immunity, and reduced presence of dendritic cells, they said.

However, they also found high expression of targetable molecules in metastatic lesions. Those included macrophage markers such as CD68 and CD163, cytokine ligand/receptor pairs that mediate pro-tumorigenic effects, such as CCL2/CCR2 and CXCR4/CXCL12, and signaling molecules such as STAT-3 and JAK2, among others.

“We suggest that targeting these molecules may lead to synergy with PD1/PD-L1 blockade in metastatic breast cancer,” they wrote.

The work by Dr. Pusztai and his colleagues was supported by the Breast Cancer Research Foundation, Susan G Komen for the Cure, Department of Defense Breast Cancer Research Program Awards, and the Rosztoczy Foundation. The authors declared no conflicts of interest.

SOURCE: Szekely B, et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy399.

The immune microenvironment of metastatic breast cancer lesions is relatively inert and depleted versus primary tumors, results of a recent study suggest.

“These results predict that immune therapy may be more successful in early stage breast cancers rather than in metastatic disease,” Lajos Pusztai, MD, and study coinvestigators reported in Annals of Oncology.

However, metastatic breast cancers showed high expression levels of some targetable molecules that may provide a “foundation for rational immunotherapy combination strategies,” wrote Dr. Pusztai, director of breast cancer translational research at Yale Cancer Center, New Haven, Conn., and his coinvestigators.

The investigators looked at tumor PD-L1 protein expression, tumor infiltrating lymphocyte (TIL) count, and mRNA expression for 730 immune-related genes in both primary and metastatic cancer samples obtained from pathologists at Yale.

The study included one cohort with full sections of paired metastatic and primary tumors from 45 patients, and a second cohort of tissue microarrays from 55 other patients.

Compared with primary lesions, metastatic lesions had substantially lower levels of PD-L1 expression and TIL counts, the investigators found.

Staining of PD-L1 was primarily seen in stromal immune cells, rather than tumor cells, according to investigators. The median stromal PD-L1 positivity was 14% for metastases and 52% for primary tumors in the first cohort (P = .0004), and 7% for metastases and 22% for primary tumors in the second cohort (P = .03).

They also reported significant decreased TIL counts in metastatic lesions for both the first (P = .026) and second (P = .089) cohorts, the report shows.

Immune gene expression profiling results, similarly, showed that most immune cell types and functions were “depleted” in the metastatic lesions, including a decreased mRNA expression of CTLA4, Dr. Pusztai and his colleagues reported.

The “lesser immunogenicity” of metastatic breast cancer cells was shown by decreased expression of immune proteasome and MHC class I genes, along with increased expression of HLA-E, which has been shown to suppress immunity, and reduced presence of dendritic cells, they said.

However, they also found high expression of targetable molecules in metastatic lesions. Those included macrophage markers such as CD68 and CD163, cytokine ligand/receptor pairs that mediate pro-tumorigenic effects, such as CCL2/CCR2 and CXCR4/CXCL12, and signaling molecules such as STAT-3 and JAK2, among others.

“We suggest that targeting these molecules may lead to synergy with PD1/PD-L1 blockade in metastatic breast cancer,” they wrote.

The work by Dr. Pusztai and his colleagues was supported by the Breast Cancer Research Foundation, Susan G Komen for the Cure, Department of Defense Breast Cancer Research Program Awards, and the Rosztoczy Foundation. The authors declared no conflicts of interest.

SOURCE: Szekely B, et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy399.

The immune microenvironment of metastatic breast cancer lesions is relatively inert and depleted versus primary tumors, results of a recent study suggest.

“These results predict that immune therapy may be more successful in early stage breast cancers rather than in metastatic disease,” Lajos Pusztai, MD, and study coinvestigators reported in Annals of Oncology.

However, metastatic breast cancers showed high expression levels of some targetable molecules that may provide a “foundation for rational immunotherapy combination strategies,” wrote Dr. Pusztai, director of breast cancer translational research at Yale Cancer Center, New Haven, Conn., and his coinvestigators.

The investigators looked at tumor PD-L1 protein expression, tumor infiltrating lymphocyte (TIL) count, and mRNA expression for 730 immune-related genes in both primary and metastatic cancer samples obtained from pathologists at Yale.

The study included one cohort with full sections of paired metastatic and primary tumors from 45 patients, and a second cohort of tissue microarrays from 55 other patients.

Compared with primary lesions, metastatic lesions had substantially lower levels of PD-L1 expression and TIL counts, the investigators found.

Staining of PD-L1 was primarily seen in stromal immune cells, rather than tumor cells, according to investigators. The median stromal PD-L1 positivity was 14% for metastases and 52% for primary tumors in the first cohort (P = .0004), and 7% for metastases and 22% for primary tumors in the second cohort (P = .03).

They also reported significant decreased TIL counts in metastatic lesions for both the first (P = .026) and second (P = .089) cohorts, the report shows.

Immune gene expression profiling results, similarly, showed that most immune cell types and functions were “depleted” in the metastatic lesions, including a decreased mRNA expression of CTLA4, Dr. Pusztai and his colleagues reported.

The “lesser immunogenicity” of metastatic breast cancer cells was shown by decreased expression of immune proteasome and MHC class I genes, along with increased expression of HLA-E, which has been shown to suppress immunity, and reduced presence of dendritic cells, they said.

However, they also found high expression of targetable molecules in metastatic lesions. Those included macrophage markers such as CD68 and CD163, cytokine ligand/receptor pairs that mediate pro-tumorigenic effects, such as CCL2/CCR2 and CXCR4/CXCL12, and signaling molecules such as STAT-3 and JAK2, among others.

“We suggest that targeting these molecules may lead to synergy with PD1/PD-L1 blockade in metastatic breast cancer,” they wrote.

The work by Dr. Pusztai and his colleagues was supported by the Breast Cancer Research Foundation, Susan G Komen for the Cure, Department of Defense Breast Cancer Research Program Awards, and the Rosztoczy Foundation. The authors declared no conflicts of interest.

SOURCE: Szekely B, et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy399.

Outcomes for women with operable HER2-positive breast cancer were similar whether they received standard combination chemotherapy with either concurrent or sequential paclitaxel/trastuzumab, long-term results of the phase 3, randomized American College of Surgeons Oncology Group Z1041 trial showed.

Among 280 women with HER-2 positive breast cancer followed for a median of 5.1 years, there were no significant differences in either pathological complete response rates (pCR), disease-free survival (DFS), or overall survival with either concurrent or sequential therapy, wrote Aman U. Buzdar, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

“A previous publication of this study’s primary analysis reported that breast pCR in patients treated with paclitaxel and trastuzumab followed by FEC [fluorouracil, epirubicin, cyclophosphamide] and trastuzumab did not differ significantly from that of patients receiving FEC followed by paclitaxel and trastuzumab. We now report the findings concerning the secondary outcomes, that is, with a median follow-up of approximately 5 years, DFS is similar among the two treatment arms,” they wrote in JAMA Oncology.

The purpose of the current analysis was to evaluate long-term outcomes associated with the two treatment approaches.

In the trial, conducted at 36 centers in the continental United States and Puerto Rico, 280 women (median age, 50 years; range, 28-76 years) were treated with 500 mg/m² of fluorouracil, 75 mg/m² epirubicin, and 500 mg/m² cyclophosphamide every 3 weeks for 12 weeks with concurrent weekly paclitaxel at 80 mg/m² and trastuzumab at 2 mg/kg – after an initial dose of 4 mg/kg – or the same paclitaxel/trastuzumab combination delivered weekly for 12 weeks, followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks.

Women who also had hormone receptor–positive disease received endocrine therapy. Radiotherapy was delivered at the discretion of the attending physician.

As noted, there were no differences in either DFS rates (adjusted hazard ratio, 1.02; P = .96) or overall survival rates (adjusted HR, 1.17; P = .73) between the trial arms.

The authors concluded that “concurrent administration of trastuzumab with FEC was not found to offer additional clinical benefit and is not warranted.”

The study was supported by grants to participating institutions from the National Cancer Institute. Dr. Buzdar reported no conflicts of interest. Three coauthors reported research support, consulting fees, travel support, and/or other relationships with multiple companies.

SOURCE: Buzdar AU et al. JAMA Oncol. 2018 Sept 6. doi: 10.1001/jamaoncol.2018.3691.

Outcomes for women with operable HER2-positive breast cancer were similar whether they received standard combination chemotherapy with either concurrent or sequential paclitaxel/trastuzumab, long-term results of the phase 3, randomized American College of Surgeons Oncology Group Z1041 trial showed.

Among 280 women with HER-2 positive breast cancer followed for a median of 5.1 years, there were no significant differences in either pathological complete response rates (pCR), disease-free survival (DFS), or overall survival with either concurrent or sequential therapy, wrote Aman U. Buzdar, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

“A previous publication of this study’s primary analysis reported that breast pCR in patients treated with paclitaxel and trastuzumab followed by FEC [fluorouracil, epirubicin, cyclophosphamide] and trastuzumab did not differ significantly from that of patients receiving FEC followed by paclitaxel and trastuzumab. We now report the findings concerning the secondary outcomes, that is, with a median follow-up of approximately 5 years, DFS is similar among the two treatment arms,” they wrote in JAMA Oncology.

The purpose of the current analysis was to evaluate long-term outcomes associated with the two treatment approaches.

In the trial, conducted at 36 centers in the continental United States and Puerto Rico, 280 women (median age, 50 years; range, 28-76 years) were treated with 500 mg/m² of fluorouracil, 75 mg/m² epirubicin, and 500 mg/m² cyclophosphamide every 3 weeks for 12 weeks with concurrent weekly paclitaxel at 80 mg/m² and trastuzumab at 2 mg/kg – after an initial dose of 4 mg/kg – or the same paclitaxel/trastuzumab combination delivered weekly for 12 weeks, followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks.

Women who also had hormone receptor–positive disease received endocrine therapy. Radiotherapy was delivered at the discretion of the attending physician.

As noted, there were no differences in either DFS rates (adjusted hazard ratio, 1.02; P = .96) or overall survival rates (adjusted HR, 1.17; P = .73) between the trial arms.

The authors concluded that “concurrent administration of trastuzumab with FEC was not found to offer additional clinical benefit and is not warranted.”

The study was supported by grants to participating institutions from the National Cancer Institute. Dr. Buzdar reported no conflicts of interest. Three coauthors reported research support, consulting fees, travel support, and/or other relationships with multiple companies.

SOURCE: Buzdar AU et al. JAMA Oncol. 2018 Sept 6. doi: 10.1001/jamaoncol.2018.3691.

Outcomes for women with operable HER2-positive breast cancer were similar whether they received standard combination chemotherapy with either concurrent or sequential paclitaxel/trastuzumab, long-term results of the phase 3, randomized American College of Surgeons Oncology Group Z1041 trial showed.

Among 280 women with HER-2 positive breast cancer followed for a median of 5.1 years, there were no significant differences in either pathological complete response rates (pCR), disease-free survival (DFS), or overall survival with either concurrent or sequential therapy, wrote Aman U. Buzdar, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

“A previous publication of this study’s primary analysis reported that breast pCR in patients treated with paclitaxel and trastuzumab followed by FEC [fluorouracil, epirubicin, cyclophosphamide] and trastuzumab did not differ significantly from that of patients receiving FEC followed by paclitaxel and trastuzumab. We now report the findings concerning the secondary outcomes, that is, with a median follow-up of approximately 5 years, DFS is similar among the two treatment arms,” they wrote in JAMA Oncology.

The purpose of the current analysis was to evaluate long-term outcomes associated with the two treatment approaches.

In the trial, conducted at 36 centers in the continental United States and Puerto Rico, 280 women (median age, 50 years; range, 28-76 years) were treated with 500 mg/m² of fluorouracil, 75 mg/m² epirubicin, and 500 mg/m² cyclophosphamide every 3 weeks for 12 weeks with concurrent weekly paclitaxel at 80 mg/m² and trastuzumab at 2 mg/kg – after an initial dose of 4 mg/kg – or the same paclitaxel/trastuzumab combination delivered weekly for 12 weeks, followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks.

Women who also had hormone receptor–positive disease received endocrine therapy. Radiotherapy was delivered at the discretion of the attending physician.

As noted, there were no differences in either DFS rates (adjusted hazard ratio, 1.02; P = .96) or overall survival rates (adjusted HR, 1.17; P = .73) between the trial arms.

The authors concluded that “concurrent administration of trastuzumab with FEC was not found to offer additional clinical benefit and is not warranted.”

The study was supported by grants to participating institutions from the National Cancer Institute. Dr. Buzdar reported no conflicts of interest. Three coauthors reported research support, consulting fees, travel support, and/or other relationships with multiple companies.

SOURCE: Buzdar AU et al. JAMA Oncol. 2018 Sept 6. doi: 10.1001/jamaoncol.2018.3691.

This article was produced in partnership with The New York Times.

One of the world’s top breast cancer doctors failed to disclose millions of dollars in payments from drug and health care companies in recent years, omitting his financial ties from dozens of research articles in prestigious publications like the New England Journal of Medicine and the Lancet.

The researcher, José Baselga, MD, a towering figure in the cancer world, is the chief medical officer at Memorial Sloan Kettering Cancer Center in New York. He has held board memberships or advisory roles with Roche and Bristol-Myers Squibb, among other corporations; has had a stake in start-ups testing cancer therapies; and played a key role in the development of breakthrough drugs that have revolutionized treatments for breast cancer.

According to an analysis by ProPublica and the New York Times, Dr. Baselga did not follow financial disclosure rules set by the American Association for Cancer Research when he was president of the group. He also left out payments he received from companies connected to cancer research in his articles published in the group’s journal, Cancer Discovery. At the same time, he has been one of the journal’s two editors in chief.

At a conference this year and before analysts in 2017, he put a positive spin on the results of two Roche-sponsored clinical trials that many others considered disappointments, without disclosing his relationship to the company. Since 2014, he has received more than $3 million from Roche in consulting fees and for his stake in a company it acquired.

Dr. Baselga did not dispute his relationships with at least a dozen companies. In an interview, he said the disclosure lapses were unintentional.

He stressed that much of his industry work was publicly known although he declined to provide payment figures from his involvement with some biotech start-ups. “I acknowledge that there have been inconsistencies, but that’s what it is,” he said. “It’s not that I do not appreciate the importance.”

Dr. Baselga’s extensive corporate relationships – and his frequent failure to disclose them – illustrate how permeable the boundaries remain between academic research and industry, and how weakly reporting requirements are enforced by the medical journals and professional societies charged with policing them.

A decade ago, a series of scandals involving the secret influence of the pharmaceutical industry on drug research prompted the medical community to beef up its conflict-of-interest disclosure requirements. Ethicists worry that outside entanglements can shape the way studies are designed and medications are prescribed to patients, allowing bias to influence medical practice. Disclosing those connections allows the public, other scientists, and doctors to evaluate the research and weigh potential conflicts.

If leaders don’t follow the rules, then we don’t really have rules,” said Walid Gellad, MD, an of the department of medicine at the University of Pittsburgh and director of its Center for Pharmaceutical Policy and Prescribing. “It says that the rules don’t matter.”

The penalties for such ethical lapses are not severe. The cancer research group, the American Association for Cancer Research, warns authors who fill out disclosure forms for its journals that they face a 3-year ban on publishing if they are found to have financial relationships that they did not disclose. But the ban is not included in the conflict-of-interest policy posted on its website, and the group said no author had ever been barred.

Many journals and professional societies do not check conflicts and simply require authors to correct the record.

Officials at the AACR, the American Society of Clinical Oncology and the New England Journal of Medicine said they were looking into Dr. Baselga’s omissions after inquiries from the Times and ProPublica. The Lancet declined to say whether it would look into the matter.

Christine Hickey, a spokeswoman for Memorial Sloan Kettering, said that Dr. Baselga had properly informed the hospital of his outside industry work and that it was Dr. Baselga’s responsibility to disclose such relationships to entities such as medical journals. The cancer center, she said, “has a rigorous and comprehensive compliance program in place to promote honesty and objectivity in scientific research.”

Asked if he planned to correct his disclosures, Dr. Baselga asked reporters what they would recommend. In a statement several days later, he said he would correct his conflict-of-interest reporting for 17 articles, including in the New England Journal of Medicine, the Lancet, and the publication he edits, Cancer Discovery. He said that he did not believe disclosure was required for dozens of other articles detailing early stages of research.

“I have spent my career caring for cancer patients and bringing new therapies to the clinic with the goal of extending and saving lives,” Dr. Baselga said in the statement. “While I have been inconsistent with disclosures and acknowledge that fact, that is a far cry from compromising my responsibilities as a physician, as a scientist and as a clinical leader.”
 

The corporate imprint on cancer research

Dr. Baselga, 59, supervises clinical operations at Memorial Sloan Kettering, one of the nation’s top cancer centers and wields influence over the lives of patients and companies wishing to conduct trials there. He was paid more than $1.5 million in compensation by the cancer center in 2016, according to the hospital’s latest available tax disclosures, but that does not include his consulting or board fees from outside companies.

Many top medical researchers have ties to the for-profit health care industry, and some overlap is seen as a good thing – after all, these are the companies charged with developing the drugs, medical devices and diagnostic tests of the future.

Dr. Baselga’s relationship to industry is extensive. In addition to sitting on the board of Bristol-Myers Squibb, he is a director of Varian Medical Systems, which sells radiation equipment and for whom Memorial Sloan Kettering is a client.

In all, Dr. Baselga has served on the boards of at least six companies since 2013, positions that have required him to assume a fiduciary responsibility to protect the interests of those companies, even as he oversees the cancer center’s medical operations.

The hospital and Dr. Baselga said steps had been taken to prevent him from having a say in any business between the cancer center and the companies on whose boards he sits.

The chief executive of Memorial Sloan Kettering, Craig B. Thompson, MD, settled lawsuits several years ago that were filed by the University of Pennsylvania, Philadelphia, and an affiliated research center. They contended that he hid research conducted while he was at Penn to start a new company, Agios Pharmaceuticals, and did not share the earnings. Dr. Thompson disputed the allegations. He now sits on the board of Merck, which manufactures Keytruda, a blockbuster cancer therapy.

Ms. Hickey said the cancer center cannot fulfill its charitable mission without working with industry. “We encourage collaboration and are proud that our work has led to the approval of novel, lifesaving cancer treatments for patients around the world,” she said.
 

Some disclosures are required; others aren’t

After the scandals a decade ago over lack of disclosure, the federal government began requiring drug and device manufacturers to publicly disclose payments to doctors in 2013.

From August 2013 through 2017, Dr. Baselga received nearly $3.5 million from nine companies, according to the federal Open Payments database, which compiles disclosures filed by drug and device companies.

Dr. Baselga has disclosed in other forums investments and advisory roles in biotech start-ups, but he declined to provide a tally of financial interests in those firms. Companies that have not received approval from the Food and Drug Administration for their products – projects still in the testing phases – do not have to report payments they make to doctors.

Serving on boards can be lucrative. In 2017, Dr. Baselga received $260,000 in cash and stock awards to sit on Varian’s board of directors, according to the company’s corporate filings.

ProPublica and the Times analyzed Dr. Baselga’s publications in medical journals since 2013, the year he joined Memorial Sloan Kettering. He failed to disclose any industry relationships in more than 100, or about 60% of the time, a figure that has increased with each passing year. Last year, he did not list any potential conflicts in 87% of the articles that he wrote or cowrote.

Dr. Baselga compiled a color-coded list of his articles and offered a different interpretation. Sixty-two of the papers for which he did not disclose any potential conflict represented “conceptual, basic laboratory or translational work,” and did not require one, he said. Questions could be raised about others, he said, but he added that most “had no clinical nor financial implications.” That left the 17 papers he plans to correct.

Early-stage research often carries financial weight because it helps companies decide whether to move ahead with a product. In about two-thirds of Dr. Baselga’s articles that lacked details of his industry ties, one or more of his coauthors listed theirs.

In 2015, Dr. Baselga published an article in the New England Journal about a Roche-sponsored trial of one of the company’s drugs, Zelboraf. Despite his financial ties to Roche, he declared that he had “nothing to disclose.” Fourteen of his coauthors reported ties to Roche.

Dr. Baselga defended the articles, saying that “these are high-quality manuscripts reporting on important clinical trials that led to a better understanding of cancer treatments.”

The guidelines enacted by most major medical journals and professional societies ask authors and presenters to list recent financial relationships that could pose a conflict.

But much of this reporting still relies on the honor system. A study in August in the journal JAMA Oncology found that one-third of authors in a sample of cancer trials did not report all payments from the studies’ sponsors.

“We don’t routinely check because we don’t have those kind of resources,” said Rita F. Redberg, MD, the editor of JAMA Internal Medicine, who has been critical of the influence of industry on medical practice. “We rely on trust and integrity. It’s kind of an assumed part of the professional relationship.”

Jennifer Zeis, a spokeswoman for the New England Journal of Medicine, said in an email that it had now asked Dr. Baselga to amend his disclosures. She said the journal planned to overhaul its tracking of industry relationships.

The AACR said it had begun an “extensive review” of the disclosure forms submitted by Dr. Baselga.

It said that it had never barred an author from publishing, and that “such an action would be necessary only in cases of egregious, consistent violations of the rules.”

Among the most prominent relationships that Dr. Baselga has often failed to disclose is with the Swiss pharmaceutical giant Roche and its United States subsidiary Genentech.

In June 2017, at the annual meeting of the ASCO in Chicago, Dr. Baselga spoke at a Roche-sponsored investor event about study results that the company had been counting on to persuade oncologists to move patients from Herceptin – which was facing competition from cheaper alternatives – to a combination treatment involving Herceptin and a newer, more expensive drug, Perjeta.

The results were so underwhelming that Roche’s stock fell 5 % on the news. One analyst described the results as a “lead balloon,” and an editorial in the New England Journal called it a “disappointment.”

Dr. Baselga, however, told analysts that critiques were “weird” and “strange.”

This June, at the same cancer conference, Dr. Baselga struck an upbeat note about the results of a Roche trial of the drug taselisib, saying in a blog post published on the cancer center website that the results were “incredibly exciting” while conceding the side effects from the drug were high.

That same day, Roche announced it was scrapping plans to develop the drug. The news was another disappointment involving the class of drugs called PI3K inhibitors, which is a major focus of Dr. Baselga’s current research.

In neither case did Dr. Baselga reveal that his ties to Roche and Genentech went beyond serving as a trial investigator. In 2014, Roche acquired Seragon, a cancer research company in which Dr. Baselga had an ownership stake, for $725 million. Dr. Baselga received more than $3 million in 2014 and 2015 for his stake in the company, according to the federal Open Payments database.

From 2013 to 2017, Roche also paid Dr. Baselga more than $50,000 in consulting fees, according to the database.

These details were not included in the conflict-of-interest statements that are required of all presenters at the ASCO conference, although he did disclose ownership interests and consulting relationships with several other companies in the prior two years.

ASCO said it would conduct an internal review of Dr. Baselga’s disclosures and would refer the findings to a panel.

Dr. Baselga said that he played no role in the Seragon acquisition and that he had cut ties with Roche since joining the board of a competitor, Bristol-Myers, in March. As for his presentations at the ASCO meetings in the last 2 years, he said he had also noted shortcomings in the studies.

The combination of Perjeta with Herceptin was later approved by the FDA for certain high-risk patients. As for taselisib, Dr. Baselga stands by his belief that the PI3K class of drugs will be an important target for fighting cancer.
 

Katie Thomas covers the pharmaceutical industry for the New York Times.

This article was produced in partnership with The New York Times.

One of the world’s top breast cancer doctors failed to disclose millions of dollars in payments from drug and health care companies in recent years, omitting his financial ties from dozens of research articles in prestigious publications like the New England Journal of Medicine and the Lancet.

The researcher, José Baselga, MD, a towering figure in the cancer world, is the chief medical officer at Memorial Sloan Kettering Cancer Center in New York. He has held board memberships or advisory roles with Roche and Bristol-Myers Squibb, among other corporations; has had a stake in start-ups testing cancer therapies; and played a key role in the development of breakthrough drugs that have revolutionized treatments for breast cancer.

According to an analysis by ProPublica and the New York Times, Dr. Baselga did not follow financial disclosure rules set by the American Association for Cancer Research when he was president of the group. He also left out payments he received from companies connected to cancer research in his articles published in the group’s journal, Cancer Discovery. At the same time, he has been one of the journal’s two editors in chief.

At a conference this year and before analysts in 2017, he put a positive spin on the results of two Roche-sponsored clinical trials that many others considered disappointments, without disclosing his relationship to the company. Since 2014, he has received more than $3 million from Roche in consulting fees and for his stake in a company it acquired.

Dr. Baselga did not dispute his relationships with at least a dozen companies. In an interview, he said the disclosure lapses were unintentional.

He stressed that much of his industry work was publicly known although he declined to provide payment figures from his involvement with some biotech start-ups. “I acknowledge that there have been inconsistencies, but that’s what it is,” he said. “It’s not that I do not appreciate the importance.”

Dr. Baselga’s extensive corporate relationships – and his frequent failure to disclose them – illustrate how permeable the boundaries remain between academic research and industry, and how weakly reporting requirements are enforced by the medical journals and professional societies charged with policing them.

A decade ago, a series of scandals involving the secret influence of the pharmaceutical industry on drug research prompted the medical community to beef up its conflict-of-interest disclosure requirements. Ethicists worry that outside entanglements can shape the way studies are designed and medications are prescribed to patients, allowing bias to influence medical practice. Disclosing those connections allows the public, other scientists, and doctors to evaluate the research and weigh potential conflicts.

If leaders don’t follow the rules, then we don’t really have rules,” said Walid Gellad, MD, an of the department of medicine at the University of Pittsburgh and director of its Center for Pharmaceutical Policy and Prescribing. “It says that the rules don’t matter.”

The penalties for such ethical lapses are not severe. The cancer research group, the American Association for Cancer Research, warns authors who fill out disclosure forms for its journals that they face a 3-year ban on publishing if they are found to have financial relationships that they did not disclose. But the ban is not included in the conflict-of-interest policy posted on its website, and the group said no author had ever been barred.

Many journals and professional societies do not check conflicts and simply require authors to correct the record.

Officials at the AACR, the American Society of Clinical Oncology and the New England Journal of Medicine said they were looking into Dr. Baselga’s omissions after inquiries from the Times and ProPublica. The Lancet declined to say whether it would look into the matter.

Christine Hickey, a spokeswoman for Memorial Sloan Kettering, said that Dr. Baselga had properly informed the hospital of his outside industry work and that it was Dr. Baselga’s responsibility to disclose such relationships to entities such as medical journals. The cancer center, she said, “has a rigorous and comprehensive compliance program in place to promote honesty and objectivity in scientific research.”

Asked if he planned to correct his disclosures, Dr. Baselga asked reporters what they would recommend. In a statement several days later, he said he would correct his conflict-of-interest reporting for 17 articles, including in the New England Journal of Medicine, the Lancet, and the publication he edits, Cancer Discovery. He said that he did not believe disclosure was required for dozens of other articles detailing early stages of research.

“I have spent my career caring for cancer patients and bringing new therapies to the clinic with the goal of extending and saving lives,” Dr. Baselga said in the statement. “While I have been inconsistent with disclosures and acknowledge that fact, that is a far cry from compromising my responsibilities as a physician, as a scientist and as a clinical leader.”
 

The corporate imprint on cancer research

Dr. Baselga, 59, supervises clinical operations at Memorial Sloan Kettering, one of the nation’s top cancer centers and wields influence over the lives of patients and companies wishing to conduct trials there. He was paid more than $1.5 million in compensation by the cancer center in 2016, according to the hospital’s latest available tax disclosures, but that does not include his consulting or board fees from outside companies.

Many top medical researchers have ties to the for-profit health care industry, and some overlap is seen as a good thing – after all, these are the companies charged with developing the drugs, medical devices and diagnostic tests of the future.

Dr. Baselga’s relationship to industry is extensive. In addition to sitting on the board of Bristol-Myers Squibb, he is a director of Varian Medical Systems, which sells radiation equipment and for whom Memorial Sloan Kettering is a client.

In all, Dr. Baselga has served on the boards of at least six companies since 2013, positions that have required him to assume a fiduciary responsibility to protect the interests of those companies, even as he oversees the cancer center’s medical operations.

The hospital and Dr. Baselga said steps had been taken to prevent him from having a say in any business between the cancer center and the companies on whose boards he sits.

The chief executive of Memorial Sloan Kettering, Craig B. Thompson, MD, settled lawsuits several years ago that were filed by the University of Pennsylvania, Philadelphia, and an affiliated research center. They contended that he hid research conducted while he was at Penn to start a new company, Agios Pharmaceuticals, and did not share the earnings. Dr. Thompson disputed the allegations. He now sits on the board of Merck, which manufactures Keytruda, a blockbuster cancer therapy.

Ms. Hickey said the cancer center cannot fulfill its charitable mission without working with industry. “We encourage collaboration and are proud that our work has led to the approval of novel, lifesaving cancer treatments for patients around the world,” she said.
 

Some disclosures are required; others aren’t

After the scandals a decade ago over lack of disclosure, the federal government began requiring drug and device manufacturers to publicly disclose payments to doctors in 2013.

From August 2013 through 2017, Dr. Baselga received nearly $3.5 million from nine companies, according to the federal Open Payments database, which compiles disclosures filed by drug and device companies.

Dr. Baselga has disclosed in other forums investments and advisory roles in biotech start-ups, but he declined to provide a tally of financial interests in those firms. Companies that have not received approval from the Food and Drug Administration for their products – projects still in the testing phases – do not have to report payments they make to doctors.

Serving on boards can be lucrative. In 2017, Dr. Baselga received $260,000 in cash and stock awards to sit on Varian’s board of directors, according to the company’s corporate filings.

ProPublica and the Times analyzed Dr. Baselga’s publications in medical journals since 2013, the year he joined Memorial Sloan Kettering. He failed to disclose any industry relationships in more than 100, or about 60% of the time, a figure that has increased with each passing year. Last year, he did not list any potential conflicts in 87% of the articles that he wrote or cowrote.

Dr. Baselga compiled a color-coded list of his articles and offered a different interpretation. Sixty-two of the papers for which he did not disclose any potential conflict represented “conceptual, basic laboratory or translational work,” and did not require one, he said. Questions could be raised about others, he said, but he added that most “had no clinical nor financial implications.” That left the 17 papers he plans to correct.

Early-stage research often carries financial weight because it helps companies decide whether to move ahead with a product. In about two-thirds of Dr. Baselga’s articles that lacked details of his industry ties, one or more of his coauthors listed theirs.

In 2015, Dr. Baselga published an article in the New England Journal about a Roche-sponsored trial of one of the company’s drugs, Zelboraf. Despite his financial ties to Roche, he declared that he had “nothing to disclose.” Fourteen of his coauthors reported ties to Roche.

Dr. Baselga defended the articles, saying that “these are high-quality manuscripts reporting on important clinical trials that led to a better understanding of cancer treatments.”

The guidelines enacted by most major medical journals and professional societies ask authors and presenters to list recent financial relationships that could pose a conflict.

But much of this reporting still relies on the honor system. A study in August in the journal JAMA Oncology found that one-third of authors in a sample of cancer trials did not report all payments from the studies’ sponsors.

“We don’t routinely check because we don’t have those kind of resources,” said Rita F. Redberg, MD, the editor of JAMA Internal Medicine, who has been critical of the influence of industry on medical practice. “We rely on trust and integrity. It’s kind of an assumed part of the professional relationship.”

Jennifer Zeis, a spokeswoman for the New England Journal of Medicine, said in an email that it had now asked Dr. Baselga to amend his disclosures. She said the journal planned to overhaul its tracking of industry relationships.

The AACR said it had begun an “extensive review” of the disclosure forms submitted by Dr. Baselga.

It said that it had never barred an author from publishing, and that “such an action would be necessary only in cases of egregious, consistent violations of the rules.”

Among the most prominent relationships that Dr. Baselga has often failed to disclose is with the Swiss pharmaceutical giant Roche and its United States subsidiary Genentech.

In June 2017, at the annual meeting of the ASCO in Chicago, Dr. Baselga spoke at a Roche-sponsored investor event about study results that the company had been counting on to persuade oncologists to move patients from Herceptin – which was facing competition from cheaper alternatives – to a combination treatment involving Herceptin and a newer, more expensive drug, Perjeta.

The results were so underwhelming that Roche’s stock fell 5 % on the news. One analyst described the results as a “lead balloon,” and an editorial in the New England Journal called it a “disappointment.”

Dr. Baselga, however, told analysts that critiques were “weird” and “strange.”

This June, at the same cancer conference, Dr. Baselga struck an upbeat note about the results of a Roche trial of the drug taselisib, saying in a blog post published on the cancer center website that the results were “incredibly exciting” while conceding the side effects from the drug were high.

That same day, Roche announced it was scrapping plans to develop the drug. The news was another disappointment involving the class of drugs called PI3K inhibitors, which is a major focus of Dr. Baselga’s current research.

In neither case did Dr. Baselga reveal that his ties to Roche and Genentech went beyond serving as a trial investigator. In 2014, Roche acquired Seragon, a cancer research company in which Dr. Baselga had an ownership stake, for $725 million. Dr. Baselga received more than $3 million in 2014 and 2015 for his stake in the company, according to the federal Open Payments database.

From 2013 to 2017, Roche also paid Dr. Baselga more than $50,000 in consulting fees, according to the database.

These details were not included in the conflict-of-interest statements that are required of all presenters at the ASCO conference, although he did disclose ownership interests and consulting relationships with several other companies in the prior two years.

ASCO said it would conduct an internal review of Dr. Baselga’s disclosures and would refer the findings to a panel.

Dr. Baselga said that he played no role in the Seragon acquisition and that he had cut ties with Roche since joining the board of a competitor, Bristol-Myers, in March. As for his presentations at the ASCO meetings in the last 2 years, he said he had also noted shortcomings in the studies.

The combination of Perjeta with Herceptin was later approved by the FDA for certain high-risk patients. As for taselisib, Dr. Baselga stands by his belief that the PI3K class of drugs will be an important target for fighting cancer.
 

Katie Thomas covers the pharmaceutical industry for the New York Times.

This article was produced in partnership with The New York Times.

One of the world’s top breast cancer doctors failed to disclose millions of dollars in payments from drug and health care companies in recent years, omitting his financial ties from dozens of research articles in prestigious publications like the New England Journal of Medicine and the Lancet.

The researcher, José Baselga, MD, a towering figure in the cancer world, is the chief medical officer at Memorial Sloan Kettering Cancer Center in New York. He has held board memberships or advisory roles with Roche and Bristol-Myers Squibb, among other corporations; has had a stake in start-ups testing cancer therapies; and played a key role in the development of breakthrough drugs that have revolutionized treatments for breast cancer.

According to an analysis by ProPublica and the New York Times, Dr. Baselga did not follow financial disclosure rules set by the American Association for Cancer Research when he was president of the group. He also left out payments he received from companies connected to cancer research in his articles published in the group’s journal, Cancer Discovery. At the same time, he has been one of the journal’s two editors in chief.

At a conference this year and before analysts in 2017, he put a positive spin on the results of two Roche-sponsored clinical trials that many others considered disappointments, without disclosing his relationship to the company. Since 2014, he has received more than $3 million from Roche in consulting fees and for his stake in a company it acquired.

Dr. Baselga did not dispute his relationships with at least a dozen companies. In an interview, he said the disclosure lapses were unintentional.

He stressed that much of his industry work was publicly known although he declined to provide payment figures from his involvement with some biotech start-ups. “I acknowledge that there have been inconsistencies, but that’s what it is,” he said. “It’s not that I do not appreciate the importance.”

Dr. Baselga’s extensive corporate relationships – and his frequent failure to disclose them – illustrate how permeable the boundaries remain between academic research and industry, and how weakly reporting requirements are enforced by the medical journals and professional societies charged with policing them.

A decade ago, a series of scandals involving the secret influence of the pharmaceutical industry on drug research prompted the medical community to beef up its conflict-of-interest disclosure requirements. Ethicists worry that outside entanglements can shape the way studies are designed and medications are prescribed to patients, allowing bias to influence medical practice. Disclosing those connections allows the public, other scientists, and doctors to evaluate the research and weigh potential conflicts.

If leaders don’t follow the rules, then we don’t really have rules,” said Walid Gellad, MD, an of the department of medicine at the University of Pittsburgh and director of its Center for Pharmaceutical Policy and Prescribing. “It says that the rules don’t matter.”

The penalties for such ethical lapses are not severe. The cancer research group, the American Association for Cancer Research, warns authors who fill out disclosure forms for its journals that they face a 3-year ban on publishing if they are found to have financial relationships that they did not disclose. But the ban is not included in the conflict-of-interest policy posted on its website, and the group said no author had ever been barred.

Many journals and professional societies do not check conflicts and simply require authors to correct the record.

Officials at the AACR, the American Society of Clinical Oncology and the New England Journal of Medicine said they were looking into Dr. Baselga’s omissions after inquiries from the Times and ProPublica. The Lancet declined to say whether it would look into the matter.

Christine Hickey, a spokeswoman for Memorial Sloan Kettering, said that Dr. Baselga had properly informed the hospital of his outside industry work and that it was Dr. Baselga’s responsibility to disclose such relationships to entities such as medical journals. The cancer center, she said, “has a rigorous and comprehensive compliance program in place to promote honesty and objectivity in scientific research.”

Asked if he planned to correct his disclosures, Dr. Baselga asked reporters what they would recommend. In a statement several days later, he said he would correct his conflict-of-interest reporting for 17 articles, including in the New England Journal of Medicine, the Lancet, and the publication he edits, Cancer Discovery. He said that he did not believe disclosure was required for dozens of other articles detailing early stages of research.

“I have spent my career caring for cancer patients and bringing new therapies to the clinic with the goal of extending and saving lives,” Dr. Baselga said in the statement. “While I have been inconsistent with disclosures and acknowledge that fact, that is a far cry from compromising my responsibilities as a physician, as a scientist and as a clinical leader.”
 

The corporate imprint on cancer research

Dr. Baselga, 59, supervises clinical operations at Memorial Sloan Kettering, one of the nation’s top cancer centers and wields influence over the lives of patients and companies wishing to conduct trials there. He was paid more than $1.5 million in compensation by the cancer center in 2016, according to the hospital’s latest available tax disclosures, but that does not include his consulting or board fees from outside companies.

Many top medical researchers have ties to the for-profit health care industry, and some overlap is seen as a good thing – after all, these are the companies charged with developing the drugs, medical devices and diagnostic tests of the future.

Dr. Baselga’s relationship to industry is extensive. In addition to sitting on the board of Bristol-Myers Squibb, he is a director of Varian Medical Systems, which sells radiation equipment and for whom Memorial Sloan Kettering is a client.

In all, Dr. Baselga has served on the boards of at least six companies since 2013, positions that have required him to assume a fiduciary responsibility to protect the interests of those companies, even as he oversees the cancer center’s medical operations.

The hospital and Dr. Baselga said steps had been taken to prevent him from having a say in any business between the cancer center and the companies on whose boards he sits.

The chief executive of Memorial Sloan Kettering, Craig B. Thompson, MD, settled lawsuits several years ago that were filed by the University of Pennsylvania, Philadelphia, and an affiliated research center. They contended that he hid research conducted while he was at Penn to start a new company, Agios Pharmaceuticals, and did not share the earnings. Dr. Thompson disputed the allegations. He now sits on the board of Merck, which manufactures Keytruda, a blockbuster cancer therapy.

Ms. Hickey said the cancer center cannot fulfill its charitable mission without working with industry. “We encourage collaboration and are proud that our work has led to the approval of novel, lifesaving cancer treatments for patients around the world,” she said.
 

Some disclosures are required; others aren’t

After the scandals a decade ago over lack of disclosure, the federal government began requiring drug and device manufacturers to publicly disclose payments to doctors in 2013.

From August 2013 through 2017, Dr. Baselga received nearly $3.5 million from nine companies, according to the federal Open Payments database, which compiles disclosures filed by drug and device companies.

Dr. Baselga has disclosed in other forums investments and advisory roles in biotech start-ups, but he declined to provide a tally of financial interests in those firms. Companies that have not received approval from the Food and Drug Administration for their products – projects still in the testing phases – do not have to report payments they make to doctors.

Serving on boards can be lucrative. In 2017, Dr. Baselga received $260,000 in cash and stock awards to sit on Varian’s board of directors, according to the company’s corporate filings.

ProPublica and the Times analyzed Dr. Baselga’s publications in medical journals since 2013, the year he joined Memorial Sloan Kettering. He failed to disclose any industry relationships in more than 100, or about 60% of the time, a figure that has increased with each passing year. Last year, he did not list any potential conflicts in 87% of the articles that he wrote or cowrote.

Dr. Baselga compiled a color-coded list of his articles and offered a different interpretation. Sixty-two of the papers for which he did not disclose any potential conflict represented “conceptual, basic laboratory or translational work,” and did not require one, he said. Questions could be raised about others, he said, but he added that most “had no clinical nor financial implications.” That left the 17 papers he plans to correct.

Early-stage research often carries financial weight because it helps companies decide whether to move ahead with a product. In about two-thirds of Dr. Baselga’s articles that lacked details of his industry ties, one or more of his coauthors listed theirs.

In 2015, Dr. Baselga published an article in the New England Journal about a Roche-sponsored trial of one of the company’s drugs, Zelboraf. Despite his financial ties to Roche, he declared that he had “nothing to disclose.” Fourteen of his coauthors reported ties to Roche.

Dr. Baselga defended the articles, saying that “these are high-quality manuscripts reporting on important clinical trials that led to a better understanding of cancer treatments.”

The guidelines enacted by most major medical journals and professional societies ask authors and presenters to list recent financial relationships that could pose a conflict.

But much of this reporting still relies on the honor system. A study in August in the journal JAMA Oncology found that one-third of authors in a sample of cancer trials did not report all payments from the studies’ sponsors.

“We don’t routinely check because we don’t have those kind of resources,” said Rita F. Redberg, MD, the editor of JAMA Internal Medicine, who has been critical of the influence of industry on medical practice. “We rely on trust and integrity. It’s kind of an assumed part of the professional relationship.”

Jennifer Zeis, a spokeswoman for the New England Journal of Medicine, said in an email that it had now asked Dr. Baselga to amend his disclosures. She said the journal planned to overhaul its tracking of industry relationships.

The AACR said it had begun an “extensive review” of the disclosure forms submitted by Dr. Baselga.

It said that it had never barred an author from publishing, and that “such an action would be necessary only in cases of egregious, consistent violations of the rules.”

Among the most prominent relationships that Dr. Baselga has often failed to disclose is with the Swiss pharmaceutical giant Roche and its United States subsidiary Genentech.

In June 2017, at the annual meeting of the ASCO in Chicago, Dr. Baselga spoke at a Roche-sponsored investor event about study results that the company had been counting on to persuade oncologists to move patients from Herceptin – which was facing competition from cheaper alternatives – to a combination treatment involving Herceptin and a newer, more expensive drug, Perjeta.

The results were so underwhelming that Roche’s stock fell 5 % on the news. One analyst described the results as a “lead balloon,” and an editorial in the New England Journal called it a “disappointment.”

Dr. Baselga, however, told analysts that critiques were “weird” and “strange.”

This June, at the same cancer conference, Dr. Baselga struck an upbeat note about the results of a Roche trial of the drug taselisib, saying in a blog post published on the cancer center website that the results were “incredibly exciting” while conceding the side effects from the drug were high.

That same day, Roche announced it was scrapping plans to develop the drug. The news was another disappointment involving the class of drugs called PI3K inhibitors, which is a major focus of Dr. Baselga’s current research.

In neither case did Dr. Baselga reveal that his ties to Roche and Genentech went beyond serving as a trial investigator. In 2014, Roche acquired Seragon, a cancer research company in which Dr. Baselga had an ownership stake, for $725 million. Dr. Baselga received more than $3 million in 2014 and 2015 for his stake in the company, according to the federal Open Payments database.

From 2013 to 2017, Roche also paid Dr. Baselga more than $50,000 in consulting fees, according to the database.

These details were not included in the conflict-of-interest statements that are required of all presenters at the ASCO conference, although he did disclose ownership interests and consulting relationships with several other companies in the prior two years.

ASCO said it would conduct an internal review of Dr. Baselga’s disclosures and would refer the findings to a panel.

Dr. Baselga said that he played no role in the Seragon acquisition and that he had cut ties with Roche since joining the board of a competitor, Bristol-Myers, in March. As for his presentations at the ASCO meetings in the last 2 years, he said he had also noted shortcomings in the studies.

The combination of Perjeta with Herceptin was later approved by the FDA for certain high-risk patients. As for taselisib, Dr. Baselga stands by his belief that the PI3K class of drugs will be an important target for fighting cancer.
 

Katie Thomas covers the pharmaceutical industry for the New York Times.

Nearly 3% of patients with multiple sclerosis (MS) are estimated to have a truly benign course of disease over at least 15 years without the use of disease-modifying therapy, based on findings from a U.K. population-based study that also showed how poorly benign disease tracks with disability measures and lacks agreement between patients and physicians.

designer491/Thinkstock

“The study of the individuals with extremely favorable outcomes may uncover insights about disease pathogenesis or repair. However, the insensitivity of EDSS [Expanded Disability Status Scale]–based definitions of benign MS and the discrepancy between patient and clinician perception of benign MS undermine use of the term ‘benign’ in the clinical setting,” Emma Clare Tallantyre, MD, of Cardiff (Wales) University, and her colleagues wrote in the Journal of Neurology, Neurosurgery & Psychiatry.

Dr. Tallantyre and her colleagues found that, of 1,049 patients with disease duration longer than 15 years, 200 had a recent EDSS score of less than 4.0. Of those 200, 60 were clinically assessed and 9 (15%) were found to have truly benign MS, defined as having an EDSS less than 3.0 and having no significant fatigue, mood disturbance, cognitive impairment, or disruption to employment in the absence of disease-modifying therapy at least 15 years after symptom onset.

The investigators extrapolated these data to estimate that 30 patients in the study population of 1,049 had truly benign MS, for a prevalence of 2.9%. However, of the 60 patients who were clinically assessed, 39 thought they had benign MS based on the lay definition provided: “When referring to illness, ‘benign’ usually means a condition which has little or no harmful effects on a person. There are no complications and there is a good outcome or prognosis.”

Patients who self-reported benign MS had significantly lower EDSS scores, fewer depressive symptoms, lower fatigue severity, and lower reported MS impact than did patients who did not report benign MS. “Self-reported benign MS status showed poor agreement with our composite definition of benign MS status and only fair agreement with EDSS-based definitions of benign MS status,” the investigators wrote.

jevans@mdedge.com

SOURCE: Tallantyre EC et al. J Neurol Neurosurg Psychiatry. 2018 Sep 3. doi: 10.1136/jnnp-2018-318802.

Nearly 3% of patients with multiple sclerosis (MS) are estimated to have a truly benign course of disease over at least 15 years without the use of disease-modifying therapy, based on findings from a U.K. population-based study that also showed how poorly benign disease tracks with disability measures and lacks agreement between patients and physicians.

designer491/Thinkstock

“The study of the individuals with extremely favorable outcomes may uncover insights about disease pathogenesis or repair. However, the insensitivity of EDSS [Expanded Disability Status Scale]–based definitions of benign MS and the discrepancy between patient and clinician perception of benign MS undermine use of the term ‘benign’ in the clinical setting,” Emma Clare Tallantyre, MD, of Cardiff (Wales) University, and her colleagues wrote in the Journal of Neurology, Neurosurgery & Psychiatry.

Dr. Tallantyre and her colleagues found that, of 1,049 patients with disease duration longer than 15 years, 200 had a recent EDSS score of less than 4.0. Of those 200, 60 were clinically assessed and 9 (15%) were found to have truly benign MS, defined as having an EDSS less than 3.0 and having no significant fatigue, mood disturbance, cognitive impairment, or disruption to employment in the absence of disease-modifying therapy at least 15 years after symptom onset.

The investigators extrapolated these data to estimate that 30 patients in the study population of 1,049 had truly benign MS, for a prevalence of 2.9%. However, of the 60 patients who were clinically assessed, 39 thought they had benign MS based on the lay definition provided: “When referring to illness, ‘benign’ usually means a condition which has little or no harmful effects on a person. There are no complications and there is a good outcome or prognosis.”

Patients who self-reported benign MS had significantly lower EDSS scores, fewer depressive symptoms, lower fatigue severity, and lower reported MS impact than did patients who did not report benign MS. “Self-reported benign MS status showed poor agreement with our composite definition of benign MS status and only fair agreement with EDSS-based definitions of benign MS status,” the investigators wrote.

jevans@mdedge.com

SOURCE: Tallantyre EC et al. J Neurol Neurosurg Psychiatry. 2018 Sep 3. doi: 10.1136/jnnp-2018-318802.

Nearly 3% of patients with multiple sclerosis (MS) are estimated to have a truly benign course of disease over at least 15 years without the use of disease-modifying therapy, based on findings from a U.K. population-based study that also showed how poorly benign disease tracks with disability measures and lacks agreement between patients and physicians.

designer491/Thinkstock

“The study of the individuals with extremely favorable outcomes may uncover insights about disease pathogenesis or repair. However, the insensitivity of EDSS [Expanded Disability Status Scale]–based definitions of benign MS and the discrepancy between patient and clinician perception of benign MS undermine use of the term ‘benign’ in the clinical setting,” Emma Clare Tallantyre, MD, of Cardiff (Wales) University, and her colleagues wrote in the Journal of Neurology, Neurosurgery & Psychiatry.

Dr. Tallantyre and her colleagues found that, of 1,049 patients with disease duration longer than 15 years, 200 had a recent EDSS score of less than 4.0. Of those 200, 60 were clinically assessed and 9 (15%) were found to have truly benign MS, defined as having an EDSS less than 3.0 and having no significant fatigue, mood disturbance, cognitive impairment, or disruption to employment in the absence of disease-modifying therapy at least 15 years after symptom onset.

The investigators extrapolated these data to estimate that 30 patients in the study population of 1,049 had truly benign MS, for a prevalence of 2.9%. However, of the 60 patients who were clinically assessed, 39 thought they had benign MS based on the lay definition provided: “When referring to illness, ‘benign’ usually means a condition which has little or no harmful effects on a person. There are no complications and there is a good outcome or prognosis.”

Patients who self-reported benign MS had significantly lower EDSS scores, fewer depressive symptoms, lower fatigue severity, and lower reported MS impact than did patients who did not report benign MS. “Self-reported benign MS status showed poor agreement with our composite definition of benign MS status and only fair agreement with EDSS-based definitions of benign MS status,” the investigators wrote.

jevans@mdedge.com

SOURCE: Tallantyre EC et al. J Neurol Neurosurg Psychiatry. 2018 Sep 3. doi: 10.1136/jnnp-2018-318802.

The European Society for Medical Oncology (ESMO) has published a proposed scale that would rank molecular targets for various cancers by how well they can be treated with new or emerging drugs.

The ESMO Scale of Clinical Actionability for Molecular Targets is designed to “harmonize and standardize the reporting and interpretation of clinically relevant genomics data,” according to Joaquin Mateo, MD, PhD, from the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and his fellow members of the ESMO Translational Research and Precision Medicine Working Group.

“A major challenge for oncologists in the clinic is to distinguish between findings that represent proven clinical value or potential value based on preliminary clinical or preclinical evidence from hypothetical gene-drug matches and findings that are currently irrelevant for clinical practice,” they wrote in Annals of Oncology.

The scale groups targets into one of six tiers based on levels of evidence ranging from the gold standard of prospective, randomized clinical trials to targets for which there are no evidence and only hypothetical actionability. The primary goal is to help oncologists assign priority to potential targets when they review results of gene-sequencing panels for individual patients, according to the developers.

Briefly, the six tiers are:

Tier I includes targets that are agreed to be suitable for routine use and a recommended specific drug when a specific molecular alteration is detected. Examples include trastuzumab for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, and inhibitors of epidermal growth factor receptor (EGFR) in patients with non–small cell lung cancer positive for EGFR mutations.

Tier II includes “investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed.” This tier includes agents that work in the phosphatidylinostiol 3-kinase pathway.

Tier III is similar to Tier II, in that it includes investigational targets that define a patient population with proven benefit from a targeted therapy, but in this case the target is detected in a different tumor type that has not previously been studied. For example, the targeted agent vemurafenib (Zelboraf), which extends survival of patients with metastatic melanomas carrying the BRAF V600E mutation, has only limited activity against BRAF-mutated colorectal cancers.

Tier IV includes targets with preclinical evidence of actionability.

Tier V includes targets with “evidence of relevant antitumor activity, not resulting in clinical meaningful benefit as single treatment but supporting development of cotargeting approaches.” The authors cite the example of PIK3CA inhibitors in patients with estrogen receptor–positive, HER2-negative breast cancers who also have PIK3CA activating mutations. In clinical trials, this strategy led to objective responses but not change outcomes.

The final tier is not Tier VI, as might be expected, but Tier X, with the X in this case being the unknown – that is, alterations/mutations for which there is neither preclinical nor clinical evidence to support their hypothetical use as a drug target.

“This clinical benefit–centered classification system offers a common language for all the actors involved in clinical cancer drug development. Its implementation in sequencing reports, tumor boards, and scientific communication can enable precise treatment decisions and facilitate discussions with patients about novel therapeutic options,” Dr. Mateo and his associates wrote in their conclusion.

The development process was supported by ESMO. Multiple coauthors reported financial relationships with various companies as well as grants/support from other foundations or charities.

SOURCE: Mateo J et al. Ann Oncol. 2018 Aug 21. doi: 10.1093/annonc/mdy263.

The European Society for Medical Oncology (ESMO) has published a proposed scale that would rank molecular targets for various cancers by how well they can be treated with new or emerging drugs.

The ESMO Scale of Clinical Actionability for Molecular Targets is designed to “harmonize and standardize the reporting and interpretation of clinically relevant genomics data,” according to Joaquin Mateo, MD, PhD, from the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and his fellow members of the ESMO Translational Research and Precision Medicine Working Group.

“A major challenge for oncologists in the clinic is to distinguish between findings that represent proven clinical value or potential value based on preliminary clinical or preclinical evidence from hypothetical gene-drug matches and findings that are currently irrelevant for clinical practice,” they wrote in Annals of Oncology.

The scale groups targets into one of six tiers based on levels of evidence ranging from the gold standard of prospective, randomized clinical trials to targets for which there are no evidence and only hypothetical actionability. The primary goal is to help oncologists assign priority to potential targets when they review results of gene-sequencing panels for individual patients, according to the developers.

Briefly, the six tiers are:

Tier I includes targets that are agreed to be suitable for routine use and a recommended specific drug when a specific molecular alteration is detected. Examples include trastuzumab for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, and inhibitors of epidermal growth factor receptor (EGFR) in patients with non–small cell lung cancer positive for EGFR mutations.

Tier II includes “investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed.” This tier includes agents that work in the phosphatidylinostiol 3-kinase pathway.

Tier III is similar to Tier II, in that it includes investigational targets that define a patient population with proven benefit from a targeted therapy, but in this case the target is detected in a different tumor type that has not previously been studied. For example, the targeted agent vemurafenib (Zelboraf), which extends survival of patients with metastatic melanomas carrying the BRAF V600E mutation, has only limited activity against BRAF-mutated colorectal cancers.

Tier IV includes targets with preclinical evidence of actionability.

Tier V includes targets with “evidence of relevant antitumor activity, not resulting in clinical meaningful benefit as single treatment but supporting development of cotargeting approaches.” The authors cite the example of PIK3CA inhibitors in patients with estrogen receptor–positive, HER2-negative breast cancers who also have PIK3CA activating mutations. In clinical trials, this strategy led to objective responses but not change outcomes.

The final tier is not Tier VI, as might be expected, but Tier X, with the X in this case being the unknown – that is, alterations/mutations for which there is neither preclinical nor clinical evidence to support their hypothetical use as a drug target.

“This clinical benefit–centered classification system offers a common language for all the actors involved in clinical cancer drug development. Its implementation in sequencing reports, tumor boards, and scientific communication can enable precise treatment decisions and facilitate discussions with patients about novel therapeutic options,” Dr. Mateo and his associates wrote in their conclusion.

The development process was supported by ESMO. Multiple coauthors reported financial relationships with various companies as well as grants/support from other foundations or charities.

SOURCE: Mateo J et al. Ann Oncol. 2018 Aug 21. doi: 10.1093/annonc/mdy263.

The European Society for Medical Oncology (ESMO) has published a proposed scale that would rank molecular targets for various cancers by how well they can be treated with new or emerging drugs.

The ESMO Scale of Clinical Actionability for Molecular Targets is designed to “harmonize and standardize the reporting and interpretation of clinically relevant genomics data,” according to Joaquin Mateo, MD, PhD, from the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and his fellow members of the ESMO Translational Research and Precision Medicine Working Group.

“A major challenge for oncologists in the clinic is to distinguish between findings that represent proven clinical value or potential value based on preliminary clinical or preclinical evidence from hypothetical gene-drug matches and findings that are currently irrelevant for clinical practice,” they wrote in Annals of Oncology.

The scale groups targets into one of six tiers based on levels of evidence ranging from the gold standard of prospective, randomized clinical trials to targets for which there are no evidence and only hypothetical actionability. The primary goal is to help oncologists assign priority to potential targets when they review results of gene-sequencing panels for individual patients, according to the developers.

Briefly, the six tiers are:

Tier I includes targets that are agreed to be suitable for routine use and a recommended specific drug when a specific molecular alteration is detected. Examples include trastuzumab for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, and inhibitors of epidermal growth factor receptor (EGFR) in patients with non–small cell lung cancer positive for EGFR mutations.

Tier II includes “investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed.” This tier includes agents that work in the phosphatidylinostiol 3-kinase pathway.

Tier III is similar to Tier II, in that it includes investigational targets that define a patient population with proven benefit from a targeted therapy, but in this case the target is detected in a different tumor type that has not previously been studied. For example, the targeted agent vemurafenib (Zelboraf), which extends survival of patients with metastatic melanomas carrying the BRAF V600E mutation, has only limited activity against BRAF-mutated colorectal cancers.

Tier IV includes targets with preclinical evidence of actionability.

Tier V includes targets with “evidence of relevant antitumor activity, not resulting in clinical meaningful benefit as single treatment but supporting development of cotargeting approaches.” The authors cite the example of PIK3CA inhibitors in patients with estrogen receptor–positive, HER2-negative breast cancers who also have PIK3CA activating mutations. In clinical trials, this strategy led to objective responses but not change outcomes.

The final tier is not Tier VI, as might be expected, but Tier X, with the X in this case being the unknown – that is, alterations/mutations for which there is neither preclinical nor clinical evidence to support their hypothetical use as a drug target.

“This clinical benefit–centered classification system offers a common language for all the actors involved in clinical cancer drug development. Its implementation in sequencing reports, tumor boards, and scientific communication can enable precise treatment decisions and facilitate discussions with patients about novel therapeutic options,” Dr. Mateo and his associates wrote in their conclusion.

The development process was supported by ESMO. Multiple coauthors reported financial relationships with various companies as well as grants/support from other foundations or charities.

SOURCE: Mateo J et al. Ann Oncol. 2018 Aug 21. doi: 10.1093/annonc/mdy263.