Breast Cancer ICYMI

Lillie Shockney, RN, MAS, a two-time breast cancer survivor and adjunct professor at Johns Hopkins School of Nursing in Baltimore, Maryland, mourns the many losses that her patients with advanced cancer now face in the midst of the COVID-19 pandemic. But in the void of the usual support networks and treatment plans, she sees the resurgence of something that has recently been crowded out: hospice.

The pandemic has forced patients and their physicians to reassess the risk/benefit balance of continuing or embarking on yet another cancer treatment.

“It’s one of the pearls that we will get out of this nightmare,” said Ms. Shockney, who recently retired as administrative director of the cancer survivorship programs at the Sidney Kimmel Comprehensive Cancer Center.

“Physicians have been taught to treat the disease – so as long as there’s a treatment they give another treatment,” she told Medscape Medical News during a Zoom call from her home. “But for some patients with advanced disease, those treatments were making them very sick, so they were trading longevity over quality of life.”

Of course, longevity has never been a guarantee with cancer treatment, and even less so now, with the risk of COVID-19.

“This is going to bring them to some hard discussions,” says Brenda Nevidjon, RN, MSN, chief executive officer at the Oncology Nursing Society.

“We’ve known for a long time that there are patients who are on third- and fourth-round treatment options that have very little evidence of prolonging life or quality of life,” she told Medscape Medical News. “Do we bring these people out of their home to a setting where there could be a fair number of COVID-positive patients? Do we expose them to that?”

Across the world, these dilemmas are pushing cancer specialists to initiate discussions of hospice sooner with patients who have advanced disease, and with more clarity than before.

One of the reasons such conversations have often been avoided is that the concept of hospice is generally misunderstood, said Ms. Shockney.

“Patients think ‘you’re giving up on me, you’ve abandoned me’, but hospice is all about preserving the remainder of their quality of life and letting them have time with family and time to fulfill those elements of experiencing a good and peaceful death,” she said.

Indeed, hospice is “a benefit meant for somebody with at least a 6-month horizon,” agrees Ms. Nevidjon. Yet the average length of hospice in the United States is just 5 days. “It’s at the very, very end, and yet for some of these patients the 6 months they could get in hospice might be a better quality of life than the 4 months on another whole plan of chemotherapy. I can’t imagine that on the backside of this pandemic we will not have learned and we won’t start to change practices around initiating more of these conversations.”
 

Silver lining of this pandemic?

It’s too early into the pandemic to have hard data on whether hospice uptake has increased, but “it’s encouraging to hear that hospice is being discussed and offered sooner as an alternative to that third- or fourth-round chemo,” said Lori Bishop, MHA, RN, vice president of palliative and advanced care at the National Hospice and Palliative Care Organization.

“I agree that improving informed-decision discussions and timely access to hospice is a silver lining of the pandemic,” she told Medscape Medical News.

But she points out that today’s hospice looks quite different than it did before the pandemic, with the immediate and very obvious difference being telehealth, which was not widely utilized previously.

In March, the Centers for Medicare & Medicaid Services expanded telehealth options for hospice providers, something that Ms. Bishop and other hospice providers hope will remain in place after the pandemic passes.

“Telehealth visits are offered to replace some in-home visits both to minimize risk of exposure to COVID-19 and reduce the drain on personal protective equipment,” Bishop explained.

“In-patient hospice programs are also finding unique ways to provide support and connect patients to their loved ones: visitors are allowed but limited to one or two. Music and pet therapy are being provided through the window or virtually and devices such as iPads are being used to help patients connect with loved ones,” she said.

Telehealth links patients out of loneliness, but the one thing it cannot do is provide the comfort of touch – an important part of any hospice program.

“Hand-holding ... I miss that a lot,” says Ms. Shockney, her eyes filling with tears. “When you take somebody’s hand, you don’t even have to speak; that connection, and eye contact, is all you need to help that person emotionally heal.”

This article first appeared on Medscape.com.

Lillie Shockney, RN, MAS, a two-time breast cancer survivor and adjunct professor at Johns Hopkins School of Nursing in Baltimore, Maryland, mourns the many losses that her patients with advanced cancer now face in the midst of the COVID-19 pandemic. But in the void of the usual support networks and treatment plans, she sees the resurgence of something that has recently been crowded out: hospice.

The pandemic has forced patients and their physicians to reassess the risk/benefit balance of continuing or embarking on yet another cancer treatment.

“It’s one of the pearls that we will get out of this nightmare,” said Ms. Shockney, who recently retired as administrative director of the cancer survivorship programs at the Sidney Kimmel Comprehensive Cancer Center.

“Physicians have been taught to treat the disease – so as long as there’s a treatment they give another treatment,” she told Medscape Medical News during a Zoom call from her home. “But for some patients with advanced disease, those treatments were making them very sick, so they were trading longevity over quality of life.”

Of course, longevity has never been a guarantee with cancer treatment, and even less so now, with the risk of COVID-19.

“This is going to bring them to some hard discussions,” says Brenda Nevidjon, RN, MSN, chief executive officer at the Oncology Nursing Society.

“We’ve known for a long time that there are patients who are on third- and fourth-round treatment options that have very little evidence of prolonging life or quality of life,” she told Medscape Medical News. “Do we bring these people out of their home to a setting where there could be a fair number of COVID-positive patients? Do we expose them to that?”

Across the world, these dilemmas are pushing cancer specialists to initiate discussions of hospice sooner with patients who have advanced disease, and with more clarity than before.

One of the reasons such conversations have often been avoided is that the concept of hospice is generally misunderstood, said Ms. Shockney.

“Patients think ‘you’re giving up on me, you’ve abandoned me’, but hospice is all about preserving the remainder of their quality of life and letting them have time with family and time to fulfill those elements of experiencing a good and peaceful death,” she said.

Indeed, hospice is “a benefit meant for somebody with at least a 6-month horizon,” agrees Ms. Nevidjon. Yet the average length of hospice in the United States is just 5 days. “It’s at the very, very end, and yet for some of these patients the 6 months they could get in hospice might be a better quality of life than the 4 months on another whole plan of chemotherapy. I can’t imagine that on the backside of this pandemic we will not have learned and we won’t start to change practices around initiating more of these conversations.”
 

Silver lining of this pandemic?

It’s too early into the pandemic to have hard data on whether hospice uptake has increased, but “it’s encouraging to hear that hospice is being discussed and offered sooner as an alternative to that third- or fourth-round chemo,” said Lori Bishop, MHA, RN, vice president of palliative and advanced care at the National Hospice and Palliative Care Organization.

“I agree that improving informed-decision discussions and timely access to hospice is a silver lining of the pandemic,” she told Medscape Medical News.

But she points out that today’s hospice looks quite different than it did before the pandemic, with the immediate and very obvious difference being telehealth, which was not widely utilized previously.

In March, the Centers for Medicare & Medicaid Services expanded telehealth options for hospice providers, something that Ms. Bishop and other hospice providers hope will remain in place after the pandemic passes.

“Telehealth visits are offered to replace some in-home visits both to minimize risk of exposure to COVID-19 and reduce the drain on personal protective equipment,” Bishop explained.

“In-patient hospice programs are also finding unique ways to provide support and connect patients to their loved ones: visitors are allowed but limited to one or two. Music and pet therapy are being provided through the window or virtually and devices such as iPads are being used to help patients connect with loved ones,” she said.

Telehealth links patients out of loneliness, but the one thing it cannot do is provide the comfort of touch – an important part of any hospice program.

“Hand-holding ... I miss that a lot,” says Ms. Shockney, her eyes filling with tears. “When you take somebody’s hand, you don’t even have to speak; that connection, and eye contact, is all you need to help that person emotionally heal.”

This article first appeared on Medscape.com.

Lillie Shockney, RN, MAS, a two-time breast cancer survivor and adjunct professor at Johns Hopkins School of Nursing in Baltimore, Maryland, mourns the many losses that her patients with advanced cancer now face in the midst of the COVID-19 pandemic. But in the void of the usual support networks and treatment plans, she sees the resurgence of something that has recently been crowded out: hospice.

The pandemic has forced patients and their physicians to reassess the risk/benefit balance of continuing or embarking on yet another cancer treatment.

“It’s one of the pearls that we will get out of this nightmare,” said Ms. Shockney, who recently retired as administrative director of the cancer survivorship programs at the Sidney Kimmel Comprehensive Cancer Center.

“Physicians have been taught to treat the disease – so as long as there’s a treatment they give another treatment,” she told Medscape Medical News during a Zoom call from her home. “But for some patients with advanced disease, those treatments were making them very sick, so they were trading longevity over quality of life.”

Of course, longevity has never been a guarantee with cancer treatment, and even less so now, with the risk of COVID-19.

“This is going to bring them to some hard discussions,” says Brenda Nevidjon, RN, MSN, chief executive officer at the Oncology Nursing Society.

“We’ve known for a long time that there are patients who are on third- and fourth-round treatment options that have very little evidence of prolonging life or quality of life,” she told Medscape Medical News. “Do we bring these people out of their home to a setting where there could be a fair number of COVID-positive patients? Do we expose them to that?”

Across the world, these dilemmas are pushing cancer specialists to initiate discussions of hospice sooner with patients who have advanced disease, and with more clarity than before.

One of the reasons such conversations have often been avoided is that the concept of hospice is generally misunderstood, said Ms. Shockney.

“Patients think ‘you’re giving up on me, you’ve abandoned me’, but hospice is all about preserving the remainder of their quality of life and letting them have time with family and time to fulfill those elements of experiencing a good and peaceful death,” she said.

Indeed, hospice is “a benefit meant for somebody with at least a 6-month horizon,” agrees Ms. Nevidjon. Yet the average length of hospice in the United States is just 5 days. “It’s at the very, very end, and yet for some of these patients the 6 months they could get in hospice might be a better quality of life than the 4 months on another whole plan of chemotherapy. I can’t imagine that on the backside of this pandemic we will not have learned and we won’t start to change practices around initiating more of these conversations.”
 

Silver lining of this pandemic?

It’s too early into the pandemic to have hard data on whether hospice uptake has increased, but “it’s encouraging to hear that hospice is being discussed and offered sooner as an alternative to that third- or fourth-round chemo,” said Lori Bishop, MHA, RN, vice president of palliative and advanced care at the National Hospice and Palliative Care Organization.

“I agree that improving informed-decision discussions and timely access to hospice is a silver lining of the pandemic,” she told Medscape Medical News.

But she points out that today’s hospice looks quite different than it did before the pandemic, with the immediate and very obvious difference being telehealth, which was not widely utilized previously.

In March, the Centers for Medicare & Medicaid Services expanded telehealth options for hospice providers, something that Ms. Bishop and other hospice providers hope will remain in place after the pandemic passes.

“Telehealth visits are offered to replace some in-home visits both to minimize risk of exposure to COVID-19 and reduce the drain on personal protective equipment,” Bishop explained.

“In-patient hospice programs are also finding unique ways to provide support and connect patients to their loved ones: visitors are allowed but limited to one or two. Music and pet therapy are being provided through the window or virtually and devices such as iPads are being used to help patients connect with loved ones,” she said.

Telehealth links patients out of loneliness, but the one thing it cannot do is provide the comfort of touch – an important part of any hospice program.

“Hand-holding ... I miss that a lot,” says Ms. Shockney, her eyes filling with tears. “When you take somebody’s hand, you don’t even have to speak; that connection, and eye contact, is all you need to help that person emotionally heal.”

This article first appeared on Medscape.com.

Neurologic effects can be a significant part of COVID-19, but does the SARS-CoV-2 virus directly damage the central nervous system or are the neurologic symptoms attributable to secondary mechanisms? A new review article summarizes what is known so far, and what clinicians need to look out for.

“We frequently see neurological conditions in people with COVID-19, but we understand very little about these effects. Is it the virus entering the brain/nerves or are they a result of a general inflammation or immune response – a bystander effect of people being severely ill. It is probably a combination of both,” said senior author Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology; division chief of neurological infections & global neurology; and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.

“Our message is that there are fairly frequent neurological sequelae of COVID-19 and we need to be alert to these, and to try to understand the potential long-term consequences,” she said.

The review was published online May 29 in JAMA Neurology.
 

Brain changes linked to loss of smell

In a separate article also published online in JAMA Neurology the same day, an Italian group describes a COVID-19 patient with anosmia (loss of sense of smell) who showed brain abnormalities on MRI in the areas associated with smell – the right gyrus rectus and the olfactory bulbs. These changes were resolved on later scan and the patient recovered her sense of smell.

“Based on the MRI findings, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway,” conclude the researchers, led by first author Letterio S. Politi, MD, of the department of neuroradiology at IRCCS Istituto Clinico Humanitas and Humanitas University, Milan, Italy.
 

Can coronaviruses enter the CNS?

Dr. Spudich described this case report as “compelling evidence suggesting that loss of smell is a neurologic effect.”

“Loss of smell and/or taste is a common symptom in COVID-19, so this may suggest that an awful lot of people have some neurological involvement,” Dr. Spudich commented. “While a transient loss of smell or taste is not serious, if the virus has infected brain tissue the question is could this then spread to other parts of the brain and cause other more serious neurological effects,” she added.

In their review article, Dr. Spudich and colleagues present evidence showing that coronaviruses can enter the CNS.

“We know that SARS-1 and MERS have been shown to enter the nervous system and several coronaviruses have been shown to cause direct brain effects,” she said. “There is also some evidence that SARS-CoV-2 can do this too. As well as these latest MRI findings linked to loss of smell, there is a report of the virus being found in endothelial cells in the brain and a French autopsy study has also detected virus in the brain.”
 

Complications of other systemic effects?

Dr. Spudich is a neurologist specializing in neurologic consequences of infectious disease. “We don’t normally have such vast numbers of patients but in the last 3 months there has been an avalanche,” she says. From her personal experience, she believes the majority of neurologic symptoms in COVID-19 patients are most probably complications of other systemic effects, such as kidney, heart, or liver problems. But there is likely also a direct viral effect on the CNS in some patients.

“Reports from China suggested that serious neurologic effects were present in about one-third of hospitalized COVID-19 patients. I would say in our experience the figure would be less than that – maybe around 10%,” she noted.

Some COVID-19 patients are presenting with primary neurologic symptoms. For example, an elderly person may first develop confusion rather than a cough or shortness of breath; others have had severe headache as an initial COVID-19 symptom, Dr. Spudich reported. “Medical staff need to be aware of this – a severe headache in a patient who doesn’t normally get headaches could be a sign of the virus.”

Some of the neurologic symptoms could be caused by autoimmunity. Dr. Spudich explained that, in acute HIV infection a small proportion of patients can first present with autoimmune neurologic effects such as Guillain-Barré syndrome, an autoimmune condition of the nerves which causes a tingling sensation in the hands and feet. “This is well described in HIV, but we are also now seeing this in COVID-19 patients too,” she said. “A panoply of conditions can be caused by autoimmunity.”

On the increase in strokes that has been reported in COVID-19 patients, Dr. Spudich said, “this could be due to direct effects of the virus (e.g., causing an increase in coagulation or infecting the endothelial cells in the brain) or it could just be the final trigger for patients who were at risk of stroke anyway.”

There have been some very high-profile reports of younger patients with major strokes, she said, “but we haven’t seen that in our hospital. For the most part in my experience, strokes are happening in older COVID-19 patients with stroke risk factors such as AF [atrial fibrillation], hypertension, and diabetes. We haven’t seen a preponderance of strokes in young, otherwise healthy people.”

Even in patients who have neurologic effects as the first sign of COVID-19 infection, it is not known whether these symptoms are caused directly by the virus.

“We know that flu can cause people to have headaches, but that is because of an increase in inflammatory cytokines. On the other hand, patients with acute HIV infection often have headaches as a result of the virus getting into the brain. We don’t know where in this [cluster] COVID-19 virus falls,” Dr. Spudich said.
 

Much is still unknown

“The information we have is very sparse at this point. We need far more systematic information on this from CSF samples and imaging.” Dr. Spudich urged clinicians to try to collect such information in patients with neurologic symptoms.

Acknowledging that fewer such tests are being done at present because of concerns over infection risk, Dr. Spudich suggested that some changes in procedure may help. “In our hospital we have a portable MRI scanner which can be brought to the patient. This means the patient does not have to move across the hospital for a scan. This helps us to decide whether the patient has had a stroke, which can be missed when patients are on a ventilator.”

It is also unclear whether the neurologic effects seen during COVID-19 infection will last long term.

Dr. Spudich noted that there have been reports of COVID-19 patients discharged from intensive care having difficulty with higher cognitive function for some time thereafter. “This can happen after being in ICU but is it more pronounced in COVID-19 patients? An ongoing study is underway to look at this,” she said.

This article first appeared on Medscape.com.

Neurologic effects can be a significant part of COVID-19, but does the SARS-CoV-2 virus directly damage the central nervous system or are the neurologic symptoms attributable to secondary mechanisms? A new review article summarizes what is known so far, and what clinicians need to look out for.

“We frequently see neurological conditions in people with COVID-19, but we understand very little about these effects. Is it the virus entering the brain/nerves or are they a result of a general inflammation or immune response – a bystander effect of people being severely ill. It is probably a combination of both,” said senior author Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology; division chief of neurological infections & global neurology; and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.

“Our message is that there are fairly frequent neurological sequelae of COVID-19 and we need to be alert to these, and to try to understand the potential long-term consequences,” she said.

The review was published online May 29 in JAMA Neurology.
 

Brain changes linked to loss of smell

In a separate article also published online in JAMA Neurology the same day, an Italian group describes a COVID-19 patient with anosmia (loss of sense of smell) who showed brain abnormalities on MRI in the areas associated with smell – the right gyrus rectus and the olfactory bulbs. These changes were resolved on later scan and the patient recovered her sense of smell.

“Based on the MRI findings, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway,” conclude the researchers, led by first author Letterio S. Politi, MD, of the department of neuroradiology at IRCCS Istituto Clinico Humanitas and Humanitas University, Milan, Italy.
 

Can coronaviruses enter the CNS?

Dr. Spudich described this case report as “compelling evidence suggesting that loss of smell is a neurologic effect.”

“Loss of smell and/or taste is a common symptom in COVID-19, so this may suggest that an awful lot of people have some neurological involvement,” Dr. Spudich commented. “While a transient loss of smell or taste is not serious, if the virus has infected brain tissue the question is could this then spread to other parts of the brain and cause other more serious neurological effects,” she added.

In their review article, Dr. Spudich and colleagues present evidence showing that coronaviruses can enter the CNS.

“We know that SARS-1 and MERS have been shown to enter the nervous system and several coronaviruses have been shown to cause direct brain effects,” she said. “There is also some evidence that SARS-CoV-2 can do this too. As well as these latest MRI findings linked to loss of smell, there is a report of the virus being found in endothelial cells in the brain and a French autopsy study has also detected virus in the brain.”
 

Complications of other systemic effects?

Dr. Spudich is a neurologist specializing in neurologic consequences of infectious disease. “We don’t normally have such vast numbers of patients but in the last 3 months there has been an avalanche,” she says. From her personal experience, she believes the majority of neurologic symptoms in COVID-19 patients are most probably complications of other systemic effects, such as kidney, heart, or liver problems. But there is likely also a direct viral effect on the CNS in some patients.

“Reports from China suggested that serious neurologic effects were present in about one-third of hospitalized COVID-19 patients. I would say in our experience the figure would be less than that – maybe around 10%,” she noted.

Some COVID-19 patients are presenting with primary neurologic symptoms. For example, an elderly person may first develop confusion rather than a cough or shortness of breath; others have had severe headache as an initial COVID-19 symptom, Dr. Spudich reported. “Medical staff need to be aware of this – a severe headache in a patient who doesn’t normally get headaches could be a sign of the virus.”

Some of the neurologic symptoms could be caused by autoimmunity. Dr. Spudich explained that, in acute HIV infection a small proportion of patients can first present with autoimmune neurologic effects such as Guillain-Barré syndrome, an autoimmune condition of the nerves which causes a tingling sensation in the hands and feet. “This is well described in HIV, but we are also now seeing this in COVID-19 patients too,” she said. “A panoply of conditions can be caused by autoimmunity.”

On the increase in strokes that has been reported in COVID-19 patients, Dr. Spudich said, “this could be due to direct effects of the virus (e.g., causing an increase in coagulation or infecting the endothelial cells in the brain) or it could just be the final trigger for patients who were at risk of stroke anyway.”

There have been some very high-profile reports of younger patients with major strokes, she said, “but we haven’t seen that in our hospital. For the most part in my experience, strokes are happening in older COVID-19 patients with stroke risk factors such as AF [atrial fibrillation], hypertension, and diabetes. We haven’t seen a preponderance of strokes in young, otherwise healthy people.”

Even in patients who have neurologic effects as the first sign of COVID-19 infection, it is not known whether these symptoms are caused directly by the virus.

“We know that flu can cause people to have headaches, but that is because of an increase in inflammatory cytokines. On the other hand, patients with acute HIV infection often have headaches as a result of the virus getting into the brain. We don’t know where in this [cluster] COVID-19 virus falls,” Dr. Spudich said.
 

Much is still unknown

“The information we have is very sparse at this point. We need far more systematic information on this from CSF samples and imaging.” Dr. Spudich urged clinicians to try to collect such information in patients with neurologic symptoms.

Acknowledging that fewer such tests are being done at present because of concerns over infection risk, Dr. Spudich suggested that some changes in procedure may help. “In our hospital we have a portable MRI scanner which can be brought to the patient. This means the patient does not have to move across the hospital for a scan. This helps us to decide whether the patient has had a stroke, which can be missed when patients are on a ventilator.”

It is also unclear whether the neurologic effects seen during COVID-19 infection will last long term.

Dr. Spudich noted that there have been reports of COVID-19 patients discharged from intensive care having difficulty with higher cognitive function for some time thereafter. “This can happen after being in ICU but is it more pronounced in COVID-19 patients? An ongoing study is underway to look at this,” she said.

This article first appeared on Medscape.com.

Neurologic effects can be a significant part of COVID-19, but does the SARS-CoV-2 virus directly damage the central nervous system or are the neurologic symptoms attributable to secondary mechanisms? A new review article summarizes what is known so far, and what clinicians need to look out for.

“We frequently see neurological conditions in people with COVID-19, but we understand very little about these effects. Is it the virus entering the brain/nerves or are they a result of a general inflammation or immune response – a bystander effect of people being severely ill. It is probably a combination of both,” said senior author Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology; division chief of neurological infections & global neurology; and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.

“Our message is that there are fairly frequent neurological sequelae of COVID-19 and we need to be alert to these, and to try to understand the potential long-term consequences,” she said.

The review was published online May 29 in JAMA Neurology.
 

Brain changes linked to loss of smell

In a separate article also published online in JAMA Neurology the same day, an Italian group describes a COVID-19 patient with anosmia (loss of sense of smell) who showed brain abnormalities on MRI in the areas associated with smell – the right gyrus rectus and the olfactory bulbs. These changes were resolved on later scan and the patient recovered her sense of smell.

“Based on the MRI findings, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway,” conclude the researchers, led by first author Letterio S. Politi, MD, of the department of neuroradiology at IRCCS Istituto Clinico Humanitas and Humanitas University, Milan, Italy.
 

Can coronaviruses enter the CNS?

Dr. Spudich described this case report as “compelling evidence suggesting that loss of smell is a neurologic effect.”

“Loss of smell and/or taste is a common symptom in COVID-19, so this may suggest that an awful lot of people have some neurological involvement,” Dr. Spudich commented. “While a transient loss of smell or taste is not serious, if the virus has infected brain tissue the question is could this then spread to other parts of the brain and cause other more serious neurological effects,” she added.

In their review article, Dr. Spudich and colleagues present evidence showing that coronaviruses can enter the CNS.

“We know that SARS-1 and MERS have been shown to enter the nervous system and several coronaviruses have been shown to cause direct brain effects,” she said. “There is also some evidence that SARS-CoV-2 can do this too. As well as these latest MRI findings linked to loss of smell, there is a report of the virus being found in endothelial cells in the brain and a French autopsy study has also detected virus in the brain.”
 

Complications of other systemic effects?

Dr. Spudich is a neurologist specializing in neurologic consequences of infectious disease. “We don’t normally have such vast numbers of patients but in the last 3 months there has been an avalanche,” she says. From her personal experience, she believes the majority of neurologic symptoms in COVID-19 patients are most probably complications of other systemic effects, such as kidney, heart, or liver problems. But there is likely also a direct viral effect on the CNS in some patients.

“Reports from China suggested that serious neurologic effects were present in about one-third of hospitalized COVID-19 patients. I would say in our experience the figure would be less than that – maybe around 10%,” she noted.

Some COVID-19 patients are presenting with primary neurologic symptoms. For example, an elderly person may first develop confusion rather than a cough or shortness of breath; others have had severe headache as an initial COVID-19 symptom, Dr. Spudich reported. “Medical staff need to be aware of this – a severe headache in a patient who doesn’t normally get headaches could be a sign of the virus.”

Some of the neurologic symptoms could be caused by autoimmunity. Dr. Spudich explained that, in acute HIV infection a small proportion of patients can first present with autoimmune neurologic effects such as Guillain-Barré syndrome, an autoimmune condition of the nerves which causes a tingling sensation in the hands and feet. “This is well described in HIV, but we are also now seeing this in COVID-19 patients too,” she said. “A panoply of conditions can be caused by autoimmunity.”

On the increase in strokes that has been reported in COVID-19 patients, Dr. Spudich said, “this could be due to direct effects of the virus (e.g., causing an increase in coagulation or infecting the endothelial cells in the brain) or it could just be the final trigger for patients who were at risk of stroke anyway.”

There have been some very high-profile reports of younger patients with major strokes, she said, “but we haven’t seen that in our hospital. For the most part in my experience, strokes are happening in older COVID-19 patients with stroke risk factors such as AF [atrial fibrillation], hypertension, and diabetes. We haven’t seen a preponderance of strokes in young, otherwise healthy people.”

Even in patients who have neurologic effects as the first sign of COVID-19 infection, it is not known whether these symptoms are caused directly by the virus.

“We know that flu can cause people to have headaches, but that is because of an increase in inflammatory cytokines. On the other hand, patients with acute HIV infection often have headaches as a result of the virus getting into the brain. We don’t know where in this [cluster] COVID-19 virus falls,” Dr. Spudich said.
 

Much is still unknown

“The information we have is very sparse at this point. We need far more systematic information on this from CSF samples and imaging.” Dr. Spudich urged clinicians to try to collect such information in patients with neurologic symptoms.

Acknowledging that fewer such tests are being done at present because of concerns over infection risk, Dr. Spudich suggested that some changes in procedure may help. “In our hospital we have a portable MRI scanner which can be brought to the patient. This means the patient does not have to move across the hospital for a scan. This helps us to decide whether the patient has had a stroke, which can be missed when patients are on a ventilator.”

It is also unclear whether the neurologic effects seen during COVID-19 infection will last long term.

Dr. Spudich noted that there have been reports of COVID-19 patients discharged from intensive care having difficulty with higher cognitive function for some time thereafter. “This can happen after being in ICU but is it more pronounced in COVID-19 patients? An ongoing study is underway to look at this,” she said.

This article first appeared on Medscape.com.

From 7% to nearly 9% of patients with advanced cancer were found to harbor a germline variant with targeted therapeutic actionability in the first study of its kind.

The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.

This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.

“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.

“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.

Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.

Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.

“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.

An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
 

Implications in cancer treatment

For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.

“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”

A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.

BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.

The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).

Therapeutic action

For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.

Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.

Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.

For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.

Looking ahead

The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”

Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”

It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?

“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”

An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.

The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.

This article first appeared on Medscape.com.

From 7% to nearly 9% of patients with advanced cancer were found to harbor a germline variant with targeted therapeutic actionability in the first study of its kind.

The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.

This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.

“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.

“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.

Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.

Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.

“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.

An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
 

Implications in cancer treatment

For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.

“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”

A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.

BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.

The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).

Therapeutic action

For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.

Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.

Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.

For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.

Looking ahead

The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”

Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”

It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?

“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”

An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.

The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.

This article first appeared on Medscape.com.

From 7% to nearly 9% of patients with advanced cancer were found to harbor a germline variant with targeted therapeutic actionability in the first study of its kind.

The study involved 11,974 patients with various tumor types. All the patients underwent germline genetic testing from 2015 to 2019 at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York, using the next-generation sequencing panel MSK-IMPACT.

This testing showed that 17.1% of patients had variants in cancer predisposition genes, and 7.1%-8.6% had variants that could potentially be targeted.

“Of course, these numbers are not static,” commented lead author Zsofia K. Stadler, MD, a medical oncologist at MSKCC. “And with the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time.

“Our study demonstrates the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” she added.

Dr. Stadler presented the study results during a virtual scientific program of the American Society of Clinical Oncology 2020.

Testing for somatic mutations is evolving as the standard of care in many cancer types, and somatic genomic testing is rapidly becoming an integral part of the regimen for patients with advanced disease. Some studies suggest that 9%-11% of patients harbor actionable genetic alterations, as determined on the basis of tumor profiling.

“The take-home message from this is that now, more than ever before, germline testing is indicated for the selection of cancer treatment,” said Erin Wysong Hofstatter, MD, from Yale University, New Haven, Conn., in a Highlights of the Day session.

An emerging indication for germline testing is the selection of treatment in the advanced setting, she noted. “And it is important to know your test. Remember that tumor sequencing is not a substitute for comprehensive germline testing.”
 

Implications in cancer treatment

For their study, Dr. Stadler and colleagues reviewed the medical records of patients with likely pathogenic/pathogenic germline (LP/P) alterations in genes that had known therapeutic targets so as to identify germline-targeted treatment either in a clinical or research setting.

“Since 2015, patients undergoing MSK-IMPACT may also choose to provide additional consent for secondary germline genetic analysis, wherein up to 88 genes known to be associated with cancer predisposition are analyzed,” she said. “Likely pathogenic and pathogenic germline alterations identified are disclosed to the patient and treating physician via the Clinical Genetic Service.”

A total of 2043 (17.1%) patients who harbored LP/P variants in a cancer predisposition gene were identified. Of these, 11% of patients harbored pathogenic alterations in high or moderate penetrance cancer predisposition genes. When the analysis was limited to genes with targeted therapeutic actionability, or what the authors defined as tier 1 and tier 2 genes, 7.1% of patients (n = 849) harbored a targetable pathogenic germline alteration.

BRCA alterations accounted for half (52%) of the findings, and 20% were associated with Lynch syndrome.

The tier 2 genes, which included PALB2, ATM, RAD51C, and RAD51D, accounted for about a quarter of the findings. Dr. Hofstatter noted that, using strict criteria, 7.1% of patients (n = 849) were found to harbor a pathogenic alteration and a targetable gene. Using less stringent criteria, additional tier 3 genes and additional genes associated with DNA homologous recombination repair brought the number up to 8.6% (n = 1,003).

Therapeutic action

For determining therapeutic actionability, the strict criteria were used; 593 patients (4.95%) with recurrent or metastatic disease were identified. For these patients, consideration of a targeted therapy, either as part of standard care or as part of an investigation or research protocol, was important.

Of this group, 44% received therapy targeting the germline alteration. Regarding specific genes, 50% of BRCA1/2 carriers and 58% of Lynch syndrome patients received targeted treatment. With respect to tier 2 genes, 40% of patients with PALB2, 19% with ATM, and 37% with RAD51C or 51D received a poly (ADP-ribose) polymerase (PARP) inhibitor.

Among patients with a BRCA1/2 mutation who received a PARP inhibitor, 55.1% had breast or ovarian cancer, and 44.8% had other tumor types, including pancreas, prostate, bile duct, gastric cancers. These patients received the drug in a research setting.

For patients with PALB2 alterations who received PARP inhibitors, 53.3% had breast or pancreas cancer, and 46.7% had cancer of the prostate, ovary, or an unknown primary.

Looking ahead

The discussant for the paper, Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, pointed out that most of the BRCA-positive patients had cancers traditionally associated with the mutation. “There were no patients with PTEN mutations treated, and interestingly, no patients with NF1 were treated,” she said. “But actionability is evolving, as the MEK inhibitor selumitinib was recently approved for NF1.”

Some questions remain unanswered, she noted, such as: “What percentage of patients undergoing tumor-normal testing signed a germline protocol?” and “Does the population introduce a bias – such as younger patients, family history, and so on?”

It is also unknown what percentage of germline alterations were known in comparison with those identified through tumor/normal testing. Also of importance is the fact that in this study, the results of germline testing were delivered in an academic setting, she emphasized. “What if they were delivered elsewhere? What would be the impact of identifying these alterations in an environment with less access to trials?

“But to be fair, it is not easy to seek the germline mutations,” Dr. Meric-Bernstam continued. “These studies were done under institutional review board protocols, and it is important to note that most profiling is done as standard of care without consenting and soliciting patient preference on the return of germline results.”

An infrastructure is needed to return/counsel/offer cascade testing, and “analyses need to be facilitated to ensure that findings can be acted upon in a timely fashion,” she added.

The study was supported by MSKCC internal funding. Dr. Stadler reported relationships (institutional) with Adverum, Alimera Sciences, Allergan, Biomarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Meric-Bernstram reported relationships with numerous pharmaceutical companies.

This article first appeared on Medscape.com.

In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.

The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.

Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.

PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.

Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.

Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
 

Updated results, predictors of pCR

At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.

The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.

Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.

Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.

In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.

At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.

Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
 

An imperfect surrogate

By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.

As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.

However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.

In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.

Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.

Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.

Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
 

Clinical implications

PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.

It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.

Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.

Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.

For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.

PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.

In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.

The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.

Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.

PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.

Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.

Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
 

Updated results, predictors of pCR

At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.

The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.

Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.

Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.

In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.

At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.

Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
 

An imperfect surrogate

By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.

As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.

However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.

In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.

Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.

Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.

Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
 

Clinical implications

PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.

It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.

Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.

Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.

For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.

PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.

In an update of the PREDIX-HER2 trial, trastuzumab emtansine (T-DM1) remained equivalent to standard neoadjuvant chemotherapy plus dual-targeted HER2 therapy in producing pathologic complete remissions (pCRs) among patients with HER2-positive, metastatic breast cancer.

The new data also suggest tumor-infiltrating lymphocytes (TILs) and dramatic improvements in PET-CT scans can predict favorable outcomes in both treatment groups. Though these findings will be useful for research purposes, they likely won’t influence routine clinical practice.

Thomas Hatschek, MD, PhD, of Karolinska Institutet in Stockholm, presented the updated results from PREDIX-HER2 during the European Society for Medical Oncology: Breast Cancer virtual meeting.

PREDIX-HER2 included patients with HER2-positive breast cancer and tumor size greater than 20 mm or lymph node metastases.

Patients received neoadjuvant therapy (NAT) with docetaxel and trastuzumab plus pertuzumab (DTP) or T-DM1 every 3 weeks for a planned total of six courses. The protocol permitted switching to the competing treatment for progression, lack of response, or drug-related severe toxicity.

Postoperatively, all patients received triweekly epirubicin plus cyclophosphamide – four courses for the T-DM1 arm and two courses for the DTP arm. All patients then received triweekly adjuvant trastuzumab for 11 courses. The 62% of patients whose tumors were hormone receptor (HR)–positive received standard endocrine therapy postoperatively.
 

Updated results, predictors of pCR

At the 2019 ASCO annual meeting, PREDIX-HER2 investigators reported that, when compared with DTP, T-DM1 produced the same likelihood of pCR with less toxicity (ASCO 2019, Abstract 501). Updated data presented at ESMO Breast Cancer 2020 showed similar results.

The pCR rate was 45.5% in the DTP arm and 43.9% in the T-DM1 arm (P = .824). pCR rates were higher for HR-negative tumors – 63.6% in the DTP arm and 59% in the T-DM1 arm – than for HR-positive tumors – 36.4% in the DTP arm and 33.9% in the TDM-1 arm.

Three patients had disease progression with T-DM1, and none progressed with DTP. However, almost twice as many patients switched from DTP to T-DM1, compared with the other sequence.

Dr. Hatschek reported that the presence of at least 10% TILs predicted pCR in both treatment groups. Among patients who achieved a pCR, 52.2% had at least 10% TILs in baseline biopsies, and 30.4% had less than 10% TILs.

In addition, a decrease of FDG maximum standardized uptake value by more than 75% on protocol-required PET-CT scans was highly predictive of pCR. Among patients who achieved a pCR, 70.3% had a maximum standardized uptake value decrease of more than 75%, and 22.5% had a decrease of 75% or less.

At median follow-up of 28.5 months, event-free survival was similar between the treatment arms. Overall, there were 13 cases of progression, relapse, contralateral breast cancer, distant metastases, or death from any cause. There were five such events in the DTP arm and eight in the TDM-1 arm.

Dr. Hatschek concluded that neoadjuvant T-DM1 may be as effective as standard NAT in all clinical subgroups evaluated. Both TILs and PET-CT showed the potential to predict pCR and merit further study in the NAT setting.
 

An imperfect surrogate

By definition, a surrogate is “one appointed to act in place of another.” In the case of PREDIX-HER2 and most other NAT studies in HER2-positive breast cancer patients, pCR is a surrogate for the endpoint about which doctors and patients really care – cancer-free survival.

As such, pCR is not a perfect surrogate. Reproducibly, pCR has been highly predictive of disease-free survival and overall survival, especially in the HR-negative subset of HER2-positive patients.

However, despite improvements with dual targeting of HER2 in the TRYPHAENA trial (Eur J Cancer. 2018;89:27-35) and the use of T-DM1 for patients failing to achieve pCR in the immediately practice-changing KATHERINE trial (N Engl J Med. 2019;380:617-28), eventual relapse is seen in 10%-20% of patients in various clinical-pathologic subgroups.

In PREDIX-HER2, the pCR rate for node-positive patients was considerably lower with T-DM1 than with DTP (54.1% vs. 38%), noted Valentina Guarneri, MD, of the University of Padova (Italy), in her discussion of the trial at ESMO Breast Cancer 2020.

Patients with larger initial tumor size and multiple involved axillary nodes at diagnosis remain at increased risk of death because of cancer relapse.

Central nervous system relapse remains a vexing problem. Among patients with triple-positive breast cancer, relapses may occur late, despite pCR.

Patients whose tumors transform from HER2 positive to HER2 negative with NAT, seen in approximately 8% of cases in the KATHERINE trial (ESMO Breast Cancer 2020, Abstract 96O), may be another poor-risk group.
 

Clinical implications

PREDIX-HER2 is an important study. At the early time point of 2.4 years (especially early since most patients were HR-positive), if pCR is achieved, event-free survival is excellent with T-DM1 or an aggressive multiagent cytotoxic combination plus dual HER2 targeting followed by anthracyclines.

It is ideal to have clinical-pathologic tests to distinguish those patients destined to achieve the surrogate endpoint of pCR from those who will not achieve it.

Despite linkage of TILs to improved outcome for triple-negative and HER2-enriched molecular subtypes (Lancet Oncol. 2018 Jan;19[1]:40-50), analysis of TILs is not standard practice in HER2-positive breast cancer in community settings. Optimal cutoffs are not well established, and TILs have not been linked to the choice of particular treatment options.

Currently, PET-CT scans are not part of National Comprehensive Cancer Network guidelines for pretreatment evaluation, except in patients for whom there is clinical suspicion of distant disease.

For those reasons, the main results of PREDIX-HER2 remain research tools that will focus our attention on the clinical-pathologic correlations Dr. Hatschek highlighted, but the results should have no influence on routine clinical practice at this time.

PREDIX-HER2 was funded by the Swedish Cancer Society, Radiumhemmet of Karolinska Institutet, Region Stockholm, and Roche Sweden. Dr. Hatschek disclosed relationships with Roche Sweden, Pfizer Sweden, and Pierre Fabre Sweden. Dr. Guarneri disclosed relationships with Roche, Novartis, and Eli Lilly.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Hatschek T et al. ESMO Breast Cancer 2020, Abstract 97O.

In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.

Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.

Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.

Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.

“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.

Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.

“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
 

Past data

An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.

The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.

She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
 

E2108 details

In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.

In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.

A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.

In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.

Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
 

Survival, progression, and HRQOL

At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).

An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.

Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).

At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).

“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.

She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.

The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.

SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.

In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.

Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.

Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.

Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.

“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.

Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.

“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
 

Past data

An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.

The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.

She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
 

E2108 details

In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.

In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.

A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.

In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.

Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
 

Survival, progression, and HRQOL

At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).

An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.

Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).

At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).

“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.

She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.

The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.

SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.

In patients with newly diagnosed stage IV breast cancer and an intact primary tumor, locoregional therapy after optimal systemic therapy does not improve survival or quality of life, results of the phase 3 E2108 trial suggest.

Among 256 patients with stage IV breast cancer with intact primary tumors who had no disease progression for 4-8 months after the start of optimal systemic therapy, there were no significant differences in overall survival or progression-free survival between patients randomized to receive locoregional therapy and those who did not receive the locoregional treatment.

Although patients who did not receive locoregional treatment had a 150% higher rate of local recurrence/progression, health-related quality of life (HRQOL) was actually worse at 18 months among the patients who underwent locoregional therapy. There were no HRQOL differences at 6 months, 12 months, or 30 months of follow-up.

Seema A. Khan, MD, of Northwestern University, Chicago, reported these results during a plenary session broadcast as a part of the American Society of Clinical Oncology virtual scientific program.

“There is no hint here of an advantage in terms of survival with the use of early locoregional therapy for the primary site,” Dr. Khan said.

Although neither the E2108 trial nor similar trials showed an overall survival advantage for locoregional therapy, as many as 20% of patients who are treated with systemic therapy alone may need locoregional therapy with surgery and/or radiation at some point for palliation or progression, said invited discussant Julia R. White, MD, professor of radiation oncology at the Ohio State University, Columbus.

“Locoregional therapy should be reserved for these patients that become symptomatic or progress locally. There may be a role for routine locoregional therapy for de novo oligometastatic breast cancer in combination with systemic therapy plus ablative therapy” to secure long-term remission or cure, questions that are being addressed in ongoing clinical trials, Dr. White said.
 

Past data

An estimated 6% of newly diagnosed breast cancer patients present with stage IV disease and an intact primary tumor.

The rationale for locoregional therapy of the primary tumor in patients with metastatic disease is based on retrospective data suggesting a survival advantage. However, the studies were biased because of younger patient populations with small tumors, a higher proportion of estrogen receptor–positive disease, and a generally lower metastatic burden than that seen in the E2108 population, according to Dr. Khan.

She went on to cite two randomized trials with differing outcomes. One trial showed no survival advantage with locoregional therapy at 2 years (Lancet Oncol. 2015 Oct;16[13]:1380-8). The other showed an improvement in survival with locoregional therapy at 5 years (Ann Surg Oncol. 2018 Oct;25[11]:3141-9).
 

E2108 details

In the E2108 trial, patients first received optimal systemic therapy based on individual patient and disease features. Patients who had no disease progression or distant disease for at least 4-8 months of therapy were then randomized to additional therapy.

In one randomized arm, patients received continued systemic therapy alone. The other arm received early local therapy, which included complete tumor resection with free surgical margins and postoperative radiotherapy according to the standard of care.

A total of 390 patients were registered, and 256 went on to randomization. Of those subjects, 131 were randomized to the continued systemic therapy arm and 125 to the early local therapy arm. All patients in each arm were included in the efficacy analysis.

In all, 59.6% of randomized patients had hormone receptor–positive/HER2-negative disease, 8.2% had triple-negative disease, and 32.2% had HER2-positive disease. Metastases included bone-only disease in 37.9% of patients, visceral-only disease in 24.2%, and 40.9% in both sites.

Among the patients randomized to early local therapy, 14 did not have surgery for personal, clinical, or insurance reasons. Of the 109 who went on to surgery, 87 had clear surgical margins, and 74 received locoregional radiation therapy.
 

Survival, progression, and HRQOL

At a median follow-up of 53 months, the median overall survival was 54 months in each arm. There was no significant difference in survival between the study arms, with superimposable survival curves (hazard ratio, 1.09; P = .63).

An analysis of overall survival by tumor type showed that, for the 20 women with triple-negative disease, survival was worse with early local therapy (HR, 3.50). There were no differences in survival either for the 79 patients with HER2-positive disease or for the 137 patients with hormone receptor–positive/HER2-negative disease.

Locoregional progression occurred in 25.6% of patients assigned to continued systemic therapy, compared with 10.2% assigned to early local therapy. However, progression-free survival was virtually identical between the study arms (P = .40).

At most time points, there were no significant between-arm differences in HRQOL. The exception was at 18 months of follow-up, when the HRQOL was significantly lower among patients who had undergone early local therapy (P = .001).

“Based on available data, locoregional therapy for the primary tumor should not be offered to women with stage IV breast cancer with the expectation of a survival benefit. When systemic disease is well controlled with systemic therapy but the primary site is progressing, as does happen occasionally, locoregional treatment can be considered,” Dr. Khan concluded.

She noted there is an ongoing trial of similar design in Japan (JCOG-1017), with results expected in 2022.

The current trial was supported by the National Cancer Institute and Canadian Cancer Society. Dr. Khan reported no conflicts of interest. Dr. White reported institutional research funding from Intraop Medical.

SOURCE: Khan SA et al. ASCO 2020, Abstract LBA2.

The combination of pyrotinib and capecitabine significantly prolonged progression-free survival (PFS), when compared with lapatinib and capecitabine, among patients with previously treated HER2-positive metastatic breast cancer in a phase 3 trial.

PFS was extended by nearly 6 months among patients who received pyrotinib, a novel pan-HER2 inhibitor, combined with capecitabine. Grade 3 diarrhea occurred in nearly 31% of patients receiving the pyrotinib-capecitabine combination, though none of the patients discontinued treatment due to this adverse event.

Binghe Xu, MD, PhD, of the National Cancer Center/Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, presented these results, from the phase 3 PHOEBE trial, as part of the American Society of Clinical Oncology virtual scientific program.
 

The value of pyrotinib

Although there are already many targeted therapies for HER2-positive metastatic breast cancer, accessibility can be an issue, with drugs such as pertuzumab and trastuzumab emtansine (T-DM1) not available in all regions of the world, according to Dr. Xu.

“Before we initiated this clinical trial, lapatinib plus capecitabine was the only second-line standard of care against HER2-positive metastatic breast cancer in China,” he said.

Based, in part, on results of the PHOEBE trial, the combination of pyrotinib and capecitabine was approved in China as a second-line standard of care for patients with HER2-positive metastatic breast cancer, according to Dr. Xu.

Pyrotinib has now demonstrated “clinical value” in two phase 3 clinical trials, but its value in relation to pertuzumab, T-DM1, tucatinib, trastuzumab deruxtecan, or neratinib is less clear, said Aleix Prat, MD, PhD, of Hospital Clinic of Barcelona.

“Also, in my opinion, the toxicity profile needs attention,” Dr. Prat said in a discussion of the PHOEBE results that was also part of the virtual ASCO meeting.

The 31% incidence of grade 3 diarrhea was “very similar,” he said, to what was seen in PHENIX, another phase 3 trial of pyrotinib plus capecitabine that was presented at the 2019 ASCO annual meeting (J Clin Oncol 37, 2019 suppl; abstr 1001).

“What is the current therapy landscape? In my opinion, today, the first line remains taxane, trastuzumab, and pertuzumab; the second line T-DM1; and the third line tucatinib, trastuzumab, and capecitabine, with other treatment strategies reserved for later lines,” Dr. Prat said.

Study details

PHOEBE included 267 patients with HER2-positive metastatic breast cancer. They had previously received trastuzumab and taxanes, and/or anthracyclines, with up to two prior lines of chemotherapy for metastatic disease.

The patients’ median age was 50 years, 79% had visceral metastases at screening, and about 26% had trastuzumab resistance, Dr. Xu said. Resistance was defined as relapse within 6 months after adjuvant treatment or progression within 3 months of treatment for metastatic disease.

A statistically significant and clinically meaningful improvement was seen in PFS, the primary endpoint of the study, Dr. Xu said.

Median PFS by blinded independent central review was 12.5 months for the pyrotinib-capecitabine combination, compared with 6.8 months for lapatinib-capecitabine (hazard ratio, 0.39; 95% confidence interval, 0.27-0.56; P < .0001).

The PFS benefit was consistently observed across all predefined subgroups, including by trastuzumab resistance.

In trastuzumab-resistant patients, the median PFS was 12.5 months for the pyrotinib combination and 6.9 months for the lapatinib combination (HR, 0.60; 95% CI, 0.29-1.21). In patients without trastuzumab resistance, the median PFS was 12.5 months and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21-0.51).

Although overall survival (OS) data were not yet mature, there was a “strong trend” toward a benefit with pyrotinib, Dr. Xu said. The 12-month OS rate was 91.3% for the pyrotinib combination and 77.4% for lapatinib. The median OS was not reached in either arm at the time of analysis.

Treatment-related adverse events of grade 3 or greater occurred in 57.5% of the pyrotinib arm and 34.1% of the lapatinib arm.

Diarrhea was the most common grade 3 or greater treatment-related adverse event, occurring in 30.6% of patients in the pyrotinib arm and 8.3% of those in the lapatinib arm. No grade 4 or 5 diarrhea was seen.

Overall, diarrhea occurred in 94.8% of patients in the pyrotinib arm and 62.1% of those in the lapatinib arm. However, pyrotinib-associated diarrhea was generally of low severity, occurred early, had a short duration, was reversible, and did not lead to treatment termination, according to Dr. Xu.

This study was funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Xu reported additional disclosures related to AstraZeneca, Eisai, Pfizer, and Roche. Dr. Prat disclosed relationships with Amgen, Daiichi Sankyo, Lilly, MSD Oncology, and other companies.

SOURCE: Xu B et al. ASCO 2020, Abstract 1003

The combination of pyrotinib and capecitabine significantly prolonged progression-free survival (PFS), when compared with lapatinib and capecitabine, among patients with previously treated HER2-positive metastatic breast cancer in a phase 3 trial.

PFS was extended by nearly 6 months among patients who received pyrotinib, a novel pan-HER2 inhibitor, combined with capecitabine. Grade 3 diarrhea occurred in nearly 31% of patients receiving the pyrotinib-capecitabine combination, though none of the patients discontinued treatment due to this adverse event.

Binghe Xu, MD, PhD, of the National Cancer Center/Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, presented these results, from the phase 3 PHOEBE trial, as part of the American Society of Clinical Oncology virtual scientific program.
 

The value of pyrotinib

Although there are already many targeted therapies for HER2-positive metastatic breast cancer, accessibility can be an issue, with drugs such as pertuzumab and trastuzumab emtansine (T-DM1) not available in all regions of the world, according to Dr. Xu.

“Before we initiated this clinical trial, lapatinib plus capecitabine was the only second-line standard of care against HER2-positive metastatic breast cancer in China,” he said.

Based, in part, on results of the PHOEBE trial, the combination of pyrotinib and capecitabine was approved in China as a second-line standard of care for patients with HER2-positive metastatic breast cancer, according to Dr. Xu.

Pyrotinib has now demonstrated “clinical value” in two phase 3 clinical trials, but its value in relation to pertuzumab, T-DM1, tucatinib, trastuzumab deruxtecan, or neratinib is less clear, said Aleix Prat, MD, PhD, of Hospital Clinic of Barcelona.

“Also, in my opinion, the toxicity profile needs attention,” Dr. Prat said in a discussion of the PHOEBE results that was also part of the virtual ASCO meeting.

The 31% incidence of grade 3 diarrhea was “very similar,” he said, to what was seen in PHENIX, another phase 3 trial of pyrotinib plus capecitabine that was presented at the 2019 ASCO annual meeting (J Clin Oncol 37, 2019 suppl; abstr 1001).

“What is the current therapy landscape? In my opinion, today, the first line remains taxane, trastuzumab, and pertuzumab; the second line T-DM1; and the third line tucatinib, trastuzumab, and capecitabine, with other treatment strategies reserved for later lines,” Dr. Prat said.

Study details

PHOEBE included 267 patients with HER2-positive metastatic breast cancer. They had previously received trastuzumab and taxanes, and/or anthracyclines, with up to two prior lines of chemotherapy for metastatic disease.

The patients’ median age was 50 years, 79% had visceral metastases at screening, and about 26% had trastuzumab resistance, Dr. Xu said. Resistance was defined as relapse within 6 months after adjuvant treatment or progression within 3 months of treatment for metastatic disease.

A statistically significant and clinically meaningful improvement was seen in PFS, the primary endpoint of the study, Dr. Xu said.

Median PFS by blinded independent central review was 12.5 months for the pyrotinib-capecitabine combination, compared with 6.8 months for lapatinib-capecitabine (hazard ratio, 0.39; 95% confidence interval, 0.27-0.56; P < .0001).

The PFS benefit was consistently observed across all predefined subgroups, including by trastuzumab resistance.

In trastuzumab-resistant patients, the median PFS was 12.5 months for the pyrotinib combination and 6.9 months for the lapatinib combination (HR, 0.60; 95% CI, 0.29-1.21). In patients without trastuzumab resistance, the median PFS was 12.5 months and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21-0.51).

Although overall survival (OS) data were not yet mature, there was a “strong trend” toward a benefit with pyrotinib, Dr. Xu said. The 12-month OS rate was 91.3% for the pyrotinib combination and 77.4% for lapatinib. The median OS was not reached in either arm at the time of analysis.

Treatment-related adverse events of grade 3 or greater occurred in 57.5% of the pyrotinib arm and 34.1% of the lapatinib arm.

Diarrhea was the most common grade 3 or greater treatment-related adverse event, occurring in 30.6% of patients in the pyrotinib arm and 8.3% of those in the lapatinib arm. No grade 4 or 5 diarrhea was seen.

Overall, diarrhea occurred in 94.8% of patients in the pyrotinib arm and 62.1% of those in the lapatinib arm. However, pyrotinib-associated diarrhea was generally of low severity, occurred early, had a short duration, was reversible, and did not lead to treatment termination, according to Dr. Xu.

This study was funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Xu reported additional disclosures related to AstraZeneca, Eisai, Pfizer, and Roche. Dr. Prat disclosed relationships with Amgen, Daiichi Sankyo, Lilly, MSD Oncology, and other companies.

SOURCE: Xu B et al. ASCO 2020, Abstract 1003

The combination of pyrotinib and capecitabine significantly prolonged progression-free survival (PFS), when compared with lapatinib and capecitabine, among patients with previously treated HER2-positive metastatic breast cancer in a phase 3 trial.

PFS was extended by nearly 6 months among patients who received pyrotinib, a novel pan-HER2 inhibitor, combined with capecitabine. Grade 3 diarrhea occurred in nearly 31% of patients receiving the pyrotinib-capecitabine combination, though none of the patients discontinued treatment due to this adverse event.

Binghe Xu, MD, PhD, of the National Cancer Center/Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, presented these results, from the phase 3 PHOEBE trial, as part of the American Society of Clinical Oncology virtual scientific program.
 

The value of pyrotinib

Although there are already many targeted therapies for HER2-positive metastatic breast cancer, accessibility can be an issue, with drugs such as pertuzumab and trastuzumab emtansine (T-DM1) not available in all regions of the world, according to Dr. Xu.

“Before we initiated this clinical trial, lapatinib plus capecitabine was the only second-line standard of care against HER2-positive metastatic breast cancer in China,” he said.

Based, in part, on results of the PHOEBE trial, the combination of pyrotinib and capecitabine was approved in China as a second-line standard of care for patients with HER2-positive metastatic breast cancer, according to Dr. Xu.

Pyrotinib has now demonstrated “clinical value” in two phase 3 clinical trials, but its value in relation to pertuzumab, T-DM1, tucatinib, trastuzumab deruxtecan, or neratinib is less clear, said Aleix Prat, MD, PhD, of Hospital Clinic of Barcelona.

“Also, in my opinion, the toxicity profile needs attention,” Dr. Prat said in a discussion of the PHOEBE results that was also part of the virtual ASCO meeting.

The 31% incidence of grade 3 diarrhea was “very similar,” he said, to what was seen in PHENIX, another phase 3 trial of pyrotinib plus capecitabine that was presented at the 2019 ASCO annual meeting (J Clin Oncol 37, 2019 suppl; abstr 1001).

“What is the current therapy landscape? In my opinion, today, the first line remains taxane, trastuzumab, and pertuzumab; the second line T-DM1; and the third line tucatinib, trastuzumab, and capecitabine, with other treatment strategies reserved for later lines,” Dr. Prat said.

Study details

PHOEBE included 267 patients with HER2-positive metastatic breast cancer. They had previously received trastuzumab and taxanes, and/or anthracyclines, with up to two prior lines of chemotherapy for metastatic disease.

The patients’ median age was 50 years, 79% had visceral metastases at screening, and about 26% had trastuzumab resistance, Dr. Xu said. Resistance was defined as relapse within 6 months after adjuvant treatment or progression within 3 months of treatment for metastatic disease.

A statistically significant and clinically meaningful improvement was seen in PFS, the primary endpoint of the study, Dr. Xu said.

Median PFS by blinded independent central review was 12.5 months for the pyrotinib-capecitabine combination, compared with 6.8 months for lapatinib-capecitabine (hazard ratio, 0.39; 95% confidence interval, 0.27-0.56; P < .0001).

The PFS benefit was consistently observed across all predefined subgroups, including by trastuzumab resistance.

In trastuzumab-resistant patients, the median PFS was 12.5 months for the pyrotinib combination and 6.9 months for the lapatinib combination (HR, 0.60; 95% CI, 0.29-1.21). In patients without trastuzumab resistance, the median PFS was 12.5 months and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21-0.51).

Although overall survival (OS) data were not yet mature, there was a “strong trend” toward a benefit with pyrotinib, Dr. Xu said. The 12-month OS rate was 91.3% for the pyrotinib combination and 77.4% for lapatinib. The median OS was not reached in either arm at the time of analysis.

Treatment-related adverse events of grade 3 or greater occurred in 57.5% of the pyrotinib arm and 34.1% of the lapatinib arm.

Diarrhea was the most common grade 3 or greater treatment-related adverse event, occurring in 30.6% of patients in the pyrotinib arm and 8.3% of those in the lapatinib arm. No grade 4 or 5 diarrhea was seen.

Overall, diarrhea occurred in 94.8% of patients in the pyrotinib arm and 62.1% of those in the lapatinib arm. However, pyrotinib-associated diarrhea was generally of low severity, occurred early, had a short duration, was reversible, and did not lead to treatment termination, according to Dr. Xu.

This study was funded by Jiangsu Hengrui Medicine Co. Ltd. Dr. Xu reported additional disclosures related to AstraZeneca, Eisai, Pfizer, and Roche. Dr. Prat disclosed relationships with Amgen, Daiichi Sankyo, Lilly, MSD Oncology, and other companies.

SOURCE: Xu B et al. ASCO 2020, Abstract 1003

For patients with BRCA-like triple-negative breast cancer (TNBC), adding veliparib to cisplatin chemotherapy may extend survival, based on results from the phase 3 SWOG S1416 trial.

All patients with BRCA-like TNBC had a significant improvement in progression-free survival (PFS) when they received veliparib plus cisplatin. Previously untreated patients with BRCA-like TNBC had a significant improvement in overall survival (OS) as well.

The results are a “very positive step towards expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” reported lead author Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.

According to Dr. Sharma, PARP inhibitors have demonstrated efficacy for certain patients with BRCA wild-type ovarian cancer, such as those with homologous recombination deficiency, which also occurs in approximately half of patients with BRCA wild-type TNBC. In TNBC, homologous recombination deficiency and other aberrations lead to a BRCA-like disease phenotype, which may respond to PARP inhibitors.

Dr. Sharma noted that previous attempts to use PARP inhibitors for BRCA wild-type TNBC have revealed obstacles, such as the inefficacy of PARP inhibitor monotherapy and dose-limiting myelosuppression when PARP inhibitors were added to chemotherapy. The issue of bone marrow toxicity may be mitigated by veliparib, which has minimal PARP-trapping activity, she explained.

“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with the near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” Dr. Sharma said.

She and her colleagues put this finding to the test in a phase 3 trial that enrolled 335 patients with metastatic and/or loco-regionally recurrent TNBC or BRCA-associated HER2-negative breast cancer. Patients could be previously untreated or have received one prior cytotoxic chemotherapy for metastatic disease.

Of the patients enrolled, 321 met eligibility criteria, 294 had germline BRCA testing, and 209 had BRCA-like assessment.

Patients were divided into the following groups: germline BRCA-associated disease (n = 37), BRCA-like disease (n = 99), non-BRCA-like disease (n = 110), and unclassified (n = 75).

In each group, patients were randomized in a 1:1 ratio to receive cisplatin (75 mg/m²on day 1) plus veliparib (300 mg twice daily on days 1-14) every 3 weeks, or cisplatin with placebo. The primary endpoint was PFS.

Results

Among patients with BRCA-like disease, there was a significant improvement in PFS and a trend toward improved OS when veliparib was added to cisplatin. The median PFS was 5.9 months with veliparib and 4.2 months with placebo (P = .006). The median OS was 14.0 months and 12.1 months, respectively (P = .067).

Among patients with previously untreated BRCA-like disease, there were significant improvements in both PFS and OS.

The median PFS in this group was 6.1 months with veliparib and 4.2 months with placebo (P = .008). The 12-month PFS rates were 23% and 3%, respectively.

The median OS in this group was 17.8 months with veliparib and 10.3 months with placebo (P = .048). The 24-month OS rates were 43% and 20%, respectively.

There were no survival benefits with veliparib among patients with unclassified disease, non-BRCA-like disease, or BRCA-associated disease.

Dr. Sharma noted that the lack of significant improvement in the BRCA-associated group was likely due to the small sample size. “FDA approval of PARP inhibitors for treatment of germline BRCA-associated metastatic breast cancer during the course of this trial impacted accrual to this group,” she said.

Veliparib was associated with a higher rate of grade 3-4 hematologic toxicities, including neutropenia (46% vs. 19%), leukopenia (27% vs. 7%), anemia (23% vs. 7%), and thrombocytopenia (19% vs. 3%).

Dr. Sharma said results from this trial should prompt further research. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC,” she said.

Invited discussant Catherine M. Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, called the trial “an ambitious study” that has created a “valuable tissue bank” for future translational research. She agreed that more work is necessary.

“Further research is needed to identify the optimal homologous recombination deficiency biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings,” Dr. Kelly said.

SWOG S1416 was funded by the National Institutes of Health and AbbVie. Dr. Sharma disclosed relationships with AstraZeneca, Merck, Novartis, and other companies. Dr. Kelly reported affiliations with Pfizer, Novartis, Roche, and MSD Oncology.

SOURCE: Sharma et al. ASCO 2020, Abstract 1001.

For patients with BRCA-like triple-negative breast cancer (TNBC), adding veliparib to cisplatin chemotherapy may extend survival, based on results from the phase 3 SWOG S1416 trial.

All patients with BRCA-like TNBC had a significant improvement in progression-free survival (PFS) when they received veliparib plus cisplatin. Previously untreated patients with BRCA-like TNBC had a significant improvement in overall survival (OS) as well.

The results are a “very positive step towards expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” reported lead author Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.

According to Dr. Sharma, PARP inhibitors have demonstrated efficacy for certain patients with BRCA wild-type ovarian cancer, such as those with homologous recombination deficiency, which also occurs in approximately half of patients with BRCA wild-type TNBC. In TNBC, homologous recombination deficiency and other aberrations lead to a BRCA-like disease phenotype, which may respond to PARP inhibitors.

Dr. Sharma noted that previous attempts to use PARP inhibitors for BRCA wild-type TNBC have revealed obstacles, such as the inefficacy of PARP inhibitor monotherapy and dose-limiting myelosuppression when PARP inhibitors were added to chemotherapy. The issue of bone marrow toxicity may be mitigated by veliparib, which has minimal PARP-trapping activity, she explained.

“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with the near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” Dr. Sharma said.

She and her colleagues put this finding to the test in a phase 3 trial that enrolled 335 patients with metastatic and/or loco-regionally recurrent TNBC or BRCA-associated HER2-negative breast cancer. Patients could be previously untreated or have received one prior cytotoxic chemotherapy for metastatic disease.

Of the patients enrolled, 321 met eligibility criteria, 294 had germline BRCA testing, and 209 had BRCA-like assessment.

Patients were divided into the following groups: germline BRCA-associated disease (n = 37), BRCA-like disease (n = 99), non-BRCA-like disease (n = 110), and unclassified (n = 75).

In each group, patients were randomized in a 1:1 ratio to receive cisplatin (75 mg/m²on day 1) plus veliparib (300 mg twice daily on days 1-14) every 3 weeks, or cisplatin with placebo. The primary endpoint was PFS.

Results

Among patients with BRCA-like disease, there was a significant improvement in PFS and a trend toward improved OS when veliparib was added to cisplatin. The median PFS was 5.9 months with veliparib and 4.2 months with placebo (P = .006). The median OS was 14.0 months and 12.1 months, respectively (P = .067).

Among patients with previously untreated BRCA-like disease, there were significant improvements in both PFS and OS.

The median PFS in this group was 6.1 months with veliparib and 4.2 months with placebo (P = .008). The 12-month PFS rates were 23% and 3%, respectively.

The median OS in this group was 17.8 months with veliparib and 10.3 months with placebo (P = .048). The 24-month OS rates were 43% and 20%, respectively.

There were no survival benefits with veliparib among patients with unclassified disease, non-BRCA-like disease, or BRCA-associated disease.

Dr. Sharma noted that the lack of significant improvement in the BRCA-associated group was likely due to the small sample size. “FDA approval of PARP inhibitors for treatment of germline BRCA-associated metastatic breast cancer during the course of this trial impacted accrual to this group,” she said.

Veliparib was associated with a higher rate of grade 3-4 hematologic toxicities, including neutropenia (46% vs. 19%), leukopenia (27% vs. 7%), anemia (23% vs. 7%), and thrombocytopenia (19% vs. 3%).

Dr. Sharma said results from this trial should prompt further research. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC,” she said.

Invited discussant Catherine M. Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, called the trial “an ambitious study” that has created a “valuable tissue bank” for future translational research. She agreed that more work is necessary.

“Further research is needed to identify the optimal homologous recombination deficiency biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings,” Dr. Kelly said.

SWOG S1416 was funded by the National Institutes of Health and AbbVie. Dr. Sharma disclosed relationships with AstraZeneca, Merck, Novartis, and other companies. Dr. Kelly reported affiliations with Pfizer, Novartis, Roche, and MSD Oncology.

SOURCE: Sharma et al. ASCO 2020, Abstract 1001.

For patients with BRCA-like triple-negative breast cancer (TNBC), adding veliparib to cisplatin chemotherapy may extend survival, based on results from the phase 3 SWOG S1416 trial.

All patients with BRCA-like TNBC had a significant improvement in progression-free survival (PFS) when they received veliparib plus cisplatin. Previously untreated patients with BRCA-like TNBC had a significant improvement in overall survival (OS) as well.

The results are a “very positive step towards expanding the role of PARP inhibitors beyond germline BRCA in breast cancer,” reported lead author Priyanka Sharma, MD, of the University of Kansas Medical Center in Kansas City, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.

According to Dr. Sharma, PARP inhibitors have demonstrated efficacy for certain patients with BRCA wild-type ovarian cancer, such as those with homologous recombination deficiency, which also occurs in approximately half of patients with BRCA wild-type TNBC. In TNBC, homologous recombination deficiency and other aberrations lead to a BRCA-like disease phenotype, which may respond to PARP inhibitors.

Dr. Sharma noted that previous attempts to use PARP inhibitors for BRCA wild-type TNBC have revealed obstacles, such as the inefficacy of PARP inhibitor monotherapy and dose-limiting myelosuppression when PARP inhibitors were added to chemotherapy. The issue of bone marrow toxicity may be mitigated by veliparib, which has minimal PARP-trapping activity, she explained.

“A phase 1 trial has demonstrated that adequate doses of cisplatin can be delivered safely in combination with the near-maximal single-agent dose of veliparib in patients with metastatic TNBC,” Dr. Sharma said.

She and her colleagues put this finding to the test in a phase 3 trial that enrolled 335 patients with metastatic and/or loco-regionally recurrent TNBC or BRCA-associated HER2-negative breast cancer. Patients could be previously untreated or have received one prior cytotoxic chemotherapy for metastatic disease.

Of the patients enrolled, 321 met eligibility criteria, 294 had germline BRCA testing, and 209 had BRCA-like assessment.

Patients were divided into the following groups: germline BRCA-associated disease (n = 37), BRCA-like disease (n = 99), non-BRCA-like disease (n = 110), and unclassified (n = 75).

In each group, patients were randomized in a 1:1 ratio to receive cisplatin (75 mg/m²on day 1) plus veliparib (300 mg twice daily on days 1-14) every 3 weeks, or cisplatin with placebo. The primary endpoint was PFS.

Results

Among patients with BRCA-like disease, there was a significant improvement in PFS and a trend toward improved OS when veliparib was added to cisplatin. The median PFS was 5.9 months with veliparib and 4.2 months with placebo (P = .006). The median OS was 14.0 months and 12.1 months, respectively (P = .067).

Among patients with previously untreated BRCA-like disease, there were significant improvements in both PFS and OS.

The median PFS in this group was 6.1 months with veliparib and 4.2 months with placebo (P = .008). The 12-month PFS rates were 23% and 3%, respectively.

The median OS in this group was 17.8 months with veliparib and 10.3 months with placebo (P = .048). The 24-month OS rates were 43% and 20%, respectively.

There were no survival benefits with veliparib among patients with unclassified disease, non-BRCA-like disease, or BRCA-associated disease.

Dr. Sharma noted that the lack of significant improvement in the BRCA-associated group was likely due to the small sample size. “FDA approval of PARP inhibitors for treatment of germline BRCA-associated metastatic breast cancer during the course of this trial impacted accrual to this group,” she said.

Veliparib was associated with a higher rate of grade 3-4 hematologic toxicities, including neutropenia (46% vs. 19%), leukopenia (27% vs. 7%), anemia (23% vs. 7%), and thrombocytopenia (19% vs. 3%).

Dr. Sharma said results from this trial should prompt further research. “The combination of veliparib plus cisplatin warrants further evaluation in larger randomized trials for patients with BRCA-like phenotype TNBC,” she said.

Invited discussant Catherine M. Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, called the trial “an ambitious study” that has created a “valuable tissue bank” for future translational research. She agreed that more work is necessary.

“Further research is needed to identify the optimal homologous recombination deficiency biomarkers critical in the early treatment-naive and in the advanced treatment-exposed disease settings,” Dr. Kelly said.

SWOG S1416 was funded by the National Institutes of Health and AbbVie. Dr. Sharma disclosed relationships with AstraZeneca, Merck, Novartis, and other companies. Dr. Kelly reported affiliations with Pfizer, Novartis, Roche, and MSD Oncology.

SOURCE: Sharma et al. ASCO 2020, Abstract 1001.

Neither fulvestrant alone nor fulvestrant plus anastrozole improved the endocrine-sensitive disease rate (ESDR) versus anastrozole alone as neoadjuvant endocrine therapy in postmenopausal women with locally advanced estrogen receptor-positive HER2-negative (ER+ HER2–) breast cancer in the phase 3 ALTERNATE trial.

The ESDRs were 22.7% in 431 evaluable patients randomized to receive fulvestrant alone, 20.5% in 434 patients who received fulvestrant + anastrozole, and 18.6% in 434 who received anastrozole alone, Cynthia X. Ma, MD, PhD, reported as part of the American Society of Clinical Oncology virtual scientific program.

The differences between the anastrozole-only and the fulvestrant groups did not differ significantly, said Dr. Ma, a professor at Washington University in St. Louis.

Study subjects had a median age of 64 years, clinical stage II/III ER+ HER2– breast cancer, and were randomized 1:1:1 between February 2014 and November 2018 to receive 6 months of treatment with 500 mg of intramuscular fulvestrant given every 4 weeks following a loading dose, fulvestrant plus a 1 mg daily oral does of anastrozole, or anastrozole alone prior to breast conserving surgery.

The groups were similar with respect to baseline characteristics, and more than 70% were eligible for breast conserving surgery prior to the start of neoadjuvant therapy, Dr. Ma noted, adding that the treatments were well tolerated.

Grade 3 or 4 adverse events were rare, and the percentage of patients experiencing arthralgia, myalgia, or hot flashes was low and similar across arms, she said.

“Neoadjuvant therapy downstages the tumor and improves the rate of breast conserving surgery,” Dr. Ma said, adding that pathologic tumor size, nodal status, Ki67 level, and ER status of resected tumors after neoadjuvant therapy have been shown to be independent prognostic factors for relapse-free survival.

[email protected]

SOURCE: Ma C et al. ASCO 2020: Abstract 504.

Neither fulvestrant alone nor fulvestrant plus anastrozole improved the endocrine-sensitive disease rate (ESDR) versus anastrozole alone as neoadjuvant endocrine therapy in postmenopausal women with locally advanced estrogen receptor-positive HER2-negative (ER+ HER2–) breast cancer in the phase 3 ALTERNATE trial.

The ESDRs were 22.7% in 431 evaluable patients randomized to receive fulvestrant alone, 20.5% in 434 patients who received fulvestrant + anastrozole, and 18.6% in 434 who received anastrozole alone, Cynthia X. Ma, MD, PhD, reported as part of the American Society of Clinical Oncology virtual scientific program.

The differences between the anastrozole-only and the fulvestrant groups did not differ significantly, said Dr. Ma, a professor at Washington University in St. Louis.

Study subjects had a median age of 64 years, clinical stage II/III ER+ HER2– breast cancer, and were randomized 1:1:1 between February 2014 and November 2018 to receive 6 months of treatment with 500 mg of intramuscular fulvestrant given every 4 weeks following a loading dose, fulvestrant plus a 1 mg daily oral does of anastrozole, or anastrozole alone prior to breast conserving surgery.

The groups were similar with respect to baseline characteristics, and more than 70% were eligible for breast conserving surgery prior to the start of neoadjuvant therapy, Dr. Ma noted, adding that the treatments were well tolerated.

Grade 3 or 4 adverse events were rare, and the percentage of patients experiencing arthralgia, myalgia, or hot flashes was low and similar across arms, she said.

“Neoadjuvant therapy downstages the tumor and improves the rate of breast conserving surgery,” Dr. Ma said, adding that pathologic tumor size, nodal status, Ki67 level, and ER status of resected tumors after neoadjuvant therapy have been shown to be independent prognostic factors for relapse-free survival.

[email protected]

SOURCE: Ma C et al. ASCO 2020: Abstract 504.

Neither fulvestrant alone nor fulvestrant plus anastrozole improved the endocrine-sensitive disease rate (ESDR) versus anastrozole alone as neoadjuvant endocrine therapy in postmenopausal women with locally advanced estrogen receptor-positive HER2-negative (ER+ HER2–) breast cancer in the phase 3 ALTERNATE trial.

The ESDRs were 22.7% in 431 evaluable patients randomized to receive fulvestrant alone, 20.5% in 434 patients who received fulvestrant + anastrozole, and 18.6% in 434 who received anastrozole alone, Cynthia X. Ma, MD, PhD, reported as part of the American Society of Clinical Oncology virtual scientific program.

The differences between the anastrozole-only and the fulvestrant groups did not differ significantly, said Dr. Ma, a professor at Washington University in St. Louis.

Study subjects had a median age of 64 years, clinical stage II/III ER+ HER2– breast cancer, and were randomized 1:1:1 between February 2014 and November 2018 to receive 6 months of treatment with 500 mg of intramuscular fulvestrant given every 4 weeks following a loading dose, fulvestrant plus a 1 mg daily oral does of anastrozole, or anastrozole alone prior to breast conserving surgery.

The groups were similar with respect to baseline characteristics, and more than 70% were eligible for breast conserving surgery prior to the start of neoadjuvant therapy, Dr. Ma noted, adding that the treatments were well tolerated.

Grade 3 or 4 adverse events were rare, and the percentage of patients experiencing arthralgia, myalgia, or hot flashes was low and similar across arms, she said.

“Neoadjuvant therapy downstages the tumor and improves the rate of breast conserving surgery,” Dr. Ma said, adding that pathologic tumor size, nodal status, Ki67 level, and ER status of resected tumors after neoadjuvant therapy have been shown to be independent prognostic factors for relapse-free survival.

[email protected]

SOURCE: Ma C et al. ASCO 2020: Abstract 504.

In HER2-positive breast cancer patients with brain metastases treated with trastuzumab and capecitabine, add-on tucatinib increased median overall survival from 12 months to 18.1 months in a phase 2 trial.

The results were presented as part of the American Society of Clinical Oncology virtual scientific program and published simultaneously in the Journal of Clinical Oncology.

At 1 year, 70% of the 198 patients who had been randomized to tucatinib were alive versus 47% of the 93 patients randomized to placebo. Tucatinib reduced the risk of death by 42% (P = .005).

“This is the first double-blind, randomized trial of systemic therapy to our knowledge [that demonstrated] clinically meaningful gains in [overall survival] among patients with [brain metastases], including those with active metastases,” Nancy Lin, MD, associate chief of the division of breast oncology at Dana-Farber Cancer Institute in Boston and colleagues wrote in the Journal of Clinical Oncology.

The findings come from a substudy of the HER2CLIMB trial, which had similar outcomes but didn’t separate women with brain metastases from others. The study won tucatinib’s maker, Seattle Genetics, Food and Drug Administration approval for tucatinib in combination with trastuzumab and capecitabine for patients with unresectable or metastatic HER2-postive disease after failure of at least one treatment for advanced disease. In the United States, tucatinib costs over $18,000 a month, according to GoodRX and other sources.



The newly approved indication for tucatinib includes patients with brain metastases, but Dr. Lin and colleagues drove the point home by analyzing HER2CLIMB data solely in the 291 subjects who had baseline CNS lesions, which occur in up to half of women with advanced HER2-positive breast cancer.

Amy Tiersten, MD, a professor at Mount Sinai Hospital in New York, was not involved in the study but is convinced of the clinical benefit of tucatinib. Tucatinib “will be the standard of care for all patients with brain metastases ... regardless of” previous treatments, she said.

“It’s a total game changer. The addition of tucatinib made a large difference, including a hefty impact on overall survival. It will be interesting to see if this drug will be useful in earlier stages to help prevent brain metastases,” Dr. Tiersten said.

Among the large benefits she alluded to, the median CNS progression-free survival (PFS) – free of lesion progression or death – was 9.9 months with tucatinib versus 4.2 months with placebo (P < .00001).

At 1 year, 40% of tucatinib patients, but no patients in the placebo arm, were alive and free of CNS progression. Tucatinib reduced the risk of intracranial progression or death by 68%.

 

Active vs. stable brain metastasis

Among the 117 patients who entered the trial with stable, treated brain metastases – most by radiation, the rest by surgery – the median CNS PFS was 13.9 months with tucatinib versus 5.6 months with placebo (P = .002). In this group, the median overall survival was 15.7 months in the tucatinib arm and 13.6 month in the placebo arm (P = .70).

“Overall survival [in stable patients] numerically favored tucatinib to a small extent, but this did not reach statistical significance, albeit in a relatively small number of patients,” Dr. Lin said in her presentation.

Between-arm differences were significant in the 174 patients who entered the trial with active brain metastases, which refers to those that were either known but untreated, newly discovered on baseline MRI, or progressed after treatment. At 1 year, 35% of these patients in the tucatinib arm were still alive and free of CNS progression; however, there were no such patients in the placebo arm.

The median CNS PFS among patients with active brain metastases at study entrance was 9.5 months with tucatinib versus 4.1 months in the placebo arm (P < .0001). The median overall survival was 20.7 months and 11.6 months, respectively (P = .004).

Intracranial response was confirmed by MRI in 47% of tucatinib-treated patients with active brain metastasis at baseline versus 20% of patients on placebo (P = .03).
 

Re-treatment after progression

Thirty subjects – 21 on tucatinib and 9 on placebo – returned to their study arm after radiation for brain lesion progression.

The risk of second progression or death was reduced 67% when patients restarted tucatinib instead of placebo.

The median time from first CNS progression to a second progression or death was 7.6 months with tucatinib versus 3.1 months with placebo (P = .02).

“The data suggest a potential benefit for continuation of tucatinib beyond first isolated CNS progression,” Dr. Lin said.

As for why tucatinib helps, she and her colleagues speculated that, because tyrosine kinase inhibitors are small molecules, they can cross the blood brain barrier and effectively treat CNS lesions, while larger, antibody-based anti-HER2 agents, such as trastuzumab and pertuzumab, cannot.

Study entry required prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine, as well as an Eastern Cooperative Oncology Group performance score of 0 or 1. More than 99% of the subjects in the analysis were women, and the median age was 52 years.

The treatment groups were well balanced. A bit over half of the subjects in both arms were in North America, and 57% were estrogen and/or progesterone receptor positive. Adverse events were reported previously.

This research was funded by tucatinib’s maker, Seattle Genetics. Dr. Lin and colleagues disclosed financial relationships with Seattle Genetics, including employment. Dr. Tiersten reported no relevant conflicts of interest.

[email protected]

SOURCE: Lin NU et al. ASCO 2020, Abstract 1005; J Clin Oncol. 2020 May 29. doi: 10.1200/JCO.20.00775

In HER2-positive breast cancer patients with brain metastases treated with trastuzumab and capecitabine, add-on tucatinib increased median overall survival from 12 months to 18.1 months in a phase 2 trial.

The results were presented as part of the American Society of Clinical Oncology virtual scientific program and published simultaneously in the Journal of Clinical Oncology.

At 1 year, 70% of the 198 patients who had been randomized to tucatinib were alive versus 47% of the 93 patients randomized to placebo. Tucatinib reduced the risk of death by 42% (P = .005).

“This is the first double-blind, randomized trial of systemic therapy to our knowledge [that demonstrated] clinically meaningful gains in [overall survival] among patients with [brain metastases], including those with active metastases,” Nancy Lin, MD, associate chief of the division of breast oncology at Dana-Farber Cancer Institute in Boston and colleagues wrote in the Journal of Clinical Oncology.

The findings come from a substudy of the HER2CLIMB trial, which had similar outcomes but didn’t separate women with brain metastases from others. The study won tucatinib’s maker, Seattle Genetics, Food and Drug Administration approval for tucatinib in combination with trastuzumab and capecitabine for patients with unresectable or metastatic HER2-postive disease after failure of at least one treatment for advanced disease. In the United States, tucatinib costs over $18,000 a month, according to GoodRX and other sources.



The newly approved indication for tucatinib includes patients with brain metastases, but Dr. Lin and colleagues drove the point home by analyzing HER2CLIMB data solely in the 291 subjects who had baseline CNS lesions, which occur in up to half of women with advanced HER2-positive breast cancer.

Amy Tiersten, MD, a professor at Mount Sinai Hospital in New York, was not involved in the study but is convinced of the clinical benefit of tucatinib. Tucatinib “will be the standard of care for all patients with brain metastases ... regardless of” previous treatments, she said.

“It’s a total game changer. The addition of tucatinib made a large difference, including a hefty impact on overall survival. It will be interesting to see if this drug will be useful in earlier stages to help prevent brain metastases,” Dr. Tiersten said.

Among the large benefits she alluded to, the median CNS progression-free survival (PFS) – free of lesion progression or death – was 9.9 months with tucatinib versus 4.2 months with placebo (P < .00001).

At 1 year, 40% of tucatinib patients, but no patients in the placebo arm, were alive and free of CNS progression. Tucatinib reduced the risk of intracranial progression or death by 68%.

 

Active vs. stable brain metastasis

Among the 117 patients who entered the trial with stable, treated brain metastases – most by radiation, the rest by surgery – the median CNS PFS was 13.9 months with tucatinib versus 5.6 months with placebo (P = .002). In this group, the median overall survival was 15.7 months in the tucatinib arm and 13.6 month in the placebo arm (P = .70).

“Overall survival [in stable patients] numerically favored tucatinib to a small extent, but this did not reach statistical significance, albeit in a relatively small number of patients,” Dr. Lin said in her presentation.

Between-arm differences were significant in the 174 patients who entered the trial with active brain metastases, which refers to those that were either known but untreated, newly discovered on baseline MRI, or progressed after treatment. At 1 year, 35% of these patients in the tucatinib arm were still alive and free of CNS progression; however, there were no such patients in the placebo arm.

The median CNS PFS among patients with active brain metastases at study entrance was 9.5 months with tucatinib versus 4.1 months in the placebo arm (P < .0001). The median overall survival was 20.7 months and 11.6 months, respectively (P = .004).

Intracranial response was confirmed by MRI in 47% of tucatinib-treated patients with active brain metastasis at baseline versus 20% of patients on placebo (P = .03).
 

Re-treatment after progression

Thirty subjects – 21 on tucatinib and 9 on placebo – returned to their study arm after radiation for brain lesion progression.

The risk of second progression or death was reduced 67% when patients restarted tucatinib instead of placebo.

The median time from first CNS progression to a second progression or death was 7.6 months with tucatinib versus 3.1 months with placebo (P = .02).

“The data suggest a potential benefit for continuation of tucatinib beyond first isolated CNS progression,” Dr. Lin said.

As for why tucatinib helps, she and her colleagues speculated that, because tyrosine kinase inhibitors are small molecules, they can cross the blood brain barrier and effectively treat CNS lesions, while larger, antibody-based anti-HER2 agents, such as trastuzumab and pertuzumab, cannot.

Study entry required prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine, as well as an Eastern Cooperative Oncology Group performance score of 0 or 1. More than 99% of the subjects in the analysis were women, and the median age was 52 years.

The treatment groups were well balanced. A bit over half of the subjects in both arms were in North America, and 57% were estrogen and/or progesterone receptor positive. Adverse events were reported previously.

This research was funded by tucatinib’s maker, Seattle Genetics. Dr. Lin and colleagues disclosed financial relationships with Seattle Genetics, including employment. Dr. Tiersten reported no relevant conflicts of interest.

[email protected]

SOURCE: Lin NU et al. ASCO 2020, Abstract 1005; J Clin Oncol. 2020 May 29. doi: 10.1200/JCO.20.00775

In HER2-positive breast cancer patients with brain metastases treated with trastuzumab and capecitabine, add-on tucatinib increased median overall survival from 12 months to 18.1 months in a phase 2 trial.

The results were presented as part of the American Society of Clinical Oncology virtual scientific program and published simultaneously in the Journal of Clinical Oncology.

At 1 year, 70% of the 198 patients who had been randomized to tucatinib were alive versus 47% of the 93 patients randomized to placebo. Tucatinib reduced the risk of death by 42% (P = .005).

“This is the first double-blind, randomized trial of systemic therapy to our knowledge [that demonstrated] clinically meaningful gains in [overall survival] among patients with [brain metastases], including those with active metastases,” Nancy Lin, MD, associate chief of the division of breast oncology at Dana-Farber Cancer Institute in Boston and colleagues wrote in the Journal of Clinical Oncology.

The findings come from a substudy of the HER2CLIMB trial, which had similar outcomes but didn’t separate women with brain metastases from others. The study won tucatinib’s maker, Seattle Genetics, Food and Drug Administration approval for tucatinib in combination with trastuzumab and capecitabine for patients with unresectable or metastatic HER2-postive disease after failure of at least one treatment for advanced disease. In the United States, tucatinib costs over $18,000 a month, according to GoodRX and other sources.



The newly approved indication for tucatinib includes patients with brain metastases, but Dr. Lin and colleagues drove the point home by analyzing HER2CLIMB data solely in the 291 subjects who had baseline CNS lesions, which occur in up to half of women with advanced HER2-positive breast cancer.

Amy Tiersten, MD, a professor at Mount Sinai Hospital in New York, was not involved in the study but is convinced of the clinical benefit of tucatinib. Tucatinib “will be the standard of care for all patients with brain metastases ... regardless of” previous treatments, she said.

“It’s a total game changer. The addition of tucatinib made a large difference, including a hefty impact on overall survival. It will be interesting to see if this drug will be useful in earlier stages to help prevent brain metastases,” Dr. Tiersten said.

Among the large benefits she alluded to, the median CNS progression-free survival (PFS) – free of lesion progression or death – was 9.9 months with tucatinib versus 4.2 months with placebo (P < .00001).

At 1 year, 40% of tucatinib patients, but no patients in the placebo arm, were alive and free of CNS progression. Tucatinib reduced the risk of intracranial progression or death by 68%.

 

Active vs. stable brain metastasis

Among the 117 patients who entered the trial with stable, treated brain metastases – most by radiation, the rest by surgery – the median CNS PFS was 13.9 months with tucatinib versus 5.6 months with placebo (P = .002). In this group, the median overall survival was 15.7 months in the tucatinib arm and 13.6 month in the placebo arm (P = .70).

“Overall survival [in stable patients] numerically favored tucatinib to a small extent, but this did not reach statistical significance, albeit in a relatively small number of patients,” Dr. Lin said in her presentation.

Between-arm differences were significant in the 174 patients who entered the trial with active brain metastases, which refers to those that were either known but untreated, newly discovered on baseline MRI, or progressed after treatment. At 1 year, 35% of these patients in the tucatinib arm were still alive and free of CNS progression; however, there were no such patients in the placebo arm.

The median CNS PFS among patients with active brain metastases at study entrance was 9.5 months with tucatinib versus 4.1 months in the placebo arm (P < .0001). The median overall survival was 20.7 months and 11.6 months, respectively (P = .004).

Intracranial response was confirmed by MRI in 47% of tucatinib-treated patients with active brain metastasis at baseline versus 20% of patients on placebo (P = .03).
 

Re-treatment after progression

Thirty subjects – 21 on tucatinib and 9 on placebo – returned to their study arm after radiation for brain lesion progression.

The risk of second progression or death was reduced 67% when patients restarted tucatinib instead of placebo.

The median time from first CNS progression to a second progression or death was 7.6 months with tucatinib versus 3.1 months with placebo (P = .02).

“The data suggest a potential benefit for continuation of tucatinib beyond first isolated CNS progression,” Dr. Lin said.

As for why tucatinib helps, she and her colleagues speculated that, because tyrosine kinase inhibitors are small molecules, they can cross the blood brain barrier and effectively treat CNS lesions, while larger, antibody-based anti-HER2 agents, such as trastuzumab and pertuzumab, cannot.

Study entry required prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine, as well as an Eastern Cooperative Oncology Group performance score of 0 or 1. More than 99% of the subjects in the analysis were women, and the median age was 52 years.

The treatment groups were well balanced. A bit over half of the subjects in both arms were in North America, and 57% were estrogen and/or progesterone receptor positive. Adverse events were reported previously.

This research was funded by tucatinib’s maker, Seattle Genetics. Dr. Lin and colleagues disclosed financial relationships with Seattle Genetics, including employment. Dr. Tiersten reported no relevant conflicts of interest.

[email protected]

SOURCE: Lin NU et al. ASCO 2020, Abstract 1005; J Clin Oncol. 2020 May 29. doi: 10.1200/JCO.20.00775

Anthracyclines add toxicity with no evidence of improved survival in patients with HER2-positive breast cancer receiving a neoadjuvant chemotherapy regimen plus dual HER2 blockade, results of a  phase 3 trial have suggested.

Event-free survival (EFS) estimates at 3 years were 93% for patients receiving anthracycline-containing chemotherapy plus trastuzumab/pertuzumab and 94% for those receiving an anthracycline-free regimen, according to long-term follow-up results of TRAIN-2, a randomized, phase 3 trial.

There was also “no evidence” that higher-risk patients would benefit from anthracyclines, said investigator Anna Van der Voort of the Netherlands Cancer Institute in Amsterdam.

“Today, anthracyclines are often used, especially in patients with higher risk of recurrence,” said Ms. Van der Voort in her presentation, which was part of the American Society of Clinical Oncology (ASCO) virtual scientific program.

“Importantly, anthracyclines increased the risk of febrile neutropenia, cardiac toxicity, and chemotherapy-associated leukemia, and therefore, a neoadjuvant anthracycline-free regimen with dual HER2 blockade should be considered in all stage II and III HER2-positive breast cancer patients,” she suggested.

With these new results, there are now “great safety data and very promising efficacy data” from two comparative studies favoring nonanthracycline regimens plus HER2 blockade over an anthracycline approach, even in patients with disease thought to be at high risk of recurrence, said Sara A. Hurvitz, MD, associate professor of medicine at the University of California Los Angeles Jonsson Comprehensive Cancer Center.

The other comparative study, BCIRG-006, demonstrated that docetaxel and carboplatin plus trastuzumab (TCH) had similar efficacy, fewer acute toxicities, and less cardiotoxicity and leukemia than did doxorubicin/cyclophosphamide followed by docetaxel (AC-T).

In a follow-up analysis focused on patients with four or more positive lymph nodes, disease-free survival was similar for the nonanthracycline and anthracycline regimens, Dr. Hurvitz noted.

“I would challenge us to think carefully about the standard use of anthracyclines when we have so many targeted therapies available for our patients with HER2-positive disease now,” Dr. Hurvitz said in her commentary on TRAIN-2 that was also part of the virtual ASCO proceedings.

The TRAIN-2 trial included 438 patients in the Netherlands with previously untreated stage II to III HER2-positive breast cancer. Patients randomized to the anthracycline-containing arm received 5-fluorouracil, epirubicin, and cyclophosphamide in three 3-week cycles followed by paclitaxel and carboplatin in six 3-week cycles.

Patients in the anthracycline-free arm received paclitaxel and carboplatin for nine 3-week cycles. Both groups also received trastuzumab and pertuzumab concurrent with chemotherapy.

The pathological complete response (pCR) rate was high with and without anthracyclines, Ms. Van der Voort said, referring to primary results of TRAIN-2 previously published in Lancet Oncology.

In that report, pCR was seen in 67% of patients in the anthracycline group, and 68% in the nonanthracycline group (P = .95), a finding that was consistent regardless of tumor size, nodal status, or hormone receptor status, said Ms. Van der Voort. She added that significantly more febrile neutropenia and hypokalemia were seen in the anthracycline group.

At virtual ASCO, Ms. Van der Voort presented results of the EFS analysis. At the time of analysis, there were 21 events among 219 patients in the nonanthracycline group (10%) and 23 events among 219 patients in the anthracycline group (11%). The corresponding 3-year EFS estimates were 93.5% and 92.7%, with a hazard ratio that favored the nonanthracycline group, though the difference between arms was not statistically significant (hazard ratio, 0.90; 95% confidence interval, 0.50-1.63).

“The results were independent of hormone receptor status, age, tumor size, nodal status, and grade, so we found no evidence that high-risk patients require anthracyclines,” said Ms. Van der Voort. Of note, results divided by nodal status suggested similar or better outcomes in the absence of anthracyclines, even in the highest-risk group, she added.

Estimated 3-year overall survival rates were likewise similar between groups, at 98.2% and 97.7% in the nonanthracycline and anthracycline arms, respectively.

Declines in left ventricular ejection fraction were more frequent in the anthracycline group (36% vs. 22% for the nonanthracycline group; P = .0016), and about one-third of patients did not recover that decline. New malignancies were found in 5% of the anthracycline group and 2% of the nonanthracycline group.

The TRAIN-2 study was sponsored by the Netherlands Cancer Institute and Roche. Ms. Van der Voort said she had no relationships to disclose. Dr. Hurwitz reported institutional research funding from multiple pharmaceutical companies including Genentech/Roche.

SOURCE: Van der Voort A et al. ASCO 2020, Abstract 501.

Anthracyclines add toxicity with no evidence of improved survival in patients with HER2-positive breast cancer receiving a neoadjuvant chemotherapy regimen plus dual HER2 blockade, results of a  phase 3 trial have suggested.

Event-free survival (EFS) estimates at 3 years were 93% for patients receiving anthracycline-containing chemotherapy plus trastuzumab/pertuzumab and 94% for those receiving an anthracycline-free regimen, according to long-term follow-up results of TRAIN-2, a randomized, phase 3 trial.

There was also “no evidence” that higher-risk patients would benefit from anthracyclines, said investigator Anna Van der Voort of the Netherlands Cancer Institute in Amsterdam.

“Today, anthracyclines are often used, especially in patients with higher risk of recurrence,” said Ms. Van der Voort in her presentation, which was part of the American Society of Clinical Oncology (ASCO) virtual scientific program.

“Importantly, anthracyclines increased the risk of febrile neutropenia, cardiac toxicity, and chemotherapy-associated leukemia, and therefore, a neoadjuvant anthracycline-free regimen with dual HER2 blockade should be considered in all stage II and III HER2-positive breast cancer patients,” she suggested.

With these new results, there are now “great safety data and very promising efficacy data” from two comparative studies favoring nonanthracycline regimens plus HER2 blockade over an anthracycline approach, even in patients with disease thought to be at high risk of recurrence, said Sara A. Hurvitz, MD, associate professor of medicine at the University of California Los Angeles Jonsson Comprehensive Cancer Center.

The other comparative study, BCIRG-006, demonstrated that docetaxel and carboplatin plus trastuzumab (TCH) had similar efficacy, fewer acute toxicities, and less cardiotoxicity and leukemia than did doxorubicin/cyclophosphamide followed by docetaxel (AC-T).

In a follow-up analysis focused on patients with four or more positive lymph nodes, disease-free survival was similar for the nonanthracycline and anthracycline regimens, Dr. Hurvitz noted.

“I would challenge us to think carefully about the standard use of anthracyclines when we have so many targeted therapies available for our patients with HER2-positive disease now,” Dr. Hurvitz said in her commentary on TRAIN-2 that was also part of the virtual ASCO proceedings.

The TRAIN-2 trial included 438 patients in the Netherlands with previously untreated stage II to III HER2-positive breast cancer. Patients randomized to the anthracycline-containing arm received 5-fluorouracil, epirubicin, and cyclophosphamide in three 3-week cycles followed by paclitaxel and carboplatin in six 3-week cycles.

Patients in the anthracycline-free arm received paclitaxel and carboplatin for nine 3-week cycles. Both groups also received trastuzumab and pertuzumab concurrent with chemotherapy.

The pathological complete response (pCR) rate was high with and without anthracyclines, Ms. Van der Voort said, referring to primary results of TRAIN-2 previously published in Lancet Oncology.

In that report, pCR was seen in 67% of patients in the anthracycline group, and 68% in the nonanthracycline group (P = .95), a finding that was consistent regardless of tumor size, nodal status, or hormone receptor status, said Ms. Van der Voort. She added that significantly more febrile neutropenia and hypokalemia were seen in the anthracycline group.

At virtual ASCO, Ms. Van der Voort presented results of the EFS analysis. At the time of analysis, there were 21 events among 219 patients in the nonanthracycline group (10%) and 23 events among 219 patients in the anthracycline group (11%). The corresponding 3-year EFS estimates were 93.5% and 92.7%, with a hazard ratio that favored the nonanthracycline group, though the difference between arms was not statistically significant (hazard ratio, 0.90; 95% confidence interval, 0.50-1.63).

“The results were independent of hormone receptor status, age, tumor size, nodal status, and grade, so we found no evidence that high-risk patients require anthracyclines,” said Ms. Van der Voort. Of note, results divided by nodal status suggested similar or better outcomes in the absence of anthracyclines, even in the highest-risk group, she added.

Estimated 3-year overall survival rates were likewise similar between groups, at 98.2% and 97.7% in the nonanthracycline and anthracycline arms, respectively.

Declines in left ventricular ejection fraction were more frequent in the anthracycline group (36% vs. 22% for the nonanthracycline group; P = .0016), and about one-third of patients did not recover that decline. New malignancies were found in 5% of the anthracycline group and 2% of the nonanthracycline group.

The TRAIN-2 study was sponsored by the Netherlands Cancer Institute and Roche. Ms. Van der Voort said she had no relationships to disclose. Dr. Hurwitz reported institutional research funding from multiple pharmaceutical companies including Genentech/Roche.

SOURCE: Van der Voort A et al. ASCO 2020, Abstract 501.

Anthracyclines add toxicity with no evidence of improved survival in patients with HER2-positive breast cancer receiving a neoadjuvant chemotherapy regimen plus dual HER2 blockade, results of a  phase 3 trial have suggested.

Event-free survival (EFS) estimates at 3 years were 93% for patients receiving anthracycline-containing chemotherapy plus trastuzumab/pertuzumab and 94% for those receiving an anthracycline-free regimen, according to long-term follow-up results of TRAIN-2, a randomized, phase 3 trial.

There was also “no evidence” that higher-risk patients would benefit from anthracyclines, said investigator Anna Van der Voort of the Netherlands Cancer Institute in Amsterdam.

“Today, anthracyclines are often used, especially in patients with higher risk of recurrence,” said Ms. Van der Voort in her presentation, which was part of the American Society of Clinical Oncology (ASCO) virtual scientific program.

“Importantly, anthracyclines increased the risk of febrile neutropenia, cardiac toxicity, and chemotherapy-associated leukemia, and therefore, a neoadjuvant anthracycline-free regimen with dual HER2 blockade should be considered in all stage II and III HER2-positive breast cancer patients,” she suggested.

With these new results, there are now “great safety data and very promising efficacy data” from two comparative studies favoring nonanthracycline regimens plus HER2 blockade over an anthracycline approach, even in patients with disease thought to be at high risk of recurrence, said Sara A. Hurvitz, MD, associate professor of medicine at the University of California Los Angeles Jonsson Comprehensive Cancer Center.

The other comparative study, BCIRG-006, demonstrated that docetaxel and carboplatin plus trastuzumab (TCH) had similar efficacy, fewer acute toxicities, and less cardiotoxicity and leukemia than did doxorubicin/cyclophosphamide followed by docetaxel (AC-T).

In a follow-up analysis focused on patients with four or more positive lymph nodes, disease-free survival was similar for the nonanthracycline and anthracycline regimens, Dr. Hurvitz noted.

“I would challenge us to think carefully about the standard use of anthracyclines when we have so many targeted therapies available for our patients with HER2-positive disease now,” Dr. Hurvitz said in her commentary on TRAIN-2 that was also part of the virtual ASCO proceedings.

The TRAIN-2 trial included 438 patients in the Netherlands with previously untreated stage II to III HER2-positive breast cancer. Patients randomized to the anthracycline-containing arm received 5-fluorouracil, epirubicin, and cyclophosphamide in three 3-week cycles followed by paclitaxel and carboplatin in six 3-week cycles.

Patients in the anthracycline-free arm received paclitaxel and carboplatin for nine 3-week cycles. Both groups also received trastuzumab and pertuzumab concurrent with chemotherapy.

The pathological complete response (pCR) rate was high with and without anthracyclines, Ms. Van der Voort said, referring to primary results of TRAIN-2 previously published in Lancet Oncology.

In that report, pCR was seen in 67% of patients in the anthracycline group, and 68% in the nonanthracycline group (P = .95), a finding that was consistent regardless of tumor size, nodal status, or hormone receptor status, said Ms. Van der Voort. She added that significantly more febrile neutropenia and hypokalemia were seen in the anthracycline group.

At virtual ASCO, Ms. Van der Voort presented results of the EFS analysis. At the time of analysis, there were 21 events among 219 patients in the nonanthracycline group (10%) and 23 events among 219 patients in the anthracycline group (11%). The corresponding 3-year EFS estimates were 93.5% and 92.7%, with a hazard ratio that favored the nonanthracycline group, though the difference between arms was not statistically significant (hazard ratio, 0.90; 95% confidence interval, 0.50-1.63).

“The results were independent of hormone receptor status, age, tumor size, nodal status, and grade, so we found no evidence that high-risk patients require anthracyclines,” said Ms. Van der Voort. Of note, results divided by nodal status suggested similar or better outcomes in the absence of anthracyclines, even in the highest-risk group, she added.

Estimated 3-year overall survival rates were likewise similar between groups, at 98.2% and 97.7% in the nonanthracycline and anthracycline arms, respectively.

Declines in left ventricular ejection fraction were more frequent in the anthracycline group (36% vs. 22% for the nonanthracycline group; P = .0016), and about one-third of patients did not recover that decline. New malignancies were found in 5% of the anthracycline group and 2% of the nonanthracycline group.

The TRAIN-2 study was sponsored by the Netherlands Cancer Institute and Roche. Ms. Van der Voort said she had no relationships to disclose. Dr. Hurwitz reported institutional research funding from multiple pharmaceutical companies including Genentech/Roche.

SOURCE: Van der Voort A et al. ASCO 2020, Abstract 501.