Pulmonology

VIENNA — Advances in genetic testing and newly discovered biomarkers can help screen newborns and monitor inflammation and pulmonary exacerbations in patients diagnosed with cystic fibrosis.

At the European Respiratory Society (ERS) 2024 International Congress, clinical researchers presented results from the Turkish context.

Cystic fibrosis is the most common genetic disorder among Caucasians. The average prevalence at birth in Europe is 1 in 5000, whereas the overall population averages 1 in 9000. Both rates vary significantly based on geographic area. In the central Anatolia region, one study found that the incidence of cystic fibrosis is 1 in 3400 live births.

Çigdem Korkmaz, a researcher at the Department of Pediatric Pulmonology at the Istanbul University-Cerrahpasa in Istanbul, Turkey, said that diagnosis in Turkey is especially challenging because of the genetic diversity of cystic fibrosis within the population. She said genetic testing might be necessary to catch missed cases by traditional screening methods.
 

Genetic Testing Picks Up Missed Cases

In 2022, 30 European countries run newborn bloodspot screening for cystic fibrosis, with 26 national programs. Screening protocols vary between countries but generally involve initial screening using an immunoreactive trypsinogen (IRT) blood test. Follow-up testing may include a second IRT test, DNA analysis for common CFTR mutations, and sweat chloride test (SCT).

Turkey introduced newborn screening for cystic fibrosis in 2015. Newborns with an elevated IRT and confirmatory SCT undergo genetic testing. However, in a retrospective study, researchers found that IRT tests turn many false-positive results, and some patients who turn a normal SCT are diagnosed with the disease through genetic testing.

The study included 205 infants referred to a tertiary care center in Istanbul between January 2015 and January 2023 following an elevator IRT result. The researchers analyzed the clinical and sociodemographic data, IRT and SCT values, and genetic analysis results.

They found that cystic fibrosis was confirmed in only 30% newborns, while genetic testing could identify nine cases otherwise missed by SCT. “The high false-positive rate of the current screening strategy suggests that the IRT thresholds used in Turkey may be too low,” said Ms. Korkmaz, who presented the study at the ERS Congress. She added that genetic testing might be important, especially in patients with normal SCT results. “Early diagnosis means these patients avoid missing or delaying treatments.”
 

Biomarkers for Monitoring Cystic Fibrosis Exacerbations

C-reactive protein (CRP) blood testing is typically used in monitoring inflammation and pulmonary exacerbations in patients who have already been diagnosed with cystic fibrosis. CRP is an inflammatory biomarker that increases in patients with cystic fibrosis during pulmonary exacerbations and settles with treatment.

Researchers at Gazi University in Ankara, Turkey, found other biomarkers to identify inflammation and pulmonary exacerbations with great sensitivity and specificity in patients with cystic fibrosis.

Over 3 years, from 2021 to 2024, the researchers analyzed blood samples from 54 children aged 1-18 years during exacerbation and non-exacerbation periods. Besides CRP, they tested CRP/albumin (ALB) ratio, neutrophil-to-lymphocyte ratio (NLR), delivered NLR (dNLR), and systemic immune inflammation (SII).

All biomarkers increased during exacerbation episodes. All showed high specificity and sensitivity:

• CPR/ALB had a specificity of 81% and a sensitivity of 90% at a cutoff of 1.7 mg/dL.
• SII had a specificity of 86% and a sensitivity of 67% at a cutoff of 426 mg/dL.
• NLR had a specificity of 62% and a sensitivity of 79% at a cutoff of 2.2 mg/dL.
• SII had a specificity of 86% and a sensitivity of 67% at a cutoff of 426 mg/dL.
• dNLR had a specificity of 71% and a sensitivity of 66% at a cutoff of 1.15 mg/dL.
• In comparison, CPR had a specificity of 85% and a sensitivity of 84% at a cutoff of 6.2 mg/dL.

Ayse Tana Aslan, a professor at the Department of Pediatric Pulmonology, Faculty of Medicine, at Gazi University in Ankara, Turkey, who presented the results at the ERS Congress, said that these biomarkers can be easily and quickly identified with a blood test while waiting on phlegm culture results, which can take days. “It is important to predict inflammation and exacerbation quickly so that patients can start a course of antibiotics as soon as possible,” she said.

Ms. Korkmaz and Ms. Aslan reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

VIENNA — Advances in genetic testing and newly discovered biomarkers can help screen newborns and monitor inflammation and pulmonary exacerbations in patients diagnosed with cystic fibrosis.

At the European Respiratory Society (ERS) 2024 International Congress, clinical researchers presented results from the Turkish context.

Cystic fibrosis is the most common genetic disorder among Caucasians. The average prevalence at birth in Europe is 1 in 5000, whereas the overall population averages 1 in 9000. Both rates vary significantly based on geographic area. In the central Anatolia region, one study found that the incidence of cystic fibrosis is 1 in 3400 live births.

Çigdem Korkmaz, a researcher at the Department of Pediatric Pulmonology at the Istanbul University-Cerrahpasa in Istanbul, Turkey, said that diagnosis in Turkey is especially challenging because of the genetic diversity of cystic fibrosis within the population. She said genetic testing might be necessary to catch missed cases by traditional screening methods.
 

Genetic Testing Picks Up Missed Cases

In 2022, 30 European countries run newborn bloodspot screening for cystic fibrosis, with 26 national programs. Screening protocols vary between countries but generally involve initial screening using an immunoreactive trypsinogen (IRT) blood test. Follow-up testing may include a second IRT test, DNA analysis for common CFTR mutations, and sweat chloride test (SCT).

Turkey introduced newborn screening for cystic fibrosis in 2015. Newborns with an elevated IRT and confirmatory SCT undergo genetic testing. However, in a retrospective study, researchers found that IRT tests turn many false-positive results, and some patients who turn a normal SCT are diagnosed with the disease through genetic testing.

The study included 205 infants referred to a tertiary care center in Istanbul between January 2015 and January 2023 following an elevator IRT result. The researchers analyzed the clinical and sociodemographic data, IRT and SCT values, and genetic analysis results.

They found that cystic fibrosis was confirmed in only 30% newborns, while genetic testing could identify nine cases otherwise missed by SCT. “The high false-positive rate of the current screening strategy suggests that the IRT thresholds used in Turkey may be too low,” said Ms. Korkmaz, who presented the study at the ERS Congress. She added that genetic testing might be important, especially in patients with normal SCT results. “Early diagnosis means these patients avoid missing or delaying treatments.”
 

Biomarkers for Monitoring Cystic Fibrosis Exacerbations

C-reactive protein (CRP) blood testing is typically used in monitoring inflammation and pulmonary exacerbations in patients who have already been diagnosed with cystic fibrosis. CRP is an inflammatory biomarker that increases in patients with cystic fibrosis during pulmonary exacerbations and settles with treatment.

Researchers at Gazi University in Ankara, Turkey, found other biomarkers to identify inflammation and pulmonary exacerbations with great sensitivity and specificity in patients with cystic fibrosis.

Over 3 years, from 2021 to 2024, the researchers analyzed blood samples from 54 children aged 1-18 years during exacerbation and non-exacerbation periods. Besides CRP, they tested CRP/albumin (ALB) ratio, neutrophil-to-lymphocyte ratio (NLR), delivered NLR (dNLR), and systemic immune inflammation (SII).

All biomarkers increased during exacerbation episodes. All showed high specificity and sensitivity:

• CPR/ALB had a specificity of 81% and a sensitivity of 90% at a cutoff of 1.7 mg/dL.
• SII had a specificity of 86% and a sensitivity of 67% at a cutoff of 426 mg/dL.
• NLR had a specificity of 62% and a sensitivity of 79% at a cutoff of 2.2 mg/dL.
• SII had a specificity of 86% and a sensitivity of 67% at a cutoff of 426 mg/dL.
• dNLR had a specificity of 71% and a sensitivity of 66% at a cutoff of 1.15 mg/dL.
• In comparison, CPR had a specificity of 85% and a sensitivity of 84% at a cutoff of 6.2 mg/dL.

Ayse Tana Aslan, a professor at the Department of Pediatric Pulmonology, Faculty of Medicine, at Gazi University in Ankara, Turkey, who presented the results at the ERS Congress, said that these biomarkers can be easily and quickly identified with a blood test while waiting on phlegm culture results, which can take days. “It is important to predict inflammation and exacerbation quickly so that patients can start a course of antibiotics as soon as possible,” she said.

Ms. Korkmaz and Ms. Aslan reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

VIENNA — Advances in genetic testing and newly discovered biomarkers can help screen newborns and monitor inflammation and pulmonary exacerbations in patients diagnosed with cystic fibrosis.

At the European Respiratory Society (ERS) 2024 International Congress, clinical researchers presented results from the Turkish context.

Cystic fibrosis is the most common genetic disorder among Caucasians. The average prevalence at birth in Europe is 1 in 5000, whereas the overall population averages 1 in 9000. Both rates vary significantly based on geographic area. In the central Anatolia region, one study found that the incidence of cystic fibrosis is 1 in 3400 live births.

Çigdem Korkmaz, a researcher at the Department of Pediatric Pulmonology at the Istanbul University-Cerrahpasa in Istanbul, Turkey, said that diagnosis in Turkey is especially challenging because of the genetic diversity of cystic fibrosis within the population. She said genetic testing might be necessary to catch missed cases by traditional screening methods.
 

Genetic Testing Picks Up Missed Cases

In 2022, 30 European countries run newborn bloodspot screening for cystic fibrosis, with 26 national programs. Screening protocols vary between countries but generally involve initial screening using an immunoreactive trypsinogen (IRT) blood test. Follow-up testing may include a second IRT test, DNA analysis for common CFTR mutations, and sweat chloride test (SCT).

Turkey introduced newborn screening for cystic fibrosis in 2015. Newborns with an elevated IRT and confirmatory SCT undergo genetic testing. However, in a retrospective study, researchers found that IRT tests turn many false-positive results, and some patients who turn a normal SCT are diagnosed with the disease through genetic testing.

The study included 205 infants referred to a tertiary care center in Istanbul between January 2015 and January 2023 following an elevator IRT result. The researchers analyzed the clinical and sociodemographic data, IRT and SCT values, and genetic analysis results.

They found that cystic fibrosis was confirmed in only 30% newborns, while genetic testing could identify nine cases otherwise missed by SCT. “The high false-positive rate of the current screening strategy suggests that the IRT thresholds used in Turkey may be too low,” said Ms. Korkmaz, who presented the study at the ERS Congress. She added that genetic testing might be important, especially in patients with normal SCT results. “Early diagnosis means these patients avoid missing or delaying treatments.”
 

Biomarkers for Monitoring Cystic Fibrosis Exacerbations

C-reactive protein (CRP) blood testing is typically used in monitoring inflammation and pulmonary exacerbations in patients who have already been diagnosed with cystic fibrosis. CRP is an inflammatory biomarker that increases in patients with cystic fibrosis during pulmonary exacerbations and settles with treatment.

Researchers at Gazi University in Ankara, Turkey, found other biomarkers to identify inflammation and pulmonary exacerbations with great sensitivity and specificity in patients with cystic fibrosis.

Over 3 years, from 2021 to 2024, the researchers analyzed blood samples from 54 children aged 1-18 years during exacerbation and non-exacerbation periods. Besides CRP, they tested CRP/albumin (ALB) ratio, neutrophil-to-lymphocyte ratio (NLR), delivered NLR (dNLR), and systemic immune inflammation (SII).

All biomarkers increased during exacerbation episodes. All showed high specificity and sensitivity:

• CPR/ALB had a specificity of 81% and a sensitivity of 90% at a cutoff of 1.7 mg/dL.
• SII had a specificity of 86% and a sensitivity of 67% at a cutoff of 426 mg/dL.
• NLR had a specificity of 62% and a sensitivity of 79% at a cutoff of 2.2 mg/dL.
• SII had a specificity of 86% and a sensitivity of 67% at a cutoff of 426 mg/dL.
• dNLR had a specificity of 71% and a sensitivity of 66% at a cutoff of 1.15 mg/dL.
• In comparison, CPR had a specificity of 85% and a sensitivity of 84% at a cutoff of 6.2 mg/dL.

Ayse Tana Aslan, a professor at the Department of Pediatric Pulmonology, Faculty of Medicine, at Gazi University in Ankara, Turkey, who presented the results at the ERS Congress, said that these biomarkers can be easily and quickly identified with a blood test while waiting on phlegm culture results, which can take days. “It is important to predict inflammation and exacerbation quickly so that patients can start a course of antibiotics as soon as possible,” she said.

Ms. Korkmaz and Ms. Aslan reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

VIENNA — The optimal course of treatment when managing acute, high-risk pulmonary embolism (PE) remains a contentious topic among respiratory specialists.

Systemic thrombolysis, specifically using recombinant tissue plasminogen activator (rtPA), is the current gold standard treatment for high-risk PE. However, the real-world application is less straightforward due to patient complexities. Some clinicians believe that advances in mechanical and surgical techniques have made rtPA a thing of the past. Others think there is still insufficient evidence to support alternatives as the standard of care.

Here at the European Respiratory Society (ERS) 2024 Congress, respiratory specialists presented contrasting viewpoints and the latest evidence on each side of the issue to provide a comprehensive framework for navigating the complex decision-making process required for effective treatment.

“High-risk PE is a mechanical problem and thus needs a mechanical solution,” said Parth M. Rali, MD, an associate professor in thoracic medicine and surgery at the Lewis Katz School of Medicine at Temple University, Philadelphia.

“The marketing on some of the mechanical techniques is very impressive,” said Olivier Sanchez, MD, a pulmonologist in the Department of Pneumology and Intensive Care at the Georges Pompidou European Hospital in France. “But what is the evidence of such treatment in the setting of pulmonary embolism?”
 

The Case Against rtPA as the Standard of Care

High-risk PE typically involves hemodynamically unstable patients presenting with conditions such as low blood pressure, cardiac arrest, or the need for mechanical circulatory support. There is a spectrum of severity within high-risk PE, making it a complex condition to manage, especially since many patients have comorbidities like anemia or active cancer, complicating treatment. “It’s a very dynamic and fluid condition, and we can’t take for granted that rtPA is a standard of care,” Dr. Rali said.

Alternative treatments such as catheter-directed therapies, extracorporeal membrane oxygenation (ECMO), and surgical embolectomy are emerging as promising options, especially for patients who do not respond to or cannot receive rtPA. Mechanical treatments offer benefits in reducing clot burden and stabilizing patients, but they come with their own challenges.

ECMO can stabilize patients who are in shock or cardiac arrest, buying time for the clot to resolve or for further interventions like surgery or catheter-based treatments, said Dr. Rali. However, it is an invasive procedure requiring cannulation of large blood vessels, often involving significant resources and expertise.

Catheter-directed thrombolysis is a minimally invasive technique where a catheter is inserted directly into the pulmonary artery to deliver thrombolytic drugs at lower doses. This method allows for more targeted treatment of the clot, reducing the risk for systemic bleeding that comes with higher doses of thrombolytic agents used in systemic therapy, Dr. Rali explained. 

Dr. Rali reported results from the FLAME study, which investigated the effectiveness of FlowTriever mechanical thrombectomy compared with conventional therapies for high-risk PE. This prospective, multicenter observational study enrolled 53 patients in the FlowTriever arm and 61 in the context arm, which included patients treated with systemic thrombolysis or anticoagulation. The primary endpoint, a composite of adverse in-hospital outcomes, was reached in 17% of FlowTriever patients, significantly lower than the 32% performance goal and the 63.9% rate in the context arm. In-hospital mortality was dramatically lower in the FlowTriever arm (1.9%) compared to the context arm (29.5%). 

When catheter-based treatment fails, surgical pulmonary embolectomy is a last-resort option. “Only a minority of the high-risk PE [patients] would qualify for rtPA without harmful side effects,” Dr. Rali concluded. “So think wise before you pull your trigger.” 
 

rtPA Not a Matter of the Past

In high-risk PE, the therapeutic priority is rapid hemodynamic stabilization and restoration of pulmonary blood flow to prevent cardiovascular collapse. Systemic thrombolysis acts quickly, reducing pulmonary vascular resistance and obstruction within hours, said Dr. Sanchez. 

Presenting at the ERS Congress, he reported numerous studies, including 15 randomized controlled trials that demonstrated its effectiveness in high-risk PE. The PEITHO trial, in particular, demonstrated the ability of systemic thrombolysis to reduce all-cause mortality and hemodynamic collapse within 7 days. 

However, this benefit comes at the cost of increased bleeding risk, including a 10% rate of major bleeding and a 2% risk for intracranial hemorrhage. “These data come from old studies using invasive diagnostic procedures, and with current diagnostic procedures, the rate of bleeding is probably lower,” Dr. Sanchez said. The risk of bleeding is also related to the type of thrombolytic agent, with tenecteplase being strongly associated with a higher risk of bleeding, while alteplase shows no increase in the risk of major bleeding, he added. New strategies like reduced-dose thrombolysis offer comparable efficacy and improved safety, as demonstrated in ongoing trials like  PEITHO-3, which aim to optimize the balance between efficacy and bleeding risk. Dr. Sanchez is the lead investigator of the PEITHO-3 study.

While rtPA might not be optimal for all patients, Dr. Sanchez thinks there is not enough evidence to replace it as a first-line treatment.

Existing studies on catheter-directed therapies often focus on surrogate endpoints, such as right-to-left ventricular ratio changes, rather than clinical outcomes like mortality, he said. Retrospective data suggest that catheter-directed therapies may reduce in-hospital mortality compared with systemic therapies, but they also increase the risk of intracranial bleeding, post-procedure complications, and device-related events.

Sanchez mentioned the same FLAME study described by Dr. Rali, which reported a 23% rate of device-related complications and 11% major bleeding in patients treated with catheter-directed therapies. 

“Systemic thrombolysis remains the first treatment of choice,” Dr. Sanchez concluded. “The use of catheter-directed treatment should be discussed as an alternative in case of contraindications.”
 

The Debate Continues

Numerous ongoing clinical studies, such as the FLARE trial, will address gaps in evidence and refine treatment protocols, potentially reshaping the standard of care in high-risk PE in the near future by providing new data on the efficacy and safety of existing and emerging therapies.

“The coming data will make it clearer what the best option is,” said Thamer Al Khouzaie, MD, a pulmonary medicine consultant at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia. For now, he said, systemic thrombolysis remains the best option for most patients because it is widely available, easily administered with intravenous infusion, and at a limited cost. Catheter-directed treatment and surgical options are only available in specialized centers, require expertise and training, and are also very expensive.

Dr. Rali, Dr. Sanchez, and Dr. Khouzaie report no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

VIENNA — The optimal course of treatment when managing acute, high-risk pulmonary embolism (PE) remains a contentious topic among respiratory specialists.

Systemic thrombolysis, specifically using recombinant tissue plasminogen activator (rtPA), is the current gold standard treatment for high-risk PE. However, the real-world application is less straightforward due to patient complexities. Some clinicians believe that advances in mechanical and surgical techniques have made rtPA a thing of the past. Others think there is still insufficient evidence to support alternatives as the standard of care.

Here at the European Respiratory Society (ERS) 2024 Congress, respiratory specialists presented contrasting viewpoints and the latest evidence on each side of the issue to provide a comprehensive framework for navigating the complex decision-making process required for effective treatment.

“High-risk PE is a mechanical problem and thus needs a mechanical solution,” said Parth M. Rali, MD, an associate professor in thoracic medicine and surgery at the Lewis Katz School of Medicine at Temple University, Philadelphia.

“The marketing on some of the mechanical techniques is very impressive,” said Olivier Sanchez, MD, a pulmonologist in the Department of Pneumology and Intensive Care at the Georges Pompidou European Hospital in France. “But what is the evidence of such treatment in the setting of pulmonary embolism?”
 

The Case Against rtPA as the Standard of Care

High-risk PE typically involves hemodynamically unstable patients presenting with conditions such as low blood pressure, cardiac arrest, or the need for mechanical circulatory support. There is a spectrum of severity within high-risk PE, making it a complex condition to manage, especially since many patients have comorbidities like anemia or active cancer, complicating treatment. “It’s a very dynamic and fluid condition, and we can’t take for granted that rtPA is a standard of care,” Dr. Rali said.

Alternative treatments such as catheter-directed therapies, extracorporeal membrane oxygenation (ECMO), and surgical embolectomy are emerging as promising options, especially for patients who do not respond to or cannot receive rtPA. Mechanical treatments offer benefits in reducing clot burden and stabilizing patients, but they come with their own challenges.

ECMO can stabilize patients who are in shock or cardiac arrest, buying time for the clot to resolve or for further interventions like surgery or catheter-based treatments, said Dr. Rali. However, it is an invasive procedure requiring cannulation of large blood vessels, often involving significant resources and expertise.

Catheter-directed thrombolysis is a minimally invasive technique where a catheter is inserted directly into the pulmonary artery to deliver thrombolytic drugs at lower doses. This method allows for more targeted treatment of the clot, reducing the risk for systemic bleeding that comes with higher doses of thrombolytic agents used in systemic therapy, Dr. Rali explained. 

Dr. Rali reported results from the FLAME study, which investigated the effectiveness of FlowTriever mechanical thrombectomy compared with conventional therapies for high-risk PE. This prospective, multicenter observational study enrolled 53 patients in the FlowTriever arm and 61 in the context arm, which included patients treated with systemic thrombolysis or anticoagulation. The primary endpoint, a composite of adverse in-hospital outcomes, was reached in 17% of FlowTriever patients, significantly lower than the 32% performance goal and the 63.9% rate in the context arm. In-hospital mortality was dramatically lower in the FlowTriever arm (1.9%) compared to the context arm (29.5%). 

When catheter-based treatment fails, surgical pulmonary embolectomy is a last-resort option. “Only a minority of the high-risk PE [patients] would qualify for rtPA without harmful side effects,” Dr. Rali concluded. “So think wise before you pull your trigger.” 
 

rtPA Not a Matter of the Past

In high-risk PE, the therapeutic priority is rapid hemodynamic stabilization and restoration of pulmonary blood flow to prevent cardiovascular collapse. Systemic thrombolysis acts quickly, reducing pulmonary vascular resistance and obstruction within hours, said Dr. Sanchez. 

Presenting at the ERS Congress, he reported numerous studies, including 15 randomized controlled trials that demonstrated its effectiveness in high-risk PE. The PEITHO trial, in particular, demonstrated the ability of systemic thrombolysis to reduce all-cause mortality and hemodynamic collapse within 7 days. 

However, this benefit comes at the cost of increased bleeding risk, including a 10% rate of major bleeding and a 2% risk for intracranial hemorrhage. “These data come from old studies using invasive diagnostic procedures, and with current diagnostic procedures, the rate of bleeding is probably lower,” Dr. Sanchez said. The risk of bleeding is also related to the type of thrombolytic agent, with tenecteplase being strongly associated with a higher risk of bleeding, while alteplase shows no increase in the risk of major bleeding, he added. New strategies like reduced-dose thrombolysis offer comparable efficacy and improved safety, as demonstrated in ongoing trials like  PEITHO-3, which aim to optimize the balance between efficacy and bleeding risk. Dr. Sanchez is the lead investigator of the PEITHO-3 study.

While rtPA might not be optimal for all patients, Dr. Sanchez thinks there is not enough evidence to replace it as a first-line treatment.

Existing studies on catheter-directed therapies often focus on surrogate endpoints, such as right-to-left ventricular ratio changes, rather than clinical outcomes like mortality, he said. Retrospective data suggest that catheter-directed therapies may reduce in-hospital mortality compared with systemic therapies, but they also increase the risk of intracranial bleeding, post-procedure complications, and device-related events.

Sanchez mentioned the same FLAME study described by Dr. Rali, which reported a 23% rate of device-related complications and 11% major bleeding in patients treated with catheter-directed therapies. 

“Systemic thrombolysis remains the first treatment of choice,” Dr. Sanchez concluded. “The use of catheter-directed treatment should be discussed as an alternative in case of contraindications.”
 

The Debate Continues

Numerous ongoing clinical studies, such as the FLARE trial, will address gaps in evidence and refine treatment protocols, potentially reshaping the standard of care in high-risk PE in the near future by providing new data on the efficacy and safety of existing and emerging therapies.

“The coming data will make it clearer what the best option is,” said Thamer Al Khouzaie, MD, a pulmonary medicine consultant at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia. For now, he said, systemic thrombolysis remains the best option for most patients because it is widely available, easily administered with intravenous infusion, and at a limited cost. Catheter-directed treatment and surgical options are only available in specialized centers, require expertise and training, and are also very expensive.

Dr. Rali, Dr. Sanchez, and Dr. Khouzaie report no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

VIENNA — The optimal course of treatment when managing acute, high-risk pulmonary embolism (PE) remains a contentious topic among respiratory specialists.

Systemic thrombolysis, specifically using recombinant tissue plasminogen activator (rtPA), is the current gold standard treatment for high-risk PE. However, the real-world application is less straightforward due to patient complexities. Some clinicians believe that advances in mechanical and surgical techniques have made rtPA a thing of the past. Others think there is still insufficient evidence to support alternatives as the standard of care.

Here at the European Respiratory Society (ERS) 2024 Congress, respiratory specialists presented contrasting viewpoints and the latest evidence on each side of the issue to provide a comprehensive framework for navigating the complex decision-making process required for effective treatment.

“High-risk PE is a mechanical problem and thus needs a mechanical solution,” said Parth M. Rali, MD, an associate professor in thoracic medicine and surgery at the Lewis Katz School of Medicine at Temple University, Philadelphia.

“The marketing on some of the mechanical techniques is very impressive,” said Olivier Sanchez, MD, a pulmonologist in the Department of Pneumology and Intensive Care at the Georges Pompidou European Hospital in France. “But what is the evidence of such treatment in the setting of pulmonary embolism?”
 

The Case Against rtPA as the Standard of Care

High-risk PE typically involves hemodynamically unstable patients presenting with conditions such as low blood pressure, cardiac arrest, or the need for mechanical circulatory support. There is a spectrum of severity within high-risk PE, making it a complex condition to manage, especially since many patients have comorbidities like anemia or active cancer, complicating treatment. “It’s a very dynamic and fluid condition, and we can’t take for granted that rtPA is a standard of care,” Dr. Rali said.

Alternative treatments such as catheter-directed therapies, extracorporeal membrane oxygenation (ECMO), and surgical embolectomy are emerging as promising options, especially for patients who do not respond to or cannot receive rtPA. Mechanical treatments offer benefits in reducing clot burden and stabilizing patients, but they come with their own challenges.

ECMO can stabilize patients who are in shock or cardiac arrest, buying time for the clot to resolve or for further interventions like surgery or catheter-based treatments, said Dr. Rali. However, it is an invasive procedure requiring cannulation of large blood vessels, often involving significant resources and expertise.

Catheter-directed thrombolysis is a minimally invasive technique where a catheter is inserted directly into the pulmonary artery to deliver thrombolytic drugs at lower doses. This method allows for more targeted treatment of the clot, reducing the risk for systemic bleeding that comes with higher doses of thrombolytic agents used in systemic therapy, Dr. Rali explained. 

Dr. Rali reported results from the FLAME study, which investigated the effectiveness of FlowTriever mechanical thrombectomy compared with conventional therapies for high-risk PE. This prospective, multicenter observational study enrolled 53 patients in the FlowTriever arm and 61 in the context arm, which included patients treated with systemic thrombolysis or anticoagulation. The primary endpoint, a composite of adverse in-hospital outcomes, was reached in 17% of FlowTriever patients, significantly lower than the 32% performance goal and the 63.9% rate in the context arm. In-hospital mortality was dramatically lower in the FlowTriever arm (1.9%) compared to the context arm (29.5%). 

When catheter-based treatment fails, surgical pulmonary embolectomy is a last-resort option. “Only a minority of the high-risk PE [patients] would qualify for rtPA without harmful side effects,” Dr. Rali concluded. “So think wise before you pull your trigger.” 
 

rtPA Not a Matter of the Past

In high-risk PE, the therapeutic priority is rapid hemodynamic stabilization and restoration of pulmonary blood flow to prevent cardiovascular collapse. Systemic thrombolysis acts quickly, reducing pulmonary vascular resistance and obstruction within hours, said Dr. Sanchez. 

Presenting at the ERS Congress, he reported numerous studies, including 15 randomized controlled trials that demonstrated its effectiveness in high-risk PE. The PEITHO trial, in particular, demonstrated the ability of systemic thrombolysis to reduce all-cause mortality and hemodynamic collapse within 7 days. 

However, this benefit comes at the cost of increased bleeding risk, including a 10% rate of major bleeding and a 2% risk for intracranial hemorrhage. “These data come from old studies using invasive diagnostic procedures, and with current diagnostic procedures, the rate of bleeding is probably lower,” Dr. Sanchez said. The risk of bleeding is also related to the type of thrombolytic agent, with tenecteplase being strongly associated with a higher risk of bleeding, while alteplase shows no increase in the risk of major bleeding, he added. New strategies like reduced-dose thrombolysis offer comparable efficacy and improved safety, as demonstrated in ongoing trials like  PEITHO-3, which aim to optimize the balance between efficacy and bleeding risk. Dr. Sanchez is the lead investigator of the PEITHO-3 study.

While rtPA might not be optimal for all patients, Dr. Sanchez thinks there is not enough evidence to replace it as a first-line treatment.

Existing studies on catheter-directed therapies often focus on surrogate endpoints, such as right-to-left ventricular ratio changes, rather than clinical outcomes like mortality, he said. Retrospective data suggest that catheter-directed therapies may reduce in-hospital mortality compared with systemic therapies, but they also increase the risk of intracranial bleeding, post-procedure complications, and device-related events.

Sanchez mentioned the same FLAME study described by Dr. Rali, which reported a 23% rate of device-related complications and 11% major bleeding in patients treated with catheter-directed therapies. 

“Systemic thrombolysis remains the first treatment of choice,” Dr. Sanchez concluded. “The use of catheter-directed treatment should be discussed as an alternative in case of contraindications.”
 

The Debate Continues

Numerous ongoing clinical studies, such as the FLARE trial, will address gaps in evidence and refine treatment protocols, potentially reshaping the standard of care in high-risk PE in the near future by providing new data on the efficacy and safety of existing and emerging therapies.

“The coming data will make it clearer what the best option is,” said Thamer Al Khouzaie, MD, a pulmonary medicine consultant at Johns Hopkins Aramco Healthcare in Dhahran, Saudi Arabia. For now, he said, systemic thrombolysis remains the best option for most patients because it is widely available, easily administered with intravenous infusion, and at a limited cost. Catheter-directed treatment and surgical options are only available in specialized centers, require expertise and training, and are also very expensive.

Dr. Rali, Dr. Sanchez, and Dr. Khouzaie report no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

First-line treatment with ivonescimab led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared with pembrolizumab (Keytruda), in patients with programmed death ligand 1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC), according to recent findings from the HARMONi-2 trial. 

“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China, 

The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC. 

Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial. 

Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.

Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater). 

Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001). 

The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55). 

The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study. 

Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%). 

Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.

The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab. 

In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).

Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said. 

Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.

He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”

Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025. 

HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more). 

Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.

A version of this article first appeared on Medscape.com.

First-line treatment with ivonescimab led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared with pembrolizumab (Keytruda), in patients with programmed death ligand 1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC), according to recent findings from the HARMONi-2 trial. 

“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China, 

The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC. 

Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial. 

Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.

Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater). 

Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001). 

The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55). 

The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study. 

Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%). 

Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.

The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab. 

In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).

Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said. 

Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.

He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”

Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025. 

HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more). 

Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.

A version of this article first appeared on Medscape.com.

First-line treatment with ivonescimab led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared with pembrolizumab (Keytruda), in patients with programmed death ligand 1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC), according to recent findings from the HARMONi-2 trial. 

“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China, 

The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC. 

Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial. 

Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.

Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater). 

Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001). 

The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55). 

The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study. 

Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%). 

Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.

The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab. 

In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).

Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said. 

Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.

He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”

Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025. 

HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more). 

Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.

A version of this article first appeared on Medscape.com.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

A version of this article first appeared on Medscape.com.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

A version of this article first appeared on Medscape.com.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

A version of this article first appeared on Medscape.com.

Click to view more from Pulmonology Data Trends 2024. 

Click to view more from Pulmonology Data Trends 2024. 

Click to view more from Pulmonology Data Trends 2024. 

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

In patients with pulmonary oligometastases from colorectal cancer (CRC), both stereotactic body radiotherapy (SBRT) and surgery led to similar overall survival rates at 5 years. However, those who received surgery had significantly better progression-free and disease-free survival rates, as well as a longer time to intrathoracic progression.
 

METHODOLOGY:

• SBRT has been shown to provide effective local control and improve short-term survival for patients with pulmonary oligometastases from CRC and has become an alternative for these patients who are ineligible or reluctant to undergo surgery. It’s unclear, however, whether SBRT should be prioritized over surgery in patients with CRC pulmonary metastases, largely because of a lack of prospective data.
• In the current analysis, researchers compared outcomes among 335 patients (median age, 61 years) with lung metastases from CRC who underwent surgery or SBRT, using data from the Peking University Cancer Hospital and Institute between March 2011 and September 2022.
• A total of 251 patients were included in the final analysis after propensity score matching, 173 (68.9%) underwent surgery and 78 (31.1%) received SBRT. The median follow-up was 61.6 months in the surgery group and 54.4 months in the SBRT group.
• The study outcomes were freedom from intrathoracic progression, progression-free survival, and overall survival.

TAKEAWAY:

• At 5 years, rates of freedom from intrathoracic progression were more than twofold higher in the surgery group than in the SBRT group (53% vs 23.4%; hazard ratio [HR], 0.46; P < .001). Progression-free survival rates were also more than twofold higher in the surgery group vs the SBRT group (43.8% vs 18.5%; HR, 0.47; P < .001), respectively. In the SBRT group, a higher percentage of patients had a disease-free interval of less than 12 months compared with the surgery group, with rates of 48.7% and 32.9%, respectively (P = 0.025). 
• Overall survival, however, was not significantly different between the two groups at 5 years (72.5% in the surgery group vs 63.7% in the SBRT group; P = .260). The number of pulmonary metastases (HR, 1.87; 95% CI, 1.11-3.14, P = .019 and tumor size (HR, 1.03; 95% CI, 1.00-1.05, P = .023) were significant prognostic factors for overall survival.
• Local recurrence was more prevalent after SBRT (33.3%) than surgery (16.9%), while new intrathoracic tumors occurred more frequently after surgery than SBRT (71.8% vs 43.1%). Repeated local treatments were common among patients with intrathoracic progression, which might have contributed to favorable survival outcomes in both groups.
• Both treatments were well-tolerated with no treatment-related mortality or grade ≥ 3 toxicities. In the surgery group, 14 patients experienced complications, including atrial fibrillation (n = 4) and prolonged air leaks (n = 7). In the SBRT group, radiation pneumonitis was the most common adverse event (n = 21).

IN PRACTICE:

SBRT yielded overall survival benefits similar to surgery despite a “higher likelihood of prior extrapulmonary metastases, a shorter disease-free interval, and a greater number of metastatic lesions,” the authors wrote. Still, SBRT should be regarded as an “effective alternative in cases in which surgical intervention is either unviable or declined by the patient,” the authors concluded.
 

SOURCE:

The study was co-led by Yaqi Wang and Xin Dong, Peking University Cancer Hospital & Institute, Beijing, China, and was published online in the International Journal of Radiation Oncology, Biology, Physics.
 

LIMITATIONS:

This single-center retrospective study had an inherent selection bias. The lack of balanced sample sizes of the surgery and SBRT groups might have affected the robustness of the statistical analyses. Detailed data on adverse events were not available.
 

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Beijing Natural Science Foundation, and Beijing Municipal Administration of Hospital’s Ascent Plan. The authors did not declare any conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved lazertinib (Lazcluze) in combination with amivantamab-vmjw (Rybrevant) for upfront treatment of adults with locally advanced or metastatic non–small-cell lung cancer (NSCLC) who have EGFR exon 19 deletions or exon 21 L858R substitution mutations as detected by an FDA-approved test. 

This marks the first approval for lazertinib. Amivantamab was initially approved by the FDA in 2021 and carries a few indications for locally advanced or metastatic NSCLC. Both drugs are manufactured by Janssen Biotech Inc.

“Patients will now have the option of a potential new first-line standard of care with significant clinical benefits over osimertinib,” study investigator Alexander Spira, MD, PhD, director, Virginia Cancer Specialists Research Institute, said in a news release from Johnson & Johnson . 

Lazertinib is an oral, highly selective, third-generation EGFR tyrosine kinase inhibitor that can penetrate the brain and amivantamab is a bispecific antibody targeting EGFR and MET.

The approval was based on results from the phase 3 MARIPOSA trial, which showed that the combination reduced the risk of disease progression or death by 30% compared with osimertinib.

The MARIPOSA trial randomly allocated 1074 patients with exon 19 deletion or exon 21 L858R substitution mutation-positive locally advanced or metastatic NSCLC and no prior systemic therapy for advanced disease to amivantamab plus lazertinib, osimertinib alone, or lazertinib alone.

Lazertinib plus amivantamab demonstrated a statistically significant improvement in progression-free survival compared with osimertinib (hazard ratio, 0.70; P < .001). Median progression-free survival was 23.7 months with the combination vs 16.6 months osimertinib alone and 18.5 months with lazertinib alone.

The median duration of response was 9 months longer with the combination compared with osimertinib (25.8 months vs 16.7 months).

The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reactions (amivantamab), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. 

“A serious safety signal of venous thromboembolic events was observed with lazertinib in combination with amivantamab and prophylactic anticoagulation should be administered for the first four months of therapy,” the FDA noted in a statement announcing the approval.

Results from MARIPOSA were first presented at the European Society for Medical Oncology 2023 Congress and published in The New England Journal of Medicine in June. Longer-term follow-up data from MARIPOSA will be presented at the International Association for the Study of Lung Cancer 2024 World Congress on Lung Cancer in September.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved lazertinib (Lazcluze) in combination with amivantamab-vmjw (Rybrevant) for upfront treatment of adults with locally advanced or metastatic non–small-cell lung cancer (NSCLC) who have EGFR exon 19 deletions or exon 21 L858R substitution mutations as detected by an FDA-approved test. 

This marks the first approval for lazertinib. Amivantamab was initially approved by the FDA in 2021 and carries a few indications for locally advanced or metastatic NSCLC. Both drugs are manufactured by Janssen Biotech Inc.

“Patients will now have the option of a potential new first-line standard of care with significant clinical benefits over osimertinib,” study investigator Alexander Spira, MD, PhD, director, Virginia Cancer Specialists Research Institute, said in a news release from Johnson & Johnson . 

Lazertinib is an oral, highly selective, third-generation EGFR tyrosine kinase inhibitor that can penetrate the brain and amivantamab is a bispecific antibody targeting EGFR and MET.

The approval was based on results from the phase 3 MARIPOSA trial, which showed that the combination reduced the risk of disease progression or death by 30% compared with osimertinib.

The MARIPOSA trial randomly allocated 1074 patients with exon 19 deletion or exon 21 L858R substitution mutation-positive locally advanced or metastatic NSCLC and no prior systemic therapy for advanced disease to amivantamab plus lazertinib, osimertinib alone, or lazertinib alone.

Lazertinib plus amivantamab demonstrated a statistically significant improvement in progression-free survival compared with osimertinib (hazard ratio, 0.70; P < .001). Median progression-free survival was 23.7 months with the combination vs 16.6 months osimertinib alone and 18.5 months with lazertinib alone.

The median duration of response was 9 months longer with the combination compared with osimertinib (25.8 months vs 16.7 months).

The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reactions (amivantamab), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. 

“A serious safety signal of venous thromboembolic events was observed with lazertinib in combination with amivantamab and prophylactic anticoagulation should be administered for the first four months of therapy,” the FDA noted in a statement announcing the approval.

Results from MARIPOSA were first presented at the European Society for Medical Oncology 2023 Congress and published in The New England Journal of Medicine in June. Longer-term follow-up data from MARIPOSA will be presented at the International Association for the Study of Lung Cancer 2024 World Congress on Lung Cancer in September.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved lazertinib (Lazcluze) in combination with amivantamab-vmjw (Rybrevant) for upfront treatment of adults with locally advanced or metastatic non–small-cell lung cancer (NSCLC) who have EGFR exon 19 deletions or exon 21 L858R substitution mutations as detected by an FDA-approved test. 

This marks the first approval for lazertinib. Amivantamab was initially approved by the FDA in 2021 and carries a few indications for locally advanced or metastatic NSCLC. Both drugs are manufactured by Janssen Biotech Inc.

“Patients will now have the option of a potential new first-line standard of care with significant clinical benefits over osimertinib,” study investigator Alexander Spira, MD, PhD, director, Virginia Cancer Specialists Research Institute, said in a news release from Johnson & Johnson . 

Lazertinib is an oral, highly selective, third-generation EGFR tyrosine kinase inhibitor that can penetrate the brain and amivantamab is a bispecific antibody targeting EGFR and MET.

The approval was based on results from the phase 3 MARIPOSA trial, which showed that the combination reduced the risk of disease progression or death by 30% compared with osimertinib.

The MARIPOSA trial randomly allocated 1074 patients with exon 19 deletion or exon 21 L858R substitution mutation-positive locally advanced or metastatic NSCLC and no prior systemic therapy for advanced disease to amivantamab plus lazertinib, osimertinib alone, or lazertinib alone.

Lazertinib plus amivantamab demonstrated a statistically significant improvement in progression-free survival compared with osimertinib (hazard ratio, 0.70; P < .001). Median progression-free survival was 23.7 months with the combination vs 16.6 months osimertinib alone and 18.5 months with lazertinib alone.

The median duration of response was 9 months longer with the combination compared with osimertinib (25.8 months vs 16.7 months).

The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reactions (amivantamab), musculoskeletal pain, edema, stomatitis, venous thromboembolism, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. 

“A serious safety signal of venous thromboembolic events was observed with lazertinib in combination with amivantamab and prophylactic anticoagulation should be administered for the first four months of therapy,” the FDA noted in a statement announcing the approval.

Results from MARIPOSA were first presented at the European Society for Medical Oncology 2023 Congress and published in The New England Journal of Medicine in June. Longer-term follow-up data from MARIPOSA will be presented at the International Association for the Study of Lung Cancer 2024 World Congress on Lung Cancer in September.
 

A version of this article appeared on Medscape.com.