Susan London

A large uptick in DNA methylation occurs at the time of progression in patients with Philadelphia chromosome–positive chronic myeloid leukemia (CML), according to results from a comparative cohort study. The observation raises the possibility of new therapeutic targets for advanced disease.

Researchers led by Gerwin Heller, PhD, of the Medical University of Vienna’s Clinical Division of Oncology and Comprehensive Cancer Center, Austria, collected peripheral blood mononuclear cells from 23 patients with CML during various disease phases (chronic phase in 17, acute phase in 5, and blast crisis in 9) and from 5 healthy controls.

©Zffoto/Thinkstock

They isolated DNA and analyzed it with a novel next-generation sequencing approach, known as reduced representation bisulfite sequencing, to identify the presence and extent of methylation.

Compared with the healthy controls, patients in chronic-phase CML had 666 differentially methylated CpG (cytosine-phosphate-guanine) sites, whereas those in blast crisis had 6,912 differentially methylated CpG sites (Leukemia. 2016;30:1861-8). Some 44% of the former but 88% of the latter affected CpG sites showed increased methylation.

Among patients with chronic-phase CML who experienced progression to the accelerated phase or blast crisis, analyses identified between 344 and 897 genes that were methylated at the time of progression but had not been at the time of diagnosis.

RNA sequencing determined that many of these newly methylated genes showed downregulated expression in the samples collected during blast crisis, compared with those collected during chronic phase disease. These genes included some tumor suppressor genes (EPB41L3, PRDX2), regulators of cell proliferation (BCL11B, NDRG2, PID1), and regulators of drug metabolism (CYP1B1), among others.

Treatment of CML cells with the epigenetically active drugs azacitidine (a DNA methyltransferase inhibitor) and trichostatin A (a histone deacetylase inhibitor) led to re-expression of the CYP1B1 gene.

“Together, our results demonstrate that CpG site methylation clearly increases during CML progression and that it may provide a useful basis for revealing new targets of therapy in advanced CML,” wrote Dr. Heller and colleagues, who disclosed that one of them has received research grants from Novartis and Ariad.

“Our findings suggest that investigating the efficacy of [DNA methyltransferase inhibitors] in patients with progressed CML should be considered,” they said.

[email protected]

A large uptick in DNA methylation occurs at the time of progression in patients with Philadelphia chromosome–positive chronic myeloid leukemia (CML), according to results from a comparative cohort study. The observation raises the possibility of new therapeutic targets for advanced disease.

Researchers led by Gerwin Heller, PhD, of the Medical University of Vienna’s Clinical Division of Oncology and Comprehensive Cancer Center, Austria, collected peripheral blood mononuclear cells from 23 patients with CML during various disease phases (chronic phase in 17, acute phase in 5, and blast crisis in 9) and from 5 healthy controls.

©Zffoto/Thinkstock

They isolated DNA and analyzed it with a novel next-generation sequencing approach, known as reduced representation bisulfite sequencing, to identify the presence and extent of methylation.

Compared with the healthy controls, patients in chronic-phase CML had 666 differentially methylated CpG (cytosine-phosphate-guanine) sites, whereas those in blast crisis had 6,912 differentially methylated CpG sites (Leukemia. 2016;30:1861-8). Some 44% of the former but 88% of the latter affected CpG sites showed increased methylation.

Among patients with chronic-phase CML who experienced progression to the accelerated phase or blast crisis, analyses identified between 344 and 897 genes that were methylated at the time of progression but had not been at the time of diagnosis.

RNA sequencing determined that many of these newly methylated genes showed downregulated expression in the samples collected during blast crisis, compared with those collected during chronic phase disease. These genes included some tumor suppressor genes (EPB41L3, PRDX2), regulators of cell proliferation (BCL11B, NDRG2, PID1), and regulators of drug metabolism (CYP1B1), among others.

Treatment of CML cells with the epigenetically active drugs azacitidine (a DNA methyltransferase inhibitor) and trichostatin A (a histone deacetylase inhibitor) led to re-expression of the CYP1B1 gene.

“Together, our results demonstrate that CpG site methylation clearly increases during CML progression and that it may provide a useful basis for revealing new targets of therapy in advanced CML,” wrote Dr. Heller and colleagues, who disclosed that one of them has received research grants from Novartis and Ariad.

“Our findings suggest that investigating the efficacy of [DNA methyltransferase inhibitors] in patients with progressed CML should be considered,” they said.

[email protected]

A large uptick in DNA methylation occurs at the time of progression in patients with Philadelphia chromosome–positive chronic myeloid leukemia (CML), according to results from a comparative cohort study. The observation raises the possibility of new therapeutic targets for advanced disease.

Researchers led by Gerwin Heller, PhD, of the Medical University of Vienna’s Clinical Division of Oncology and Comprehensive Cancer Center, Austria, collected peripheral blood mononuclear cells from 23 patients with CML during various disease phases (chronic phase in 17, acute phase in 5, and blast crisis in 9) and from 5 healthy controls.

©Zffoto/Thinkstock

They isolated DNA and analyzed it with a novel next-generation sequencing approach, known as reduced representation bisulfite sequencing, to identify the presence and extent of methylation.

Compared with the healthy controls, patients in chronic-phase CML had 666 differentially methylated CpG (cytosine-phosphate-guanine) sites, whereas those in blast crisis had 6,912 differentially methylated CpG sites (Leukemia. 2016;30:1861-8). Some 44% of the former but 88% of the latter affected CpG sites showed increased methylation.

Among patients with chronic-phase CML who experienced progression to the accelerated phase or blast crisis, analyses identified between 344 and 897 genes that were methylated at the time of progression but had not been at the time of diagnosis.

RNA sequencing determined that many of these newly methylated genes showed downregulated expression in the samples collected during blast crisis, compared with those collected during chronic phase disease. These genes included some tumor suppressor genes (EPB41L3, PRDX2), regulators of cell proliferation (BCL11B, NDRG2, PID1), and regulators of drug metabolism (CYP1B1), among others.

Treatment of CML cells with the epigenetically active drugs azacitidine (a DNA methyltransferase inhibitor) and trichostatin A (a histone deacetylase inhibitor) led to re-expression of the CYP1B1 gene.

“Together, our results demonstrate that CpG site methylation clearly increases during CML progression and that it may provide a useful basis for revealing new targets of therapy in advanced CML,” wrote Dr. Heller and colleagues, who disclosed that one of them has received research grants from Novartis and Ariad.

“Our findings suggest that investigating the efficacy of [DNA methyltransferase inhibitors] in patients with progressed CML should be considered,” they said.

[email protected]

The timing of endoscopy may make the difference between life and death in sicker patients with peptic ulcer bleeding, according to an analysis of more than 12,000 patients treated in Denmark.

Patients who were hemodynamically stable but had a higher level of comorbidity were about half as likely to die during their hospital stay if they underwent endoscopy within 12-36 hours of presentation as compared with sooner or later, results showed (Gastrointest Endosc. 2016 Sep 10. doi: 10.1016/j.gie.2016.08.049). And hemodynamically unstable patients had a roughly one-fourth reduction in the odds of death if they underwent the procedure within 6-24 hours.
[[{"attributes":{},"fields":{}}]]

“Although caution should be applied when interpreting these data, the current recommendation of endoscopy within 0-24 hours may not be optimal for all patients,” wrote the investigators, who were led by Stig B. Laursen, PhD, department of medical gastroenterology, Odense (Denmark) University Hospital.

“Our data may suggest that in patients with major comorbidities, the first few hours of hospital admission might be best used for optimising treatment of comorbidities, which may include correction of severe anaemia, reversal of anticoagulants, and investigation for possible infection that requires rapid treatment with antibiotics,” they elaborate. “Likewise, in patients with hemodynamic instability, endoscopy between 6 and 24 hours from time of admission to hospital allows time for optimal resuscitation and initiating treatment of comorbid diseases before endoscopy. However, these data should not lead to delayed endoscopy in patients with severe hemodynamic instability not responding to intensive resuscitation.”

The investigators analyzed data from 12,601 consecutive patients with peptic ulcer bleeding admitted between January 2005 and September 2013 to Danish hospitals, where all patients had access to 24-hour endoscopy. Time to endoscopy was assessed from hospital admission, defined as arrival in the emergency department, or from symptom onset in patients who developed bleeding when already hospitalized.

For analyses, the patients were stratified by hemodynamic status (a marker for the severity of bleeding) and by American Society of Anesthesiologists score (a marker for the extent of comorbidity).
 

[[{"attributes":{},"fields":{}}]]

The timing of endoscopy did not significantly influence in-hospital or 30-day mortality in hemodynamically stable patients with an American Society of Anesthesiologists score of 1-2 as a whole, Dr. Laursen and his colleagues report. Subgroup analyses suggested a reduction of in-hospital mortality when it was done between 0 and 24 hours in those patients whose bleeding began outside the hospital (adjusted odds ratio, 0.48).

In contrast, analyses revealed a U-shaped association between timing and mortality for hemodynamically stable patients with an American Society of Anesthesiologists score of 3-5. For this group, in-hospital mortality was significantly lower when endoscopy was performed within 12-36 hours as compared with times outside this window (adjusted OR, 0.48), and 30-day mortality tended to be lower as well.

Similarly, timing appeared to influence outcome for hemodynamically unstable patients, having both systolic blood pressure below 100 mm Hg and heart rate above 100 beats/min. For this group, performance of endoscopy within 6-24 hours was associated with significantly lower in-hospital mortality (adjusted OR, 0.73) and also 30-day mortality (adjusted OR, 0.66). Patients’ American Society of Anesthesiologists score did not appear to play a role here.

The study’s findings may have been affected by unmeasured and unknown confounders, acknowledge the investigators, who declared that they have no competing interests related to the research.

“Although a well-powered randomized controlled trial represents the best way to account for these problems, randomizing patients with [peptic ulcer bleeding] to early versus late endoscopy will be very difficult, including from an ethical and methodological point of view,” they note.

[email protected]

The timing of endoscopy may make the difference between life and death in sicker patients with peptic ulcer bleeding, according to an analysis of more than 12,000 patients treated in Denmark.

Patients who were hemodynamically stable but had a higher level of comorbidity were about half as likely to die during their hospital stay if they underwent endoscopy within 12-36 hours of presentation as compared with sooner or later, results showed (Gastrointest Endosc. 2016 Sep 10. doi: 10.1016/j.gie.2016.08.049). And hemodynamically unstable patients had a roughly one-fourth reduction in the odds of death if they underwent the procedure within 6-24 hours.
[[{"attributes":{},"fields":{}}]]

“Although caution should be applied when interpreting these data, the current recommendation of endoscopy within 0-24 hours may not be optimal for all patients,” wrote the investigators, who were led by Stig B. Laursen, PhD, department of medical gastroenterology, Odense (Denmark) University Hospital.

“Our data may suggest that in patients with major comorbidities, the first few hours of hospital admission might be best used for optimising treatment of comorbidities, which may include correction of severe anaemia, reversal of anticoagulants, and investigation for possible infection that requires rapid treatment with antibiotics,” they elaborate. “Likewise, in patients with hemodynamic instability, endoscopy between 6 and 24 hours from time of admission to hospital allows time for optimal resuscitation and initiating treatment of comorbid diseases before endoscopy. However, these data should not lead to delayed endoscopy in patients with severe hemodynamic instability not responding to intensive resuscitation.”

The investigators analyzed data from 12,601 consecutive patients with peptic ulcer bleeding admitted between January 2005 and September 2013 to Danish hospitals, where all patients had access to 24-hour endoscopy. Time to endoscopy was assessed from hospital admission, defined as arrival in the emergency department, or from symptom onset in patients who developed bleeding when already hospitalized.

For analyses, the patients were stratified by hemodynamic status (a marker for the severity of bleeding) and by American Society of Anesthesiologists score (a marker for the extent of comorbidity).
 

[[{"attributes":{},"fields":{}}]]

The timing of endoscopy did not significantly influence in-hospital or 30-day mortality in hemodynamically stable patients with an American Society of Anesthesiologists score of 1-2 as a whole, Dr. Laursen and his colleagues report. Subgroup analyses suggested a reduction of in-hospital mortality when it was done between 0 and 24 hours in those patients whose bleeding began outside the hospital (adjusted odds ratio, 0.48).

In contrast, analyses revealed a U-shaped association between timing and mortality for hemodynamically stable patients with an American Society of Anesthesiologists score of 3-5. For this group, in-hospital mortality was significantly lower when endoscopy was performed within 12-36 hours as compared with times outside this window (adjusted OR, 0.48), and 30-day mortality tended to be lower as well.

Similarly, timing appeared to influence outcome for hemodynamically unstable patients, having both systolic blood pressure below 100 mm Hg and heart rate above 100 beats/min. For this group, performance of endoscopy within 6-24 hours was associated with significantly lower in-hospital mortality (adjusted OR, 0.73) and also 30-day mortality (adjusted OR, 0.66). Patients’ American Society of Anesthesiologists score did not appear to play a role here.

The study’s findings may have been affected by unmeasured and unknown confounders, acknowledge the investigators, who declared that they have no competing interests related to the research.

“Although a well-powered randomized controlled trial represents the best way to account for these problems, randomizing patients with [peptic ulcer bleeding] to early versus late endoscopy will be very difficult, including from an ethical and methodological point of view,” they note.

[email protected]

The timing of endoscopy may make the difference between life and death in sicker patients with peptic ulcer bleeding, according to an analysis of more than 12,000 patients treated in Denmark.

Patients who were hemodynamically stable but had a higher level of comorbidity were about half as likely to die during their hospital stay if they underwent endoscopy within 12-36 hours of presentation as compared with sooner or later, results showed (Gastrointest Endosc. 2016 Sep 10. doi: 10.1016/j.gie.2016.08.049). And hemodynamically unstable patients had a roughly one-fourth reduction in the odds of death if they underwent the procedure within 6-24 hours.
[[{"attributes":{},"fields":{}}]]

“Although caution should be applied when interpreting these data, the current recommendation of endoscopy within 0-24 hours may not be optimal for all patients,” wrote the investigators, who were led by Stig B. Laursen, PhD, department of medical gastroenterology, Odense (Denmark) University Hospital.

“Our data may suggest that in patients with major comorbidities, the first few hours of hospital admission might be best used for optimising treatment of comorbidities, which may include correction of severe anaemia, reversal of anticoagulants, and investigation for possible infection that requires rapid treatment with antibiotics,” they elaborate. “Likewise, in patients with hemodynamic instability, endoscopy between 6 and 24 hours from time of admission to hospital allows time for optimal resuscitation and initiating treatment of comorbid diseases before endoscopy. However, these data should not lead to delayed endoscopy in patients with severe hemodynamic instability not responding to intensive resuscitation.”

The investigators analyzed data from 12,601 consecutive patients with peptic ulcer bleeding admitted between January 2005 and September 2013 to Danish hospitals, where all patients had access to 24-hour endoscopy. Time to endoscopy was assessed from hospital admission, defined as arrival in the emergency department, or from symptom onset in patients who developed bleeding when already hospitalized.

For analyses, the patients were stratified by hemodynamic status (a marker for the severity of bleeding) and by American Society of Anesthesiologists score (a marker for the extent of comorbidity).
 

[[{"attributes":{},"fields":{}}]]

The timing of endoscopy did not significantly influence in-hospital or 30-day mortality in hemodynamically stable patients with an American Society of Anesthesiologists score of 1-2 as a whole, Dr. Laursen and his colleagues report. Subgroup analyses suggested a reduction of in-hospital mortality when it was done between 0 and 24 hours in those patients whose bleeding began outside the hospital (adjusted odds ratio, 0.48).

In contrast, analyses revealed a U-shaped association between timing and mortality for hemodynamically stable patients with an American Society of Anesthesiologists score of 3-5. For this group, in-hospital mortality was significantly lower when endoscopy was performed within 12-36 hours as compared with times outside this window (adjusted OR, 0.48), and 30-day mortality tended to be lower as well.

Similarly, timing appeared to influence outcome for hemodynamically unstable patients, having both systolic blood pressure below 100 mm Hg and heart rate above 100 beats/min. For this group, performance of endoscopy within 6-24 hours was associated with significantly lower in-hospital mortality (adjusted OR, 0.73) and also 30-day mortality (adjusted OR, 0.66). Patients’ American Society of Anesthesiologists score did not appear to play a role here.

The study’s findings may have been affected by unmeasured and unknown confounders, acknowledge the investigators, who declared that they have no competing interests related to the research.

“Although a well-powered randomized controlled trial represents the best way to account for these problems, randomizing patients with [peptic ulcer bleeding] to early versus late endoscopy will be very difficult, including from an ethical and methodological point of view,” they note.

[email protected]

CHICAGO – Mutation of the estrogen receptor 1 (ESR1) gene, one of the mechanisms whereby tumors become resistant to endocrine therapy, may be prognostic but not predictive in women with hormone receptor–positive advanced breast cancer that has progressed on this therapy, two studies showed.

In a cohort of women who had experienced progression on a first-line aromatase inhibitor, those with ESR1 mutations detected in circulating cell-free DNA at the time of progression had a 70% higher risk of progression-free survival events and a 90% higher risk of death thereafter. But the presence of this mutation did not predict benefit from subsequent therapy.

Similarly, in an analysis of women who had experienced progression on prior endocrine therapy and were treated on the randomized PALOMA-3 trial with fulvestrant plus either palbociclib (a cyclin-dependent kinase inhibitor) or placebo, adding the drug reduced the risk of progression-free survival events similarly, by about 50%, regardless of the presence of ESR1 mutations before starting therapy.

Findings in context

These new findings can help guide decisions about which patients should be tested for ESR1 mutations, according to invited discussant Sarat Chandarlapaty, MD, PhD, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York.

“Putting it all together … we see ESR1 mutations arise in the metastatic setting subclonally with prolonged exposure to low-estrogen environments,” he said. “If we are going to do testing, it makes sense to do it in the setting in which there is prior exposure to an aromatase inhibitor in metastatic ER-positive breast cancer.”

The studies’ results also help clarify what the finding of an ESR1 mutation means for patient prognosis and choice of next therapy, Dr. Chandarlapaty said at the annual meeting of the American Society of Clinical Oncology.

“It’s clear from two large studies that ESR1 mutation prognosticates poorer and shorter survival, so just the finding alone may aid as sort of a clinical risk assessment for physicians,” he said. “For the question of prediction, I would say the weight of evidence—even though the clinical studies are small—all the way from biology to clinic is that ESR1-mutant patients are unlikely to benefit from a second-line aromatase inhibitor.”

However, “the question of whether testing should be made available in practice on the basis of this particular clinical decision is more complicated,” Dr. Chandarlapaty said. “For one, is second-line aromatase inhibitor alone a widely used option? Secondly, does the adoption now of palbociclib in the first-line setting change the biology and the nature of resistance at this later line – in other words, are we going to see patients going on to a second-line aromatase inhibitor after they’ve had a prior aromatase inhibitor plus palbociclib?”

Mutations after progression on first-line aromatase inhibitors

In the first study, Florian Clatot, MD, PhD, a medical oncologist at the Centre Henri Becquerel, University of Normandy, Rouen, France, and colleagues retrospectively studied 144 women who had experienced progression on a first-line aromatase inhibitor.

The investigators used digital droplet polymerase chain reaction (PCR) testing to screen for four ESR-1 mutations in circulating cell-free DNA collected before, at the time of, and after the progression.

Overall, 30.6% of women were found to have at least one of these mutations at the time of progression, Dr. Clatot reported. The prevalence was higher the longer women had been on the aromatase inhibitor.

After progression, most women went on to receive chemotherapy or alternative endocrine therapy with either the selective estrogen receptor modulator tamoxifen or the estrogen receptor antagonist fulvestrant (Faslodex). With a median follow-up of 40 months, multivariate analyses showed that the group with ESR1 mutations at progression had higher risks of subsequent progression-free survival events (hazard ratio, 1.7; P = .008) and death (hazard ratio, 1.9; P = .002).

However, the mutations were not predictive: Women having one fared more poorly, whether given chemotherapy or given tamoxifen or fulvestrant.

Kinetic analyses showed that 75% of the ESR1 mutations seen at progression were already detectable in the 3 and even 6 months before that event. “Most of the mutations detected before progression increased while aromatase inhibitor therapy was ongoing,” Dr. Clatot commented. “These results suggest that the preclinical detection of ESR1 circulating mutation may [be of] clinical interest.”

Most women who had mutations at progression saw a decrease in the amount detectable over the subsequent 3 months with therapy, including to the point of not being detectable in about half of cases with a reduction. All of those having an increase in mutational burden had progression on their next therapy, compared with only about 40% of those having a decrease in burden.

“Taken together, these results suggest that the selection pressure provided by aromatase inhibitor exposure is one of the main mechanisms of ESR1 mutation increase,” concluded Dr. Clatot. “ESR1 mutations are a strong and independent marker of poor prognosis but do not have any predictive value with the treatments used in our cohort.”

Mutations after progression on prior endocrine therapy

In the second study, Nicholas C. Turner, MD, PhD, a medical oncologist at the Royal Marsden Hospital and Institute of Cancer Research, London, and colleagues analyzed data from a subset of 395 women from PALOMA-3.

The randomized phase III trial tested fulvestrant combined with palbociclib (Ibrance), an oral inhibitor of cyclin-dependent kinases 4 and 6, or placebo. All of the women enrolled had experienced progression on prior endocrine therapy in the adjuvant, advanced, or metastatic setting.

The investigators looked for 12 ESR1 mutations in circulating tumor DNA from baseline plasma samples using the BEAMing (beads, emulsion, amplification, magnetics) digital PCR technique and droplet digital PCR screening.

Overall, 27% of the women had ESR1 mutations before starting therapy on the trial, Dr. Turner reported. Mutations were seen in those who had received a prior aromatase inhibitor, but not in those who had received only prior tamoxifen. “So it’s quite clear these mutations are not a mechanism of resistance to tamoxifen, suggesting that tamoxifen must have at least some activity against these mutations,” he commented.

In addition, ESR1 mutations were more common in patients who had been sensitive versus not to prior endocrine therapy of any type (30.3% vs. 12.8%) and in patients who had been sensitive versus not specifically to prior aromatase inhibitor therapy (34.6% vs. 11.1%).

Stratified analyses showed that palbociclib was similarly superior to placebo in terms of progression-free survival whether patients were positive for an ESR1 mutation (9.4 vs. 4.1 months; hazard ratio, 0.52; P = .0052) or negative (9.5 vs. 3.8 months; hazard ratio, 0.44; P less than .0001).

“Detection of estrogen receptor mutations was strongly associated with acquired resistance to prior aromatase inhibitors,” Dr. Turner said.

“Palbociclib offered high efficacy regardless of the estrogen receptor mutation status,” he added. “And because in this patient population estrogen receptor mutations are detected frequently, the combination of palbociclib and fulvestrant presents an attractive treatment option for patients who have been previously treated with and progressed on aromatase inhibitors.”

CHICAGO – Mutation of the estrogen receptor 1 (ESR1) gene, one of the mechanisms whereby tumors become resistant to endocrine therapy, may be prognostic but not predictive in women with hormone receptor–positive advanced breast cancer that has progressed on this therapy, two studies showed.

In a cohort of women who had experienced progression on a first-line aromatase inhibitor, those with ESR1 mutations detected in circulating cell-free DNA at the time of progression had a 70% higher risk of progression-free survival events and a 90% higher risk of death thereafter. But the presence of this mutation did not predict benefit from subsequent therapy.

Similarly, in an analysis of women who had experienced progression on prior endocrine therapy and were treated on the randomized PALOMA-3 trial with fulvestrant plus either palbociclib (a cyclin-dependent kinase inhibitor) or placebo, adding the drug reduced the risk of progression-free survival events similarly, by about 50%, regardless of the presence of ESR1 mutations before starting therapy.

Findings in context

These new findings can help guide decisions about which patients should be tested for ESR1 mutations, according to invited discussant Sarat Chandarlapaty, MD, PhD, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York.

“Putting it all together … we see ESR1 mutations arise in the metastatic setting subclonally with prolonged exposure to low-estrogen environments,” he said. “If we are going to do testing, it makes sense to do it in the setting in which there is prior exposure to an aromatase inhibitor in metastatic ER-positive breast cancer.”

The studies’ results also help clarify what the finding of an ESR1 mutation means for patient prognosis and choice of next therapy, Dr. Chandarlapaty said at the annual meeting of the American Society of Clinical Oncology.

“It’s clear from two large studies that ESR1 mutation prognosticates poorer and shorter survival, so just the finding alone may aid as sort of a clinical risk assessment for physicians,” he said. “For the question of prediction, I would say the weight of evidence—even though the clinical studies are small—all the way from biology to clinic is that ESR1-mutant patients are unlikely to benefit from a second-line aromatase inhibitor.”

However, “the question of whether testing should be made available in practice on the basis of this particular clinical decision is more complicated,” Dr. Chandarlapaty said. “For one, is second-line aromatase inhibitor alone a widely used option? Secondly, does the adoption now of palbociclib in the first-line setting change the biology and the nature of resistance at this later line – in other words, are we going to see patients going on to a second-line aromatase inhibitor after they’ve had a prior aromatase inhibitor plus palbociclib?”

Mutations after progression on first-line aromatase inhibitors

In the first study, Florian Clatot, MD, PhD, a medical oncologist at the Centre Henri Becquerel, University of Normandy, Rouen, France, and colleagues retrospectively studied 144 women who had experienced progression on a first-line aromatase inhibitor.

The investigators used digital droplet polymerase chain reaction (PCR) testing to screen for four ESR-1 mutations in circulating cell-free DNA collected before, at the time of, and after the progression.

Overall, 30.6% of women were found to have at least one of these mutations at the time of progression, Dr. Clatot reported. The prevalence was higher the longer women had been on the aromatase inhibitor.

After progression, most women went on to receive chemotherapy or alternative endocrine therapy with either the selective estrogen receptor modulator tamoxifen or the estrogen receptor antagonist fulvestrant (Faslodex). With a median follow-up of 40 months, multivariate analyses showed that the group with ESR1 mutations at progression had higher risks of subsequent progression-free survival events (hazard ratio, 1.7; P = .008) and death (hazard ratio, 1.9; P = .002).

However, the mutations were not predictive: Women having one fared more poorly, whether given chemotherapy or given tamoxifen or fulvestrant.

Kinetic analyses showed that 75% of the ESR1 mutations seen at progression were already detectable in the 3 and even 6 months before that event. “Most of the mutations detected before progression increased while aromatase inhibitor therapy was ongoing,” Dr. Clatot commented. “These results suggest that the preclinical detection of ESR1 circulating mutation may [be of] clinical interest.”

Most women who had mutations at progression saw a decrease in the amount detectable over the subsequent 3 months with therapy, including to the point of not being detectable in about half of cases with a reduction. All of those having an increase in mutational burden had progression on their next therapy, compared with only about 40% of those having a decrease in burden.

“Taken together, these results suggest that the selection pressure provided by aromatase inhibitor exposure is one of the main mechanisms of ESR1 mutation increase,” concluded Dr. Clatot. “ESR1 mutations are a strong and independent marker of poor prognosis but do not have any predictive value with the treatments used in our cohort.”

Mutations after progression on prior endocrine therapy

In the second study, Nicholas C. Turner, MD, PhD, a medical oncologist at the Royal Marsden Hospital and Institute of Cancer Research, London, and colleagues analyzed data from a subset of 395 women from PALOMA-3.

The randomized phase III trial tested fulvestrant combined with palbociclib (Ibrance), an oral inhibitor of cyclin-dependent kinases 4 and 6, or placebo. All of the women enrolled had experienced progression on prior endocrine therapy in the adjuvant, advanced, or metastatic setting.

The investigators looked for 12 ESR1 mutations in circulating tumor DNA from baseline plasma samples using the BEAMing (beads, emulsion, amplification, magnetics) digital PCR technique and droplet digital PCR screening.

Overall, 27% of the women had ESR1 mutations before starting therapy on the trial, Dr. Turner reported. Mutations were seen in those who had received a prior aromatase inhibitor, but not in those who had received only prior tamoxifen. “So it’s quite clear these mutations are not a mechanism of resistance to tamoxifen, suggesting that tamoxifen must have at least some activity against these mutations,” he commented.

In addition, ESR1 mutations were more common in patients who had been sensitive versus not to prior endocrine therapy of any type (30.3% vs. 12.8%) and in patients who had been sensitive versus not specifically to prior aromatase inhibitor therapy (34.6% vs. 11.1%).

Stratified analyses showed that palbociclib was similarly superior to placebo in terms of progression-free survival whether patients were positive for an ESR1 mutation (9.4 vs. 4.1 months; hazard ratio, 0.52; P = .0052) or negative (9.5 vs. 3.8 months; hazard ratio, 0.44; P less than .0001).

“Detection of estrogen receptor mutations was strongly associated with acquired resistance to prior aromatase inhibitors,” Dr. Turner said.

“Palbociclib offered high efficacy regardless of the estrogen receptor mutation status,” he added. “And because in this patient population estrogen receptor mutations are detected frequently, the combination of palbociclib and fulvestrant presents an attractive treatment option for patients who have been previously treated with and progressed on aromatase inhibitors.”

CHICAGO – Mutation of the estrogen receptor 1 (ESR1) gene, one of the mechanisms whereby tumors become resistant to endocrine therapy, may be prognostic but not predictive in women with hormone receptor–positive advanced breast cancer that has progressed on this therapy, two studies showed.

In a cohort of women who had experienced progression on a first-line aromatase inhibitor, those with ESR1 mutations detected in circulating cell-free DNA at the time of progression had a 70% higher risk of progression-free survival events and a 90% higher risk of death thereafter. But the presence of this mutation did not predict benefit from subsequent therapy.

Similarly, in an analysis of women who had experienced progression on prior endocrine therapy and were treated on the randomized PALOMA-3 trial with fulvestrant plus either palbociclib (a cyclin-dependent kinase inhibitor) or placebo, adding the drug reduced the risk of progression-free survival events similarly, by about 50%, regardless of the presence of ESR1 mutations before starting therapy.

Findings in context

These new findings can help guide decisions about which patients should be tested for ESR1 mutations, according to invited discussant Sarat Chandarlapaty, MD, PhD, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York.

“Putting it all together … we see ESR1 mutations arise in the metastatic setting subclonally with prolonged exposure to low-estrogen environments,” he said. “If we are going to do testing, it makes sense to do it in the setting in which there is prior exposure to an aromatase inhibitor in metastatic ER-positive breast cancer.”

The studies’ results also help clarify what the finding of an ESR1 mutation means for patient prognosis and choice of next therapy, Dr. Chandarlapaty said at the annual meeting of the American Society of Clinical Oncology.

“It’s clear from two large studies that ESR1 mutation prognosticates poorer and shorter survival, so just the finding alone may aid as sort of a clinical risk assessment for physicians,” he said. “For the question of prediction, I would say the weight of evidence—even though the clinical studies are small—all the way from biology to clinic is that ESR1-mutant patients are unlikely to benefit from a second-line aromatase inhibitor.”

However, “the question of whether testing should be made available in practice on the basis of this particular clinical decision is more complicated,” Dr. Chandarlapaty said. “For one, is second-line aromatase inhibitor alone a widely used option? Secondly, does the adoption now of palbociclib in the first-line setting change the biology and the nature of resistance at this later line – in other words, are we going to see patients going on to a second-line aromatase inhibitor after they’ve had a prior aromatase inhibitor plus palbociclib?”

Mutations after progression on first-line aromatase inhibitors

In the first study, Florian Clatot, MD, PhD, a medical oncologist at the Centre Henri Becquerel, University of Normandy, Rouen, France, and colleagues retrospectively studied 144 women who had experienced progression on a first-line aromatase inhibitor.

The investigators used digital droplet polymerase chain reaction (PCR) testing to screen for four ESR-1 mutations in circulating cell-free DNA collected before, at the time of, and after the progression.

Overall, 30.6% of women were found to have at least one of these mutations at the time of progression, Dr. Clatot reported. The prevalence was higher the longer women had been on the aromatase inhibitor.

After progression, most women went on to receive chemotherapy or alternative endocrine therapy with either the selective estrogen receptor modulator tamoxifen or the estrogen receptor antagonist fulvestrant (Faslodex). With a median follow-up of 40 months, multivariate analyses showed that the group with ESR1 mutations at progression had higher risks of subsequent progression-free survival events (hazard ratio, 1.7; P = .008) and death (hazard ratio, 1.9; P = .002).

However, the mutations were not predictive: Women having one fared more poorly, whether given chemotherapy or given tamoxifen or fulvestrant.

Kinetic analyses showed that 75% of the ESR1 mutations seen at progression were already detectable in the 3 and even 6 months before that event. “Most of the mutations detected before progression increased while aromatase inhibitor therapy was ongoing,” Dr. Clatot commented. “These results suggest that the preclinical detection of ESR1 circulating mutation may [be of] clinical interest.”

Most women who had mutations at progression saw a decrease in the amount detectable over the subsequent 3 months with therapy, including to the point of not being detectable in about half of cases with a reduction. All of those having an increase in mutational burden had progression on their next therapy, compared with only about 40% of those having a decrease in burden.

“Taken together, these results suggest that the selection pressure provided by aromatase inhibitor exposure is one of the main mechanisms of ESR1 mutation increase,” concluded Dr. Clatot. “ESR1 mutations are a strong and independent marker of poor prognosis but do not have any predictive value with the treatments used in our cohort.”

Mutations after progression on prior endocrine therapy

In the second study, Nicholas C. Turner, MD, PhD, a medical oncologist at the Royal Marsden Hospital and Institute of Cancer Research, London, and colleagues analyzed data from a subset of 395 women from PALOMA-3.

The randomized phase III trial tested fulvestrant combined with palbociclib (Ibrance), an oral inhibitor of cyclin-dependent kinases 4 and 6, or placebo. All of the women enrolled had experienced progression on prior endocrine therapy in the adjuvant, advanced, or metastatic setting.

The investigators looked for 12 ESR1 mutations in circulating tumor DNA from baseline plasma samples using the BEAMing (beads, emulsion, amplification, magnetics) digital PCR technique and droplet digital PCR screening.

Overall, 27% of the women had ESR1 mutations before starting therapy on the trial, Dr. Turner reported. Mutations were seen in those who had received a prior aromatase inhibitor, but not in those who had received only prior tamoxifen. “So it’s quite clear these mutations are not a mechanism of resistance to tamoxifen, suggesting that tamoxifen must have at least some activity against these mutations,” he commented.

In addition, ESR1 mutations were more common in patients who had been sensitive versus not to prior endocrine therapy of any type (30.3% vs. 12.8%) and in patients who had been sensitive versus not specifically to prior aromatase inhibitor therapy (34.6% vs. 11.1%).

Stratified analyses showed that palbociclib was similarly superior to placebo in terms of progression-free survival whether patients were positive for an ESR1 mutation (9.4 vs. 4.1 months; hazard ratio, 0.52; P = .0052) or negative (9.5 vs. 3.8 months; hazard ratio, 0.44; P less than .0001).

“Detection of estrogen receptor mutations was strongly associated with acquired resistance to prior aromatase inhibitors,” Dr. Turner said.

“Palbociclib offered high efficacy regardless of the estrogen receptor mutation status,” he added. “And because in this patient population estrogen receptor mutations are detected frequently, the combination of palbociclib and fulvestrant presents an attractive treatment option for patients who have been previously treated with and progressed on aromatase inhibitors.”

CHICAGO – The survival impact of resecting the primary tumor in women with de novo stage IV breast cancer depends on receipt of and response to prior systemic therapy, suggested a pair of studies reported at the annual meeting of the American Society of Clinical Oncology.

A randomized trial conducted in Turkey found that, relative to peers who received initial systemic therapy, women who underwent initial resection of the primary tumor had a one-third lower risk of death at 5 years. But a prospective registry study conducted in the United States found that elective resection after a response to first-line therapy did not significantly improve overall survival, with patients living roughly 6 years regardless of whether they had the surgery or not.

Findings in context

“I think these studies have just confirmed what we know, and that is that tumor biology is critical,” said invited discussant Elizabeth A. Mittendorf, MD, PhD, of University of Texas MD Anderson Cancer Center, Houston. “Patients who do not respond to systemic therapy will do poorly, so I don’t think it’s unwise to consider a biologic ‘stress test’ with initiation of first-line therapy, knowing that patients who do not respond will not benefit from surgery.”

Those with hormone receptor–positive or HER2-positive disease are most likely to benefit from targeted therapy and may see even higher response rates as novel targeted agents are introduced. “But despite the increase in response to therapy, we really have no data at this time to suggest any benefit from surgery,” she added. “There may be some utility in continuing to enroll these patients in a clinical trial. I would suggest that it would need to be a subtype-specific trial and would question whether we have the appetite to conduct such a study.”

More information on managing de novo stage IV breast cancer is expected from ongoing trials such as the Eastern Cooperative Oncology Group’s 2108 trial, which is randomizing patients having a response or stable disease with first-line therapy to either early local therapy or delayed local therapy only at the time of progression, according to Dr. Mittendorf.

Poor accrual necessitated redesign of the trial. “As part of that redesign, there was a decrease in the target enrollment, which causes me concern that the trial will not be powered to inform its primary endpoint of overall survival,” she commented. However, “it’s interesting to note that in early 2014, shortly after the report of the trials from India and Turkey at the San Antonio Breast Cancer Symposium, there was a significant increase in enrollment, suggesting that this is a clinically important question.”

Turkish study: MF07-01

Susan London/Frontline Medical News

The first study – trial MF07-01 of the Turkish Federation of Breast Diseases Societies – was presented by Atilla Soran, MD, of Magee-Womens Hospital of University of Pittsburgh Medical Center.

He and his colleagues enrolled in the trial women with de novo stage IV breast cancer whose primary tumor was amenable to complete surgical resection and who were healthy enough to be treated.

The women were randomized evenly either to initial systemic therapy followed by local therapy only if local progression occurred, or to initial local therapy, consisting of surgery with or without radiation therapy of the breast and axilla, followed by systemic therapy.

Among the 274 evaluable women having a median follow-up of about 40 months, the 3-year rate of overall survival did not differ significantly between the two groups, Dr. Soran reported.

However, the 5-year rate of overall survival was 41.6% in the initial surgery group and 24.4% in the initial systemic therapy group, a difference translating to a significant reduction in the risk of death (hazard ratio, 0.66; P = .005). Median survival was 46 months and 37 months, respectively.

The benefit was similar in women whose tumors had hormone receptors, whose tumors were negative for HER2, and who were younger than age 55. There was no significant benefit of up-front surgery for women with bone-only metastases, “but we believe that when we follow these patients longer, the difference is going to be statistically significant,” he said.

On the other hand, there was a trend among women who had multiple pulmonary and/or liver metastases whereby they were more likely to die if they initially had surgery instead of systemic therapy.

Locoregional progression/relapse occurred in 1% of the initial surgery group but 11% of the initial systemic therapy group. Among women who did not have locoregional progression/relapse, surgery still had a survival benefit (HR, 0.61; P = .001).

“We know that with systemic therapy, immunotherapy, radiation therapy, and imaging as developments, patients are living longer when you compare to a decade ago or 20 years ago,” said Dr. Soran. “But we also believe that there is a role for surgery of the primary tumor in those patients.”

“Performance status, age, and comorbidities must be taken into account, and the burden of metastatic disease needs to be considered,” he maintained. “The benefit of surgery at presentation is dependent on the completeness of resection, and axillary surgery and locoregional radiation therapy should be considered regardless of the metastasis.”

U.S. study: TBCRC 013

Susan London/Frontline Medical News

The second study – the Translational Breast Cancer Research Consortium’s study 013 – was presented by Tari A. King, MD, chief of breast surgery at the Dana-Farber Cancer Institute, associate division chief for breast surgery at Brigham and Women’s Hospital, and associate professor of surgery at Harvard Medical School, all in Boston.

The investigators analyzed data from the study’s cohort A, consisting of 112 patients with de novo stage IV breast cancer who had an intact primary tumor. All patients were given first-line systemic therapy; those who had a response were additionally offered elective resection of their primary tumor.

The median duration of follow-up was 54 months. Overall, 85% of the women had a response to their first-line therapy, Dr. King reported.

Some 43% of responders opted to undergo elective surgery to resect their primary tumor, defined as surgery performed in the absence of local symptoms or the need for local control, with specific type and extent left up to the treating physician.

In a multivariate analysis among responders surviving at least 6 months, median survival was 71 months with elective surgery and 65 months without it, a nonsignificant difference.

Findings were similar among subsets of women having estrogen receptor–positive tumors or HER2-positive tumors, and various combinations of these features.

In recursive partitioning analysis, response to first-line therapy, HER2 status, and age were the major determinants of survival.

“Importantly, although we were not able to demonstrate a survival benefit with the use of surgery, surgery also did not impact progression-free survival,” noted Dr. King.

Ultimately, 4% of responders who did not have elective surgery and 18% of nonresponders went on to have palliative resection of their primary.

“As this was a registry study, patients selected for surgery were more likely to have single-organ metastatic disease and to have received first-line chemotherapy, yet despite this selection bias, surgery did not impact survival in any tumor subtype,” Dr. King summarized. “Among patients who responded to therapy, HER2 status and patient age remained strong prognostic factors. Further investigation is needed to determine if subsets of patients will ultimately benefit from surgery.”

“In the absence of additional prospective data, our findings do not support surgery for the primary tumor outside of a clinical trial,” she concluded.

CHICAGO – The survival impact of resecting the primary tumor in women with de novo stage IV breast cancer depends on receipt of and response to prior systemic therapy, suggested a pair of studies reported at the annual meeting of the American Society of Clinical Oncology.

A randomized trial conducted in Turkey found that, relative to peers who received initial systemic therapy, women who underwent initial resection of the primary tumor had a one-third lower risk of death at 5 years. But a prospective registry study conducted in the United States found that elective resection after a response to first-line therapy did not significantly improve overall survival, with patients living roughly 6 years regardless of whether they had the surgery or not.

Findings in context

“I think these studies have just confirmed what we know, and that is that tumor biology is critical,” said invited discussant Elizabeth A. Mittendorf, MD, PhD, of University of Texas MD Anderson Cancer Center, Houston. “Patients who do not respond to systemic therapy will do poorly, so I don’t think it’s unwise to consider a biologic ‘stress test’ with initiation of first-line therapy, knowing that patients who do not respond will not benefit from surgery.”

Those with hormone receptor–positive or HER2-positive disease are most likely to benefit from targeted therapy and may see even higher response rates as novel targeted agents are introduced. “But despite the increase in response to therapy, we really have no data at this time to suggest any benefit from surgery,” she added. “There may be some utility in continuing to enroll these patients in a clinical trial. I would suggest that it would need to be a subtype-specific trial and would question whether we have the appetite to conduct such a study.”

More information on managing de novo stage IV breast cancer is expected from ongoing trials such as the Eastern Cooperative Oncology Group’s 2108 trial, which is randomizing patients having a response or stable disease with first-line therapy to either early local therapy or delayed local therapy only at the time of progression, according to Dr. Mittendorf.

Poor accrual necessitated redesign of the trial. “As part of that redesign, there was a decrease in the target enrollment, which causes me concern that the trial will not be powered to inform its primary endpoint of overall survival,” she commented. However, “it’s interesting to note that in early 2014, shortly after the report of the trials from India and Turkey at the San Antonio Breast Cancer Symposium, there was a significant increase in enrollment, suggesting that this is a clinically important question.”

Turkish study: MF07-01

Susan London/Frontline Medical News

The first study – trial MF07-01 of the Turkish Federation of Breast Diseases Societies – was presented by Atilla Soran, MD, of Magee-Womens Hospital of University of Pittsburgh Medical Center.

He and his colleagues enrolled in the trial women with de novo stage IV breast cancer whose primary tumor was amenable to complete surgical resection and who were healthy enough to be treated.

The women were randomized evenly either to initial systemic therapy followed by local therapy only if local progression occurred, or to initial local therapy, consisting of surgery with or without radiation therapy of the breast and axilla, followed by systemic therapy.

Among the 274 evaluable women having a median follow-up of about 40 months, the 3-year rate of overall survival did not differ significantly between the two groups, Dr. Soran reported.

However, the 5-year rate of overall survival was 41.6% in the initial surgery group and 24.4% in the initial systemic therapy group, a difference translating to a significant reduction in the risk of death (hazard ratio, 0.66; P = .005). Median survival was 46 months and 37 months, respectively.

The benefit was similar in women whose tumors had hormone receptors, whose tumors were negative for HER2, and who were younger than age 55. There was no significant benefit of up-front surgery for women with bone-only metastases, “but we believe that when we follow these patients longer, the difference is going to be statistically significant,” he said.

On the other hand, there was a trend among women who had multiple pulmonary and/or liver metastases whereby they were more likely to die if they initially had surgery instead of systemic therapy.

Locoregional progression/relapse occurred in 1% of the initial surgery group but 11% of the initial systemic therapy group. Among women who did not have locoregional progression/relapse, surgery still had a survival benefit (HR, 0.61; P = .001).

“We know that with systemic therapy, immunotherapy, radiation therapy, and imaging as developments, patients are living longer when you compare to a decade ago or 20 years ago,” said Dr. Soran. “But we also believe that there is a role for surgery of the primary tumor in those patients.”

“Performance status, age, and comorbidities must be taken into account, and the burden of metastatic disease needs to be considered,” he maintained. “The benefit of surgery at presentation is dependent on the completeness of resection, and axillary surgery and locoregional radiation therapy should be considered regardless of the metastasis.”

U.S. study: TBCRC 013

Susan London/Frontline Medical News

The second study – the Translational Breast Cancer Research Consortium’s study 013 – was presented by Tari A. King, MD, chief of breast surgery at the Dana-Farber Cancer Institute, associate division chief for breast surgery at Brigham and Women’s Hospital, and associate professor of surgery at Harvard Medical School, all in Boston.

The investigators analyzed data from the study’s cohort A, consisting of 112 patients with de novo stage IV breast cancer who had an intact primary tumor. All patients were given first-line systemic therapy; those who had a response were additionally offered elective resection of their primary tumor.

The median duration of follow-up was 54 months. Overall, 85% of the women had a response to their first-line therapy, Dr. King reported.

Some 43% of responders opted to undergo elective surgery to resect their primary tumor, defined as surgery performed in the absence of local symptoms or the need for local control, with specific type and extent left up to the treating physician.

In a multivariate analysis among responders surviving at least 6 months, median survival was 71 months with elective surgery and 65 months without it, a nonsignificant difference.

Findings were similar among subsets of women having estrogen receptor–positive tumors or HER2-positive tumors, and various combinations of these features.

In recursive partitioning analysis, response to first-line therapy, HER2 status, and age were the major determinants of survival.

“Importantly, although we were not able to demonstrate a survival benefit with the use of surgery, surgery also did not impact progression-free survival,” noted Dr. King.

Ultimately, 4% of responders who did not have elective surgery and 18% of nonresponders went on to have palliative resection of their primary.

“As this was a registry study, patients selected for surgery were more likely to have single-organ metastatic disease and to have received first-line chemotherapy, yet despite this selection bias, surgery did not impact survival in any tumor subtype,” Dr. King summarized. “Among patients who responded to therapy, HER2 status and patient age remained strong prognostic factors. Further investigation is needed to determine if subsets of patients will ultimately benefit from surgery.”

“In the absence of additional prospective data, our findings do not support surgery for the primary tumor outside of a clinical trial,” she concluded.

CHICAGO – The survival impact of resecting the primary tumor in women with de novo stage IV breast cancer depends on receipt of and response to prior systemic therapy, suggested a pair of studies reported at the annual meeting of the American Society of Clinical Oncology.

A randomized trial conducted in Turkey found that, relative to peers who received initial systemic therapy, women who underwent initial resection of the primary tumor had a one-third lower risk of death at 5 years. But a prospective registry study conducted in the United States found that elective resection after a response to first-line therapy did not significantly improve overall survival, with patients living roughly 6 years regardless of whether they had the surgery or not.

Findings in context

“I think these studies have just confirmed what we know, and that is that tumor biology is critical,” said invited discussant Elizabeth A. Mittendorf, MD, PhD, of University of Texas MD Anderson Cancer Center, Houston. “Patients who do not respond to systemic therapy will do poorly, so I don’t think it’s unwise to consider a biologic ‘stress test’ with initiation of first-line therapy, knowing that patients who do not respond will not benefit from surgery.”

Those with hormone receptor–positive or HER2-positive disease are most likely to benefit from targeted therapy and may see even higher response rates as novel targeted agents are introduced. “But despite the increase in response to therapy, we really have no data at this time to suggest any benefit from surgery,” she added. “There may be some utility in continuing to enroll these patients in a clinical trial. I would suggest that it would need to be a subtype-specific trial and would question whether we have the appetite to conduct such a study.”

More information on managing de novo stage IV breast cancer is expected from ongoing trials such as the Eastern Cooperative Oncology Group’s 2108 trial, which is randomizing patients having a response or stable disease with first-line therapy to either early local therapy or delayed local therapy only at the time of progression, according to Dr. Mittendorf.

Poor accrual necessitated redesign of the trial. “As part of that redesign, there was a decrease in the target enrollment, which causes me concern that the trial will not be powered to inform its primary endpoint of overall survival,” she commented. However, “it’s interesting to note that in early 2014, shortly after the report of the trials from India and Turkey at the San Antonio Breast Cancer Symposium, there was a significant increase in enrollment, suggesting that this is a clinically important question.”

Turkish study: MF07-01

Susan London/Frontline Medical News

The first study – trial MF07-01 of the Turkish Federation of Breast Diseases Societies – was presented by Atilla Soran, MD, of Magee-Womens Hospital of University of Pittsburgh Medical Center.

He and his colleagues enrolled in the trial women with de novo stage IV breast cancer whose primary tumor was amenable to complete surgical resection and who were healthy enough to be treated.

The women were randomized evenly either to initial systemic therapy followed by local therapy only if local progression occurred, or to initial local therapy, consisting of surgery with or without radiation therapy of the breast and axilla, followed by systemic therapy.

Among the 274 evaluable women having a median follow-up of about 40 months, the 3-year rate of overall survival did not differ significantly between the two groups, Dr. Soran reported.

However, the 5-year rate of overall survival was 41.6% in the initial surgery group and 24.4% in the initial systemic therapy group, a difference translating to a significant reduction in the risk of death (hazard ratio, 0.66; P = .005). Median survival was 46 months and 37 months, respectively.

The benefit was similar in women whose tumors had hormone receptors, whose tumors were negative for HER2, and who were younger than age 55. There was no significant benefit of up-front surgery for women with bone-only metastases, “but we believe that when we follow these patients longer, the difference is going to be statistically significant,” he said.

On the other hand, there was a trend among women who had multiple pulmonary and/or liver metastases whereby they were more likely to die if they initially had surgery instead of systemic therapy.

Locoregional progression/relapse occurred in 1% of the initial surgery group but 11% of the initial systemic therapy group. Among women who did not have locoregional progression/relapse, surgery still had a survival benefit (HR, 0.61; P = .001).

“We know that with systemic therapy, immunotherapy, radiation therapy, and imaging as developments, patients are living longer when you compare to a decade ago or 20 years ago,” said Dr. Soran. “But we also believe that there is a role for surgery of the primary tumor in those patients.”

“Performance status, age, and comorbidities must be taken into account, and the burden of metastatic disease needs to be considered,” he maintained. “The benefit of surgery at presentation is dependent on the completeness of resection, and axillary surgery and locoregional radiation therapy should be considered regardless of the metastasis.”

U.S. study: TBCRC 013

Susan London/Frontline Medical News

The second study – the Translational Breast Cancer Research Consortium’s study 013 – was presented by Tari A. King, MD, chief of breast surgery at the Dana-Farber Cancer Institute, associate division chief for breast surgery at Brigham and Women’s Hospital, and associate professor of surgery at Harvard Medical School, all in Boston.

The investigators analyzed data from the study’s cohort A, consisting of 112 patients with de novo stage IV breast cancer who had an intact primary tumor. All patients were given first-line systemic therapy; those who had a response were additionally offered elective resection of their primary tumor.

The median duration of follow-up was 54 months. Overall, 85% of the women had a response to their first-line therapy, Dr. King reported.

Some 43% of responders opted to undergo elective surgery to resect their primary tumor, defined as surgery performed in the absence of local symptoms or the need for local control, with specific type and extent left up to the treating physician.

In a multivariate analysis among responders surviving at least 6 months, median survival was 71 months with elective surgery and 65 months without it, a nonsignificant difference.

Findings were similar among subsets of women having estrogen receptor–positive tumors or HER2-positive tumors, and various combinations of these features.

In recursive partitioning analysis, response to first-line therapy, HER2 status, and age were the major determinants of survival.

“Importantly, although we were not able to demonstrate a survival benefit with the use of surgery, surgery also did not impact progression-free survival,” noted Dr. King.

Ultimately, 4% of responders who did not have elective surgery and 18% of nonresponders went on to have palliative resection of their primary.

“As this was a registry study, patients selected for surgery were more likely to have single-organ metastatic disease and to have received first-line chemotherapy, yet despite this selection bias, surgery did not impact survival in any tumor subtype,” Dr. King summarized. “Among patients who responded to therapy, HER2 status and patient age remained strong prognostic factors. Further investigation is needed to determine if subsets of patients will ultimately benefit from surgery.”

“In the absence of additional prospective data, our findings do not support surgery for the primary tumor outside of a clinical trial,” she concluded.

CHICAGO – The combination of pembrolizumab, an antibody to the human cell surface receptor programmed death-1 (PD-1), and ipilimumab, an antibody to the human T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), is highly active against advanced melanoma and has acceptable safety, finds the KEYNOTE 029 trial’s expansion cohort.

The 153 patients in the cohort received a standard dose of pembrolizumab (2 mg/kg every 3 weeks) with a reduced dose of ipilimumab (1 mg/kg every 3 weeks for four doses) on the basis of earlier data showing substantial toxicity when a standard dose of ipilimumab was combined with other immune checkpoint inhibitors.

Results reported at the annual meeting of the American Society of Clinical Oncology showed that the overall response rate was 57%, and the disease control rate was 78%. Although 42% of patients experienced grade 3 or 4 treatment-related adverse events, most of these events resolved, and there were no treatment-related deaths.

“Pembrolizumab 2 mg/kg in combination with four doses of ipilimumab 1 mg/kg has a manageable toxicity profile and provides robust antitumor activity in patients with advanced melanoma,” concluded the investigators, who were led by Georgina Long, PhD, MBBS, chair of Melanoma Medical Oncology and Translational Research at the Melanoma Institute Australia and Royal North Shore Hospital, University of Sydney.

The response rate seen in KEYNOTE 029 was almost identical to that seen in the CheckMate 067 trial with the combination of nivolumab and standard-dose ipilimumab (3 mg/kg every 3 weeks for four doses), noted invited discussant Marc S. Ernstoff, MD, professor and chair of the department of medicine at the Roswell Park Cancer Institute in Buffalo, N.Y. It was also “remarkably comparable” to the 69% seen in the COMBI-d melanoma trial with the combination of dabrafenib (a BRAF inhibitor) and trametinib (an inhibitor of MEK MAPK/ERK kinase).

“There is a significant amount of grade 3 and 4 toxicity, but the dose of ipilimumab appeared to decrease this in the pembrolizumab-ipilimumab study compared to the nivolumab-ipilimumab study,” he noted. “There was a high percent of low-grade toxicities reported in all of these studies, and I would argue that as we are seeing patients survive longer, these low-grade toxicities are going to become more of an issue for us as oncologists to be able to deal with in terms of quality of life for patients surviving.”

There is good rationale for combining CTLA4 blockade and PD1 (or PD-L1) blockade in melanoma, Dr. Long maintained when introducing the research. “We know that CTLA inhibition at the priming phase in the periphery, at antigen presentation, is effective, as is PD-1 or PD-L1 [inhibition] at the effector phase down in the tumor bed,” she elaborated.

The patients with advanced melanoma enrolled in the expansion cohort could have received any number of prior therapies other than immune checkpoint inhibitors. However, in 87%, the study regimen was their first therapy.

At the time of data cutoff, 72% of patients had received all four planned doses of ipilimumab (Yervoy), and 56% were continuing on pembrolizumab (Keytruda).

The rates of any-grade and grade 3 or 4 treatment-related adverse events were 95% and 42%, respectively. The corresponding rates of immune-mediated adverse events were 58% and 25%.

The most common grade 3 or 4 treatment-related adverse events were lipase elevation (14%) and rash (3%). The former was asymptomatic and had no sequelae in the majority of cases, Dr. Long reported.

Hepatitis, colitis, and skin reactions were the most common grade 3 or 4 immune-mediated adverse events. The majority of immune-mediated adverse events were managed with systemic treatment, usually corticosteroids, and resolved.

When it came to efficacy, the overall response rate with the combination was similar across subgroups of patients stratified by PD-L1 status in the tumor and adjacent immune tissue, treatment history, baseline lactate dehydrogenase level, and BRAF mutational status.

Responses were ongoing in 98% of patients at data cutoff, with the duration of response ranging from about 6 weeks to 43 weeks, Dr. Long said. The disease control rate was 78%.

With a median follow-up of 10.0 months, median progression-free survival and overall survival were not yet reached. However, the 6-month rates of these outcomes were 70% and 93%, respectively.

Dr. Long disclosed that she is a consultant/adviser to Amgen, Bristol-Myers Squibb, Merck, Novartis, Provectus, and Roche, and that she has received honoraria from Bristol-Myers Squibb, Merck, and Novartis. The trial was supported by Merck.

CHICAGO – The combination of pembrolizumab, an antibody to the human cell surface receptor programmed death-1 (PD-1), and ipilimumab, an antibody to the human T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), is highly active against advanced melanoma and has acceptable safety, finds the KEYNOTE 029 trial’s expansion cohort.

The 153 patients in the cohort received a standard dose of pembrolizumab (2 mg/kg every 3 weeks) with a reduced dose of ipilimumab (1 mg/kg every 3 weeks for four doses) on the basis of earlier data showing substantial toxicity when a standard dose of ipilimumab was combined with other immune checkpoint inhibitors.

Results reported at the annual meeting of the American Society of Clinical Oncology showed that the overall response rate was 57%, and the disease control rate was 78%. Although 42% of patients experienced grade 3 or 4 treatment-related adverse events, most of these events resolved, and there were no treatment-related deaths.

“Pembrolizumab 2 mg/kg in combination with four doses of ipilimumab 1 mg/kg has a manageable toxicity profile and provides robust antitumor activity in patients with advanced melanoma,” concluded the investigators, who were led by Georgina Long, PhD, MBBS, chair of Melanoma Medical Oncology and Translational Research at the Melanoma Institute Australia and Royal North Shore Hospital, University of Sydney.

The response rate seen in KEYNOTE 029 was almost identical to that seen in the CheckMate 067 trial with the combination of nivolumab and standard-dose ipilimumab (3 mg/kg every 3 weeks for four doses), noted invited discussant Marc S. Ernstoff, MD, professor and chair of the department of medicine at the Roswell Park Cancer Institute in Buffalo, N.Y. It was also “remarkably comparable” to the 69% seen in the COMBI-d melanoma trial with the combination of dabrafenib (a BRAF inhibitor) and trametinib (an inhibitor of MEK MAPK/ERK kinase).

“There is a significant amount of grade 3 and 4 toxicity, but the dose of ipilimumab appeared to decrease this in the pembrolizumab-ipilimumab study compared to the nivolumab-ipilimumab study,” he noted. “There was a high percent of low-grade toxicities reported in all of these studies, and I would argue that as we are seeing patients survive longer, these low-grade toxicities are going to become more of an issue for us as oncologists to be able to deal with in terms of quality of life for patients surviving.”

There is good rationale for combining CTLA4 blockade and PD1 (or PD-L1) blockade in melanoma, Dr. Long maintained when introducing the research. “We know that CTLA inhibition at the priming phase in the periphery, at antigen presentation, is effective, as is PD-1 or PD-L1 [inhibition] at the effector phase down in the tumor bed,” she elaborated.

The patients with advanced melanoma enrolled in the expansion cohort could have received any number of prior therapies other than immune checkpoint inhibitors. However, in 87%, the study regimen was their first therapy.

At the time of data cutoff, 72% of patients had received all four planned doses of ipilimumab (Yervoy), and 56% were continuing on pembrolizumab (Keytruda).

The rates of any-grade and grade 3 or 4 treatment-related adverse events were 95% and 42%, respectively. The corresponding rates of immune-mediated adverse events were 58% and 25%.

The most common grade 3 or 4 treatment-related adverse events were lipase elevation (14%) and rash (3%). The former was asymptomatic and had no sequelae in the majority of cases, Dr. Long reported.

Hepatitis, colitis, and skin reactions were the most common grade 3 or 4 immune-mediated adverse events. The majority of immune-mediated adverse events were managed with systemic treatment, usually corticosteroids, and resolved.

When it came to efficacy, the overall response rate with the combination was similar across subgroups of patients stratified by PD-L1 status in the tumor and adjacent immune tissue, treatment history, baseline lactate dehydrogenase level, and BRAF mutational status.

Responses were ongoing in 98% of patients at data cutoff, with the duration of response ranging from about 6 weeks to 43 weeks, Dr. Long said. The disease control rate was 78%.

With a median follow-up of 10.0 months, median progression-free survival and overall survival were not yet reached. However, the 6-month rates of these outcomes were 70% and 93%, respectively.

Dr. Long disclosed that she is a consultant/adviser to Amgen, Bristol-Myers Squibb, Merck, Novartis, Provectus, and Roche, and that she has received honoraria from Bristol-Myers Squibb, Merck, and Novartis. The trial was supported by Merck.

CHICAGO – The combination of pembrolizumab, an antibody to the human cell surface receptor programmed death-1 (PD-1), and ipilimumab, an antibody to the human T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), is highly active against advanced melanoma and has acceptable safety, finds the KEYNOTE 029 trial’s expansion cohort.

The 153 patients in the cohort received a standard dose of pembrolizumab (2 mg/kg every 3 weeks) with a reduced dose of ipilimumab (1 mg/kg every 3 weeks for four doses) on the basis of earlier data showing substantial toxicity when a standard dose of ipilimumab was combined with other immune checkpoint inhibitors.

Results reported at the annual meeting of the American Society of Clinical Oncology showed that the overall response rate was 57%, and the disease control rate was 78%. Although 42% of patients experienced grade 3 or 4 treatment-related adverse events, most of these events resolved, and there were no treatment-related deaths.

“Pembrolizumab 2 mg/kg in combination with four doses of ipilimumab 1 mg/kg has a manageable toxicity profile and provides robust antitumor activity in patients with advanced melanoma,” concluded the investigators, who were led by Georgina Long, PhD, MBBS, chair of Melanoma Medical Oncology and Translational Research at the Melanoma Institute Australia and Royal North Shore Hospital, University of Sydney.

The response rate seen in KEYNOTE 029 was almost identical to that seen in the CheckMate 067 trial with the combination of nivolumab and standard-dose ipilimumab (3 mg/kg every 3 weeks for four doses), noted invited discussant Marc S. Ernstoff, MD, professor and chair of the department of medicine at the Roswell Park Cancer Institute in Buffalo, N.Y. It was also “remarkably comparable” to the 69% seen in the COMBI-d melanoma trial with the combination of dabrafenib (a BRAF inhibitor) and trametinib (an inhibitor of MEK MAPK/ERK kinase).

“There is a significant amount of grade 3 and 4 toxicity, but the dose of ipilimumab appeared to decrease this in the pembrolizumab-ipilimumab study compared to the nivolumab-ipilimumab study,” he noted. “There was a high percent of low-grade toxicities reported in all of these studies, and I would argue that as we are seeing patients survive longer, these low-grade toxicities are going to become more of an issue for us as oncologists to be able to deal with in terms of quality of life for patients surviving.”

There is good rationale for combining CTLA4 blockade and PD1 (or PD-L1) blockade in melanoma, Dr. Long maintained when introducing the research. “We know that CTLA inhibition at the priming phase in the periphery, at antigen presentation, is effective, as is PD-1 or PD-L1 [inhibition] at the effector phase down in the tumor bed,” she elaborated.

The patients with advanced melanoma enrolled in the expansion cohort could have received any number of prior therapies other than immune checkpoint inhibitors. However, in 87%, the study regimen was their first therapy.

At the time of data cutoff, 72% of patients had received all four planned doses of ipilimumab (Yervoy), and 56% were continuing on pembrolizumab (Keytruda).

The rates of any-grade and grade 3 or 4 treatment-related adverse events were 95% and 42%, respectively. The corresponding rates of immune-mediated adverse events were 58% and 25%.

The most common grade 3 or 4 treatment-related adverse events were lipase elevation (14%) and rash (3%). The former was asymptomatic and had no sequelae in the majority of cases, Dr. Long reported.

Hepatitis, colitis, and skin reactions were the most common grade 3 or 4 immune-mediated adverse events. The majority of immune-mediated adverse events were managed with systemic treatment, usually corticosteroids, and resolved.

When it came to efficacy, the overall response rate with the combination was similar across subgroups of patients stratified by PD-L1 status in the tumor and adjacent immune tissue, treatment history, baseline lactate dehydrogenase level, and BRAF mutational status.

Responses were ongoing in 98% of patients at data cutoff, with the duration of response ranging from about 6 weeks to 43 weeks, Dr. Long said. The disease control rate was 78%.

With a median follow-up of 10.0 months, median progression-free survival and overall survival were not yet reached. However, the 6-month rates of these outcomes were 70% and 93%, respectively.

Dr. Long disclosed that she is a consultant/adviser to Amgen, Bristol-Myers Squibb, Merck, Novartis, Provectus, and Roche, and that she has received honoraria from Bristol-Myers Squibb, Merck, and Novartis. The trial was supported by Merck.

CHICAGO – Women with clinical early-stage breast cancer and a positive sentinel lymph node who receive breast-conserving therapy can safely skip an axillary lymph node dissection (ALND), and therefore avoid its associated morbidity, confirms long-term follow-up of the Z0011 trial conducted by the American College of Surgeons Oncology Group and the Alliance for Clinical Trials in Oncology.

The phase III trial enrolled 891 women with clinical T1-2,N0,M0 disease who underwent lumpectomy and were found to have sentinel node involvement. They were randomized to ALND or no further surgery, followed by whole-breast radiation therapy and, in most cases, systemic adjuvant therapy.

The trial was closed early because of low rates of accrual and events. Results at 6.3 years of follow-up showed that compared with peers who had an ALND, the women who skipped this surgery did not have inferior 5-year rates of locoregional recurrence or overall survival (JAMA. 2011;305:569-75).

“The study, however, like most breast cancer studies, contained mostly postmenopausal women with hormone receptor–positive tumors who are known to have late recurrences, and it was criticized for short follow-up,” commented first author Armando E. Giuliano, MD, executive vice chair of surgical oncology in the department of surgery, and associate director of surgical oncology in the Samuel Oschin Comprehensive Cancer Institute, Los Angeles.

In an update of the findings, now with a median follow-up of 9.3 years, the groups were statistically indistinguishable with respect to 10-year rates of the same outcomes, he reported at the annual meeting of the American Society of Clinical Oncology.

“This study... shows that sentinel node biopsy alone provides excellent 10-year locoregional control and survival comparable to completion axillary lymph node dissection for these patients, even with long-term follow-up,” he maintained. “Routine use of axillary lymph node dissection should be abandoned.”

“This was designed as a noninferiority trial, and I would suggest that based on the data we have seen, even if they had hit their target accrual, the outcomes would not be different,” said invited discussant Elizabeth A. Mittendorf, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston. “Clearly, even before today’s presentation, Z0011 has been identified as a practice-changing trial, as evidenced by the NCCN guidelines.”

In fact, a study last year showed that among patients in the general U.S. population meeting the trial’s enrollment criteria, the use of sentinel lymph node dissection alone has increased significantly since the Z0011 results were first reported (J Am Coll Surg. 2015;221:71-81).

“However, I would highlight that we have also seen an increase in omission of axillary lymph node dissection for patients who do not meet the Z0011 criteria to include those not planned for radiotherapy, those receiving APBI [accelerated partial breast irradiation], and those undergoing mastectomy,” she added. “I highlight these examples specifically because it’s been suggested that one of the reasons the patients on the trial have outstanding regional control is because of the radiation administered as part of their breast-conserving therapy.”

“We will obtain additional data on the locoregional management of these early-stage patients with clinically node-negative breast cancer,” Dr. Mittendorf predicted, pointing to the similar POSNOC trial (which is comparing systemic therapy with versus without axillary treatment) and SOUND trial (which is comparing sentinel node dissection versus no axillary surgery).

In Z0011, all women had tumor in sentinel nodes detected with hematoxylin and eosin staining. Those with sentinel node tumor detected only by immunohistochemistry were excluded, as were those who had matted nodes, three or more involved sentinel nodes, or planned third-field (nodal) irradiation.

Overall, 27.4% of the patients in the ALND group had additional positive nodes removed beyond their sentinel nodes. “There is no reason to suspect that women with sentinel node biopsy [only] had fewer involved nodes than the women treated with axillary lymph node dissection,” Dr. Giuliano commented; thus, a similar share of the former group likely had residual axillary disease that went unresected.

The updated findings showed that the women received ALND and the women who did not were statistically indistinguishable with respect to the 10-year rate of locoregional recurrence (6.2% and 5.3%). Of note, only a single regional recurrence was seen after the initial 5 years of follow-up, and it occurred in the group that did not have ALND.

The groups treated with and without ALND were also statistically indistinguishable with respect to 10-year rates of disease-free survival (78.2% and 80.2%), locoregional recurrence–free survival (81.2% and 83.0%), and overall survival (83.6% and 86.3%).

In multivariate analysis, omission of ALND did not significantly predict locoregional recurrence or overall survival, reported Dr. Giuliano. Additionally, stratified analysis showed that the lack of difference in overall survival between study groups was the same whether tumors had hormone receptors or not.

In a related analysis of radiation protocol deviations in a subset of women from the trial, 11% did not receive any radiation therapy, while 18.9% received third-field radiation, with equal distribution of the latter between study groups (J Clin Oncol. 2014;32:3600-6). Omission of radiation was associated with an increased risk of local recurrence and death, but it did not affect nodal recurrences. Receipt of third-field radiation did not influence survival.

[email protected]

CHICAGO – Women with clinical early-stage breast cancer and a positive sentinel lymph node who receive breast-conserving therapy can safely skip an axillary lymph node dissection (ALND), and therefore avoid its associated morbidity, confirms long-term follow-up of the Z0011 trial conducted by the American College of Surgeons Oncology Group and the Alliance for Clinical Trials in Oncology.

The phase III trial enrolled 891 women with clinical T1-2,N0,M0 disease who underwent lumpectomy and were found to have sentinel node involvement. They were randomized to ALND or no further surgery, followed by whole-breast radiation therapy and, in most cases, systemic adjuvant therapy.

The trial was closed early because of low rates of accrual and events. Results at 6.3 years of follow-up showed that compared with peers who had an ALND, the women who skipped this surgery did not have inferior 5-year rates of locoregional recurrence or overall survival (JAMA. 2011;305:569-75).

“The study, however, like most breast cancer studies, contained mostly postmenopausal women with hormone receptor–positive tumors who are known to have late recurrences, and it was criticized for short follow-up,” commented first author Armando E. Giuliano, MD, executive vice chair of surgical oncology in the department of surgery, and associate director of surgical oncology in the Samuel Oschin Comprehensive Cancer Institute, Los Angeles.

In an update of the findings, now with a median follow-up of 9.3 years, the groups were statistically indistinguishable with respect to 10-year rates of the same outcomes, he reported at the annual meeting of the American Society of Clinical Oncology.

“This study... shows that sentinel node biopsy alone provides excellent 10-year locoregional control and survival comparable to completion axillary lymph node dissection for these patients, even with long-term follow-up,” he maintained. “Routine use of axillary lymph node dissection should be abandoned.”

“This was designed as a noninferiority trial, and I would suggest that based on the data we have seen, even if they had hit their target accrual, the outcomes would not be different,” said invited discussant Elizabeth A. Mittendorf, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston. “Clearly, even before today’s presentation, Z0011 has been identified as a practice-changing trial, as evidenced by the NCCN guidelines.”

In fact, a study last year showed that among patients in the general U.S. population meeting the trial’s enrollment criteria, the use of sentinel lymph node dissection alone has increased significantly since the Z0011 results were first reported (J Am Coll Surg. 2015;221:71-81).

“However, I would highlight that we have also seen an increase in omission of axillary lymph node dissection for patients who do not meet the Z0011 criteria to include those not planned for radiotherapy, those receiving APBI [accelerated partial breast irradiation], and those undergoing mastectomy,” she added. “I highlight these examples specifically because it’s been suggested that one of the reasons the patients on the trial have outstanding regional control is because of the radiation administered as part of their breast-conserving therapy.”

“We will obtain additional data on the locoregional management of these early-stage patients with clinically node-negative breast cancer,” Dr. Mittendorf predicted, pointing to the similar POSNOC trial (which is comparing systemic therapy with versus without axillary treatment) and SOUND trial (which is comparing sentinel node dissection versus no axillary surgery).

In Z0011, all women had tumor in sentinel nodes detected with hematoxylin and eosin staining. Those with sentinel node tumor detected only by immunohistochemistry were excluded, as were those who had matted nodes, three or more involved sentinel nodes, or planned third-field (nodal) irradiation.

Overall, 27.4% of the patients in the ALND group had additional positive nodes removed beyond their sentinel nodes. “There is no reason to suspect that women with sentinel node biopsy [only] had fewer involved nodes than the women treated with axillary lymph node dissection,” Dr. Giuliano commented; thus, a similar share of the former group likely had residual axillary disease that went unresected.

The updated findings showed that the women received ALND and the women who did not were statistically indistinguishable with respect to the 10-year rate of locoregional recurrence (6.2% and 5.3%). Of note, only a single regional recurrence was seen after the initial 5 years of follow-up, and it occurred in the group that did not have ALND.

The groups treated with and without ALND were also statistically indistinguishable with respect to 10-year rates of disease-free survival (78.2% and 80.2%), locoregional recurrence–free survival (81.2% and 83.0%), and overall survival (83.6% and 86.3%).

In multivariate analysis, omission of ALND did not significantly predict locoregional recurrence or overall survival, reported Dr. Giuliano. Additionally, stratified analysis showed that the lack of difference in overall survival between study groups was the same whether tumors had hormone receptors or not.

In a related analysis of radiation protocol deviations in a subset of women from the trial, 11% did not receive any radiation therapy, while 18.9% received third-field radiation, with equal distribution of the latter between study groups (J Clin Oncol. 2014;32:3600-6). Omission of radiation was associated with an increased risk of local recurrence and death, but it did not affect nodal recurrences. Receipt of third-field radiation did not influence survival.

[email protected]

CHICAGO – Women with clinical early-stage breast cancer and a positive sentinel lymph node who receive breast-conserving therapy can safely skip an axillary lymph node dissection (ALND), and therefore avoid its associated morbidity, confirms long-term follow-up of the Z0011 trial conducted by the American College of Surgeons Oncology Group and the Alliance for Clinical Trials in Oncology.

The phase III trial enrolled 891 women with clinical T1-2,N0,M0 disease who underwent lumpectomy and were found to have sentinel node involvement. They were randomized to ALND or no further surgery, followed by whole-breast radiation therapy and, in most cases, systemic adjuvant therapy.

The trial was closed early because of low rates of accrual and events. Results at 6.3 years of follow-up showed that compared with peers who had an ALND, the women who skipped this surgery did not have inferior 5-year rates of locoregional recurrence or overall survival (JAMA. 2011;305:569-75).

“The study, however, like most breast cancer studies, contained mostly postmenopausal women with hormone receptor–positive tumors who are known to have late recurrences, and it was criticized for short follow-up,” commented first author Armando E. Giuliano, MD, executive vice chair of surgical oncology in the department of surgery, and associate director of surgical oncology in the Samuel Oschin Comprehensive Cancer Institute, Los Angeles.

In an update of the findings, now with a median follow-up of 9.3 years, the groups were statistically indistinguishable with respect to 10-year rates of the same outcomes, he reported at the annual meeting of the American Society of Clinical Oncology.

“This study... shows that sentinel node biopsy alone provides excellent 10-year locoregional control and survival comparable to completion axillary lymph node dissection for these patients, even with long-term follow-up,” he maintained. “Routine use of axillary lymph node dissection should be abandoned.”

“This was designed as a noninferiority trial, and I would suggest that based on the data we have seen, even if they had hit their target accrual, the outcomes would not be different,” said invited discussant Elizabeth A. Mittendorf, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston. “Clearly, even before today’s presentation, Z0011 has been identified as a practice-changing trial, as evidenced by the NCCN guidelines.”

In fact, a study last year showed that among patients in the general U.S. population meeting the trial’s enrollment criteria, the use of sentinel lymph node dissection alone has increased significantly since the Z0011 results were first reported (J Am Coll Surg. 2015;221:71-81).

“However, I would highlight that we have also seen an increase in omission of axillary lymph node dissection for patients who do not meet the Z0011 criteria to include those not planned for radiotherapy, those receiving APBI [accelerated partial breast irradiation], and those undergoing mastectomy,” she added. “I highlight these examples specifically because it’s been suggested that one of the reasons the patients on the trial have outstanding regional control is because of the radiation administered as part of their breast-conserving therapy.”

“We will obtain additional data on the locoregional management of these early-stage patients with clinically node-negative breast cancer,” Dr. Mittendorf predicted, pointing to the similar POSNOC trial (which is comparing systemic therapy with versus without axillary treatment) and SOUND trial (which is comparing sentinel node dissection versus no axillary surgery).

In Z0011, all women had tumor in sentinel nodes detected with hematoxylin and eosin staining. Those with sentinel node tumor detected only by immunohistochemistry were excluded, as were those who had matted nodes, three or more involved sentinel nodes, or planned third-field (nodal) irradiation.

Overall, 27.4% of the patients in the ALND group had additional positive nodes removed beyond their sentinel nodes. “There is no reason to suspect that women with sentinel node biopsy [only] had fewer involved nodes than the women treated with axillary lymph node dissection,” Dr. Giuliano commented; thus, a similar share of the former group likely had residual axillary disease that went unresected.

The updated findings showed that the women received ALND and the women who did not were statistically indistinguishable with respect to the 10-year rate of locoregional recurrence (6.2% and 5.3%). Of note, only a single regional recurrence was seen after the initial 5 years of follow-up, and it occurred in the group that did not have ALND.

The groups treated with and without ALND were also statistically indistinguishable with respect to 10-year rates of disease-free survival (78.2% and 80.2%), locoregional recurrence–free survival (81.2% and 83.0%), and overall survival (83.6% and 86.3%).

In multivariate analysis, omission of ALND did not significantly predict locoregional recurrence or overall survival, reported Dr. Giuliano. Additionally, stratified analysis showed that the lack of difference in overall survival between study groups was the same whether tumors had hormone receptors or not.

In a related analysis of radiation protocol deviations in a subset of women from the trial, 11% did not receive any radiation therapy, while 18.9% received third-field radiation, with equal distribution of the latter between study groups (J Clin Oncol. 2014;32:3600-6). Omission of radiation was associated with an increased risk of local recurrence and death, but it did not affect nodal recurrences. Receipt of third-field radiation did not influence survival.

[email protected]

SAN FRANCISCO – The opioid overdose crisis in the United States is now plainly evident in intensive care units (ICUs), finds a study of hospitals in 44 states conducted between 2009 and 2015.

During the study period, ICU admissions for opioid overdoses increased by almost half, investigators reported in a session and related press briefing an international conference of the American Thoracic Society. Furthermore, ICU deaths from this cause roughly doubled.

Susan London/Frontline Medical News

“This means the opioid use epidemic has probably reached a new level of crisis,” said lead investigator Jennifer P. Stevens, MD, an instructor in medicine at Harvard Medical School, and an adult intensive care physician at Beth Israel Deaconess Medical Center, both in Boston. “And this means that in spite of everything that we can do in the ICU – keeping them alive on ventilators, doing life support, doing acute dialysis, doing round-the-clock care, round-the-clock board-certified intensivist care – we are still not able to make a difference in that mortality.”

Dr. Stevens added that any ICU admission for overdose from opioids is a preventable admission. “So if we have an increase in mortality of this population, we have a number of patients who have preventable deaths in our ICU,” she said.

Efforts to track this epidemic on a national level are important, she said, and the U.S. Centers for Disease Control and Prevention has been investigating opioid overdoses in some cities, including Boston, as they would any epidemic.

The factors driving the observed trends could not be determined from the study data, Dr. Stevens said. But state-specific patterns that show, for example, higher baseline rates and greater increases over time in ICU admissions for opioid overdose in Massachusetts and Indiana may be a starting point for investigation.

Certain practices in the ICU may also be inadvertently contributing. “I imagine that a patient who comes in with an opioid overdose can cause harm to themselves in a number of ways, and the things that we try to do to help them might cause harm in other ways as well,” she said. “So in an effort to try to maintain them in a safe, ventilated state, we might give them a ton of sedation that then prolongs their time on the ventilator. That’s sort of a simple example of how the two could intersect to have a multiplicative effect of harm.”

The idea for the study arose because ICU staff anecdotally noticed an uptick in admissions for opioid use disorder. “Not only were we seeing more people coming in, but we were seeing sicker people coming in, and with the associated tragedy that comes with a lot of young people coming in with opioid use disorder,” Dr. Stevens said. “We wanted to see if this was happening nationally... We asked, is this epidemic now reaching the most technologically advanced parts of our health care system?”

The investigators studied hospitals providing data to Vizient (formerly the University HealthSystem Consortium) between 2009 and 2015. The included hospitals – about 200 for each study year – were predominantly urban and university affiliated, but representation of community hospitals increased during the study period.

Ultimately, analyses were based on a total of 28.2 million hospital discharges of patients aged 18 years or older, which included 4.9 million ICU admissions.

Results reported at the meeting showed that 27,325 patients were admitted to the study hospitals’ ICUs with opioid overdose during the study period, as ascertained from billing codes.

Opioid overdose was seen in 45 patients per 10,000 ICU admissions in 2009 but rose to 65 patients per 10,000 ICU admissions in 2015, a 46% increase.

Furthermore, ICU deaths due to opioid overdose rose by 87% during the same time period, and mortality among patients admitted to the unit with overdose rose at a pace of 0.5% per month.

“This is somewhat unusual because a lot of times, when we are admitting more people to our ICUs or examining [a trend] further, mortality actually goes down. This is partly because maybe we are doing more for them and we are taking care of them in an aggressive way. But it’s also because we are admitting less sick people because we are more aware of the issue,” Dr. Stevens said. “And we saw the opposite of this – we saw that the mortality was going up.”

The use of billing data was a specific means but not a sensitive means of identifying opioid overdoses, she noted. Therefore, the observed values are likely underestimates of these outcomes.

Addressing the opioid overdose epidemic will require a multifaceted approach, according to Dr. Stevens, who disclosed that she had no relevant conflicts of interest.

“Folks are doing very impressive work in the community trying to make sure EMTs and other first responders have access to the tools that they need in those settings,” she said. “But one thing we haven’t approached before is the care that we provide in the ICU, and maybe that’s a space that we need to think more prospectively about.”

SAN FRANCISCO – The opioid overdose crisis in the United States is now plainly evident in intensive care units (ICUs), finds a study of hospitals in 44 states conducted between 2009 and 2015.

During the study period, ICU admissions for opioid overdoses increased by almost half, investigators reported in a session and related press briefing an international conference of the American Thoracic Society. Furthermore, ICU deaths from this cause roughly doubled.

Susan London/Frontline Medical News

“This means the opioid use epidemic has probably reached a new level of crisis,” said lead investigator Jennifer P. Stevens, MD, an instructor in medicine at Harvard Medical School, and an adult intensive care physician at Beth Israel Deaconess Medical Center, both in Boston. “And this means that in spite of everything that we can do in the ICU – keeping them alive on ventilators, doing life support, doing acute dialysis, doing round-the-clock care, round-the-clock board-certified intensivist care – we are still not able to make a difference in that mortality.”

Dr. Stevens added that any ICU admission for overdose from opioids is a preventable admission. “So if we have an increase in mortality of this population, we have a number of patients who have preventable deaths in our ICU,” she said.

Efforts to track this epidemic on a national level are important, she said, and the U.S. Centers for Disease Control and Prevention has been investigating opioid overdoses in some cities, including Boston, as they would any epidemic.

The factors driving the observed trends could not be determined from the study data, Dr. Stevens said. But state-specific patterns that show, for example, higher baseline rates and greater increases over time in ICU admissions for opioid overdose in Massachusetts and Indiana may be a starting point for investigation.

Certain practices in the ICU may also be inadvertently contributing. “I imagine that a patient who comes in with an opioid overdose can cause harm to themselves in a number of ways, and the things that we try to do to help them might cause harm in other ways as well,” she said. “So in an effort to try to maintain them in a safe, ventilated state, we might give them a ton of sedation that then prolongs their time on the ventilator. That’s sort of a simple example of how the two could intersect to have a multiplicative effect of harm.”

The idea for the study arose because ICU staff anecdotally noticed an uptick in admissions for opioid use disorder. “Not only were we seeing more people coming in, but we were seeing sicker people coming in, and with the associated tragedy that comes with a lot of young people coming in with opioid use disorder,” Dr. Stevens said. “We wanted to see if this was happening nationally... We asked, is this epidemic now reaching the most technologically advanced parts of our health care system?”

The investigators studied hospitals providing data to Vizient (formerly the University HealthSystem Consortium) between 2009 and 2015. The included hospitals – about 200 for each study year – were predominantly urban and university affiliated, but representation of community hospitals increased during the study period.

Ultimately, analyses were based on a total of 28.2 million hospital discharges of patients aged 18 years or older, which included 4.9 million ICU admissions.

Results reported at the meeting showed that 27,325 patients were admitted to the study hospitals’ ICUs with opioid overdose during the study period, as ascertained from billing codes.

Opioid overdose was seen in 45 patients per 10,000 ICU admissions in 2009 but rose to 65 patients per 10,000 ICU admissions in 2015, a 46% increase.

Furthermore, ICU deaths due to opioid overdose rose by 87% during the same time period, and mortality among patients admitted to the unit with overdose rose at a pace of 0.5% per month.

“This is somewhat unusual because a lot of times, when we are admitting more people to our ICUs or examining [a trend] further, mortality actually goes down. This is partly because maybe we are doing more for them and we are taking care of them in an aggressive way. But it’s also because we are admitting less sick people because we are more aware of the issue,” Dr. Stevens said. “And we saw the opposite of this – we saw that the mortality was going up.”

The use of billing data was a specific means but not a sensitive means of identifying opioid overdoses, she noted. Therefore, the observed values are likely underestimates of these outcomes.

Addressing the opioid overdose epidemic will require a multifaceted approach, according to Dr. Stevens, who disclosed that she had no relevant conflicts of interest.

“Folks are doing very impressive work in the community trying to make sure EMTs and other first responders have access to the tools that they need in those settings,” she said. “But one thing we haven’t approached before is the care that we provide in the ICU, and maybe that’s a space that we need to think more prospectively about.”

SAN FRANCISCO – The opioid overdose crisis in the United States is now plainly evident in intensive care units (ICUs), finds a study of hospitals in 44 states conducted between 2009 and 2015.

During the study period, ICU admissions for opioid overdoses increased by almost half, investigators reported in a session and related press briefing an international conference of the American Thoracic Society. Furthermore, ICU deaths from this cause roughly doubled.

Susan London/Frontline Medical News

“This means the opioid use epidemic has probably reached a new level of crisis,” said lead investigator Jennifer P. Stevens, MD, an instructor in medicine at Harvard Medical School, and an adult intensive care physician at Beth Israel Deaconess Medical Center, both in Boston. “And this means that in spite of everything that we can do in the ICU – keeping them alive on ventilators, doing life support, doing acute dialysis, doing round-the-clock care, round-the-clock board-certified intensivist care – we are still not able to make a difference in that mortality.”

Dr. Stevens added that any ICU admission for overdose from opioids is a preventable admission. “So if we have an increase in mortality of this population, we have a number of patients who have preventable deaths in our ICU,” she said.

Efforts to track this epidemic on a national level are important, she said, and the U.S. Centers for Disease Control and Prevention has been investigating opioid overdoses in some cities, including Boston, as they would any epidemic.

The factors driving the observed trends could not be determined from the study data, Dr. Stevens said. But state-specific patterns that show, for example, higher baseline rates and greater increases over time in ICU admissions for opioid overdose in Massachusetts and Indiana may be a starting point for investigation.

Certain practices in the ICU may also be inadvertently contributing. “I imagine that a patient who comes in with an opioid overdose can cause harm to themselves in a number of ways, and the things that we try to do to help them might cause harm in other ways as well,” she said. “So in an effort to try to maintain them in a safe, ventilated state, we might give them a ton of sedation that then prolongs their time on the ventilator. That’s sort of a simple example of how the two could intersect to have a multiplicative effect of harm.”

The idea for the study arose because ICU staff anecdotally noticed an uptick in admissions for opioid use disorder. “Not only were we seeing more people coming in, but we were seeing sicker people coming in, and with the associated tragedy that comes with a lot of young people coming in with opioid use disorder,” Dr. Stevens said. “We wanted to see if this was happening nationally... We asked, is this epidemic now reaching the most technologically advanced parts of our health care system?”

The investigators studied hospitals providing data to Vizient (formerly the University HealthSystem Consortium) between 2009 and 2015. The included hospitals – about 200 for each study year – were predominantly urban and university affiliated, but representation of community hospitals increased during the study period.

Ultimately, analyses were based on a total of 28.2 million hospital discharges of patients aged 18 years or older, which included 4.9 million ICU admissions.

Results reported at the meeting showed that 27,325 patients were admitted to the study hospitals’ ICUs with opioid overdose during the study period, as ascertained from billing codes.

Opioid overdose was seen in 45 patients per 10,000 ICU admissions in 2009 but rose to 65 patients per 10,000 ICU admissions in 2015, a 46% increase.

Furthermore, ICU deaths due to opioid overdose rose by 87% during the same time period, and mortality among patients admitted to the unit with overdose rose at a pace of 0.5% per month.

“This is somewhat unusual because a lot of times, when we are admitting more people to our ICUs or examining [a trend] further, mortality actually goes down. This is partly because maybe we are doing more for them and we are taking care of them in an aggressive way. But it’s also because we are admitting less sick people because we are more aware of the issue,” Dr. Stevens said. “And we saw the opposite of this – we saw that the mortality was going up.”

The use of billing data was a specific means but not a sensitive means of identifying opioid overdoses, she noted. Therefore, the observed values are likely underestimates of these outcomes.

Addressing the opioid overdose epidemic will require a multifaceted approach, according to Dr. Stevens, who disclosed that she had no relevant conflicts of interest.

“Folks are doing very impressive work in the community trying to make sure EMTs and other first responders have access to the tools that they need in those settings,” she said. “But one thing we haven’t approached before is the care that we provide in the ICU, and maybe that’s a space that we need to think more prospectively about.”

CHICAGO – Immune checkpoint blockade, especially with a combination of agents having complementary mechanisms of action, has durable efficacy when used as initial therapy for advanced melanoma, according to an update of the CheckMate 067 trial.

The trial randomized 945 treatment-naive patients with unresectable stage III or IV melanoma evenly to double-blind treatment with nivolumab, an antibody to the cell surface receptor programmed death 1 (PD-1); ipilimumab, an antibody to the T-cell receptor cytotoxic T-lymphocyte–associated antigen 4 (CTLA4); or the combination.

Initial results, after a median follow-up of about 12.4 months, showed that the risk of progression-free survival events was 58% lower with the combination and 43% lower with nivolumab alone as compared with ipilimumab alone (N Engl J Med. 2015;373[1]:23-34).

The update, now with a median follow-up of 20.7 months, showed that these results held up, with respective 58% and 45% reductions in the risk of events, researchers reported at the annual meeting of the American Society of Clinical Oncology. The combination was also superior to nivolumab alone, netting a 24% lower risk of events. Additionally, no cumulative or new toxicities were seen.

“Based on available evidence, the combination of nivolumab and ipilimumab represents a means to improve outcomes versus nivolumab alone,” said first author Jedd D. Wolchok, MD, PhD, chief of the Melanoma & Immunotherapeutics Service at the Memorial Sloan Kettering Cancer Center in New York. “Additional insights will be gained with the emergence of overall survival data.”

Neither tumor expression of PD-L1, a ligand of PD-1, nor presence of a BRAF mutation was very helpful in identifying patients who would benefit to a greater extent from these therapies.

The findings add to evidence establishing the efficacy of combination immunotherapy in melanoma, according to invited discussant Marc S. Ernstoff, MD, professor and chair of the department of medicine at the Roswell Park Cancer Institute in Buffalo, N.Y. At the same time, the trial left unanswered questions such as what strategy should be used after progression on either or both agents, and what are the appropriate doses and durations of therapy. Also unclear is which type of therapy to use first line in patients with BRAF mutations, he added. “Whether you start with immunotherapy or targeted therapy in BRAF-mutated patients is still in equipoise, and I would encourage everyone here to participate in the ECOG 6134 trial looking at the randomization of immune checkpoint therapy versus targeted therapy in BRAF-mutated patients,” he said. “The biomarker studies are still provocative, and we still need a lot more data to be able to preselect patients who might benefit from either of these therapies.”

“One has to recognize that these agents are costly,” Dr. Ernstoff maintained, with the acquisition cost of the checkpoint inhibitors ranging from roughly $140,000 to $290,000 per year depending on the agent(s) used. This issue will also have to be addressed going forward.

“The future is very bright. There are now 76 trials listed in PDQ [Physician Data Query] of combination PD-1 therapies in melanoma alone,” he concluded. “Immunotherapy continues to capture our imagination.”

The updated intent-to-treat analyses of CheckMate 067 – conducted after all patients had at least 18 months of follow-up – showed that median progression-free survival, one of the trial’s primary endpoints, was now 11.5 months with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), 6.9 months with nivolumab alone, and 2.9 months with ipilimumab alone, Dr. Wolchok reported at the meeting.

The differences translated to significantly better outcomes with the combination (hazard ratio, 0.42) and with nivolumab (HR, 0.55) as compared with ipilimumab. Moreover, the combination was superior to nivolumab (HR, 0.76).

The overall response rate, the trial’s other primary endpoint, was 57.6% with the combination and 43.7% with nivolumab alone, both of which were superior to the 19.0% with ipilimumab alone.

“While the response rates have not changed, some partial responses have evolved into complete responses over time,” Dr. Wolchok noted.

Findings were similar when patients were stratified by BRAF mutational status. And in exploratory analyses, outcomes were numerically better with the combination than with nivolumab alone regardless of whether tumors had high or low PD-L1 expression.

Safety results were much the same as previously reported. The rate of grade 3 or 4 treatment-related adverse events was 56.5% with the combination, 19.8% with nivolumab monotherapy, and 27.0% with ipilimumab monotherapy. There were no treatment-related deaths with the combination and one with each of the monotherapies.

“There is no common signature adverse event with this combination,” Dr. Wolchok pointed out. “The majority of grade 3 or 4 adverse events resolved in all of the groups with the use of established algorithms. However, as observed in prior studies, most of the endocrine events did not resolve and required hormone replacement.”

About 40% of the combination therapy group stopped treatment because of adverse events. “Interestingly, 68% of these patients who discontinued due to treatment-related adverse events developed a response, and 50% of these responses occurred after treatment had ended,” he reported. “This is very important information for us as we talk to patients and their families about the difficulties of stopping treatment.”

Dr. Wolchok disclosed that he is a consultant for Bristol-Myers Squibb, Genentech, Jounce Therapeutics, Medimmune, Merck, Polaris, Polynoma, Potenza, Tizona, Ziopharm, F-Star, Beigene, Lilly, Advaxis, and Sellas, and that he receives grant/research support from Bristol-Myers Squibb. The trial was sponsored by Bristol-Myers Squibb. Dako collaborated on development of the automated anti–PD-L1 immunohistochemistry assay.

CHICAGO – Immune checkpoint blockade, especially with a combination of agents having complementary mechanisms of action, has durable efficacy when used as initial therapy for advanced melanoma, according to an update of the CheckMate 067 trial.

The trial randomized 945 treatment-naive patients with unresectable stage III or IV melanoma evenly to double-blind treatment with nivolumab, an antibody to the cell surface receptor programmed death 1 (PD-1); ipilimumab, an antibody to the T-cell receptor cytotoxic T-lymphocyte–associated antigen 4 (CTLA4); or the combination.

Initial results, after a median follow-up of about 12.4 months, showed that the risk of progression-free survival events was 58% lower with the combination and 43% lower with nivolumab alone as compared with ipilimumab alone (N Engl J Med. 2015;373[1]:23-34).

The update, now with a median follow-up of 20.7 months, showed that these results held up, with respective 58% and 45% reductions in the risk of events, researchers reported at the annual meeting of the American Society of Clinical Oncology. The combination was also superior to nivolumab alone, netting a 24% lower risk of events. Additionally, no cumulative or new toxicities were seen.

“Based on available evidence, the combination of nivolumab and ipilimumab represents a means to improve outcomes versus nivolumab alone,” said first author Jedd D. Wolchok, MD, PhD, chief of the Melanoma & Immunotherapeutics Service at the Memorial Sloan Kettering Cancer Center in New York. “Additional insights will be gained with the emergence of overall survival data.”

Neither tumor expression of PD-L1, a ligand of PD-1, nor presence of a BRAF mutation was very helpful in identifying patients who would benefit to a greater extent from these therapies.

The findings add to evidence establishing the efficacy of combination immunotherapy in melanoma, according to invited discussant Marc S. Ernstoff, MD, professor and chair of the department of medicine at the Roswell Park Cancer Institute in Buffalo, N.Y. At the same time, the trial left unanswered questions such as what strategy should be used after progression on either or both agents, and what are the appropriate doses and durations of therapy. Also unclear is which type of therapy to use first line in patients with BRAF mutations, he added. “Whether you start with immunotherapy or targeted therapy in BRAF-mutated patients is still in equipoise, and I would encourage everyone here to participate in the ECOG 6134 trial looking at the randomization of immune checkpoint therapy versus targeted therapy in BRAF-mutated patients,” he said. “The biomarker studies are still provocative, and we still need a lot more data to be able to preselect patients who might benefit from either of these therapies.”

“One has to recognize that these agents are costly,” Dr. Ernstoff maintained, with the acquisition cost of the checkpoint inhibitors ranging from roughly $140,000 to $290,000 per year depending on the agent(s) used. This issue will also have to be addressed going forward.

“The future is very bright. There are now 76 trials listed in PDQ [Physician Data Query] of combination PD-1 therapies in melanoma alone,” he concluded. “Immunotherapy continues to capture our imagination.”

The updated intent-to-treat analyses of CheckMate 067 – conducted after all patients had at least 18 months of follow-up – showed that median progression-free survival, one of the trial’s primary endpoints, was now 11.5 months with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), 6.9 months with nivolumab alone, and 2.9 months with ipilimumab alone, Dr. Wolchok reported at the meeting.

The differences translated to significantly better outcomes with the combination (hazard ratio, 0.42) and with nivolumab (HR, 0.55) as compared with ipilimumab. Moreover, the combination was superior to nivolumab (HR, 0.76).

The overall response rate, the trial’s other primary endpoint, was 57.6% with the combination and 43.7% with nivolumab alone, both of which were superior to the 19.0% with ipilimumab alone.

“While the response rates have not changed, some partial responses have evolved into complete responses over time,” Dr. Wolchok noted.

Findings were similar when patients were stratified by BRAF mutational status. And in exploratory analyses, outcomes were numerically better with the combination than with nivolumab alone regardless of whether tumors had high or low PD-L1 expression.

Safety results were much the same as previously reported. The rate of grade 3 or 4 treatment-related adverse events was 56.5% with the combination, 19.8% with nivolumab monotherapy, and 27.0% with ipilimumab monotherapy. There were no treatment-related deaths with the combination and one with each of the monotherapies.

“There is no common signature adverse event with this combination,” Dr. Wolchok pointed out. “The majority of grade 3 or 4 adverse events resolved in all of the groups with the use of established algorithms. However, as observed in prior studies, most of the endocrine events did not resolve and required hormone replacement.”

About 40% of the combination therapy group stopped treatment because of adverse events. “Interestingly, 68% of these patients who discontinued due to treatment-related adverse events developed a response, and 50% of these responses occurred after treatment had ended,” he reported. “This is very important information for us as we talk to patients and their families about the difficulties of stopping treatment.”

Dr. Wolchok disclosed that he is a consultant for Bristol-Myers Squibb, Genentech, Jounce Therapeutics, Medimmune, Merck, Polaris, Polynoma, Potenza, Tizona, Ziopharm, F-Star, Beigene, Lilly, Advaxis, and Sellas, and that he receives grant/research support from Bristol-Myers Squibb. The trial was sponsored by Bristol-Myers Squibb. Dako collaborated on development of the automated anti–PD-L1 immunohistochemistry assay.

CHICAGO – Immune checkpoint blockade, especially with a combination of agents having complementary mechanisms of action, has durable efficacy when used as initial therapy for advanced melanoma, according to an update of the CheckMate 067 trial.

The trial randomized 945 treatment-naive patients with unresectable stage III or IV melanoma evenly to double-blind treatment with nivolumab, an antibody to the cell surface receptor programmed death 1 (PD-1); ipilimumab, an antibody to the T-cell receptor cytotoxic T-lymphocyte–associated antigen 4 (CTLA4); or the combination.

Initial results, after a median follow-up of about 12.4 months, showed that the risk of progression-free survival events was 58% lower with the combination and 43% lower with nivolumab alone as compared with ipilimumab alone (N Engl J Med. 2015;373[1]:23-34).

The update, now with a median follow-up of 20.7 months, showed that these results held up, with respective 58% and 45% reductions in the risk of events, researchers reported at the annual meeting of the American Society of Clinical Oncology. The combination was also superior to nivolumab alone, netting a 24% lower risk of events. Additionally, no cumulative or new toxicities were seen.

“Based on available evidence, the combination of nivolumab and ipilimumab represents a means to improve outcomes versus nivolumab alone,” said first author Jedd D. Wolchok, MD, PhD, chief of the Melanoma & Immunotherapeutics Service at the Memorial Sloan Kettering Cancer Center in New York. “Additional insights will be gained with the emergence of overall survival data.”

Neither tumor expression of PD-L1, a ligand of PD-1, nor presence of a BRAF mutation was very helpful in identifying patients who would benefit to a greater extent from these therapies.

The findings add to evidence establishing the efficacy of combination immunotherapy in melanoma, according to invited discussant Marc S. Ernstoff, MD, professor and chair of the department of medicine at the Roswell Park Cancer Institute in Buffalo, N.Y. At the same time, the trial left unanswered questions such as what strategy should be used after progression on either or both agents, and what are the appropriate doses and durations of therapy. Also unclear is which type of therapy to use first line in patients with BRAF mutations, he added. “Whether you start with immunotherapy or targeted therapy in BRAF-mutated patients is still in equipoise, and I would encourage everyone here to participate in the ECOG 6134 trial looking at the randomization of immune checkpoint therapy versus targeted therapy in BRAF-mutated patients,” he said. “The biomarker studies are still provocative, and we still need a lot more data to be able to preselect patients who might benefit from either of these therapies.”

“One has to recognize that these agents are costly,” Dr. Ernstoff maintained, with the acquisition cost of the checkpoint inhibitors ranging from roughly $140,000 to $290,000 per year depending on the agent(s) used. This issue will also have to be addressed going forward.

“The future is very bright. There are now 76 trials listed in PDQ [Physician Data Query] of combination PD-1 therapies in melanoma alone,” he concluded. “Immunotherapy continues to capture our imagination.”

The updated intent-to-treat analyses of CheckMate 067 – conducted after all patients had at least 18 months of follow-up – showed that median progression-free survival, one of the trial’s primary endpoints, was now 11.5 months with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), 6.9 months with nivolumab alone, and 2.9 months with ipilimumab alone, Dr. Wolchok reported at the meeting.

The differences translated to significantly better outcomes with the combination (hazard ratio, 0.42) and with nivolumab (HR, 0.55) as compared with ipilimumab. Moreover, the combination was superior to nivolumab (HR, 0.76).

The overall response rate, the trial’s other primary endpoint, was 57.6% with the combination and 43.7% with nivolumab alone, both of which were superior to the 19.0% with ipilimumab alone.

“While the response rates have not changed, some partial responses have evolved into complete responses over time,” Dr. Wolchok noted.

Findings were similar when patients were stratified by BRAF mutational status. And in exploratory analyses, outcomes were numerically better with the combination than with nivolumab alone regardless of whether tumors had high or low PD-L1 expression.

Safety results were much the same as previously reported. The rate of grade 3 or 4 treatment-related adverse events was 56.5% with the combination, 19.8% with nivolumab monotherapy, and 27.0% with ipilimumab monotherapy. There were no treatment-related deaths with the combination and one with each of the monotherapies.

“There is no common signature adverse event with this combination,” Dr. Wolchok pointed out. “The majority of grade 3 or 4 adverse events resolved in all of the groups with the use of established algorithms. However, as observed in prior studies, most of the endocrine events did not resolve and required hormone replacement.”

About 40% of the combination therapy group stopped treatment because of adverse events. “Interestingly, 68% of these patients who discontinued due to treatment-related adverse events developed a response, and 50% of these responses occurred after treatment had ended,” he reported. “This is very important information for us as we talk to patients and their families about the difficulties of stopping treatment.”

Dr. Wolchok disclosed that he is a consultant for Bristol-Myers Squibb, Genentech, Jounce Therapeutics, Medimmune, Merck, Polaris, Polynoma, Potenza, Tizona, Ziopharm, F-Star, Beigene, Lilly, Advaxis, and Sellas, and that he receives grant/research support from Bristol-Myers Squibb. The trial was sponsored by Bristol-Myers Squibb. Dako collaborated on development of the automated anti–PD-L1 immunohistochemistry assay.

SAN FRANCISCO – The work environment for nurses and the physician staffing model in the intensive care unit influence patients’ likelihood of acquiring ventilator-associated pneumonia (VAP), based on a cohort study of 25 ICUs.

Overall, each 1-point increase in the score for the nurse work environment – indicating that nurses had a greater sense of playing an important role in patient care – was unexpectedly associated with a roughly sixfold higher rate of VAP among the ICU’s patients, according to data reported in a session and press briefing at an international conference of the American Thoracic Society. However, additional analyses showed that the rate of VAP was higher in closed units where a board-certified critical care physician (intensivist) managed and led care rather than an open unit where care is shared.

“We think that the organization of the ICU is actually influencing nursing practice, which is a really novel finding,” commented first author Deena Kelly Costa, PhD, RN, of the University of Michigan School of Nursing in Ann Arbor. “In closed ICUs, when you have a board-certified physician and an ICU team managing and leading care, even if the work environment is better, nurses may not feel as empowered to standardize their care or practice.”

“ICU nurses are the ones who are primarily responsible for VAP preventive practices: they keep the head of the bed higher than 45 degrees, they conduct oral care, they conduct (patient) surveillance. ICU physicians are involved with writing the orders and ventilator setting management. So how these providers work together could theoretically influence the risk for patients developing VAP,” Dr. Costa said.

“We need to be thinking a little bit more critically about not only the care that’s happening at the bedside... but also at an organizational level. How are these providers organized, and can we work together to improve patient outcomes?”

“I’m not suggesting that we get rid of all closed ICUs because I don’t think that’s the solution,” Dr. Costa maintained. “I think from an administrative perspective, we need to be considering what’s the organization of these clinicians and this unit, and [in a context-specific manner], how can we improve it for better patient outcomes? That may be both working on improving the work environment and making the nurses feel more empowered, or it could be potentially considering other staffing models.”

Some data have already linked a more favorable nurse work environment and the presence of a board-certified critical care physician independently with better patient outcomes in the ICU. But studies of their joint impact are lacking.

The investigators performed a secondary, unit-level analysis of nurse survey data collected during 2005 and 2006 in ICUs in southern Michigan.

In all, 462 nurses working in 25 ICUs completed the Practice Environment Scale of the Nursing Work Index, on which averaged summary scores range between 1 (unfavorable) and 4 (favorable). The scale captures environmental factors such as the adequacy of resources for nurses, support from their managers, and their level of involvement in hospital policy decisions.

The rate of VAP during the same period was assessed using data from more than 1,000 patients from each ICU.

The summary nurse work environment score averaged 2.69 points in the 21 ICUs that had a closed physician staffing model and 2.62 points in the 4 ICUs that had an open physician staffing model. The respective rates of VAP were 7.5% and 2.5%.

In adjusted analysis among all 25 ICUs, each 1-point increase in an ICU’s Practice Environment Scale score was associated with a sharply higher rate of VAP on the unit (adjusted incidence rate ratio, 5.76; P = .02).

However, there was a strong interaction between the score and physician staffing model (P less than .001). In open ICUs, as the score rose, the rate of VAP fell (from about 16% to 5%), whereas in closed ICUs, as the score rose, so did the rate of VAP (from about 3% to 14%).

Dr. Costa disclosed that she had no relevant conflicts of interest. The parent survey was funded by the Blue Cross Blue Shield Foundation of Michigan.

SAN FRANCISCO – The work environment for nurses and the physician staffing model in the intensive care unit influence patients’ likelihood of acquiring ventilator-associated pneumonia (VAP), based on a cohort study of 25 ICUs.

Overall, each 1-point increase in the score for the nurse work environment – indicating that nurses had a greater sense of playing an important role in patient care – was unexpectedly associated with a roughly sixfold higher rate of VAP among the ICU’s patients, according to data reported in a session and press briefing at an international conference of the American Thoracic Society. However, additional analyses showed that the rate of VAP was higher in closed units where a board-certified critical care physician (intensivist) managed and led care rather than an open unit where care is shared.

“We think that the organization of the ICU is actually influencing nursing practice, which is a really novel finding,” commented first author Deena Kelly Costa, PhD, RN, of the University of Michigan School of Nursing in Ann Arbor. “In closed ICUs, when you have a board-certified physician and an ICU team managing and leading care, even if the work environment is better, nurses may not feel as empowered to standardize their care or practice.”

“ICU nurses are the ones who are primarily responsible for VAP preventive practices: they keep the head of the bed higher than 45 degrees, they conduct oral care, they conduct (patient) surveillance. ICU physicians are involved with writing the orders and ventilator setting management. So how these providers work together could theoretically influence the risk for patients developing VAP,” Dr. Costa said.

“We need to be thinking a little bit more critically about not only the care that’s happening at the bedside... but also at an organizational level. How are these providers organized, and can we work together to improve patient outcomes?”

“I’m not suggesting that we get rid of all closed ICUs because I don’t think that’s the solution,” Dr. Costa maintained. “I think from an administrative perspective, we need to be considering what’s the organization of these clinicians and this unit, and [in a context-specific manner], how can we improve it for better patient outcomes? That may be both working on improving the work environment and making the nurses feel more empowered, or it could be potentially considering other staffing models.”

Some data have already linked a more favorable nurse work environment and the presence of a board-certified critical care physician independently with better patient outcomes in the ICU. But studies of their joint impact are lacking.

The investigators performed a secondary, unit-level analysis of nurse survey data collected during 2005 and 2006 in ICUs in southern Michigan.

In all, 462 nurses working in 25 ICUs completed the Practice Environment Scale of the Nursing Work Index, on which averaged summary scores range between 1 (unfavorable) and 4 (favorable). The scale captures environmental factors such as the adequacy of resources for nurses, support from their managers, and their level of involvement in hospital policy decisions.

The rate of VAP during the same period was assessed using data from more than 1,000 patients from each ICU.

The summary nurse work environment score averaged 2.69 points in the 21 ICUs that had a closed physician staffing model and 2.62 points in the 4 ICUs that had an open physician staffing model. The respective rates of VAP were 7.5% and 2.5%.

In adjusted analysis among all 25 ICUs, each 1-point increase in an ICU’s Practice Environment Scale score was associated with a sharply higher rate of VAP on the unit (adjusted incidence rate ratio, 5.76; P = .02).

However, there was a strong interaction between the score and physician staffing model (P less than .001). In open ICUs, as the score rose, the rate of VAP fell (from about 16% to 5%), whereas in closed ICUs, as the score rose, so did the rate of VAP (from about 3% to 14%).

Dr. Costa disclosed that she had no relevant conflicts of interest. The parent survey was funded by the Blue Cross Blue Shield Foundation of Michigan.

SAN FRANCISCO – The work environment for nurses and the physician staffing model in the intensive care unit influence patients’ likelihood of acquiring ventilator-associated pneumonia (VAP), based on a cohort study of 25 ICUs.

Overall, each 1-point increase in the score for the nurse work environment – indicating that nurses had a greater sense of playing an important role in patient care – was unexpectedly associated with a roughly sixfold higher rate of VAP among the ICU’s patients, according to data reported in a session and press briefing at an international conference of the American Thoracic Society. However, additional analyses showed that the rate of VAP was higher in closed units where a board-certified critical care physician (intensivist) managed and led care rather than an open unit where care is shared.

“We think that the organization of the ICU is actually influencing nursing practice, which is a really novel finding,” commented first author Deena Kelly Costa, PhD, RN, of the University of Michigan School of Nursing in Ann Arbor. “In closed ICUs, when you have a board-certified physician and an ICU team managing and leading care, even if the work environment is better, nurses may not feel as empowered to standardize their care or practice.”

“ICU nurses are the ones who are primarily responsible for VAP preventive practices: they keep the head of the bed higher than 45 degrees, they conduct oral care, they conduct (patient) surveillance. ICU physicians are involved with writing the orders and ventilator setting management. So how these providers work together could theoretically influence the risk for patients developing VAP,” Dr. Costa said.

“We need to be thinking a little bit more critically about not only the care that’s happening at the bedside... but also at an organizational level. How are these providers organized, and can we work together to improve patient outcomes?”

“I’m not suggesting that we get rid of all closed ICUs because I don’t think that’s the solution,” Dr. Costa maintained. “I think from an administrative perspective, we need to be considering what’s the organization of these clinicians and this unit, and [in a context-specific manner], how can we improve it for better patient outcomes? That may be both working on improving the work environment and making the nurses feel more empowered, or it could be potentially considering other staffing models.”

Some data have already linked a more favorable nurse work environment and the presence of a board-certified critical care physician independently with better patient outcomes in the ICU. But studies of their joint impact are lacking.

The investigators performed a secondary, unit-level analysis of nurse survey data collected during 2005 and 2006 in ICUs in southern Michigan.

In all, 462 nurses working in 25 ICUs completed the Practice Environment Scale of the Nursing Work Index, on which averaged summary scores range between 1 (unfavorable) and 4 (favorable). The scale captures environmental factors such as the adequacy of resources for nurses, support from their managers, and their level of involvement in hospital policy decisions.

The rate of VAP during the same period was assessed using data from more than 1,000 patients from each ICU.

The summary nurse work environment score averaged 2.69 points in the 21 ICUs that had a closed physician staffing model and 2.62 points in the 4 ICUs that had an open physician staffing model. The respective rates of VAP were 7.5% and 2.5%.

In adjusted analysis among all 25 ICUs, each 1-point increase in an ICU’s Practice Environment Scale score was associated with a sharply higher rate of VAP on the unit (adjusted incidence rate ratio, 5.76; P = .02).

However, there was a strong interaction between the score and physician staffing model (P less than .001). In open ICUs, as the score rose, the rate of VAP fell (from about 16% to 5%), whereas in closed ICUs, as the score rose, so did the rate of VAP (from about 3% to 14%).

Dr. Costa disclosed that she had no relevant conflicts of interest. The parent survey was funded by the Blue Cross Blue Shield Foundation of Michigan.

SAN FRANCISCO – Hospitalized patients who have a change in the medical residents responsible for their care are more likely to die, finds a retrospective cohort study of roughly a quarter million discharges from Veterans Affairs medical centers.

A monthly change in resident care was associated with 9%-20% higher adjusted odds of death during the hospital stay and after discharge, investigators reported in a poster discussion session and press briefing at an international conference of the American Thoracic Society. Analyses suggested that such transitions accounted for 718 additional deaths in the hospital alone during the 6-year study period.

“These are very strong findings,” said Dr. Joshua L. Denson, a fellow in the divisions of pulmonary sciences and critical care medicine at the University of Colorado, Aurora.

The study results represent an important initial step in bringing the problem to light, he said. “Handoffs shift to shift have been looked at, but not this end-of-month, more permanent switching, which I think is a much more substantial transition in care.”

The factors driving the increased mortality are unclear, according to Dr. Denson; however, “when you go on to a new service [as a resident] ... you are now responsible for 20 new people all of a sudden that night.” Therefore, these transitions can be a hectic time characterized by reduced communication and inefficient discharges. In addition, the incoming residents lack familiarity with their new patients’ particulars.

“The handoffs are definitely not preventable, so this is something that has to be dealt with,” he maintained. The study’s findings hint at several possible areas for improvement.

None of the 10 residency programs surveyed provided formal education for monthly resident handoffs, focusing instead on handoffs at shift changes, and most programs lacked a standard procedure, with just one requiring that the handoff be done in person. The programs also varied greatly in their staggering of handoffs – separating transitions of interns (first-year residents) and higher-level residents by at least a few days – to minimize impact.

Despite the absence of outcomes data in this area, some hospitals are forging ahead with their own interventions intended to smooth care transitions, Dr. Denson reported. “In at least two hospitals that I’ve worked in, they are implementing what is called a warm handoff,” he explained. “Basically, a resident from the prior rotation comes the next day and rounds with the new team so he can tell them, ‘Oh, this guy looks a little worse today, you may want to watch him,’ or ‘He looks a little better.’ ”

In the study, conducted while Dr. Denson was chief resident at the NYU School of Medicine, he and his colleagues analyzed data from 10 university-affiliated Veterans Affairs hospitals and internal medicine residency programs that provided their residents’ schedules. Analyses were based on a total of 230,701 discharges of adult medical patients between July 2008 and June 2014.

Hospitalized patients were categorized as having a transition in resident care if they were admitted before the date of an end-of-month house staff transition in care and were discharged in the week after it.

In unadjusted analyses, patients who had a transition of care – whether of intern only, resident only, or both – had significantly higher odds of inpatient mortality and of 30-day mortality and 90-day postdischarge mortality, compared with counterparts who did not have the corresponding transition of care.

In adjusted analyses, patients who had an intern transition still had higher odds of in-hospital mortality (odds ratio, 1.14). In addition, patients had persistently elevated odds of 30-day mortality and 90-day postdischarge mortality if they had an intern transition (odds ratios, 1.20 and 1.17, respectively), a resident transition (1.15 and 1.14), or both (1.10 and 1.09).

The findings “suggest possibly a level-of-training effect to these transitions, as it’s the most inexperienced people that have the higher rate of mortality,” noted Dr. Denson, who disclosed that he had no relevant conflicts of interest. “Interns, being the first-years, tend to carry the bulk of the work in most hospitals, which is an interesting paradigm in our organization. And that may be a good explanation for why we are seeing this.”

SAN FRANCISCO – Hospitalized patients who have a change in the medical residents responsible for their care are more likely to die, finds a retrospective cohort study of roughly a quarter million discharges from Veterans Affairs medical centers.

A monthly change in resident care was associated with 9%-20% higher adjusted odds of death during the hospital stay and after discharge, investigators reported in a poster discussion session and press briefing at an international conference of the American Thoracic Society. Analyses suggested that such transitions accounted for 718 additional deaths in the hospital alone during the 6-year study period.

“These are very strong findings,” said Dr. Joshua L. Denson, a fellow in the divisions of pulmonary sciences and critical care medicine at the University of Colorado, Aurora.

The study results represent an important initial step in bringing the problem to light, he said. “Handoffs shift to shift have been looked at, but not this end-of-month, more permanent switching, which I think is a much more substantial transition in care.”

The factors driving the increased mortality are unclear, according to Dr. Denson; however, “when you go on to a new service [as a resident] ... you are now responsible for 20 new people all of a sudden that night.” Therefore, these transitions can be a hectic time characterized by reduced communication and inefficient discharges. In addition, the incoming residents lack familiarity with their new patients’ particulars.

“The handoffs are definitely not preventable, so this is something that has to be dealt with,” he maintained. The study’s findings hint at several possible areas for improvement.

None of the 10 residency programs surveyed provided formal education for monthly resident handoffs, focusing instead on handoffs at shift changes, and most programs lacked a standard procedure, with just one requiring that the handoff be done in person. The programs also varied greatly in their staggering of handoffs – separating transitions of interns (first-year residents) and higher-level residents by at least a few days – to minimize impact.

Despite the absence of outcomes data in this area, some hospitals are forging ahead with their own interventions intended to smooth care transitions, Dr. Denson reported. “In at least two hospitals that I’ve worked in, they are implementing what is called a warm handoff,” he explained. “Basically, a resident from the prior rotation comes the next day and rounds with the new team so he can tell them, ‘Oh, this guy looks a little worse today, you may want to watch him,’ or ‘He looks a little better.’ ”

In the study, conducted while Dr. Denson was chief resident at the NYU School of Medicine, he and his colleagues analyzed data from 10 university-affiliated Veterans Affairs hospitals and internal medicine residency programs that provided their residents’ schedules. Analyses were based on a total of 230,701 discharges of adult medical patients between July 2008 and June 2014.

Hospitalized patients were categorized as having a transition in resident care if they were admitted before the date of an end-of-month house staff transition in care and were discharged in the week after it.

In unadjusted analyses, patients who had a transition of care – whether of intern only, resident only, or both – had significantly higher odds of inpatient mortality and of 30-day mortality and 90-day postdischarge mortality, compared with counterparts who did not have the corresponding transition of care.

In adjusted analyses, patients who had an intern transition still had higher odds of in-hospital mortality (odds ratio, 1.14). In addition, patients had persistently elevated odds of 30-day mortality and 90-day postdischarge mortality if they had an intern transition (odds ratios, 1.20 and 1.17, respectively), a resident transition (1.15 and 1.14), or both (1.10 and 1.09).

The findings “suggest possibly a level-of-training effect to these transitions, as it’s the most inexperienced people that have the higher rate of mortality,” noted Dr. Denson, who disclosed that he had no relevant conflicts of interest. “Interns, being the first-years, tend to carry the bulk of the work in most hospitals, which is an interesting paradigm in our organization. And that may be a good explanation for why we are seeing this.”

SAN FRANCISCO – Hospitalized patients who have a change in the medical residents responsible for their care are more likely to die, finds a retrospective cohort study of roughly a quarter million discharges from Veterans Affairs medical centers.

A monthly change in resident care was associated with 9%-20% higher adjusted odds of death during the hospital stay and after discharge, investigators reported in a poster discussion session and press briefing at an international conference of the American Thoracic Society. Analyses suggested that such transitions accounted for 718 additional deaths in the hospital alone during the 6-year study period.

“These are very strong findings,” said Dr. Joshua L. Denson, a fellow in the divisions of pulmonary sciences and critical care medicine at the University of Colorado, Aurora.

The study results represent an important initial step in bringing the problem to light, he said. “Handoffs shift to shift have been looked at, but not this end-of-month, more permanent switching, which I think is a much more substantial transition in care.”

The factors driving the increased mortality are unclear, according to Dr. Denson; however, “when you go on to a new service [as a resident] ... you are now responsible for 20 new people all of a sudden that night.” Therefore, these transitions can be a hectic time characterized by reduced communication and inefficient discharges. In addition, the incoming residents lack familiarity with their new patients’ particulars.

“The handoffs are definitely not preventable, so this is something that has to be dealt with,” he maintained. The study’s findings hint at several possible areas for improvement.

None of the 10 residency programs surveyed provided formal education for monthly resident handoffs, focusing instead on handoffs at shift changes, and most programs lacked a standard procedure, with just one requiring that the handoff be done in person. The programs also varied greatly in their staggering of handoffs – separating transitions of interns (first-year residents) and higher-level residents by at least a few days – to minimize impact.

Despite the absence of outcomes data in this area, some hospitals are forging ahead with their own interventions intended to smooth care transitions, Dr. Denson reported. “In at least two hospitals that I’ve worked in, they are implementing what is called a warm handoff,” he explained. “Basically, a resident from the prior rotation comes the next day and rounds with the new team so he can tell them, ‘Oh, this guy looks a little worse today, you may want to watch him,’ or ‘He looks a little better.’ ”

In the study, conducted while Dr. Denson was chief resident at the NYU School of Medicine, he and his colleagues analyzed data from 10 university-affiliated Veterans Affairs hospitals and internal medicine residency programs that provided their residents’ schedules. Analyses were based on a total of 230,701 discharges of adult medical patients between July 2008 and June 2014.

Hospitalized patients were categorized as having a transition in resident care if they were admitted before the date of an end-of-month house staff transition in care and were discharged in the week after it.

In unadjusted analyses, patients who had a transition of care – whether of intern only, resident only, or both – had significantly higher odds of inpatient mortality and of 30-day mortality and 90-day postdischarge mortality, compared with counterparts who did not have the corresponding transition of care.

In adjusted analyses, patients who had an intern transition still had higher odds of in-hospital mortality (odds ratio, 1.14). In addition, patients had persistently elevated odds of 30-day mortality and 90-day postdischarge mortality if they had an intern transition (odds ratios, 1.20 and 1.17, respectively), a resident transition (1.15 and 1.14), or both (1.10 and 1.09).

The findings “suggest possibly a level-of-training effect to these transitions, as it’s the most inexperienced people that have the higher rate of mortality,” noted Dr. Denson, who disclosed that he had no relevant conflicts of interest. “Interns, being the first-years, tend to carry the bulk of the work in most hospitals, which is an interesting paradigm in our organization. And that may be a good explanation for why we are seeing this.”