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IL-2 and IL-8 elevated after gluten ingestion on gluten-free diet
CHICAGO – A gluten-free diet is often implemented by patients before they are evaluated for celiac disease, which, in turn, does not allow for accurate celiac disease testing.
A new study shows, however, that measuring serum cytokines following a gluten challenge may allow an accurate diagnosis of celiac disease to be made, even after patients have been on a gluten-free diet.
Levels of IL-2 and IL-8 were increased 2-4 hours after ingestion of gluten. Elevations in other cytokines occurred less frequently, and changes in cytokine levels were similar in both serum and plasma.
“IL-2 is a cytokine produced exclusively by T cells and goes up from 2 hours after gluten consumption in celiac patients and is highly specific,” said study author Robert P. Anderson, MD, of Immusant, Cambridge, Mass., who presented the findings of his study at Digestive Disease Week®. “Rises in IL 8 are less but significant as well.”
The authors note that individuals who are already on a gluten-free diet and who would like a definitive diagnosis of celiac disease all too often refuse or are unable to tolerate a gluten challenge for the time period that is needed – usually 4 or more weeks – for the serologic and histologic markers of celiac disease to become abnormal.
Dr. Anderson pointed out that elevated plasma levels of IL-2 and IL-8 accompanied by gastrointestinal symptoms have been observed 4 hours after receiving a single dose of Nexvax2, a therapeutic vaccine being developed by Immusant. The peptide-based vaccine is intended to protect against the effects of gluten exposure while maintaining a gluten-free diet in HLA-DQ2.5+ patients with celiac disease.
In this study, Dr. Anderson and his colleagues hypothesized that patients with celiac disease who were on a gluten-free diet would also exhibit elevated serum IL-2 and IL-8 after an oral gluten versus placebo challenge.
The cohort was comprised of 21 adults with HLA-DQ2.5+ celiac disease who were compliant with a gluten-free diet and who were randomized to consume either vital wheat gluten flour (5 g; ~ 3 g gluten) or a matched gluten-free flour drink (placebo) over 10 minutes.
Blood was collected prior to the challenge and then at 4, 6, and 24 hours afterwards. In addition, patient vital signs and reported outcomes were recorded hourly, and adverse events were tracked from day 1 to day 6.
At 4 hours after ingesting gluten, serum IL-2 and IL-8 were both significantly higher, compared with placebo.
“There was a 20-fold increase in IL-2 after gluten was consumed, between 3 and 5 hours afterwards,” said Dr. Anderson. “IL-8 went up but not as much.”
The median change from baseline for IL-2 after gluten intake was 19.5 ([7.0-47.1], vs. 0.7 [0.5-1.2] for placebo; P = .0001). For IL-8 it was 2.4 (1.2-4.9) vs. 1.1 (0.8-1.2) (P = .012).
Patient-reported outcomes were worse among those in the gluten group (7/12), compared with the placebo group (3/9), after 3 hours but did not reach statistical significance.
He added that his team is in the process of conducting a further study to assess the diagnostic utility of measuring cytokine activity.
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
CHICAGO – A gluten-free diet is often implemented by patients before they are evaluated for celiac disease, which, in turn, does not allow for accurate celiac disease testing.
A new study shows, however, that measuring serum cytokines following a gluten challenge may allow an accurate diagnosis of celiac disease to be made, even after patients have been on a gluten-free diet.
Levels of IL-2 and IL-8 were increased 2-4 hours after ingestion of gluten. Elevations in other cytokines occurred less frequently, and changes in cytokine levels were similar in both serum and plasma.
“IL-2 is a cytokine produced exclusively by T cells and goes up from 2 hours after gluten consumption in celiac patients and is highly specific,” said study author Robert P. Anderson, MD, of Immusant, Cambridge, Mass., who presented the findings of his study at Digestive Disease Week®. “Rises in IL 8 are less but significant as well.”
The authors note that individuals who are already on a gluten-free diet and who would like a definitive diagnosis of celiac disease all too often refuse or are unable to tolerate a gluten challenge for the time period that is needed – usually 4 or more weeks – for the serologic and histologic markers of celiac disease to become abnormal.
Dr. Anderson pointed out that elevated plasma levels of IL-2 and IL-8 accompanied by gastrointestinal symptoms have been observed 4 hours after receiving a single dose of Nexvax2, a therapeutic vaccine being developed by Immusant. The peptide-based vaccine is intended to protect against the effects of gluten exposure while maintaining a gluten-free diet in HLA-DQ2.5+ patients with celiac disease.
In this study, Dr. Anderson and his colleagues hypothesized that patients with celiac disease who were on a gluten-free diet would also exhibit elevated serum IL-2 and IL-8 after an oral gluten versus placebo challenge.
The cohort was comprised of 21 adults with HLA-DQ2.5+ celiac disease who were compliant with a gluten-free diet and who were randomized to consume either vital wheat gluten flour (5 g; ~ 3 g gluten) or a matched gluten-free flour drink (placebo) over 10 minutes.
Blood was collected prior to the challenge and then at 4, 6, and 24 hours afterwards. In addition, patient vital signs and reported outcomes were recorded hourly, and adverse events were tracked from day 1 to day 6.
At 4 hours after ingesting gluten, serum IL-2 and IL-8 were both significantly higher, compared with placebo.
“There was a 20-fold increase in IL-2 after gluten was consumed, between 3 and 5 hours afterwards,” said Dr. Anderson. “IL-8 went up but not as much.”
The median change from baseline for IL-2 after gluten intake was 19.5 ([7.0-47.1], vs. 0.7 [0.5-1.2] for placebo; P = .0001). For IL-8 it was 2.4 (1.2-4.9) vs. 1.1 (0.8-1.2) (P = .012).
Patient-reported outcomes were worse among those in the gluten group (7/12), compared with the placebo group (3/9), after 3 hours but did not reach statistical significance.
He added that his team is in the process of conducting a further study to assess the diagnostic utility of measuring cytokine activity.
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
CHICAGO – A gluten-free diet is often implemented by patients before they are evaluated for celiac disease, which, in turn, does not allow for accurate celiac disease testing.
A new study shows, however, that measuring serum cytokines following a gluten challenge may allow an accurate diagnosis of celiac disease to be made, even after patients have been on a gluten-free diet.
Levels of IL-2 and IL-8 were increased 2-4 hours after ingestion of gluten. Elevations in other cytokines occurred less frequently, and changes in cytokine levels were similar in both serum and plasma.
“IL-2 is a cytokine produced exclusively by T cells and goes up from 2 hours after gluten consumption in celiac patients and is highly specific,” said study author Robert P. Anderson, MD, of Immusant, Cambridge, Mass., who presented the findings of his study at Digestive Disease Week®. “Rises in IL 8 are less but significant as well.”
The authors note that individuals who are already on a gluten-free diet and who would like a definitive diagnosis of celiac disease all too often refuse or are unable to tolerate a gluten challenge for the time period that is needed – usually 4 or more weeks – for the serologic and histologic markers of celiac disease to become abnormal.
Dr. Anderson pointed out that elevated plasma levels of IL-2 and IL-8 accompanied by gastrointestinal symptoms have been observed 4 hours after receiving a single dose of Nexvax2, a therapeutic vaccine being developed by Immusant. The peptide-based vaccine is intended to protect against the effects of gluten exposure while maintaining a gluten-free diet in HLA-DQ2.5+ patients with celiac disease.
In this study, Dr. Anderson and his colleagues hypothesized that patients with celiac disease who were on a gluten-free diet would also exhibit elevated serum IL-2 and IL-8 after an oral gluten versus placebo challenge.
The cohort was comprised of 21 adults with HLA-DQ2.5+ celiac disease who were compliant with a gluten-free diet and who were randomized to consume either vital wheat gluten flour (5 g; ~ 3 g gluten) or a matched gluten-free flour drink (placebo) over 10 minutes.
Blood was collected prior to the challenge and then at 4, 6, and 24 hours afterwards. In addition, patient vital signs and reported outcomes were recorded hourly, and adverse events were tracked from day 1 to day 6.
At 4 hours after ingesting gluten, serum IL-2 and IL-8 were both significantly higher, compared with placebo.
“There was a 20-fold increase in IL-2 after gluten was consumed, between 3 and 5 hours afterwards,” said Dr. Anderson. “IL-8 went up but not as much.”
The median change from baseline for IL-2 after gluten intake was 19.5 ([7.0-47.1], vs. 0.7 [0.5-1.2] for placebo; P = .0001). For IL-8 it was 2.4 (1.2-4.9) vs. 1.1 (0.8-1.2) (P = .012).
Patient-reported outcomes were worse among those in the gluten group (7/12), compared with the placebo group (3/9), after 3 hours but did not reach statistical significance.
He added that his team is in the process of conducting a further study to assess the diagnostic utility of measuring cytokine activity.
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
AT DDW
Key clinical point: Measuring serum cytokines can potentially be used to diagnose celiac disease after the patient has been on a gluten-free diet.
Major finding: There was a median 19.5-fold change from baseline for IL-2 after gluten intake (7.0-fold to 47.1-fold) and 24-fold for IL-8 (1.2-fold to 4.9-fold).
Data source: Randomized trial comprising 21 volunteers with celiac disease.
Disclosures: Dr. Anderson is employed by Immusant.
Misoprostol effective in healing aspirin-induced small bowel bleeding
CHICAGO – , a small study showed.
Compared with placebo, it was superior in healing small bowel ulcers. A total of 12 patients who received misoprostol had complete healing at 8 weeks, compared with 4 in the placebo group (P = .017).
“Among patients with overt bleeding or anemia from small bowel lesions who receive continuous aspirin therapy, misoprostol is superior to placebo in achieving complete mucosal healing,” said lead author Francis Chan, MD, professor of gastroenterology and hepatology at the Chinese University of Hong Kong, who presented the findings at the annual Digestive Disease Week®.
Millions of individuals use low-dose aspirin daily to lower their risk of stroke and cardiovascular events, but they face a risk of gastrointestinal bleeding. In fact, Dr. Chan pointed out, continuous aspirin use has been associated with a threefold risk of a lower GI bleed.
“But to date, there is no effective pharmacological treatment for small bowel ulcers that are associated with use of low-dose aspirin,” he said.
Misoprostol is a synthetic prostaglandin E1 analog that is indicated for reducing the risk of NSAID–induced gastric ulcers in individuals who are at high risk of complications from gastric ulcers. In their study, Dr. Chan and his colleagues assessed the efficacy of misoprostol for healing small bowel ulcers in patients with GI bleeding who were using continuous aspirin therapy.
The primary endpoint was complete mucosal healing in 8 weeks, and secondary endpoints included changes in the number of GI erosions.
The double-blind, randomized, placebo-controlled trial included 35 patients assigned to misoprostol and 37 to placebo. All patients were on regular aspirin (at least 160 mg/day) for established cardiothrombotic diseases and had either overt bleeding of the small bowel or anemia. No bleeding source was identified on gastroscopy and colonoscopy. They had a score of 3 (more than four erosions) or 4 (large erosion or ulcer) that was confirmed by capsule endoscopy.
Those randomized to the active therapy arm received 200 mg misoprostol four times daily, and all patients continued aspirin 80 mg/day for the duration of the trial. During the study period, concomitant NSAIDs, proton pump inhibitors, sucralfate, rebamipide, antibiotics, corticosteroids, or iron supplement was prohibited.
A follow-up capsule endoscopy was performed at 8 weeks to assess mucosal healing, and all images were evaluated by a blinded panel.
The intention-to-treat population included all patients who took at least one dose of the study drug and returned for follow-up capsule endoscopy (n = 72).
In this population, 33% of patients in the misoprostol group and 10.5% on placebo had complete mucosal healing at 8 weeks.
“For the secondary endpoint of changes in small bowel erosions, there was a significant difference between the misoprostol group and placebo group with a P value of .025,” said Dr. Chan.
The study was supported by a competitive grant from the Research Grant Council of Hong Kong. Dr. Chan reported relationships with AstraZeneca, Eisai, Pfizer, and Takeda.
CHICAGO – , a small study showed.
Compared with placebo, it was superior in healing small bowel ulcers. A total of 12 patients who received misoprostol had complete healing at 8 weeks, compared with 4 in the placebo group (P = .017).
“Among patients with overt bleeding or anemia from small bowel lesions who receive continuous aspirin therapy, misoprostol is superior to placebo in achieving complete mucosal healing,” said lead author Francis Chan, MD, professor of gastroenterology and hepatology at the Chinese University of Hong Kong, who presented the findings at the annual Digestive Disease Week®.
Millions of individuals use low-dose aspirin daily to lower their risk of stroke and cardiovascular events, but they face a risk of gastrointestinal bleeding. In fact, Dr. Chan pointed out, continuous aspirin use has been associated with a threefold risk of a lower GI bleed.
“But to date, there is no effective pharmacological treatment for small bowel ulcers that are associated with use of low-dose aspirin,” he said.
Misoprostol is a synthetic prostaglandin E1 analog that is indicated for reducing the risk of NSAID–induced gastric ulcers in individuals who are at high risk of complications from gastric ulcers. In their study, Dr. Chan and his colleagues assessed the efficacy of misoprostol for healing small bowel ulcers in patients with GI bleeding who were using continuous aspirin therapy.
The primary endpoint was complete mucosal healing in 8 weeks, and secondary endpoints included changes in the number of GI erosions.
The double-blind, randomized, placebo-controlled trial included 35 patients assigned to misoprostol and 37 to placebo. All patients were on regular aspirin (at least 160 mg/day) for established cardiothrombotic diseases and had either overt bleeding of the small bowel or anemia. No bleeding source was identified on gastroscopy and colonoscopy. They had a score of 3 (more than four erosions) or 4 (large erosion or ulcer) that was confirmed by capsule endoscopy.
Those randomized to the active therapy arm received 200 mg misoprostol four times daily, and all patients continued aspirin 80 mg/day for the duration of the trial. During the study period, concomitant NSAIDs, proton pump inhibitors, sucralfate, rebamipide, antibiotics, corticosteroids, or iron supplement was prohibited.
A follow-up capsule endoscopy was performed at 8 weeks to assess mucosal healing, and all images were evaluated by a blinded panel.
The intention-to-treat population included all patients who took at least one dose of the study drug and returned for follow-up capsule endoscopy (n = 72).
In this population, 33% of patients in the misoprostol group and 10.5% on placebo had complete mucosal healing at 8 weeks.
“For the secondary endpoint of changes in small bowel erosions, there was a significant difference between the misoprostol group and placebo group with a P value of .025,” said Dr. Chan.
The study was supported by a competitive grant from the Research Grant Council of Hong Kong. Dr. Chan reported relationships with AstraZeneca, Eisai, Pfizer, and Takeda.
CHICAGO – , a small study showed.
Compared with placebo, it was superior in healing small bowel ulcers. A total of 12 patients who received misoprostol had complete healing at 8 weeks, compared with 4 in the placebo group (P = .017).
“Among patients with overt bleeding or anemia from small bowel lesions who receive continuous aspirin therapy, misoprostol is superior to placebo in achieving complete mucosal healing,” said lead author Francis Chan, MD, professor of gastroenterology and hepatology at the Chinese University of Hong Kong, who presented the findings at the annual Digestive Disease Week®.
Millions of individuals use low-dose aspirin daily to lower their risk of stroke and cardiovascular events, but they face a risk of gastrointestinal bleeding. In fact, Dr. Chan pointed out, continuous aspirin use has been associated with a threefold risk of a lower GI bleed.
“But to date, there is no effective pharmacological treatment for small bowel ulcers that are associated with use of low-dose aspirin,” he said.
Misoprostol is a synthetic prostaglandin E1 analog that is indicated for reducing the risk of NSAID–induced gastric ulcers in individuals who are at high risk of complications from gastric ulcers. In their study, Dr. Chan and his colleagues assessed the efficacy of misoprostol for healing small bowel ulcers in patients with GI bleeding who were using continuous aspirin therapy.
The primary endpoint was complete mucosal healing in 8 weeks, and secondary endpoints included changes in the number of GI erosions.
The double-blind, randomized, placebo-controlled trial included 35 patients assigned to misoprostol and 37 to placebo. All patients were on regular aspirin (at least 160 mg/day) for established cardiothrombotic diseases and had either overt bleeding of the small bowel or anemia. No bleeding source was identified on gastroscopy and colonoscopy. They had a score of 3 (more than four erosions) or 4 (large erosion or ulcer) that was confirmed by capsule endoscopy.
Those randomized to the active therapy arm received 200 mg misoprostol four times daily, and all patients continued aspirin 80 mg/day for the duration of the trial. During the study period, concomitant NSAIDs, proton pump inhibitors, sucralfate, rebamipide, antibiotics, corticosteroids, or iron supplement was prohibited.
A follow-up capsule endoscopy was performed at 8 weeks to assess mucosal healing, and all images were evaluated by a blinded panel.
The intention-to-treat population included all patients who took at least one dose of the study drug and returned for follow-up capsule endoscopy (n = 72).
In this population, 33% of patients in the misoprostol group and 10.5% on placebo had complete mucosal healing at 8 weeks.
“For the secondary endpoint of changes in small bowel erosions, there was a significant difference between the misoprostol group and placebo group with a P value of .025,” said Dr. Chan.
The study was supported by a competitive grant from the Research Grant Council of Hong Kong. Dr. Chan reported relationships with AstraZeneca, Eisai, Pfizer, and Takeda.
AT DDW
Key clinical point: Misoprostol was more effective than placebo in healing small bowel ulcers in patients who used daily low-dose aspirin.
Major finding: 33% of patients in the misoprostol group and 10.5% on placebo had complete mucosal healing at 8 weeks.
Data source: An 8-week, double-blind, randomized placebo-controlled trial of 72 patients that assessed misoprostol vs. placebo for healing small bowel ulcers.
Disclosures: The study was supported by a competitive grant from the Research Grant Council of Hong Kong. Dr. Chan reported relationships with AstraZeneca, Eisai, Pfizer, and Takeda.
CRC in Lynch syndrome is lower than previously reported
CHICAGO – Lynch syndrome can predispose individuals to a number of different cancer types, including colorectal tumors, but the results of a preliminary study found that the incidence may be lower than what has been previously reported.
New findings presented at Digestive Disease Week® showed that the incidence of colorectal cancer after screening with colonoscopy ranged from 6.3% to 25.9%, depending on the specific mutated gene. This is in contrast to other reports which have found a 50% increase in the incidence of colorectal cancer in individuals with Lynch syndrome.
“We looked at the incidence of colorectal cancer and other associated cancers in individuals with Lynch syndrome and how screening can have an impact on that,” said study author Ariadna Sanchez, MD, from the Hospital Clínic de Barcelona, Spain.
She emphasized that the results being presented at the meeting are preliminary and, thus, will need further confirmation, but it is a multicenter study and is being conducted in more than 1,100 patients.
“The diagnosis of colorectal cancer with screening colonoscopy is lower than results that have been previously published,” she said. “This finding reinforces the importance of screening colonoscopies in patients with Lynch syndrome.”
As to why their rates are lower, Dr. Sanchez speculated that it may be because precancerous polyps are being removed with screening.
“Our thinking is that, as we perform screening and remove the polyps, then in theory, cancer will be prevented,” she explained, “since they didn’t have the opportunity to continue to progress into cancer.”
In other words, screening this high-risk population may not only identify those who have cancer but may prevent it from developing in others.
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer, including colorectal and cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, ovaries, and endometrium.
Caused by germline mutations in the mismatch DNA repair system (MLH1, MSH2, MSH6, PMS2), it has been difficult to make precise estimates of cancer risk in individuals with the syndrome because of retrospective studies and small cohorts.
Dr. Sanchez and her colleagues conducted a multicenter nation-wide study in Spain with the goal of establishing the cumulative incidence of colorectal cancer and other tumor types in Lynch syndrome and to evaluate the effect of screening surveillance on cancer incidence. Cancer-specific survival will also be assessed.
The cohort included 1,108 patients with Lynch syndrome from 25 centers, who were followed-up for a mean of 67.5 (± 57.8 months).
The first colonoscopy screening detected cancer in 49 patients (MLH1, n = 23/268; MSH2, n = 18/249; MSH6, n = 4/154; PMS2, n = 2/47; EPCAM, n = 2/13), extrapolating to a cumulative incidence of 25.6% for MLH1, 22.1% for MSH2, 6.3% for MSH6, and 25.9% for PMS2 mutation carriers.
Most patients were diagnosed with stage 1 disease (45.7%) and, to a lesser degree, with stage II (28.6%), stage III (22.9%), and stage IV (2.9%).
The 10-year cumulative incidences for subsequent colorectal cancers for patients who had a previous diagnosis of the disease were 9.4% (95% CI, 5-17) for MLH1, 12.6% (95% CI, 5.6-27.6) for MSH2, and 17.2% (95% CI, 6.6-40) for MSH6.
Digestive Disease Week is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
CHICAGO – Lynch syndrome can predispose individuals to a number of different cancer types, including colorectal tumors, but the results of a preliminary study found that the incidence may be lower than what has been previously reported.
New findings presented at Digestive Disease Week® showed that the incidence of colorectal cancer after screening with colonoscopy ranged from 6.3% to 25.9%, depending on the specific mutated gene. This is in contrast to other reports which have found a 50% increase in the incidence of colorectal cancer in individuals with Lynch syndrome.
“We looked at the incidence of colorectal cancer and other associated cancers in individuals with Lynch syndrome and how screening can have an impact on that,” said study author Ariadna Sanchez, MD, from the Hospital Clínic de Barcelona, Spain.
She emphasized that the results being presented at the meeting are preliminary and, thus, will need further confirmation, but it is a multicenter study and is being conducted in more than 1,100 patients.
“The diagnosis of colorectal cancer with screening colonoscopy is lower than results that have been previously published,” she said. “This finding reinforces the importance of screening colonoscopies in patients with Lynch syndrome.”
As to why their rates are lower, Dr. Sanchez speculated that it may be because precancerous polyps are being removed with screening.
“Our thinking is that, as we perform screening and remove the polyps, then in theory, cancer will be prevented,” she explained, “since they didn’t have the opportunity to continue to progress into cancer.”
In other words, screening this high-risk population may not only identify those who have cancer but may prevent it from developing in others.
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer, including colorectal and cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, ovaries, and endometrium.
Caused by germline mutations in the mismatch DNA repair system (MLH1, MSH2, MSH6, PMS2), it has been difficult to make precise estimates of cancer risk in individuals with the syndrome because of retrospective studies and small cohorts.
Dr. Sanchez and her colleagues conducted a multicenter nation-wide study in Spain with the goal of establishing the cumulative incidence of colorectal cancer and other tumor types in Lynch syndrome and to evaluate the effect of screening surveillance on cancer incidence. Cancer-specific survival will also be assessed.
The cohort included 1,108 patients with Lynch syndrome from 25 centers, who were followed-up for a mean of 67.5 (± 57.8 months).
The first colonoscopy screening detected cancer in 49 patients (MLH1, n = 23/268; MSH2, n = 18/249; MSH6, n = 4/154; PMS2, n = 2/47; EPCAM, n = 2/13), extrapolating to a cumulative incidence of 25.6% for MLH1, 22.1% for MSH2, 6.3% for MSH6, and 25.9% for PMS2 mutation carriers.
Most patients were diagnosed with stage 1 disease (45.7%) and, to a lesser degree, with stage II (28.6%), stage III (22.9%), and stage IV (2.9%).
The 10-year cumulative incidences for subsequent colorectal cancers for patients who had a previous diagnosis of the disease were 9.4% (95% CI, 5-17) for MLH1, 12.6% (95% CI, 5.6-27.6) for MSH2, and 17.2% (95% CI, 6.6-40) for MSH6.
Digestive Disease Week is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
CHICAGO – Lynch syndrome can predispose individuals to a number of different cancer types, including colorectal tumors, but the results of a preliminary study found that the incidence may be lower than what has been previously reported.
New findings presented at Digestive Disease Week® showed that the incidence of colorectal cancer after screening with colonoscopy ranged from 6.3% to 25.9%, depending on the specific mutated gene. This is in contrast to other reports which have found a 50% increase in the incidence of colorectal cancer in individuals with Lynch syndrome.
“We looked at the incidence of colorectal cancer and other associated cancers in individuals with Lynch syndrome and how screening can have an impact on that,” said study author Ariadna Sanchez, MD, from the Hospital Clínic de Barcelona, Spain.
She emphasized that the results being presented at the meeting are preliminary and, thus, will need further confirmation, but it is a multicenter study and is being conducted in more than 1,100 patients.
“The diagnosis of colorectal cancer with screening colonoscopy is lower than results that have been previously published,” she said. “This finding reinforces the importance of screening colonoscopies in patients with Lynch syndrome.”
As to why their rates are lower, Dr. Sanchez speculated that it may be because precancerous polyps are being removed with screening.
“Our thinking is that, as we perform screening and remove the polyps, then in theory, cancer will be prevented,” she explained, “since they didn’t have the opportunity to continue to progress into cancer.”
In other words, screening this high-risk population may not only identify those who have cancer but may prevent it from developing in others.
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer, including colorectal and cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, ovaries, and endometrium.
Caused by germline mutations in the mismatch DNA repair system (MLH1, MSH2, MSH6, PMS2), it has been difficult to make precise estimates of cancer risk in individuals with the syndrome because of retrospective studies and small cohorts.
Dr. Sanchez and her colleagues conducted a multicenter nation-wide study in Spain with the goal of establishing the cumulative incidence of colorectal cancer and other tumor types in Lynch syndrome and to evaluate the effect of screening surveillance on cancer incidence. Cancer-specific survival will also be assessed.
The cohort included 1,108 patients with Lynch syndrome from 25 centers, who were followed-up for a mean of 67.5 (± 57.8 months).
The first colonoscopy screening detected cancer in 49 patients (MLH1, n = 23/268; MSH2, n = 18/249; MSH6, n = 4/154; PMS2, n = 2/47; EPCAM, n = 2/13), extrapolating to a cumulative incidence of 25.6% for MLH1, 22.1% for MSH2, 6.3% for MSH6, and 25.9% for PMS2 mutation carriers.
Most patients were diagnosed with stage 1 disease (45.7%) and, to a lesser degree, with stage II (28.6%), stage III (22.9%), and stage IV (2.9%).
The 10-year cumulative incidences for subsequent colorectal cancers for patients who had a previous diagnosis of the disease were 9.4% (95% CI, 5-17) for MLH1, 12.6% (95% CI, 5.6-27.6) for MSH2, and 17.2% (95% CI, 6.6-40) for MSH6.
Digestive Disease Week is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
Key clinical point: Colorectal cancer screening may lower the incidence of disease in a high-risk population of individuals with Lynch syndrome.
Major finding: The incidence of colorectal cancer was lower than has been previously reported in Lynch syndrome, possibly because of the removal of polyps during screening.
Data source: Prospective multicenter study that included 1,108 patients with Lynch syndrome who underwent colonoscopy screening.
Disclosures: Dr. Sanchez has no disclosures.
Anti-TNF drugs reduce mortality in Crohn’s disease
CHICAGO – As compared with prolonged use of corticosteroids, the use of anti–tumor necrosis factor (TNF) drugs was associated with reduced mortality in patients with Crohn’s disease, according to new findings presented here at Digestive Disease Week®.
The reduced mortality seen in this population may be secondary to the lower rates of major adverse cardiovascular events and hip fracture that are associated with anti-TNF use as compared to corticosteroid use. However, the same reduction in mortality risk was not observed in patients with ulcerative colitis using anti-TNF drugs.
Anti-TNF therapy has become a cornerstone in the management of inflammatory bowel disease (IBD), and Dr. Lewis noted that these agents have been shown to be useful for induction, maintenance, and remission, and to reduce surgical and hospitalization rates.
“However, fear of adverse events and cost has deterred greater use of these agents,” he told attendees.
In their study, Dr. Lewis and his colleagues compared the mortality risk with prolonged corticosteroids use versus anti-TNF drugs in patients with IBD.
They conducted a retrospective cohort study using data from 2006-2013 of a population of Medicaid and Medicare beneficiaries in the United States. The cohort included individuals who had received treatment with corticosteroids within the prior year and subsequently had been treated with either additional corticosteroid therapy for a total of greater than 3,000 mg of prednisone or equivalent within 12 months or newly initiated anti-TNF therapy.
The primary outcome of the study was all-cause mortality and secondary outcomes included common causes of death.
Dr. Lewis explained that 57 potential confounding variables were thought to be associated with the choice between corticosteroid use or anti-TNF therapy. These variables, which included demographic characteristics, medications, diagnostic tests, and comorbidities, were measured.
Among Crohn’s disease patients, 7,694 who were prolonged corticosteroid users and 1,879 were new to anti-TNF therapy. Among patients with ulcerative colitis, 3,224 were long-term corticosteroid users and 459 were new anti-TNF users.
The researchers found that the weighted annual incidences of death per 1,000 Crohn’s disease treated patients were 21.4 for those using anti-TNF therapy and 30.1 for those with prolonged corticosteroid use. For those with ulcerative colitis, these figures were 23.0 and 30.9, respectively.
The risk of death was statistically significantly reduced in Crohn’s disease patients who used anti-TNF therapy (odds ratio, 0.78; 95% confidence interval, 0.65-0.93). However, the benefit was not as pronounced in ulcerative colitis.
“We did not see the same effect for ulcerative colitis but for mortality, it was in the same direction, with a hazard ratio of 0.87,” he said.
Among the Crohn’s disease patients, anti-TNF therapy was associated with lower rates of major adverse cardiovascular events (OR, 0.68; 95% CI, 0.55-0.85) and hip fracture (OR, 0.5; 95% CI, 0.34-0.83), which were statistically significant. The use of anti-TNF therapy also reduced the risk of stroke in Crohn’s disease patients (OR, 0.72; 95% CI, 0.51-1.03), but there was also an increase in the risk of cancer (OR, 0.27; 95% CI, 0.98-1.65). Both of these findings nearly reached statistical significance.
In the model that censored for any of the secondary outcomes, the lower mortality risk was attenuated and very close to a null result (OR, 0.97; 95% CI 0.63-1.47).
Dr. Lewis also pointed out that in some of their models, the magnitude of benefit with anti-TNF therapy appears to be greatest in the patients with the most comorbidities.
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
Dr. Lewis has disclosed financial relationships with Takeda, Pfizer, Lilly, Gilead, Johnson and Johnson, Samsung Bioepis, AbbVie, and Dark Canyon Laboratories.
CHICAGO – As compared with prolonged use of corticosteroids, the use of anti–tumor necrosis factor (TNF) drugs was associated with reduced mortality in patients with Crohn’s disease, according to new findings presented here at Digestive Disease Week®.
The reduced mortality seen in this population may be secondary to the lower rates of major adverse cardiovascular events and hip fracture that are associated with anti-TNF use as compared to corticosteroid use. However, the same reduction in mortality risk was not observed in patients with ulcerative colitis using anti-TNF drugs.
Anti-TNF therapy has become a cornerstone in the management of inflammatory bowel disease (IBD), and Dr. Lewis noted that these agents have been shown to be useful for induction, maintenance, and remission, and to reduce surgical and hospitalization rates.
“However, fear of adverse events and cost has deterred greater use of these agents,” he told attendees.
In their study, Dr. Lewis and his colleagues compared the mortality risk with prolonged corticosteroids use versus anti-TNF drugs in patients with IBD.
They conducted a retrospective cohort study using data from 2006-2013 of a population of Medicaid and Medicare beneficiaries in the United States. The cohort included individuals who had received treatment with corticosteroids within the prior year and subsequently had been treated with either additional corticosteroid therapy for a total of greater than 3,000 mg of prednisone or equivalent within 12 months or newly initiated anti-TNF therapy.
The primary outcome of the study was all-cause mortality and secondary outcomes included common causes of death.
Dr. Lewis explained that 57 potential confounding variables were thought to be associated with the choice between corticosteroid use or anti-TNF therapy. These variables, which included demographic characteristics, medications, diagnostic tests, and comorbidities, were measured.
Among Crohn’s disease patients, 7,694 who were prolonged corticosteroid users and 1,879 were new to anti-TNF therapy. Among patients with ulcerative colitis, 3,224 were long-term corticosteroid users and 459 were new anti-TNF users.
The researchers found that the weighted annual incidences of death per 1,000 Crohn’s disease treated patients were 21.4 for those using anti-TNF therapy and 30.1 for those with prolonged corticosteroid use. For those with ulcerative colitis, these figures were 23.0 and 30.9, respectively.
The risk of death was statistically significantly reduced in Crohn’s disease patients who used anti-TNF therapy (odds ratio, 0.78; 95% confidence interval, 0.65-0.93). However, the benefit was not as pronounced in ulcerative colitis.
“We did not see the same effect for ulcerative colitis but for mortality, it was in the same direction, with a hazard ratio of 0.87,” he said.
Among the Crohn’s disease patients, anti-TNF therapy was associated with lower rates of major adverse cardiovascular events (OR, 0.68; 95% CI, 0.55-0.85) and hip fracture (OR, 0.5; 95% CI, 0.34-0.83), which were statistically significant. The use of anti-TNF therapy also reduced the risk of stroke in Crohn’s disease patients (OR, 0.72; 95% CI, 0.51-1.03), but there was also an increase in the risk of cancer (OR, 0.27; 95% CI, 0.98-1.65). Both of these findings nearly reached statistical significance.
In the model that censored for any of the secondary outcomes, the lower mortality risk was attenuated and very close to a null result (OR, 0.97; 95% CI 0.63-1.47).
Dr. Lewis also pointed out that in some of their models, the magnitude of benefit with anti-TNF therapy appears to be greatest in the patients with the most comorbidities.
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
Dr. Lewis has disclosed financial relationships with Takeda, Pfizer, Lilly, Gilead, Johnson and Johnson, Samsung Bioepis, AbbVie, and Dark Canyon Laboratories.
CHICAGO – As compared with prolonged use of corticosteroids, the use of anti–tumor necrosis factor (TNF) drugs was associated with reduced mortality in patients with Crohn’s disease, according to new findings presented here at Digestive Disease Week®.
The reduced mortality seen in this population may be secondary to the lower rates of major adverse cardiovascular events and hip fracture that are associated with anti-TNF use as compared to corticosteroid use. However, the same reduction in mortality risk was not observed in patients with ulcerative colitis using anti-TNF drugs.
Anti-TNF therapy has become a cornerstone in the management of inflammatory bowel disease (IBD), and Dr. Lewis noted that these agents have been shown to be useful for induction, maintenance, and remission, and to reduce surgical and hospitalization rates.
“However, fear of adverse events and cost has deterred greater use of these agents,” he told attendees.
In their study, Dr. Lewis and his colleagues compared the mortality risk with prolonged corticosteroids use versus anti-TNF drugs in patients with IBD.
They conducted a retrospective cohort study using data from 2006-2013 of a population of Medicaid and Medicare beneficiaries in the United States. The cohort included individuals who had received treatment with corticosteroids within the prior year and subsequently had been treated with either additional corticosteroid therapy for a total of greater than 3,000 mg of prednisone or equivalent within 12 months or newly initiated anti-TNF therapy.
The primary outcome of the study was all-cause mortality and secondary outcomes included common causes of death.
Dr. Lewis explained that 57 potential confounding variables were thought to be associated with the choice between corticosteroid use or anti-TNF therapy. These variables, which included demographic characteristics, medications, diagnostic tests, and comorbidities, were measured.
Among Crohn’s disease patients, 7,694 who were prolonged corticosteroid users and 1,879 were new to anti-TNF therapy. Among patients with ulcerative colitis, 3,224 were long-term corticosteroid users and 459 were new anti-TNF users.
The researchers found that the weighted annual incidences of death per 1,000 Crohn’s disease treated patients were 21.4 for those using anti-TNF therapy and 30.1 for those with prolonged corticosteroid use. For those with ulcerative colitis, these figures were 23.0 and 30.9, respectively.
The risk of death was statistically significantly reduced in Crohn’s disease patients who used anti-TNF therapy (odds ratio, 0.78; 95% confidence interval, 0.65-0.93). However, the benefit was not as pronounced in ulcerative colitis.
“We did not see the same effect for ulcerative colitis but for mortality, it was in the same direction, with a hazard ratio of 0.87,” he said.
Among the Crohn’s disease patients, anti-TNF therapy was associated with lower rates of major adverse cardiovascular events (OR, 0.68; 95% CI, 0.55-0.85) and hip fracture (OR, 0.5; 95% CI, 0.34-0.83), which were statistically significant. The use of anti-TNF therapy also reduced the risk of stroke in Crohn’s disease patients (OR, 0.72; 95% CI, 0.51-1.03), but there was also an increase in the risk of cancer (OR, 0.27; 95% CI, 0.98-1.65). Both of these findings nearly reached statistical significance.
In the model that censored for any of the secondary outcomes, the lower mortality risk was attenuated and very close to a null result (OR, 0.97; 95% CI 0.63-1.47).
Dr. Lewis also pointed out that in some of their models, the magnitude of benefit with anti-TNF therapy appears to be greatest in the patients with the most comorbidities.
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
Dr. Lewis has disclosed financial relationships with Takeda, Pfizer, Lilly, Gilead, Johnson and Johnson, Samsung Bioepis, AbbVie, and Dark Canyon Laboratories.
AT DDW
Key clinical point:
Major finding: Anti-TNF drugs were associated with reduced mortality in patients with Crohn’s disease (OR, 0.78) but to a much lesser extent in ulcerative colitis (OR, 0.87).
Data source: Database of Medicare and Medicaid recipients with 9,573 patients with Crohn’s disease and 3,683 with ulcerative colitis.
Disclosures: Dr. Lewis has disclosed financial relationships with Takeda, Pfizer, Lilly, Gilead, Johnson and Johnson, Samsung Bioepis, AbbVie, and Dark Canyon Laboratories.
Novel agent varlilumab shows activity in RCC
A novel, first-in-class, agonist anti-CD27 monoclonal antibody was found to be clinically and biologically active, according to early findings published in the Journal of Clinical Oncology.
In this phase I first-in-human study of varlilumab, doses at 0.1 to 10 mg/kg were well tolerated by patients with advanced solid tumors. In addition, antitumor activity was also observed. One heavily pretreated patient with stage IV disease renal cell carcinoma (RCC) experienced durable and significant tumor regression, with 78% tumor shrinkage and a partial response that persisted for 2.3 years without additional anticancer therapy, reported Howard A. Burris, MD, of the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, and his colleagues (J Clin Oncol. 2017 May 2. doi: 10.1200/JCO.2016.70.1508).
In addition, eight patients achieved stable disease for more than 3 months while on the study.
“This phase I study of varlilumab provides proof of concept and a rationale for further study in combination with immunotherapies and traditional therapies,” wrote Dr. Burris and his colleagues. “Therapy that targets multiple nonredundant pathways that regulate immune responses may be synergistic and enhance antitumor immune responses.”
The study was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and activity of varlilumab when used as a single agent in patients with advanced solid tumors.
The entire cohort included 56 patients enrolled at nine centers, and the dose escalation component included 25 patients. The expansion part of the trial included 16 patients with melanoma and 15 patients with RCC.
The most common cancer type in the dose-escalation phase was colorectal cancer (40%) followed by melanoma (28%). All patients had stage IV disease and, in general, were heavily pretreated.
A median of 4 doses was administered to the cohort (1-21), and, in the dose escalation phase, the 10 mg/kg was reached without identifying a maximum tolerated dose. Only one patient experienced a dose limiting toxicity, which was grade 3 asymptomatic hyponatremia (129 mmol/L) that occurred at the 1.0-mg/kg dose level.
A total of eight patients achieved stable disease, including four with RCC (duration of stable disease: 5.3, 5.6, 9.3, and 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one patient with colorectal adenocarcinoma (5.7 months).
A novel, first-in-class, agonist anti-CD27 monoclonal antibody was found to be clinically and biologically active, according to early findings published in the Journal of Clinical Oncology.
In this phase I first-in-human study of varlilumab, doses at 0.1 to 10 mg/kg were well tolerated by patients with advanced solid tumors. In addition, antitumor activity was also observed. One heavily pretreated patient with stage IV disease renal cell carcinoma (RCC) experienced durable and significant tumor regression, with 78% tumor shrinkage and a partial response that persisted for 2.3 years without additional anticancer therapy, reported Howard A. Burris, MD, of the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, and his colleagues (J Clin Oncol. 2017 May 2. doi: 10.1200/JCO.2016.70.1508).
In addition, eight patients achieved stable disease for more than 3 months while on the study.
“This phase I study of varlilumab provides proof of concept and a rationale for further study in combination with immunotherapies and traditional therapies,” wrote Dr. Burris and his colleagues. “Therapy that targets multiple nonredundant pathways that regulate immune responses may be synergistic and enhance antitumor immune responses.”
The study was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and activity of varlilumab when used as a single agent in patients with advanced solid tumors.
The entire cohort included 56 patients enrolled at nine centers, and the dose escalation component included 25 patients. The expansion part of the trial included 16 patients with melanoma and 15 patients with RCC.
The most common cancer type in the dose-escalation phase was colorectal cancer (40%) followed by melanoma (28%). All patients had stage IV disease and, in general, were heavily pretreated.
A median of 4 doses was administered to the cohort (1-21), and, in the dose escalation phase, the 10 mg/kg was reached without identifying a maximum tolerated dose. Only one patient experienced a dose limiting toxicity, which was grade 3 asymptomatic hyponatremia (129 mmol/L) that occurred at the 1.0-mg/kg dose level.
A total of eight patients achieved stable disease, including four with RCC (duration of stable disease: 5.3, 5.6, 9.3, and 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one patient with colorectal adenocarcinoma (5.7 months).
A novel, first-in-class, agonist anti-CD27 monoclonal antibody was found to be clinically and biologically active, according to early findings published in the Journal of Clinical Oncology.
In this phase I first-in-human study of varlilumab, doses at 0.1 to 10 mg/kg were well tolerated by patients with advanced solid tumors. In addition, antitumor activity was also observed. One heavily pretreated patient with stage IV disease renal cell carcinoma (RCC) experienced durable and significant tumor regression, with 78% tumor shrinkage and a partial response that persisted for 2.3 years without additional anticancer therapy, reported Howard A. Burris, MD, of the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, and his colleagues (J Clin Oncol. 2017 May 2. doi: 10.1200/JCO.2016.70.1508).
In addition, eight patients achieved stable disease for more than 3 months while on the study.
“This phase I study of varlilumab provides proof of concept and a rationale for further study in combination with immunotherapies and traditional therapies,” wrote Dr. Burris and his colleagues. “Therapy that targets multiple nonredundant pathways that regulate immune responses may be synergistic and enhance antitumor immune responses.”
The study was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and activity of varlilumab when used as a single agent in patients with advanced solid tumors.
The entire cohort included 56 patients enrolled at nine centers, and the dose escalation component included 25 patients. The expansion part of the trial included 16 patients with melanoma and 15 patients with RCC.
The most common cancer type in the dose-escalation phase was colorectal cancer (40%) followed by melanoma (28%). All patients had stage IV disease and, in general, were heavily pretreated.
A median of 4 doses was administered to the cohort (1-21), and, in the dose escalation phase, the 10 mg/kg was reached without identifying a maximum tolerated dose. Only one patient experienced a dose limiting toxicity, which was grade 3 asymptomatic hyponatremia (129 mmol/L) that occurred at the 1.0-mg/kg dose level.
A total of eight patients achieved stable disease, including four with RCC (duration of stable disease: 5.3, 5.6, 9.3, and 47.3 months), three with melanoma (3.8, 7.3, and 11.5 months), and one patient with colorectal adenocarcinoma (5.7 months).
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: A novel, first-in-class, agonist anti-CD27 monoclonal antibody showed activity in solid tumors when used as monotherapy.
Major finding: Two patients with advanced renal cell carcinoma experienced tumor shrinkage and durable responses while eight achieved stable disease.
Data source: Phase I first-in-human study comprising 56 patients with advanced colorectal cancer, renal cell carcinoma, and melanoma.
Disclosures: The study was supported by Celldex Therapeutics. Dr. Burris has no disclosures, and several coauthors have declared relationships with the industry.
High CD86+pDC counts may predict CML relapses
Patients with chronic myeloid leukemia (CML) with high CD86+pDC counts had a higher risk of relapse after discontinuing tyrosine kinase inhibitor (TKI) therapy, according to new findings published in Leukemia.
Of patients who achieve a deep molecular remission, only a minority are able to sustain it and remain off therapy. Even when deep remission is achieved, TKI therapy fails to eradicate CML stem cells, which can perpetuate disease.
“This is clinically reflected by the long-term persistence of BCR-ABL messenger RNA (mRNA) in the majority of patients,” wrote C. Schütz, MD, of the University Hospital Marburg (Germany) and colleagues (Leukemia. 2017 Apr;31[4]:829-36). “Even with undetectable BCR-ABL mRNA levels, patients frequently relapse after TKI cessation.”
The researchers investigated whether the expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) could have an effect on the risk of relapse in CML patients who discontinue TKI therapy after achieving remission.
The frequency of CD86+pDC was analyzed in 14 CML patients who were in treatment-free remission, in 130 patients in molecular remission who were part of the CML-V study, and prospectively in 122 EURO-SKI patients right before they discontinued TKI therapy.
The authors found that CML patients in molecular remission had a significantly higher frequency of CD86+pDC expression, compared with normal donors (P less than .0024). In contrast, those who were in treatment-free remission had consistently low CD86+pDC.
These results suggest that low CD86+pDC could be predictive of treatment-free remission.
To test the hypothesis that low CD86+pDC frequencies during TKI-induced molecular remission were associated with a lower risk of molecular relapse after stopping TKI therapy, the study authors measured CD86+pDC levels in the 122 EURO-SKI patients before they stopped therapy, and then prospectively monitored them for relapse.
Findings showed that the 122 EURO-SKI patients had a significantly higher CD86+pDC frequency than did 8 healthy donors (median, 20.8% vs. 7.3%; P = .0024).
When matched with the treatment-free remission patients, the 73 patients in the EURO-SKI group who did not relapse within the first 12 months after stopping therapy had a significantly lower median frequency of CD86+pDC at baseline, compared with the 49 patients who did relapse (P = .014).
Patients who relapsed also demonstrated higher absolute CD86+pDC counts (CD86+pDC per 105 lymphocytes) at baseline (median, 86.1 vs. 50.6; P = .0147).
Based on the findings, the authors noted that they provided “for the first time evidence that relapse biology after TKI discontinuation depends on the quantity of activated pDC and a T-cell exhaustion phenotype, rather than TKI pretreatment duration per se.”
The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.
Patients with chronic myeloid leukemia (CML) with high CD86+pDC counts had a higher risk of relapse after discontinuing tyrosine kinase inhibitor (TKI) therapy, according to new findings published in Leukemia.
Of patients who achieve a deep molecular remission, only a minority are able to sustain it and remain off therapy. Even when deep remission is achieved, TKI therapy fails to eradicate CML stem cells, which can perpetuate disease.
“This is clinically reflected by the long-term persistence of BCR-ABL messenger RNA (mRNA) in the majority of patients,” wrote C. Schütz, MD, of the University Hospital Marburg (Germany) and colleagues (Leukemia. 2017 Apr;31[4]:829-36). “Even with undetectable BCR-ABL mRNA levels, patients frequently relapse after TKI cessation.”
The researchers investigated whether the expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) could have an effect on the risk of relapse in CML patients who discontinue TKI therapy after achieving remission.
The frequency of CD86+pDC was analyzed in 14 CML patients who were in treatment-free remission, in 130 patients in molecular remission who were part of the CML-V study, and prospectively in 122 EURO-SKI patients right before they discontinued TKI therapy.
The authors found that CML patients in molecular remission had a significantly higher frequency of CD86+pDC expression, compared with normal donors (P less than .0024). In contrast, those who were in treatment-free remission had consistently low CD86+pDC.
These results suggest that low CD86+pDC could be predictive of treatment-free remission.
To test the hypothesis that low CD86+pDC frequencies during TKI-induced molecular remission were associated with a lower risk of molecular relapse after stopping TKI therapy, the study authors measured CD86+pDC levels in the 122 EURO-SKI patients before they stopped therapy, and then prospectively monitored them for relapse.
Findings showed that the 122 EURO-SKI patients had a significantly higher CD86+pDC frequency than did 8 healthy donors (median, 20.8% vs. 7.3%; P = .0024).
When matched with the treatment-free remission patients, the 73 patients in the EURO-SKI group who did not relapse within the first 12 months after stopping therapy had a significantly lower median frequency of CD86+pDC at baseline, compared with the 49 patients who did relapse (P = .014).
Patients who relapsed also demonstrated higher absolute CD86+pDC counts (CD86+pDC per 105 lymphocytes) at baseline (median, 86.1 vs. 50.6; P = .0147).
Based on the findings, the authors noted that they provided “for the first time evidence that relapse biology after TKI discontinuation depends on the quantity of activated pDC and a T-cell exhaustion phenotype, rather than TKI pretreatment duration per se.”
The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.
Patients with chronic myeloid leukemia (CML) with high CD86+pDC counts had a higher risk of relapse after discontinuing tyrosine kinase inhibitor (TKI) therapy, according to new findings published in Leukemia.
Of patients who achieve a deep molecular remission, only a minority are able to sustain it and remain off therapy. Even when deep remission is achieved, TKI therapy fails to eradicate CML stem cells, which can perpetuate disease.
“This is clinically reflected by the long-term persistence of BCR-ABL messenger RNA (mRNA) in the majority of patients,” wrote C. Schütz, MD, of the University Hospital Marburg (Germany) and colleagues (Leukemia. 2017 Apr;31[4]:829-36). “Even with undetectable BCR-ABL mRNA levels, patients frequently relapse after TKI cessation.”
The researchers investigated whether the expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) could have an effect on the risk of relapse in CML patients who discontinue TKI therapy after achieving remission.
The frequency of CD86+pDC was analyzed in 14 CML patients who were in treatment-free remission, in 130 patients in molecular remission who were part of the CML-V study, and prospectively in 122 EURO-SKI patients right before they discontinued TKI therapy.
The authors found that CML patients in molecular remission had a significantly higher frequency of CD86+pDC expression, compared with normal donors (P less than .0024). In contrast, those who were in treatment-free remission had consistently low CD86+pDC.
These results suggest that low CD86+pDC could be predictive of treatment-free remission.
To test the hypothesis that low CD86+pDC frequencies during TKI-induced molecular remission were associated with a lower risk of molecular relapse after stopping TKI therapy, the study authors measured CD86+pDC levels in the 122 EURO-SKI patients before they stopped therapy, and then prospectively monitored them for relapse.
Findings showed that the 122 EURO-SKI patients had a significantly higher CD86+pDC frequency than did 8 healthy donors (median, 20.8% vs. 7.3%; P = .0024).
When matched with the treatment-free remission patients, the 73 patients in the EURO-SKI group who did not relapse within the first 12 months after stopping therapy had a significantly lower median frequency of CD86+pDC at baseline, compared with the 49 patients who did relapse (P = .014).
Patients who relapsed also demonstrated higher absolute CD86+pDC counts (CD86+pDC per 105 lymphocytes) at baseline (median, 86.1 vs. 50.6; P = .0147).
Based on the findings, the authors noted that they provided “for the first time evidence that relapse biology after TKI discontinuation depends on the quantity of activated pDC and a T-cell exhaustion phenotype, rather than TKI pretreatment duration per se.”
The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.
FROM LEUKEMIA
Key clinical point: High CD86+pDC counts predicted relapses in CML patients who stopped TKI therapy.
Major finding: CML patients in molecular remission had significantly higher CD86+pDC frequencies, while patients in treatment-free remission had consistently low CD86+pDC.
Data source: A study that used patient cohorts (n = 14, n = 130, n = 122) at different stages of TKI discontinuation and remission.
Disclosures: The Clinical Research Group of the German Research Foundation and the German José Carreras Leukaemia Foundation funded the study. Several of the authors report relationships with Ariad, Bristol-Myers Squibb, Novartis, and Pfizer.
Neoadjuvant therapy timing may impact pancreatic cancer outcomes
SEATTLE – In patients with pancreatic cancer, an interval of 8 weeks between receiving neoadjuvant chemoradiation and surgical resection may improve resection margins, according to findings presented at the annual Society of Surgical Oncology Cancer Symposium.
The delay in resection did not negatively impact outcomes, and there was a modest improvement in overall survival among patients who had an 8-10 week interval between treatments.
“Attention should be focused on the treatment interval to time of resection in prospective studies,” said lead study author Raphael J. Louie, MD, of Dartmouth (N.H.) Hitchcock Norris Cotton Cancer Center.
Dr. Louie explained that for patients with pancreatic adenocarcinoma who receive neoadjuvant chemoradiation, it is unclear how long the optimal interval should be between therapy completion and surgical resection.
For this study, Dr. Louie and his colleagues sought to determine the optimal interval between neoadjuvant therapy and surgery to maximize response and oncologic outcomes.
“We hypothesized that there may be benefit to a delay,” he said.
The retrospective analysis included 637 patients who had been diagnosed with pancreatic adenocarcinoma at the Norris Cotton Cancer Center, and who had completed neoadjuvant chemoradiation and underwent R0 surgical resection between Jan. 1, 2004, and Dec. 31, 2015.
Of this group, 195 patients had metastatic disease, 28 underwent upfront surgical exploration, and 94 were lost to follow-up or had a poor performance status and were not included in the final analysis.
The cohort was grouped according to time from chemoradiation completion to surgery: 6-8 weeks, 8-10 weeks, and more than 10 weeks.
A total of 320 patients received neoadjuvant chemoradiation and 288 completed the full course. Of this group, 128 were evaluable by pathologic review.
Among patients with a 6- to 8-week interval, 61% had an R0 resection margin. This percentage rose to 72% for those who had an 8- to 10-week interval, and in similar fashion, 70% for those who had a 10- to 13-week interval (P = .6)
However, there was no statistical difference when the three groups were compared collectively.
Of 26 patients who were resected within 6-8 weeks of chemoradiation, 11% achieved a complete response (CR), 27% had a partial response (PR), and 61% had recurrence for an average disease-free survival of 20 months.
In the group (n = 58) of patients who were resected within 8-10 weeks, 7% had CR, 71% had PR, and 62% had recurrence, for an average disease-free survival of 17 months. Finally, the 44 patients who were resected within 10-13 weeks had similar outcomes; 5% had CR, 61% had PR, and 61% of patients had recurrence for an average disease-free survival of 14 months.
Dr. Louie noted that even though they observed improved PR in the 8- to 10-week group, there was no statistical significance in disease-free survival (P = .71) or overall survival (P = .19).
“Allowing more time from neoadjuvant therapy completion to surgical resection may improve the pathologic response,” said Dr. Louie. “Larger studies are needed to determine if the time interval to surgical resection has oncologic benefit for these patients.”
Dr. Louie has no disclosures.
SEATTLE – In patients with pancreatic cancer, an interval of 8 weeks between receiving neoadjuvant chemoradiation and surgical resection may improve resection margins, according to findings presented at the annual Society of Surgical Oncology Cancer Symposium.
The delay in resection did not negatively impact outcomes, and there was a modest improvement in overall survival among patients who had an 8-10 week interval between treatments.
“Attention should be focused on the treatment interval to time of resection in prospective studies,” said lead study author Raphael J. Louie, MD, of Dartmouth (N.H.) Hitchcock Norris Cotton Cancer Center.
Dr. Louie explained that for patients with pancreatic adenocarcinoma who receive neoadjuvant chemoradiation, it is unclear how long the optimal interval should be between therapy completion and surgical resection.
For this study, Dr. Louie and his colleagues sought to determine the optimal interval between neoadjuvant therapy and surgery to maximize response and oncologic outcomes.
“We hypothesized that there may be benefit to a delay,” he said.
The retrospective analysis included 637 patients who had been diagnosed with pancreatic adenocarcinoma at the Norris Cotton Cancer Center, and who had completed neoadjuvant chemoradiation and underwent R0 surgical resection between Jan. 1, 2004, and Dec. 31, 2015.
Of this group, 195 patients had metastatic disease, 28 underwent upfront surgical exploration, and 94 were lost to follow-up or had a poor performance status and were not included in the final analysis.
The cohort was grouped according to time from chemoradiation completion to surgery: 6-8 weeks, 8-10 weeks, and more than 10 weeks.
A total of 320 patients received neoadjuvant chemoradiation and 288 completed the full course. Of this group, 128 were evaluable by pathologic review.
Among patients with a 6- to 8-week interval, 61% had an R0 resection margin. This percentage rose to 72% for those who had an 8- to 10-week interval, and in similar fashion, 70% for those who had a 10- to 13-week interval (P = .6)
However, there was no statistical difference when the three groups were compared collectively.
Of 26 patients who were resected within 6-8 weeks of chemoradiation, 11% achieved a complete response (CR), 27% had a partial response (PR), and 61% had recurrence for an average disease-free survival of 20 months.
In the group (n = 58) of patients who were resected within 8-10 weeks, 7% had CR, 71% had PR, and 62% had recurrence, for an average disease-free survival of 17 months. Finally, the 44 patients who were resected within 10-13 weeks had similar outcomes; 5% had CR, 61% had PR, and 61% of patients had recurrence for an average disease-free survival of 14 months.
Dr. Louie noted that even though they observed improved PR in the 8- to 10-week group, there was no statistical significance in disease-free survival (P = .71) or overall survival (P = .19).
“Allowing more time from neoadjuvant therapy completion to surgical resection may improve the pathologic response,” said Dr. Louie. “Larger studies are needed to determine if the time interval to surgical resection has oncologic benefit for these patients.”
Dr. Louie has no disclosures.
SEATTLE – In patients with pancreatic cancer, an interval of 8 weeks between receiving neoadjuvant chemoradiation and surgical resection may improve resection margins, according to findings presented at the annual Society of Surgical Oncology Cancer Symposium.
The delay in resection did not negatively impact outcomes, and there was a modest improvement in overall survival among patients who had an 8-10 week interval between treatments.
“Attention should be focused on the treatment interval to time of resection in prospective studies,” said lead study author Raphael J. Louie, MD, of Dartmouth (N.H.) Hitchcock Norris Cotton Cancer Center.
Dr. Louie explained that for patients with pancreatic adenocarcinoma who receive neoadjuvant chemoradiation, it is unclear how long the optimal interval should be between therapy completion and surgical resection.
For this study, Dr. Louie and his colleagues sought to determine the optimal interval between neoadjuvant therapy and surgery to maximize response and oncologic outcomes.
“We hypothesized that there may be benefit to a delay,” he said.
The retrospective analysis included 637 patients who had been diagnosed with pancreatic adenocarcinoma at the Norris Cotton Cancer Center, and who had completed neoadjuvant chemoradiation and underwent R0 surgical resection between Jan. 1, 2004, and Dec. 31, 2015.
Of this group, 195 patients had metastatic disease, 28 underwent upfront surgical exploration, and 94 were lost to follow-up or had a poor performance status and were not included in the final analysis.
The cohort was grouped according to time from chemoradiation completion to surgery: 6-8 weeks, 8-10 weeks, and more than 10 weeks.
A total of 320 patients received neoadjuvant chemoradiation and 288 completed the full course. Of this group, 128 were evaluable by pathologic review.
Among patients with a 6- to 8-week interval, 61% had an R0 resection margin. This percentage rose to 72% for those who had an 8- to 10-week interval, and in similar fashion, 70% for those who had a 10- to 13-week interval (P = .6)
However, there was no statistical difference when the three groups were compared collectively.
Of 26 patients who were resected within 6-8 weeks of chemoradiation, 11% achieved a complete response (CR), 27% had a partial response (PR), and 61% had recurrence for an average disease-free survival of 20 months.
In the group (n = 58) of patients who were resected within 8-10 weeks, 7% had CR, 71% had PR, and 62% had recurrence, for an average disease-free survival of 17 months. Finally, the 44 patients who were resected within 10-13 weeks had similar outcomes; 5% had CR, 61% had PR, and 61% of patients had recurrence for an average disease-free survival of 14 months.
Dr. Louie noted that even though they observed improved PR in the 8- to 10-week group, there was no statistical significance in disease-free survival (P = .71) or overall survival (P = .19).
“Allowing more time from neoadjuvant therapy completion to surgical resection may improve the pathologic response,” said Dr. Louie. “Larger studies are needed to determine if the time interval to surgical resection has oncologic benefit for these patients.”
Dr. Louie has no disclosures.
AT SSO 2017
Key clinical point: A longer interval between neoadjuvant therapy and surgical resection could improve some outcomes in pancreatic cancer.
Major finding: Resection after 8 weeks may improve resection margins and may provide a modest improvement in survival for some patients.
Data source: Retrospective cohort study of 128 evaluable patients with biopsy-proven pancreatic adenocarcinoma who received neoadjuvant chemoradiation.
Disclosures: Dr. Louie has no disclosures.
NET can benefit breast cancer patients with delayed surgery
SEATTLE – A short course of neoadjuvant therapy could be considered in breast cancer patients with expected delays to resection, while they are awaiting surgery, according to study findings presented at the annual Society of Surgical Oncology Cancer Symposium.
More than half of breast cancer patients who undergo surgical resection as the initial modality will experience delays to surgery of more than 4 weeks. Of this group, more than half of patients receive shorter than standard courses of neoadjuvant therapy (NET), and the patients most likely to benefit were those older than 50 years, with ductal tumors, and the effect was seen in all T stages.
Recent reports show that NET is increasing. However, Dr. De Andrade pointed out, delays in receiving surgery remain a problem in breast cancer treatment and are associated with worse overall and cancer specific survival.
“Off-label use of NET is sometimes used in patients undergoing surgical delays,” he said.
NET use for 3 months has been associated with decreasing the size of tumors in patients with hormone receptor–positive (HR+) invasive breast cancer and allowing for breast conservation therapy. While short-term NET is sometimes used in women who are experiencing delay to surgery, the incidence and efficacy of this regimen remains undefined.
In the current study, Dr. De Andrade and his colleagues sought to answer three clinical questions:
• How long are patients with operable breast cancer waiting to undergo surgery?
• What is the pattern of use of short-course NET?
• What are the effects of short-course NET on outcomes?
The investigators used the National Cancer Database (NCDB) to identify women who had undergone surgery for stage 1-3 HR+ invasive breast cancer from 2004 to 2013. A total of 530,009 patients met inclusion criteria.
The primary outcomes of the study were time to surgery, the duration of NET, and if the pathologic stage at surgery was lower than clinical stage.
Among patients who did not receive NET, 49.3% underwent surgery within 30 days of diagnosis. More than a third (37.2%) underwent surgery within 60 days of diagnosis, and 13.5% did not have surgery until more than 60 days after their initial diagnosis. A total of 1.8% (9,664) patients underwent NET.
When looking at NET duration, 48% underwent NET for 12 or more weeks, while 52% received NET for less than 12 weeks; 27% received NET for less than 4 weeks, 17% for 4-8 weeks, and 9% for 8-12 weeks.
Downstaging from clinical stage to final pathology stage increased with longer duration of NET. It was 5.5% for less than 1 month on therapy, 9.7% for 1-2 months, and 17.2% for 2-3 months.
“For less than 4 weeks, there was no improvement in N or T downstaging,” said Dr. De Andrade. “As the amount of time on NET increased, it was associated with greater T downstaging. But for N downstaging, it was only at the standard of 12 or more weeks that a difference was seen in nodal downstaging.”
Standard NET of 12 or more weeks was associated with reduced mastectomy rates, but mastectomy rates were not lower in short-course NET.
Among patients undergoing breast conservation therapy, longer duration NET was also associated with a lower risk for re-excision (1-2 months: odds ratio, 0.82, P = .02; 2-3 months: OR, 0.40, P < .001). There was no reduction in re-excision for shorter courses of therapy.
Dr. De Andrade had no disclosures.
SEATTLE – A short course of neoadjuvant therapy could be considered in breast cancer patients with expected delays to resection, while they are awaiting surgery, according to study findings presented at the annual Society of Surgical Oncology Cancer Symposium.
More than half of breast cancer patients who undergo surgical resection as the initial modality will experience delays to surgery of more than 4 weeks. Of this group, more than half of patients receive shorter than standard courses of neoadjuvant therapy (NET), and the patients most likely to benefit were those older than 50 years, with ductal tumors, and the effect was seen in all T stages.
Recent reports show that NET is increasing. However, Dr. De Andrade pointed out, delays in receiving surgery remain a problem in breast cancer treatment and are associated with worse overall and cancer specific survival.
“Off-label use of NET is sometimes used in patients undergoing surgical delays,” he said.
NET use for 3 months has been associated with decreasing the size of tumors in patients with hormone receptor–positive (HR+) invasive breast cancer and allowing for breast conservation therapy. While short-term NET is sometimes used in women who are experiencing delay to surgery, the incidence and efficacy of this regimen remains undefined.
In the current study, Dr. De Andrade and his colleagues sought to answer three clinical questions:
• How long are patients with operable breast cancer waiting to undergo surgery?
• What is the pattern of use of short-course NET?
• What are the effects of short-course NET on outcomes?
The investigators used the National Cancer Database (NCDB) to identify women who had undergone surgery for stage 1-3 HR+ invasive breast cancer from 2004 to 2013. A total of 530,009 patients met inclusion criteria.
The primary outcomes of the study were time to surgery, the duration of NET, and if the pathologic stage at surgery was lower than clinical stage.
Among patients who did not receive NET, 49.3% underwent surgery within 30 days of diagnosis. More than a third (37.2%) underwent surgery within 60 days of diagnosis, and 13.5% did not have surgery until more than 60 days after their initial diagnosis. A total of 1.8% (9,664) patients underwent NET.
When looking at NET duration, 48% underwent NET for 12 or more weeks, while 52% received NET for less than 12 weeks; 27% received NET for less than 4 weeks, 17% for 4-8 weeks, and 9% for 8-12 weeks.
Downstaging from clinical stage to final pathology stage increased with longer duration of NET. It was 5.5% for less than 1 month on therapy, 9.7% for 1-2 months, and 17.2% for 2-3 months.
“For less than 4 weeks, there was no improvement in N or T downstaging,” said Dr. De Andrade. “As the amount of time on NET increased, it was associated with greater T downstaging. But for N downstaging, it was only at the standard of 12 or more weeks that a difference was seen in nodal downstaging.”
Standard NET of 12 or more weeks was associated with reduced mastectomy rates, but mastectomy rates were not lower in short-course NET.
Among patients undergoing breast conservation therapy, longer duration NET was also associated with a lower risk for re-excision (1-2 months: odds ratio, 0.82, P = .02; 2-3 months: OR, 0.40, P < .001). There was no reduction in re-excision for shorter courses of therapy.
Dr. De Andrade had no disclosures.
SEATTLE – A short course of neoadjuvant therapy could be considered in breast cancer patients with expected delays to resection, while they are awaiting surgery, according to study findings presented at the annual Society of Surgical Oncology Cancer Symposium.
More than half of breast cancer patients who undergo surgical resection as the initial modality will experience delays to surgery of more than 4 weeks. Of this group, more than half of patients receive shorter than standard courses of neoadjuvant therapy (NET), and the patients most likely to benefit were those older than 50 years, with ductal tumors, and the effect was seen in all T stages.
Recent reports show that NET is increasing. However, Dr. De Andrade pointed out, delays in receiving surgery remain a problem in breast cancer treatment and are associated with worse overall and cancer specific survival.
“Off-label use of NET is sometimes used in patients undergoing surgical delays,” he said.
NET use for 3 months has been associated with decreasing the size of tumors in patients with hormone receptor–positive (HR+) invasive breast cancer and allowing for breast conservation therapy. While short-term NET is sometimes used in women who are experiencing delay to surgery, the incidence and efficacy of this regimen remains undefined.
In the current study, Dr. De Andrade and his colleagues sought to answer three clinical questions:
• How long are patients with operable breast cancer waiting to undergo surgery?
• What is the pattern of use of short-course NET?
• What are the effects of short-course NET on outcomes?
The investigators used the National Cancer Database (NCDB) to identify women who had undergone surgery for stage 1-3 HR+ invasive breast cancer from 2004 to 2013. A total of 530,009 patients met inclusion criteria.
The primary outcomes of the study were time to surgery, the duration of NET, and if the pathologic stage at surgery was lower than clinical stage.
Among patients who did not receive NET, 49.3% underwent surgery within 30 days of diagnosis. More than a third (37.2%) underwent surgery within 60 days of diagnosis, and 13.5% did not have surgery until more than 60 days after their initial diagnosis. A total of 1.8% (9,664) patients underwent NET.
When looking at NET duration, 48% underwent NET for 12 or more weeks, while 52% received NET for less than 12 weeks; 27% received NET for less than 4 weeks, 17% for 4-8 weeks, and 9% for 8-12 weeks.
Downstaging from clinical stage to final pathology stage increased with longer duration of NET. It was 5.5% for less than 1 month on therapy, 9.7% for 1-2 months, and 17.2% for 2-3 months.
“For less than 4 weeks, there was no improvement in N or T downstaging,” said Dr. De Andrade. “As the amount of time on NET increased, it was associated with greater T downstaging. But for N downstaging, it was only at the standard of 12 or more weeks that a difference was seen in nodal downstaging.”
Standard NET of 12 or more weeks was associated with reduced mastectomy rates, but mastectomy rates were not lower in short-course NET.
Among patients undergoing breast conservation therapy, longer duration NET was also associated with a lower risk for re-excision (1-2 months: odds ratio, 0.82, P = .02; 2-3 months: OR, 0.40, P < .001). There was no reduction in re-excision for shorter courses of therapy.
Dr. De Andrade had no disclosures.
AT SSO 2017
Key clinical point: Short-course neoadjuvant therapy is an option for breast cancer patients with expected delays to surgery.
Major finding: Use of neoadjuvant therapy was associated with downstaging from clinical stage to final pathology stage and reducing re-excision in breast conservation surgery.
Data source: The National Cancer Database was used to identify 530,009 patients.
Disclosures: Dr. De Andrade had no disclosures.
Atezolizumab improved survival in triple-negative breast cancer
Treatment with the anti-PD-L1 cancer immunotherapy atezolizumab produced a durable clinical benefit in patients with metastatic triple-negative breast cancer who responded to treatment, according to results from a phase I study.
Overall survival (OS) rates were 41% at 1 year and 22% at both year 2 and year 3. Patients with PD-L1 on 5% or more of tumor-infiltrating immune cells (IC2/3) achieved even better clinical outcomes: Their OS rates at 1, 2, and 3 years were 45%, 28%, and 28%.
The findings from this early phase I trial, which were presented at the annual meeting of the American Association for Cancer Research, also demonstrated that response rates were higher in the first-line setting, and an exploratory biomarker analysis suggested that higher CD8 T cell and tumor-infiltrating lymphocyte counts also contributed to a better response.
“We have no targeted therapy at the moment for triple-negative breast cancer,” said study lead author Dr. Peter Schmid, director of the St. Bartholomew’s Breast Centre at St. Bartholomew’s Hospital and Barts Cancer Institute in London, during a media briefing. “The treatment we have is chemotherapy, and most patients develop resistance relatively quickly.”
Dr. Schmid noted that the median survival for these patients is still relatively short – about 9-12 months – so, the data from this trial need to be seen in that context.
“On the other hand, triple-negative breast cancer is probably the best subtype of breast cancer in terms of selecting patients for immune therapy,” said Dr. Schmid. “This is based on a high degree of genetic instability, a high rate of mutations, higher levels of PD-L1 expression, and tumor infiltrating lymphocytes inside the tumor.”
Atezolizumab is a humanized monoclonal antibody that disrupts the PD pathway, inhibits the binding of PD-L1 to PD-1 and B7.1, and, in doing so, restores tumor-specific T-cell immunity.
In this study, Dr Schmid and colleagues recruited patients with metastatic triple-negative breast cancer to one of the expansion cohorts of a phase I trial. A total of 112 patients were evaluable for response. Of this group, 19 received atezolizumab as first-line treatment, and 93 had received at least two lines of prior therapy.
Atezolizumab was administered every 3 weeks at 15 mg/kg or 20 mg/kg, and the level of PD-L1 expression on tumor-infiltrating immune cells was evaluated. The primary endpoint of the study was safety, with overall response rate, duration of response, and progression-free survival as key secondary endpoints.
The 1- and 2-year overall survival rates for responders were 100%, but that dropped to 33% and 11%, respectively, for nonresponders. Of the 11 responders, 5 received atezolizumab as first-line therapy, while 9 had high PD-L1 expression (IC2/3).
For patients who received atezolizumab in the first-line setting, 1-year overall survival was 63%, and 2-year overall survival was 47%. The rates were lower for second-line and beyond; 37% and 18%, respectively.
For IC2/3 patients, 1-year overall survival was 45%, compared with 37% for those with low to no PD-L1 expression (IC0/1).
Only 11% of patients experienced treatment-related grade 3 or greater adverse events, and side effects led to treatment discontinuation in 3% of patients.
A key message was that the duration of response had a median of 21 months, and that is significant in this disease setting, explained Dr. Schmid. Another important point was that “overall survival was significantly longer that what we see with chemotherapy.”
Genentech funded the study. Dr Schmid’s spouse is a consultant to Roche/Genentech.
Treatment with the anti-PD-L1 cancer immunotherapy atezolizumab produced a durable clinical benefit in patients with metastatic triple-negative breast cancer who responded to treatment, according to results from a phase I study.
Overall survival (OS) rates were 41% at 1 year and 22% at both year 2 and year 3. Patients with PD-L1 on 5% or more of tumor-infiltrating immune cells (IC2/3) achieved even better clinical outcomes: Their OS rates at 1, 2, and 3 years were 45%, 28%, and 28%.
The findings from this early phase I trial, which were presented at the annual meeting of the American Association for Cancer Research, also demonstrated that response rates were higher in the first-line setting, and an exploratory biomarker analysis suggested that higher CD8 T cell and tumor-infiltrating lymphocyte counts also contributed to a better response.
“We have no targeted therapy at the moment for triple-negative breast cancer,” said study lead author Dr. Peter Schmid, director of the St. Bartholomew’s Breast Centre at St. Bartholomew’s Hospital and Barts Cancer Institute in London, during a media briefing. “The treatment we have is chemotherapy, and most patients develop resistance relatively quickly.”
Dr. Schmid noted that the median survival for these patients is still relatively short – about 9-12 months – so, the data from this trial need to be seen in that context.
“On the other hand, triple-negative breast cancer is probably the best subtype of breast cancer in terms of selecting patients for immune therapy,” said Dr. Schmid. “This is based on a high degree of genetic instability, a high rate of mutations, higher levels of PD-L1 expression, and tumor infiltrating lymphocytes inside the tumor.”
Atezolizumab is a humanized monoclonal antibody that disrupts the PD pathway, inhibits the binding of PD-L1 to PD-1 and B7.1, and, in doing so, restores tumor-specific T-cell immunity.
In this study, Dr Schmid and colleagues recruited patients with metastatic triple-negative breast cancer to one of the expansion cohorts of a phase I trial. A total of 112 patients were evaluable for response. Of this group, 19 received atezolizumab as first-line treatment, and 93 had received at least two lines of prior therapy.
Atezolizumab was administered every 3 weeks at 15 mg/kg or 20 mg/kg, and the level of PD-L1 expression on tumor-infiltrating immune cells was evaluated. The primary endpoint of the study was safety, with overall response rate, duration of response, and progression-free survival as key secondary endpoints.
The 1- and 2-year overall survival rates for responders were 100%, but that dropped to 33% and 11%, respectively, for nonresponders. Of the 11 responders, 5 received atezolizumab as first-line therapy, while 9 had high PD-L1 expression (IC2/3).
For patients who received atezolizumab in the first-line setting, 1-year overall survival was 63%, and 2-year overall survival was 47%. The rates were lower for second-line and beyond; 37% and 18%, respectively.
For IC2/3 patients, 1-year overall survival was 45%, compared with 37% for those with low to no PD-L1 expression (IC0/1).
Only 11% of patients experienced treatment-related grade 3 or greater adverse events, and side effects led to treatment discontinuation in 3% of patients.
A key message was that the duration of response had a median of 21 months, and that is significant in this disease setting, explained Dr. Schmid. Another important point was that “overall survival was significantly longer that what we see with chemotherapy.”
Genentech funded the study. Dr Schmid’s spouse is a consultant to Roche/Genentech.
Treatment with the anti-PD-L1 cancer immunotherapy atezolizumab produced a durable clinical benefit in patients with metastatic triple-negative breast cancer who responded to treatment, according to results from a phase I study.
Overall survival (OS) rates were 41% at 1 year and 22% at both year 2 and year 3. Patients with PD-L1 on 5% or more of tumor-infiltrating immune cells (IC2/3) achieved even better clinical outcomes: Their OS rates at 1, 2, and 3 years were 45%, 28%, and 28%.
The findings from this early phase I trial, which were presented at the annual meeting of the American Association for Cancer Research, also demonstrated that response rates were higher in the first-line setting, and an exploratory biomarker analysis suggested that higher CD8 T cell and tumor-infiltrating lymphocyte counts also contributed to a better response.
“We have no targeted therapy at the moment for triple-negative breast cancer,” said study lead author Dr. Peter Schmid, director of the St. Bartholomew’s Breast Centre at St. Bartholomew’s Hospital and Barts Cancer Institute in London, during a media briefing. “The treatment we have is chemotherapy, and most patients develop resistance relatively quickly.”
Dr. Schmid noted that the median survival for these patients is still relatively short – about 9-12 months – so, the data from this trial need to be seen in that context.
“On the other hand, triple-negative breast cancer is probably the best subtype of breast cancer in terms of selecting patients for immune therapy,” said Dr. Schmid. “This is based on a high degree of genetic instability, a high rate of mutations, higher levels of PD-L1 expression, and tumor infiltrating lymphocytes inside the tumor.”
Atezolizumab is a humanized monoclonal antibody that disrupts the PD pathway, inhibits the binding of PD-L1 to PD-1 and B7.1, and, in doing so, restores tumor-specific T-cell immunity.
In this study, Dr Schmid and colleagues recruited patients with metastatic triple-negative breast cancer to one of the expansion cohorts of a phase I trial. A total of 112 patients were evaluable for response. Of this group, 19 received atezolizumab as first-line treatment, and 93 had received at least two lines of prior therapy.
Atezolizumab was administered every 3 weeks at 15 mg/kg or 20 mg/kg, and the level of PD-L1 expression on tumor-infiltrating immune cells was evaluated. The primary endpoint of the study was safety, with overall response rate, duration of response, and progression-free survival as key secondary endpoints.
The 1- and 2-year overall survival rates for responders were 100%, but that dropped to 33% and 11%, respectively, for nonresponders. Of the 11 responders, 5 received atezolizumab as first-line therapy, while 9 had high PD-L1 expression (IC2/3).
For patients who received atezolizumab in the first-line setting, 1-year overall survival was 63%, and 2-year overall survival was 47%. The rates were lower for second-line and beyond; 37% and 18%, respectively.
For IC2/3 patients, 1-year overall survival was 45%, compared with 37% for those with low to no PD-L1 expression (IC0/1).
Only 11% of patients experienced treatment-related grade 3 or greater adverse events, and side effects led to treatment discontinuation in 3% of patients.
A key message was that the duration of response had a median of 21 months, and that is significant in this disease setting, explained Dr. Schmid. Another important point was that “overall survival was significantly longer that what we see with chemotherapy.”
Genentech funded the study. Dr Schmid’s spouse is a consultant to Roche/Genentech.
FROM THE AACR ANNUAL MEETING
Key clinical point: In a phase I trial, the immunotherapy agent atezolizumab improved survival in triple-negative breast cancer.
Major finding: Overall survival rates were 41% at 1 year and 22% at both year 2 and year 3.
Data source: A phase I trial with a total of 112 patients who were evaluable for response.
Disclosures: Genentech funded the study. Dr Schmid’s spouse is a consultant to Roche/Genentech.
Avelumab produces durable responses in Merkel cell carcinoma
Avelumab (Bavencio) is the first drug to receive approval from the Food and Drug Administration for Merkel cell carcinoma, and new findings show that it elicited durable responses in this hard-to-treat population.
The majority of responses were durable beyond 1 year, with an objective response rate of 33%.
“Merkel cell carcinoma is rare, aggressive skin cancer with a poor prognosis,” said lead author Howard L. Kaufman, MD, a surgical oncologist at the Rutgers Cancer Institute of New Jersey in New Brunswick, who discussed the findings during a presscast held at the annual meeting of the American Association for Cancer Research.
Even though Merkel cell carcinoma is a chemosensitive disease, long-term survival beyond 6 months has not been reported with chemotherapy, explained Dr. Kaufman.
In this phase II trial, Dr. Kaufman and his colleagues assessed the use of avelumab, a fully human anti–PD-L1 monoclonal antibody, in 88 patients with metastatic Merkel cell carcinoma that had progressed after treatment with chemotherapy.
All patients received 10 mg/kg avelumab as an intravenous infusion over one hour every 2 weeks. The primary endpoint was the best objective response and secondary endpoints included progression-free and overall survival.
At a median follow-up of 10.4 months, the response rate was 31.8% (28 responses), and this included 8 complete responses and 20 partial responses.
The estimated proportion of patients with duration of response of 6 months or longer was 92%, and the 6-month progression-free survival rate was 40%.
“The purpose of the presentation now is to report on longer 1-year follow-up data,” said Dr. Kaufman.
In the updated results, the objective response rate was 33.0% (95% confidence interval, 23.3%-43.8%) as two more patients moved into a total response. There were now a total of 10 (11.4%) complete responses and 19 (21.6%) partial responses.
The 6-month durable response rate was 30.6% (95% CI, 20.9%-40.3%), and the median duration of response has not yet been reached (range, 2.8–23.3-plus months; 95% CI, 18.0–not estimable). Responses were ongoing in 21 patients at the time of this analysis.
The estimated proportion of patients with a duration of response lasting 1 year or longer was 74% (95% CI, 53%-87%), and estimated 1-year progression-free survival was 30% (95% CI, 21%-41%). The 1-year overall survival rate was 52% (95% CI, 41%-62%) and median overall survival was 12.9 months (95% CI, 7.5–not estimable).
The maturing survival data suggest that there may be a long-term benefit for a proportion of patients.
“The findings of long-term responses and well-tolerated safety profile suggest that avelumab could be an important new agent for patients with Merkel cell carcinoma who have failed prior chemotherapy,” said Dr. Kaufman. “Given these results, it will be interesting to determine whether response rates could be increased by giving avelumab prior to chemotherapy or in combination with other treatments.”
Avelumab (Bavencio) is the first drug to receive approval from the Food and Drug Administration for Merkel cell carcinoma, and new findings show that it elicited durable responses in this hard-to-treat population.
The majority of responses were durable beyond 1 year, with an objective response rate of 33%.
“Merkel cell carcinoma is rare, aggressive skin cancer with a poor prognosis,” said lead author Howard L. Kaufman, MD, a surgical oncologist at the Rutgers Cancer Institute of New Jersey in New Brunswick, who discussed the findings during a presscast held at the annual meeting of the American Association for Cancer Research.
Even though Merkel cell carcinoma is a chemosensitive disease, long-term survival beyond 6 months has not been reported with chemotherapy, explained Dr. Kaufman.
In this phase II trial, Dr. Kaufman and his colleagues assessed the use of avelumab, a fully human anti–PD-L1 monoclonal antibody, in 88 patients with metastatic Merkel cell carcinoma that had progressed after treatment with chemotherapy.
All patients received 10 mg/kg avelumab as an intravenous infusion over one hour every 2 weeks. The primary endpoint was the best objective response and secondary endpoints included progression-free and overall survival.
At a median follow-up of 10.4 months, the response rate was 31.8% (28 responses), and this included 8 complete responses and 20 partial responses.
The estimated proportion of patients with duration of response of 6 months or longer was 92%, and the 6-month progression-free survival rate was 40%.
“The purpose of the presentation now is to report on longer 1-year follow-up data,” said Dr. Kaufman.
In the updated results, the objective response rate was 33.0% (95% confidence interval, 23.3%-43.8%) as two more patients moved into a total response. There were now a total of 10 (11.4%) complete responses and 19 (21.6%) partial responses.
The 6-month durable response rate was 30.6% (95% CI, 20.9%-40.3%), and the median duration of response has not yet been reached (range, 2.8–23.3-plus months; 95% CI, 18.0–not estimable). Responses were ongoing in 21 patients at the time of this analysis.
The estimated proportion of patients with a duration of response lasting 1 year or longer was 74% (95% CI, 53%-87%), and estimated 1-year progression-free survival was 30% (95% CI, 21%-41%). The 1-year overall survival rate was 52% (95% CI, 41%-62%) and median overall survival was 12.9 months (95% CI, 7.5–not estimable).
The maturing survival data suggest that there may be a long-term benefit for a proportion of patients.
“The findings of long-term responses and well-tolerated safety profile suggest that avelumab could be an important new agent for patients with Merkel cell carcinoma who have failed prior chemotherapy,” said Dr. Kaufman. “Given these results, it will be interesting to determine whether response rates could be increased by giving avelumab prior to chemotherapy or in combination with other treatments.”
Avelumab (Bavencio) is the first drug to receive approval from the Food and Drug Administration for Merkel cell carcinoma, and new findings show that it elicited durable responses in this hard-to-treat population.
The majority of responses were durable beyond 1 year, with an objective response rate of 33%.
“Merkel cell carcinoma is rare, aggressive skin cancer with a poor prognosis,” said lead author Howard L. Kaufman, MD, a surgical oncologist at the Rutgers Cancer Institute of New Jersey in New Brunswick, who discussed the findings during a presscast held at the annual meeting of the American Association for Cancer Research.
Even though Merkel cell carcinoma is a chemosensitive disease, long-term survival beyond 6 months has not been reported with chemotherapy, explained Dr. Kaufman.
In this phase II trial, Dr. Kaufman and his colleagues assessed the use of avelumab, a fully human anti–PD-L1 monoclonal antibody, in 88 patients with metastatic Merkel cell carcinoma that had progressed after treatment with chemotherapy.
All patients received 10 mg/kg avelumab as an intravenous infusion over one hour every 2 weeks. The primary endpoint was the best objective response and secondary endpoints included progression-free and overall survival.
At a median follow-up of 10.4 months, the response rate was 31.8% (28 responses), and this included 8 complete responses and 20 partial responses.
The estimated proportion of patients with duration of response of 6 months or longer was 92%, and the 6-month progression-free survival rate was 40%.
“The purpose of the presentation now is to report on longer 1-year follow-up data,” said Dr. Kaufman.
In the updated results, the objective response rate was 33.0% (95% confidence interval, 23.3%-43.8%) as two more patients moved into a total response. There were now a total of 10 (11.4%) complete responses and 19 (21.6%) partial responses.
The 6-month durable response rate was 30.6% (95% CI, 20.9%-40.3%), and the median duration of response has not yet been reached (range, 2.8–23.3-plus months; 95% CI, 18.0–not estimable). Responses were ongoing in 21 patients at the time of this analysis.
The estimated proportion of patients with a duration of response lasting 1 year or longer was 74% (95% CI, 53%-87%), and estimated 1-year progression-free survival was 30% (95% CI, 21%-41%). The 1-year overall survival rate was 52% (95% CI, 41%-62%) and median overall survival was 12.9 months (95% CI, 7.5–not estimable).
The maturing survival data suggest that there may be a long-term benefit for a proportion of patients.
“The findings of long-term responses and well-tolerated safety profile suggest that avelumab could be an important new agent for patients with Merkel cell carcinoma who have failed prior chemotherapy,” said Dr. Kaufman. “Given these results, it will be interesting to determine whether response rates could be increased by giving avelumab prior to chemotherapy or in combination with other treatments.”
Key clinical point: Treatment with avelumab resulted in an objective response rate of 33% in patients with progressive Merkel cell carcinoma.
Major finding: The estimated proportion of patients with a duration of response lasting 1 year or longer was 74% and estimated 1-year progression-free survival was 30%.
Data source: Updated results from a phase II study that included 88 patients with progressive Merkel cell carcinoma.
Disclosures: This study was funded by EMD Serono. Dr. Kaufman has served on advisory boards for Amgen, Celldex, Compass Therapeutics, EMD Serono, Merck, Prometheus, and Turnstone Biologics.