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Study eyes biomarkers of regorafenib response in hepatocellular carcinoma
.
“In the absence of established or predefined biomarkers for regorafenib, we performed a broad exploratory biomarker analyses at the DNA, RNA, and protein level that represents a much more comprehensive approach than previous studies of regorafenib or sorafenib,” wrote Michael Teufel, PhD, of Bayer Healthcare Pharmaceuticals in Whippany, N.J., and his associates. The preplanned, retrospective analysis of data from the phase 3 RESOURCE trial was reported in Gastroenterology.
The randomized trial included 567 patients whose hepatocellular carcinoma had progressed on sorafenib. Regorafenib significantly outperformed placebo with regard to overall survival (OS). Dr. Teufel and his associates performed next-generation sequencing on 17 archived tumor samples containing sufficient tissue (all from regorafenib recipients). They also performed immune profiling on 46 tumor samples (32 from regorafenib recipients and 14 from placebo recipients), protein analysis on 499 plasma samples (332 from regorafenib recipients and 167 from placebo recipients), and microRNA analysis on 343 plasma samples (234 regorafenib recipients and 109 placebo recipients).
Among 266 proteins tested, decreased levels of 5 proteins correlated with significantly longer OS on regorafenib therapy. These proteins are involved in inflammation or hepatocellular carcinogenesis, the researchers noted. Importantly, none were associated with survival independent of treatment. These five proteins included angiopoietin 1 (hazard ratio for OS, 0.53; 95% confidence interval, 0.38-0.73), cystatin B (hazard ratio, 0.47; 95% CI, 0.34-0.64); the latency-associated peptide of transforming growth factor beta (HR, 0.46; 95% CI, 0.33-0.64), oxidized low-density lipoprotein receptor 1 (HR, 0.54; 95% CI, 0.41-0.72), and C-C motif chemokine ligand 3 (HR, 0.54; 95% CI, 0.39-0.74).
Additionally, baseline concentrations of 47 of the 266 proteins correlated with a time to progression (TPP) benefit on regorafenib therapy (adjusted P less than or equal to .05 for each). The 47 proteins included all 5 that predicted an OS benefit. All but two proteins (calbindin and gelsolin) showed the same directional effect as for OS (that is, low expression predicted response).
Nine plasma microRNA’s levels correlated with improved OS on regorafenib (adjusted P less than or equal to .05): MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645. Notably, expression was linked to longer OS specifically among patients with the Hoshida S3 subtype of hepatocellular carcinoma. Next-generation sequencing of tumor samples also identified 49 variants in 27 oncogenes or tumor-suppressor genes. Mutations in CTNNB1 were found in 3 of 10 patients who progressed on regorafenib, and VEGFA amplification was found in 1 of 7 regorafenib responders.
“Thus far, rational biomarker selection has been unsuccessful in identifying predictive markers for regorafenib in colorectal cancer and gastrointestinal stromal tumors,” the researchers commented. “The broader approach used in this study is not only biologically warranted considering the heterogeneity of hepatocellular carcinoma tumors, but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with hepatocellular carcinoma most likely to respond to regorafenib.”
Bayer funded the study, provided the study drug, and was involved in all aspects of the study. Dr. Teufel and three coinvestigators are Bayer employees. Dr. Teufel and two coinvestigators own stock in Bayer. Three other coinvestigators disclosed ties to Bayer and other pharmaceutical companies.
SOURCE: Teufel M et al. Gastroenterology. 2019 Jan 30. doi: 10.1053/j.gastro.2019.01.261.
.
“In the absence of established or predefined biomarkers for regorafenib, we performed a broad exploratory biomarker analyses at the DNA, RNA, and protein level that represents a much more comprehensive approach than previous studies of regorafenib or sorafenib,” wrote Michael Teufel, PhD, of Bayer Healthcare Pharmaceuticals in Whippany, N.J., and his associates. The preplanned, retrospective analysis of data from the phase 3 RESOURCE trial was reported in Gastroenterology.
The randomized trial included 567 patients whose hepatocellular carcinoma had progressed on sorafenib. Regorafenib significantly outperformed placebo with regard to overall survival (OS). Dr. Teufel and his associates performed next-generation sequencing on 17 archived tumor samples containing sufficient tissue (all from regorafenib recipients). They also performed immune profiling on 46 tumor samples (32 from regorafenib recipients and 14 from placebo recipients), protein analysis on 499 plasma samples (332 from regorafenib recipients and 167 from placebo recipients), and microRNA analysis on 343 plasma samples (234 regorafenib recipients and 109 placebo recipients).
Among 266 proteins tested, decreased levels of 5 proteins correlated with significantly longer OS on regorafenib therapy. These proteins are involved in inflammation or hepatocellular carcinogenesis, the researchers noted. Importantly, none were associated with survival independent of treatment. These five proteins included angiopoietin 1 (hazard ratio for OS, 0.53; 95% confidence interval, 0.38-0.73), cystatin B (hazard ratio, 0.47; 95% CI, 0.34-0.64); the latency-associated peptide of transforming growth factor beta (HR, 0.46; 95% CI, 0.33-0.64), oxidized low-density lipoprotein receptor 1 (HR, 0.54; 95% CI, 0.41-0.72), and C-C motif chemokine ligand 3 (HR, 0.54; 95% CI, 0.39-0.74).
Additionally, baseline concentrations of 47 of the 266 proteins correlated with a time to progression (TPP) benefit on regorafenib therapy (adjusted P less than or equal to .05 for each). The 47 proteins included all 5 that predicted an OS benefit. All but two proteins (calbindin and gelsolin) showed the same directional effect as for OS (that is, low expression predicted response).
Nine plasma microRNA’s levels correlated with improved OS on regorafenib (adjusted P less than or equal to .05): MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645. Notably, expression was linked to longer OS specifically among patients with the Hoshida S3 subtype of hepatocellular carcinoma. Next-generation sequencing of tumor samples also identified 49 variants in 27 oncogenes or tumor-suppressor genes. Mutations in CTNNB1 were found in 3 of 10 patients who progressed on regorafenib, and VEGFA amplification was found in 1 of 7 regorafenib responders.
“Thus far, rational biomarker selection has been unsuccessful in identifying predictive markers for regorafenib in colorectal cancer and gastrointestinal stromal tumors,” the researchers commented. “The broader approach used in this study is not only biologically warranted considering the heterogeneity of hepatocellular carcinoma tumors, but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with hepatocellular carcinoma most likely to respond to regorafenib.”
Bayer funded the study, provided the study drug, and was involved in all aspects of the study. Dr. Teufel and three coinvestigators are Bayer employees. Dr. Teufel and two coinvestigators own stock in Bayer. Three other coinvestigators disclosed ties to Bayer and other pharmaceutical companies.
SOURCE: Teufel M et al. Gastroenterology. 2019 Jan 30. doi: 10.1053/j.gastro.2019.01.261.
.
“In the absence of established or predefined biomarkers for regorafenib, we performed a broad exploratory biomarker analyses at the DNA, RNA, and protein level that represents a much more comprehensive approach than previous studies of regorafenib or sorafenib,” wrote Michael Teufel, PhD, of Bayer Healthcare Pharmaceuticals in Whippany, N.J., and his associates. The preplanned, retrospective analysis of data from the phase 3 RESOURCE trial was reported in Gastroenterology.
The randomized trial included 567 patients whose hepatocellular carcinoma had progressed on sorafenib. Regorafenib significantly outperformed placebo with regard to overall survival (OS). Dr. Teufel and his associates performed next-generation sequencing on 17 archived tumor samples containing sufficient tissue (all from regorafenib recipients). They also performed immune profiling on 46 tumor samples (32 from regorafenib recipients and 14 from placebo recipients), protein analysis on 499 plasma samples (332 from regorafenib recipients and 167 from placebo recipients), and microRNA analysis on 343 plasma samples (234 regorafenib recipients and 109 placebo recipients).
Among 266 proteins tested, decreased levels of 5 proteins correlated with significantly longer OS on regorafenib therapy. These proteins are involved in inflammation or hepatocellular carcinogenesis, the researchers noted. Importantly, none were associated with survival independent of treatment. These five proteins included angiopoietin 1 (hazard ratio for OS, 0.53; 95% confidence interval, 0.38-0.73), cystatin B (hazard ratio, 0.47; 95% CI, 0.34-0.64); the latency-associated peptide of transforming growth factor beta (HR, 0.46; 95% CI, 0.33-0.64), oxidized low-density lipoprotein receptor 1 (HR, 0.54; 95% CI, 0.41-0.72), and C-C motif chemokine ligand 3 (HR, 0.54; 95% CI, 0.39-0.74).
Additionally, baseline concentrations of 47 of the 266 proteins correlated with a time to progression (TPP) benefit on regorafenib therapy (adjusted P less than or equal to .05 for each). The 47 proteins included all 5 that predicted an OS benefit. All but two proteins (calbindin and gelsolin) showed the same directional effect as for OS (that is, low expression predicted response).
Nine plasma microRNA’s levels correlated with improved OS on regorafenib (adjusted P less than or equal to .05): MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645. Notably, expression was linked to longer OS specifically among patients with the Hoshida S3 subtype of hepatocellular carcinoma. Next-generation sequencing of tumor samples also identified 49 variants in 27 oncogenes or tumor-suppressor genes. Mutations in CTNNB1 were found in 3 of 10 patients who progressed on regorafenib, and VEGFA amplification was found in 1 of 7 regorafenib responders.
“Thus far, rational biomarker selection has been unsuccessful in identifying predictive markers for regorafenib in colorectal cancer and gastrointestinal stromal tumors,” the researchers commented. “The broader approach used in this study is not only biologically warranted considering the heterogeneity of hepatocellular carcinoma tumors, but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with hepatocellular carcinoma most likely to respond to regorafenib.”
Bayer funded the study, provided the study drug, and was involved in all aspects of the study. Dr. Teufel and three coinvestigators are Bayer employees. Dr. Teufel and two coinvestigators own stock in Bayer. Three other coinvestigators disclosed ties to Bayer and other pharmaceutical companies.
SOURCE: Teufel M et al. Gastroenterology. 2019 Jan 30. doi: 10.1053/j.gastro.2019.01.261.
FROM GASTROENTEROLOGY
Ibrutinib sustained responses in refractory CLL in long-term follow-up
Prolonged exposure to ibrutinib showed sustained progression-free and overall survival and had tolerable safety outcomes in patients with relapsed or refractory chronic lymphocytic leukemia, according to a post hoc analysis of the phase 3 RESONATE trial.
“This study ... provides further evidence for efficacy and safety with prolonged treatment across multiple high-risk genomic and clinical disease features and with increasing depth of response,” John C. Byrd, MD, of the Ohio State University, Columbus, and his colleagues wrote in Blood.
RESONATE included 391 high-risk patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Study participants were randomized in a 1:1 fashion to receive ibrutinib 420 mg daily or ofatumumab (initial infusion of 300 mg followed by seven weekly infusions and four monthly infusions of 2,000 mg) for a maximum of 24 weeks. Drug therapy was continued until cancer progression or intolerable toxicity of either agent was seen.
“Primary analysis at median follow-up of 9.7 months demonstrated superiority of ibrutinib over ofatumumab in PFS [progression-free survival], OS [overall survival], and overall response,” the researchers wrote. “With extended follow-up of median 44 months, these same results persist; a plateau of PFS has not yet been reached in this long-term follow-up. We also observe very durable remissions among patients of all genomic groups, including those with del(17)(p13.1), del(11)(q22.3), or unmutated IgHV [immunoglobulin heavy chain gene], who are traditionally considered high-risk populations.”
After an extended follow-up (median, 44 months), the team found that the PFS benefit with ibrutinib was sustained, compared with ofatumumab (hazard ratio, 0.133; 95% confidence interval, 0.099-0.178; P less than .0001). The 3-year PFS rate was 59% for ibrutinib, compared with 3% for ofatumumab. Similar PFS benefits were seen among subgroups of high- and very high–risk patients, based on their scores on the International Prognostic Index for CLL.
The OS benefit was also sustained in those randomized to ibrutinib (HR, 0.591; 95% CI, 0.378-0.926; P = .0208). The continued OS benefit with ibrutinib versus ofatumumab continued even after a sensitivity analysis adjusted for crossover of patients to ibrutinib.
With respect to safety, adverse events of any grade were similar to previous reports of ibrutinib. In fact, the prevalence of adverse events (grade 3 or higher) decreased over time for participants that continued on ibrutinib.
“Multiple studies are ongoing to investigate ibrutinib earlier in the course of CLL therapy, including phase 3 studies of first-line ibrutinib [or ibrutinib combined with anti-CD20 therapy], compared with standard chemoimmunotherapy regimens,” they wrote.
The study was sponsored by Pharmacyclics and Janssen. The authors reported financial disclosures related to the sponsors and several other companies.
SOURCE: Byrd JC et al. Blood. 2019 Mar 6. doi: 10.1182/blood-2018-08-870238.
Prolonged exposure to ibrutinib showed sustained progression-free and overall survival and had tolerable safety outcomes in patients with relapsed or refractory chronic lymphocytic leukemia, according to a post hoc analysis of the phase 3 RESONATE trial.
“This study ... provides further evidence for efficacy and safety with prolonged treatment across multiple high-risk genomic and clinical disease features and with increasing depth of response,” John C. Byrd, MD, of the Ohio State University, Columbus, and his colleagues wrote in Blood.
RESONATE included 391 high-risk patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Study participants were randomized in a 1:1 fashion to receive ibrutinib 420 mg daily or ofatumumab (initial infusion of 300 mg followed by seven weekly infusions and four monthly infusions of 2,000 mg) for a maximum of 24 weeks. Drug therapy was continued until cancer progression or intolerable toxicity of either agent was seen.
“Primary analysis at median follow-up of 9.7 months demonstrated superiority of ibrutinib over ofatumumab in PFS [progression-free survival], OS [overall survival], and overall response,” the researchers wrote. “With extended follow-up of median 44 months, these same results persist; a plateau of PFS has not yet been reached in this long-term follow-up. We also observe very durable remissions among patients of all genomic groups, including those with del(17)(p13.1), del(11)(q22.3), or unmutated IgHV [immunoglobulin heavy chain gene], who are traditionally considered high-risk populations.”
After an extended follow-up (median, 44 months), the team found that the PFS benefit with ibrutinib was sustained, compared with ofatumumab (hazard ratio, 0.133; 95% confidence interval, 0.099-0.178; P less than .0001). The 3-year PFS rate was 59% for ibrutinib, compared with 3% for ofatumumab. Similar PFS benefits were seen among subgroups of high- and very high–risk patients, based on their scores on the International Prognostic Index for CLL.
The OS benefit was also sustained in those randomized to ibrutinib (HR, 0.591; 95% CI, 0.378-0.926; P = .0208). The continued OS benefit with ibrutinib versus ofatumumab continued even after a sensitivity analysis adjusted for crossover of patients to ibrutinib.
With respect to safety, adverse events of any grade were similar to previous reports of ibrutinib. In fact, the prevalence of adverse events (grade 3 or higher) decreased over time for participants that continued on ibrutinib.
“Multiple studies are ongoing to investigate ibrutinib earlier in the course of CLL therapy, including phase 3 studies of first-line ibrutinib [or ibrutinib combined with anti-CD20 therapy], compared with standard chemoimmunotherapy regimens,” they wrote.
The study was sponsored by Pharmacyclics and Janssen. The authors reported financial disclosures related to the sponsors and several other companies.
SOURCE: Byrd JC et al. Blood. 2019 Mar 6. doi: 10.1182/blood-2018-08-870238.
Prolonged exposure to ibrutinib showed sustained progression-free and overall survival and had tolerable safety outcomes in patients with relapsed or refractory chronic lymphocytic leukemia, according to a post hoc analysis of the phase 3 RESONATE trial.
“This study ... provides further evidence for efficacy and safety with prolonged treatment across multiple high-risk genomic and clinical disease features and with increasing depth of response,” John C. Byrd, MD, of the Ohio State University, Columbus, and his colleagues wrote in Blood.
RESONATE included 391 high-risk patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Study participants were randomized in a 1:1 fashion to receive ibrutinib 420 mg daily or ofatumumab (initial infusion of 300 mg followed by seven weekly infusions and four monthly infusions of 2,000 mg) for a maximum of 24 weeks. Drug therapy was continued until cancer progression or intolerable toxicity of either agent was seen.
“Primary analysis at median follow-up of 9.7 months demonstrated superiority of ibrutinib over ofatumumab in PFS [progression-free survival], OS [overall survival], and overall response,” the researchers wrote. “With extended follow-up of median 44 months, these same results persist; a plateau of PFS has not yet been reached in this long-term follow-up. We also observe very durable remissions among patients of all genomic groups, including those with del(17)(p13.1), del(11)(q22.3), or unmutated IgHV [immunoglobulin heavy chain gene], who are traditionally considered high-risk populations.”
After an extended follow-up (median, 44 months), the team found that the PFS benefit with ibrutinib was sustained, compared with ofatumumab (hazard ratio, 0.133; 95% confidence interval, 0.099-0.178; P less than .0001). The 3-year PFS rate was 59% for ibrutinib, compared with 3% for ofatumumab. Similar PFS benefits were seen among subgroups of high- and very high–risk patients, based on their scores on the International Prognostic Index for CLL.
The OS benefit was also sustained in those randomized to ibrutinib (HR, 0.591; 95% CI, 0.378-0.926; P = .0208). The continued OS benefit with ibrutinib versus ofatumumab continued even after a sensitivity analysis adjusted for crossover of patients to ibrutinib.
With respect to safety, adverse events of any grade were similar to previous reports of ibrutinib. In fact, the prevalence of adverse events (grade 3 or higher) decreased over time for participants that continued on ibrutinib.
“Multiple studies are ongoing to investigate ibrutinib earlier in the course of CLL therapy, including phase 3 studies of first-line ibrutinib [or ibrutinib combined with anti-CD20 therapy], compared with standard chemoimmunotherapy regimens,” they wrote.
The study was sponsored by Pharmacyclics and Janssen. The authors reported financial disclosures related to the sponsors and several other companies.
SOURCE: Byrd JC et al. Blood. 2019 Mar 6. doi: 10.1182/blood-2018-08-870238.
FROM BLOOD
FDA panel calls for changes to breast implant rupture screening
A Food and Drug Administration advisory panel urged the agency to switch its recommended screening method for silent breast implant ruptures from MRI to ultrasound and to push the first screening examination back from the current 3 years post implant to 5 years.
Members of the FDA’s General and Plastic Surgery Advisory Panel also made suggestions to the FDA regarding how it might improve communication about the risks of breast implants to the public in general and to people considering implants in particular.
The panel also discussed the sort of safety and efficacy assessments the FDA should require for acellular dermal matrix (ADM), also known as mesh, to add the material’s label for use during breast reconstruction or implant augmentation. Surgeons have used mesh routinely as a surgical aid at other body sites, such as the abdomen. Although ADM is now also widely used during breast surgery, it has never undergone testing or labeling for use in that setting.
The FDA convened the advisory committee meeting largely to assess and discuss data and concerns about two recently appreciated complications of breast implant placement – breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) and a still poorly defined and described constellation of autoimmune and rheumatoid-like symptoms reported anecdotally by some breast implant recipients called Breast Implant Illness (BII). But agency officials asked the panel to also address these other issues related to the safety of breast implants and implant surgery.
The revised screening recommendations were primarily a response to a lack of compliance with current FDA recommendations to screen for breast implant rupture with MRI starting 3 years after placement and then every 2 years.
The problem is that a screening MRI costs about $1,500-$2,000 and is generally not covered by insurance when done for this purpose, although it is often covered when used to investigate a suspected rupture. The result is that less than 5% of implanted patients comply with the recommended screening schedule, noted committee chair Frank R. Lewis Jr., MD, executive director, emeritus, of the American Board of Surgery in Philadelphia.
“Effectively it’s a useless recommendation,” he said. “Ultrasound is far easier, quicker, and cheaper” and seems effective for screening.
The advisory panel recommended starting ultrasound screening 5 years after implantation, based on MRI screening data showing that virtually all ruptures don’t occur until after 5 years, and then following with ultrasound screening every 3 years after that. The panel recommended using MRI when the ultrasound result is equivocal or when the patient has symptoms suggesting rupture.
After hearing testimony during the sessions from several dozen women who told horror stories of the complications they experienced from breast implants, panel member Karen E. Burke, MD, PhD, spoke for many on the panel when she said “no doubt patients feel that the informed consent process failed them, that they were not aware of the risks.”
Dr. Burke suggested that patients must be informed so that they realize that breast implants are not static objects that will always sit unchanged in their body for the rest of their lives, that certain factors such as allergy or family history of tissue disease might predispose them to autoimmune-type reactions and that the diverse symptoms described for BII are possible sequelae.
A black box warning for the potential of developing anaplastic large-cell lymphoma should also go into the label, said Dr. Burke, a dermatologist who practices in New York City.
Dr. Lewis ridiculed the information booklets that implant manufacturers currently provide for patients as too long and dense. “They were not constructed to inform patients in the best way; they were constructed to provide legal protection.” He called for creating a two- or three-page list of potential adverse effects and points to consider.
Other panel members suggested public service advertisements similar to what is used to inform consumers about the risk from cigarettes. Dr. Burke recommended getting the word out about BII to other medical specialties that are more likely to see affected patients first, such as rheumatologists, immunologists, and dermatologists. She vowed to speak about these complications at an upcoming meeting of the American Academy of Dermatology. But other panel members noted that BII right now remains without any official medical definition nor clear causal link to breast implants.
The question of exactly what safety and efficacy data the FDA might require from manufacturers seeking a breast surgery indication for ADM was less clear.
Binita Ashar, MD, director of the FDA’s Division of Surgical Devices, highlighted the agency’s dilemma about considering data for a breast surgery indication. “The challenge for us is that we can’t expect a control arm because everyone today is using” mesh, she explained. “We’re looking for guidance on how to understand the risk-to-benefit profile” of ADM.
A plastic surgeon on the advisory panel, Pierre M. Chevray, MD, PhD, from Houston Methodist Hospital summarized the way ADM mesh reached its current niche in routine, U.S. breast surgery.
About 20 years ago, plastic surgeons began using mesh during implant surgery to improve eventual breast cosmesis. Surgeons began to wrap the implant in mesh and then attached the mesh to the pectoral muscle so that the implant could go on top of the muscle and not beneath it. It greatly diminished capsular contraction around the implant over time, reduced the risk for implant movement, and allowed for more natural positioning of the breast with the implant inside, he said.
Another factor in the growing use of mesh was heavy promotion by manufacturers to a generation of plastic surgeons, Dr. Chevray said. But use of ADM may also lead to a slightly increased rate of seromas and infections.
“The benefit from mesh is hard to prove and is questionable” because it largely depends on a subjective assessment by a surgeon or patient, Dr. Chevray said. “The cost [of ADM] is substantial, but no data have shown that outcomes are better” with its use. Despite that, “nearly every surgeon uses mesh” these days, he noted.
A Food and Drug Administration advisory panel urged the agency to switch its recommended screening method for silent breast implant ruptures from MRI to ultrasound and to push the first screening examination back from the current 3 years post implant to 5 years.
Members of the FDA’s General and Plastic Surgery Advisory Panel also made suggestions to the FDA regarding how it might improve communication about the risks of breast implants to the public in general and to people considering implants in particular.
The panel also discussed the sort of safety and efficacy assessments the FDA should require for acellular dermal matrix (ADM), also known as mesh, to add the material’s label for use during breast reconstruction or implant augmentation. Surgeons have used mesh routinely as a surgical aid at other body sites, such as the abdomen. Although ADM is now also widely used during breast surgery, it has never undergone testing or labeling for use in that setting.
The FDA convened the advisory committee meeting largely to assess and discuss data and concerns about two recently appreciated complications of breast implant placement – breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) and a still poorly defined and described constellation of autoimmune and rheumatoid-like symptoms reported anecdotally by some breast implant recipients called Breast Implant Illness (BII). But agency officials asked the panel to also address these other issues related to the safety of breast implants and implant surgery.
The revised screening recommendations were primarily a response to a lack of compliance with current FDA recommendations to screen for breast implant rupture with MRI starting 3 years after placement and then every 2 years.
The problem is that a screening MRI costs about $1,500-$2,000 and is generally not covered by insurance when done for this purpose, although it is often covered when used to investigate a suspected rupture. The result is that less than 5% of implanted patients comply with the recommended screening schedule, noted committee chair Frank R. Lewis Jr., MD, executive director, emeritus, of the American Board of Surgery in Philadelphia.
“Effectively it’s a useless recommendation,” he said. “Ultrasound is far easier, quicker, and cheaper” and seems effective for screening.
The advisory panel recommended starting ultrasound screening 5 years after implantation, based on MRI screening data showing that virtually all ruptures don’t occur until after 5 years, and then following with ultrasound screening every 3 years after that. The panel recommended using MRI when the ultrasound result is equivocal or when the patient has symptoms suggesting rupture.
After hearing testimony during the sessions from several dozen women who told horror stories of the complications they experienced from breast implants, panel member Karen E. Burke, MD, PhD, spoke for many on the panel when she said “no doubt patients feel that the informed consent process failed them, that they were not aware of the risks.”
Dr. Burke suggested that patients must be informed so that they realize that breast implants are not static objects that will always sit unchanged in their body for the rest of their lives, that certain factors such as allergy or family history of tissue disease might predispose them to autoimmune-type reactions and that the diverse symptoms described for BII are possible sequelae.
A black box warning for the potential of developing anaplastic large-cell lymphoma should also go into the label, said Dr. Burke, a dermatologist who practices in New York City.
Dr. Lewis ridiculed the information booklets that implant manufacturers currently provide for patients as too long and dense. “They were not constructed to inform patients in the best way; they were constructed to provide legal protection.” He called for creating a two- or three-page list of potential adverse effects and points to consider.
Other panel members suggested public service advertisements similar to what is used to inform consumers about the risk from cigarettes. Dr. Burke recommended getting the word out about BII to other medical specialties that are more likely to see affected patients first, such as rheumatologists, immunologists, and dermatologists. She vowed to speak about these complications at an upcoming meeting of the American Academy of Dermatology. But other panel members noted that BII right now remains without any official medical definition nor clear causal link to breast implants.
The question of exactly what safety and efficacy data the FDA might require from manufacturers seeking a breast surgery indication for ADM was less clear.
Binita Ashar, MD, director of the FDA’s Division of Surgical Devices, highlighted the agency’s dilemma about considering data for a breast surgery indication. “The challenge for us is that we can’t expect a control arm because everyone today is using” mesh, she explained. “We’re looking for guidance on how to understand the risk-to-benefit profile” of ADM.
A plastic surgeon on the advisory panel, Pierre M. Chevray, MD, PhD, from Houston Methodist Hospital summarized the way ADM mesh reached its current niche in routine, U.S. breast surgery.
About 20 years ago, plastic surgeons began using mesh during implant surgery to improve eventual breast cosmesis. Surgeons began to wrap the implant in mesh and then attached the mesh to the pectoral muscle so that the implant could go on top of the muscle and not beneath it. It greatly diminished capsular contraction around the implant over time, reduced the risk for implant movement, and allowed for more natural positioning of the breast with the implant inside, he said.
Another factor in the growing use of mesh was heavy promotion by manufacturers to a generation of plastic surgeons, Dr. Chevray said. But use of ADM may also lead to a slightly increased rate of seromas and infections.
“The benefit from mesh is hard to prove and is questionable” because it largely depends on a subjective assessment by a surgeon or patient, Dr. Chevray said. “The cost [of ADM] is substantial, but no data have shown that outcomes are better” with its use. Despite that, “nearly every surgeon uses mesh” these days, he noted.
A Food and Drug Administration advisory panel urged the agency to switch its recommended screening method for silent breast implant ruptures from MRI to ultrasound and to push the first screening examination back from the current 3 years post implant to 5 years.
Members of the FDA’s General and Plastic Surgery Advisory Panel also made suggestions to the FDA regarding how it might improve communication about the risks of breast implants to the public in general and to people considering implants in particular.
The panel also discussed the sort of safety and efficacy assessments the FDA should require for acellular dermal matrix (ADM), also known as mesh, to add the material’s label for use during breast reconstruction or implant augmentation. Surgeons have used mesh routinely as a surgical aid at other body sites, such as the abdomen. Although ADM is now also widely used during breast surgery, it has never undergone testing or labeling for use in that setting.
The FDA convened the advisory committee meeting largely to assess and discuss data and concerns about two recently appreciated complications of breast implant placement – breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) and a still poorly defined and described constellation of autoimmune and rheumatoid-like symptoms reported anecdotally by some breast implant recipients called Breast Implant Illness (BII). But agency officials asked the panel to also address these other issues related to the safety of breast implants and implant surgery.
The revised screening recommendations were primarily a response to a lack of compliance with current FDA recommendations to screen for breast implant rupture with MRI starting 3 years after placement and then every 2 years.
The problem is that a screening MRI costs about $1,500-$2,000 and is generally not covered by insurance when done for this purpose, although it is often covered when used to investigate a suspected rupture. The result is that less than 5% of implanted patients comply with the recommended screening schedule, noted committee chair Frank R. Lewis Jr., MD, executive director, emeritus, of the American Board of Surgery in Philadelphia.
“Effectively it’s a useless recommendation,” he said. “Ultrasound is far easier, quicker, and cheaper” and seems effective for screening.
The advisory panel recommended starting ultrasound screening 5 years after implantation, based on MRI screening data showing that virtually all ruptures don’t occur until after 5 years, and then following with ultrasound screening every 3 years after that. The panel recommended using MRI when the ultrasound result is equivocal or when the patient has symptoms suggesting rupture.
After hearing testimony during the sessions from several dozen women who told horror stories of the complications they experienced from breast implants, panel member Karen E. Burke, MD, PhD, spoke for many on the panel when she said “no doubt patients feel that the informed consent process failed them, that they were not aware of the risks.”
Dr. Burke suggested that patients must be informed so that they realize that breast implants are not static objects that will always sit unchanged in their body for the rest of their lives, that certain factors such as allergy or family history of tissue disease might predispose them to autoimmune-type reactions and that the diverse symptoms described for BII are possible sequelae.
A black box warning for the potential of developing anaplastic large-cell lymphoma should also go into the label, said Dr. Burke, a dermatologist who practices in New York City.
Dr. Lewis ridiculed the information booklets that implant manufacturers currently provide for patients as too long and dense. “They were not constructed to inform patients in the best way; they were constructed to provide legal protection.” He called for creating a two- or three-page list of potential adverse effects and points to consider.
Other panel members suggested public service advertisements similar to what is used to inform consumers about the risk from cigarettes. Dr. Burke recommended getting the word out about BII to other medical specialties that are more likely to see affected patients first, such as rheumatologists, immunologists, and dermatologists. She vowed to speak about these complications at an upcoming meeting of the American Academy of Dermatology. But other panel members noted that BII right now remains without any official medical definition nor clear causal link to breast implants.
The question of exactly what safety and efficacy data the FDA might require from manufacturers seeking a breast surgery indication for ADM was less clear.
Binita Ashar, MD, director of the FDA’s Division of Surgical Devices, highlighted the agency’s dilemma about considering data for a breast surgery indication. “The challenge for us is that we can’t expect a control arm because everyone today is using” mesh, she explained. “We’re looking for guidance on how to understand the risk-to-benefit profile” of ADM.
A plastic surgeon on the advisory panel, Pierre M. Chevray, MD, PhD, from Houston Methodist Hospital summarized the way ADM mesh reached its current niche in routine, U.S. breast surgery.
About 20 years ago, plastic surgeons began using mesh during implant surgery to improve eventual breast cosmesis. Surgeons began to wrap the implant in mesh and then attached the mesh to the pectoral muscle so that the implant could go on top of the muscle and not beneath it. It greatly diminished capsular contraction around the implant over time, reduced the risk for implant movement, and allowed for more natural positioning of the breast with the implant inside, he said.
Another factor in the growing use of mesh was heavy promotion by manufacturers to a generation of plastic surgeons, Dr. Chevray said. But use of ADM may also lead to a slightly increased rate of seromas and infections.
“The benefit from mesh is hard to prove and is questionable” because it largely depends on a subjective assessment by a surgeon or patient, Dr. Chevray said. “The cost [of ADM] is substantial, but no data have shown that outcomes are better” with its use. Despite that, “nearly every surgeon uses mesh” these days, he noted.
AT AN FDA ADVISORY PANEL MEETING
Proinflammatory microbiome tied to colorectal adenoma
MIAMI – The fecal presence of least two genes harbored by toxin-producing or proinflammatory bacteria conferred a nearly 200% rise in the odds of colorectal adenoma, investigators reported.
Moreover, the fecal presence of usp (uropathogenic-specific protein), a bacterial gene encoding a genotoxin that damages DNA, correlated with nearly 1,200% greater odds of colorectal adenoma (P =.08), said senior investigator María González-Pons, PhD, of the University of Puerto Rico Comprehensive Cancer Center in San Juan.
“We are continuing to enlarge this study. We need more power to assess statistical significance and look at associations for individual combinations of bacterial genes,” Dr. Pons said in an interview. “Our ultimate goal is to risk-stratify patients so that we know whom to target for [colorectal cancer] prevention.”
Dr. Pons and the study’s lead author, Noe Crespo-Hernandez, of the University of Puerto Rico, presented the findings with their associates in a poster at the the annual Gut Microbiota for Health World Summit.
Colorectal cancer is the most lethal cancer and the second-most common malignancy in Puerto Rico. Despite recommendations for screening colonoscopy, many patients are diagnosed in late-stage disease, when treatment options are limited. Intestinal inflammation is itself key to colorectal carcinogenesis and also promotes the enteric proliferation of gram-negative bacteria that produce potentially carcinogenic toxins. Thus, gut inflammation and the microbiome are of great interest to researchers who are working to develop reliable, minimally invasive tests that assess future colorectal cancer risk.
For their study presented at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Pons and her coinvestigators compared stool samples from 67 adults with colonoscopically confirmed colorectal adenomas and 39 controls with negative screening colonoscopies. Both groups were captured in the Puerto Rico Familial Colorectal Cancer Registry. The researchers used TaqMan SNP Genotyping to look for single-nucleotide polymorphisms (SNPs) from promoter regions of genes encoding interleukin-1 beta, IL-6, and IL-10, cytokines that regulate gut inflammation. They found nonsignificant associations between colorectal adenoma and two of the three SNPs: rs143627 (encoding IL-1B) and rs1800795 (IL-6).
The real-time polymerase chain reaction results were even more striking. Using SYBR Green, the researchers tested stool for six genotoxic or proinflammatory bacterial genes and identified five, each of which correlated with colorectal adenoma. Colorectal adenoma also was linked with the fecal presence of a nonpathogenic housekeeping gene that is a surrogate for a mucolytic bacterium abundant in the stool of colorectal cancer patients.
Odds ratios for these associations ranged from 1.17 (for cnf, or cytotoxic necrotizing factor) to 12.83 (for usp), the researchers reported. Dr. Pons commented that Hurricane Maria greatly delayed this study and thus the cohort was underpowered to test for statistical significance. Nonetheless, P values approached significance for the usp gene (OR, 12.83; 95% confidence interval, 0.73-226.8; P = .08) and the fecal presence of at least two genes in combination (OR, 2.84; 95% CI, 1.01-8.90; P = .05).
Next, Dr. Pons and her team will expand the study to assess links between colorectal adenoma and these pathogenic bacterial genes, individually and in various combinations. They also plan to compare genes in normal and adenomatous colon tissue and to use enteroid (small intestinal organoid) models to tease out the carcinogenic mechanisms of these bacterial toxins.
The National Institutes of Health provided funding. The researchers disclosed no competing interests.
MIAMI – The fecal presence of least two genes harbored by toxin-producing or proinflammatory bacteria conferred a nearly 200% rise in the odds of colorectal adenoma, investigators reported.
Moreover, the fecal presence of usp (uropathogenic-specific protein), a bacterial gene encoding a genotoxin that damages DNA, correlated with nearly 1,200% greater odds of colorectal adenoma (P =.08), said senior investigator María González-Pons, PhD, of the University of Puerto Rico Comprehensive Cancer Center in San Juan.
“We are continuing to enlarge this study. We need more power to assess statistical significance and look at associations for individual combinations of bacterial genes,” Dr. Pons said in an interview. “Our ultimate goal is to risk-stratify patients so that we know whom to target for [colorectal cancer] prevention.”
Dr. Pons and the study’s lead author, Noe Crespo-Hernandez, of the University of Puerto Rico, presented the findings with their associates in a poster at the the annual Gut Microbiota for Health World Summit.
Colorectal cancer is the most lethal cancer and the second-most common malignancy in Puerto Rico. Despite recommendations for screening colonoscopy, many patients are diagnosed in late-stage disease, when treatment options are limited. Intestinal inflammation is itself key to colorectal carcinogenesis and also promotes the enteric proliferation of gram-negative bacteria that produce potentially carcinogenic toxins. Thus, gut inflammation and the microbiome are of great interest to researchers who are working to develop reliable, minimally invasive tests that assess future colorectal cancer risk.
For their study presented at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Pons and her coinvestigators compared stool samples from 67 adults with colonoscopically confirmed colorectal adenomas and 39 controls with negative screening colonoscopies. Both groups were captured in the Puerto Rico Familial Colorectal Cancer Registry. The researchers used TaqMan SNP Genotyping to look for single-nucleotide polymorphisms (SNPs) from promoter regions of genes encoding interleukin-1 beta, IL-6, and IL-10, cytokines that regulate gut inflammation. They found nonsignificant associations between colorectal adenoma and two of the three SNPs: rs143627 (encoding IL-1B) and rs1800795 (IL-6).
The real-time polymerase chain reaction results were even more striking. Using SYBR Green, the researchers tested stool for six genotoxic or proinflammatory bacterial genes and identified five, each of which correlated with colorectal adenoma. Colorectal adenoma also was linked with the fecal presence of a nonpathogenic housekeeping gene that is a surrogate for a mucolytic bacterium abundant in the stool of colorectal cancer patients.
Odds ratios for these associations ranged from 1.17 (for cnf, or cytotoxic necrotizing factor) to 12.83 (for usp), the researchers reported. Dr. Pons commented that Hurricane Maria greatly delayed this study and thus the cohort was underpowered to test for statistical significance. Nonetheless, P values approached significance for the usp gene (OR, 12.83; 95% confidence interval, 0.73-226.8; P = .08) and the fecal presence of at least two genes in combination (OR, 2.84; 95% CI, 1.01-8.90; P = .05).
Next, Dr. Pons and her team will expand the study to assess links between colorectal adenoma and these pathogenic bacterial genes, individually and in various combinations. They also plan to compare genes in normal and adenomatous colon tissue and to use enteroid (small intestinal organoid) models to tease out the carcinogenic mechanisms of these bacterial toxins.
The National Institutes of Health provided funding. The researchers disclosed no competing interests.
MIAMI – The fecal presence of least two genes harbored by toxin-producing or proinflammatory bacteria conferred a nearly 200% rise in the odds of colorectal adenoma, investigators reported.
Moreover, the fecal presence of usp (uropathogenic-specific protein), a bacterial gene encoding a genotoxin that damages DNA, correlated with nearly 1,200% greater odds of colorectal adenoma (P =.08), said senior investigator María González-Pons, PhD, of the University of Puerto Rico Comprehensive Cancer Center in San Juan.
“We are continuing to enlarge this study. We need more power to assess statistical significance and look at associations for individual combinations of bacterial genes,” Dr. Pons said in an interview. “Our ultimate goal is to risk-stratify patients so that we know whom to target for [colorectal cancer] prevention.”
Dr. Pons and the study’s lead author, Noe Crespo-Hernandez, of the University of Puerto Rico, presented the findings with their associates in a poster at the the annual Gut Microbiota for Health World Summit.
Colorectal cancer is the most lethal cancer and the second-most common malignancy in Puerto Rico. Despite recommendations for screening colonoscopy, many patients are diagnosed in late-stage disease, when treatment options are limited. Intestinal inflammation is itself key to colorectal carcinogenesis and also promotes the enteric proliferation of gram-negative bacteria that produce potentially carcinogenic toxins. Thus, gut inflammation and the microbiome are of great interest to researchers who are working to develop reliable, minimally invasive tests that assess future colorectal cancer risk.
For their study presented at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Pons and her coinvestigators compared stool samples from 67 adults with colonoscopically confirmed colorectal adenomas and 39 controls with negative screening colonoscopies. Both groups were captured in the Puerto Rico Familial Colorectal Cancer Registry. The researchers used TaqMan SNP Genotyping to look for single-nucleotide polymorphisms (SNPs) from promoter regions of genes encoding interleukin-1 beta, IL-6, and IL-10, cytokines that regulate gut inflammation. They found nonsignificant associations between colorectal adenoma and two of the three SNPs: rs143627 (encoding IL-1B) and rs1800795 (IL-6).
The real-time polymerase chain reaction results were even more striking. Using SYBR Green, the researchers tested stool for six genotoxic or proinflammatory bacterial genes and identified five, each of which correlated with colorectal adenoma. Colorectal adenoma also was linked with the fecal presence of a nonpathogenic housekeeping gene that is a surrogate for a mucolytic bacterium abundant in the stool of colorectal cancer patients.
Odds ratios for these associations ranged from 1.17 (for cnf, or cytotoxic necrotizing factor) to 12.83 (for usp), the researchers reported. Dr. Pons commented that Hurricane Maria greatly delayed this study and thus the cohort was underpowered to test for statistical significance. Nonetheless, P values approached significance for the usp gene (OR, 12.83; 95% confidence interval, 0.73-226.8; P = .08) and the fecal presence of at least two genes in combination (OR, 2.84; 95% CI, 1.01-8.90; P = .05).
Next, Dr. Pons and her team will expand the study to assess links between colorectal adenoma and these pathogenic bacterial genes, individually and in various combinations. They also plan to compare genes in normal and adenomatous colon tissue and to use enteroid (small intestinal organoid) models to tease out the carcinogenic mechanisms of these bacterial toxins.
The National Institutes of Health provided funding. The researchers disclosed no competing interests.
REPORTING FROM GUT 2019
Plasma genotyping yields actionable mutation in advanced NSCLC
Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,
Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.
“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.
Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.
Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.
“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.
They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.
A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.
Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.
Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.
In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).
In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.
Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.
“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.
The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.
SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.
Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,
Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.
“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.
Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.
Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.
“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.
They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.
A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.
Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.
Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.
In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).
In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.
Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.
“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.
The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.
SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.
Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,
Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.
“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.
Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.
Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.
“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.
They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.
A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.
Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.
Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.
In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).
In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.
Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.
“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.
The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.
SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.
FROM ANNALS OF ONCOLOGY
FDA panel leans toward more robust breast implant surveillance
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
SILVER SPRING, MD. – A mandatory, comprehensive approach to collecting adverse event data from breast implant recipients was favored during a March 25 hearing by a Food and Drug Administration advisory panel that oversees surgical devices.
This additional data could offer more complete information during the informed consent process for breast implants and potentially validate a new, autoimmune-like syndrome – breast implant illness (BII).
On the first day of a scheduled 2-day hearing, the advisory panel held no votes and took no formal actions. After a day of expert presentations and comments from more than 40 members of the public – mostly personal stories from affected patients and from plastic surgeons who place breast implants, panel members discussed a handful of questions from the FDA about relevant data to collect to better define the risks posed to breast implant recipients from breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) and BII.
The advisory panel meeting took place as reports recently appeared documenting the scope of BIA-ALCL (Plast Reconstr Surg. 2019 March;143[3S]:65S-73S) and how to diagnose and manage BIA-ALCL (Aesthetic Surg J. 2019 March;39[S1}:S3-S13), and the existence of BII (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S).
During the day’s two public comment periods, the panel heard from several women who gave brief accounts of developing and dealing with BIA-ALCL or BII.
“We think it’s important that all breast implant patients be aware of the risk for BIA-ALCL,” said Binita Ashar, MD, director of the FDAs Division of Surgical Devices. The FDA “is asking the panel what further steps need to be taken to understand the BIA-ALCL risk,” said Dr. Ashar as she opened the meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee.
While the agency, as well as the plastic surgery community, have acknowledged the existence of BIA-ALCL since 2011, only recently have good data emerged on the scope of the complication. During the hearing, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, reported on his analysis of 457 unique cases of BIA-ALCL reported to the FDA since 2011. He found that the vast majority of cases had occurred in women who had received textured implants while a relatively small minority were linked with the placement of smooth implants.
Further scrutiny of the reported details of each case showed that none of the lymphomas were linked with a confirmed instance of “pure” smooth implant exposure. He also estimated the U.S. incidence of BIA-ALCL as roughly one case for every 20,000 implants. Complete, en bloc removal of the implant seems to be the most effective way to treat the cancer; most explanted patients have a good prognosis, he said.
Despite the apparent link between textured implants specifically and onset of BIA-ALCL, some panel members did not see a ban on textured implants as the answer.
Texturing the implant helps to stabilize the implant in position. Without texturing “we would need to use something else to stabilize the implant, or there would be a tsunami of reoperations,” said panel member Mary H. McGrath, MD, professor of surgery at the University of California, San Francisco. The main alternative to texturing for stabilizing implants is to wrap them in place using surgical mesh, but that approach may also cause problems.
“Instead of just taking textured implants off the market, we need to also look at their advantages. A critical issue is informed consent,” said panel member Marc E. Lippman, MD, a professor of medicine at Georgetown University, Washington. Banning smooth implants based on what’s known so far “would be an extraordinary over reaction,” he said during the first day’s session.
Current U.S. anecdotal experience suggests that a ban may not even be necessary because “plastic surgeons are more and more walking away from textured implants” because of the apparent link to BIA-ALCL, Dr. McGrath said.
BII has been a more recent and more controversial complication of breast implants. As recently as September 2018, Dr. Ashar said in a written statement that “the agency continues to believe that the weight of the currently available scientific evidence does not conclusively demonstrate an association between breast implants and connective tissue diseases,” the types of symptoms that characterize BII.
While the panel heard no new, conclusive evidence of a causal link between breast implants and the range of symptoms that some implant recipients report and is now collectively known as BII, several participants seemed convinced that the syndrome was real and needed better surveillance and study.
“It’s in the same family as chronic fatigue syndrome and fibromyalgia. It’s not a diagnosis, but a set of symptoms.” said Benjamin O. Anderson, MD, a surgical oncologist and professor of surgery at the University of Washington in Seattle and a panel member. “It’s a giant challenge. BII is a constellation of difficult symptoms. We need to think about how we ask patients, what are your symptoms?”
Frank R. Lewis Jr., MD, committee chair, said a more standardized measure of the most common BII symptoms is needed. “That may be exceedingly difficult, with as many as a hundred reported symptoms,” said Dr. Lewis, executive director, emeritus, of the American Board of Surgery in Philadelphia.
The hearing featured results from some of the most research projects aimed at fleshing out an understanding of BII.
Diana Zuckerman, PhD, president of the National Center for Health Research, reported data she and her associates collected in an online survey completed in late 2018 and early 2019 by 449 women who had approached the Center for help in getting health insurance coverage for medically-necessary explantation of their breast implants.
Their most common symptoms included joint, muscle or back pain, weakness or stiffness; fatigue; “brain fog;” and anxiety and depression. More than two-thirds of the respondents had a family history and 3% had a personal history of an autoimmune disease, and 61% said their symptoms improved after their implants were removed, Dr. Zuckerman reported during her presentation to the panel.
During the discussion, panel members seemed intent on expanding mandatory, routine surveillance to all breast implants placed in U.S. practice.
Andrea L. Pusic, MD, president of the Plastic Surgery Foundation, summarized the recent launch of the National Breast Implant Registry by the Foundation and its parent organization, the American Society of Plastic Surgeons. These organizations, and plastic surgeons in general, would be amenable to collecting the data the FDA deemed necessary to better track BIA-ALCL and BII, said Dr. Pusic, professor of surgery at Harvard Medical School and chief of plastic and reconstructive surgery at Brigham and Women’s Hospital in Boston.
“Plastic surgeons are willing to enter these data because we know they are important,” she told the FDA panel.
Dr. Ashar, Dr. Clemens, Dr. McGrath, Dr. Lippman, Dr. Anderson, Dr. Lewis, Dr. Zuckerman, and Dr. Pusic reported having no relevant commercial disclosures.
REPORTING FROM AN FDA ADVISORY COMMITTEE MEETING
For patients with HBV, daily aspirin may reduce risk of liver cancer
Sixteen years of data showed that daily aspirin therapy reduced the risk of HBV-related HCC by 29%, reported lead author Teng-Yu Lee, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and his colleagues. Analysis also showed that antiviral nucleos(t)ide analogue therapy and statin use were independently associated with reduced risk of HCC, whereas older age, cirrhosis, and male sex increased risk.
“Therapy with [nucleos(t)ide analogues] is associated with reductions in HCC risk, but the risk is not erased,” the investigators wrote in JAMA Internal Medicine. “Therefore, using only [nucleos(t)ide analogue] therapy may not be enough for HCC prevention. Antiviral therapy is not indicated in most HBV carriers, so another effective way of reducing HCC risk needs to be developed.”
Previous studies have shown that aspirin can reduce the risk of colorectal cancer; however, data supporting aspirin for HCC prevention are limited to a few animal models and human studies, the latter of which are statistically unreliable.
“Therefore, we conducted a nationwide cohort study to evaluate the association of daily aspirin therapy with HBV-related HCC,” the investigators wrote.
They screened 204,507 patients with HBV included in the Taiwanese National Health Insurance Research Database (NHIRD) between 1997 and 2012, first excluding any with confounding conditions, such as hepatitis C infection or alcoholic liver disease. Next, 2,123 patients were identified who had taken aspirin for 90 days or longer. Finally, these cases were randomly matched with 8,492 control patients with HBV who had never received antiplatelet therapy. The main measured outcome was diagnosis with HCC. Patients were followed until this diagnosis was made, death occurred, or the end of the study period.
Analysis showed that most patients were male (72.4%) and took aspirin for about 4 years, usually prescribed for cardiovascular disease risk factors. Almost all patients in the treatment group (98%) received an aspirin dose of 100 mg or less.
After 5 years, the cumulative incidence of HCC in the aspirin group was 5.20% versus 7.87% in the control group (P less than .001). Multivariable analysis revealed that daily aspirin was associated with a significant risk reduction of 29% (HR 0.71; P less than .001), as were nucleos(t)ide analogues and statins, which lowered risk by 46% and 38%, respectively. In contrast, risk increased with older age at the rate of 1% per year, male sex carried an additional risk of 75%, and liver cirrhosis was associated with a 2.89-fold risk increase.
“In the present study, we report that daily aspirin therapy was associated with a reduced incidence of HCC in patients with [chronic hepatitis B],” the investigators wrote. “Our findings may be of help in future efforts to further improve the chemoprevention of HBV-related HCC, and a proof-of-concept study is thus warranted.”
The investigators described several mechanisms that may have contribute to the possible risk reduction provided by aspirin. For one, aspirin inhibits platelet activation, which is associated with development of HBV-related liver disease. Additional benefit may come from induction of HCC cell apoptosis, control of tumor growth, reduced liver fibrosis, and increased liver regeneration, all of which have been associated with aspirin in rodent models.
“Hepatitis B virus–related HCC is generally a consequence of chronic inflammation due to hepatitis, fibrosis, dysplasia, and tumor growth,” the investigators wrote, suggesting that aspirin-related reductions in inflammation could also explain reduced neoplastic activity.
To assess for increased risk of peptic ulcers secondary to aspirin, the investigators performed a subanalysis of peptic ulcer bleeding. These results showed that rates of peptic ulcer bleeding, at around 5%-6%, were similar between the aspirin group and the control group. Among other variables, cirrhosis didn’t significantly affect rates of peptic ulcer bleeding, and aspirin users had similar rates of peptic ulcer bleeding regardless of HBV status. Because of the study design, however, the investigators cautioned that these analyses could underestimate ulcer risk because patients who could not tolerate aspirin for at least 90 days were excluded from the study.
Although statins stood out as another possible risk reducer, the investigators noted that “randomized clinical trials are required to confirm the chemopreventive effect of statins.”
Similarly, the investigators suggested that a prospective trial is needed before aspirin can be adopted as an HCC preventive.
The study was funded by the Ministry of Science and Technology, National Health Research Institutes, and Taichung (Taiwan) Veterans General Hospital, Taiwan. One author reported financial compensation from Gilead and Bristol-Myers Squibb.
SOURCE: Lee T-Y et al. JAMA Intern Med. 2019 Mar 18. doi:10.1001/jamainternmed.2018.8342.
Sixteen years of data showed that daily aspirin therapy reduced the risk of HBV-related HCC by 29%, reported lead author Teng-Yu Lee, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and his colleagues. Analysis also showed that antiviral nucleos(t)ide analogue therapy and statin use were independently associated with reduced risk of HCC, whereas older age, cirrhosis, and male sex increased risk.
“Therapy with [nucleos(t)ide analogues] is associated with reductions in HCC risk, but the risk is not erased,” the investigators wrote in JAMA Internal Medicine. “Therefore, using only [nucleos(t)ide analogue] therapy may not be enough for HCC prevention. Antiviral therapy is not indicated in most HBV carriers, so another effective way of reducing HCC risk needs to be developed.”
Previous studies have shown that aspirin can reduce the risk of colorectal cancer; however, data supporting aspirin for HCC prevention are limited to a few animal models and human studies, the latter of which are statistically unreliable.
“Therefore, we conducted a nationwide cohort study to evaluate the association of daily aspirin therapy with HBV-related HCC,” the investigators wrote.
They screened 204,507 patients with HBV included in the Taiwanese National Health Insurance Research Database (NHIRD) between 1997 and 2012, first excluding any with confounding conditions, such as hepatitis C infection or alcoholic liver disease. Next, 2,123 patients were identified who had taken aspirin for 90 days or longer. Finally, these cases were randomly matched with 8,492 control patients with HBV who had never received antiplatelet therapy. The main measured outcome was diagnosis with HCC. Patients were followed until this diagnosis was made, death occurred, or the end of the study period.
Analysis showed that most patients were male (72.4%) and took aspirin for about 4 years, usually prescribed for cardiovascular disease risk factors. Almost all patients in the treatment group (98%) received an aspirin dose of 100 mg or less.
After 5 years, the cumulative incidence of HCC in the aspirin group was 5.20% versus 7.87% in the control group (P less than .001). Multivariable analysis revealed that daily aspirin was associated with a significant risk reduction of 29% (HR 0.71; P less than .001), as were nucleos(t)ide analogues and statins, which lowered risk by 46% and 38%, respectively. In contrast, risk increased with older age at the rate of 1% per year, male sex carried an additional risk of 75%, and liver cirrhosis was associated with a 2.89-fold risk increase.
“In the present study, we report that daily aspirin therapy was associated with a reduced incidence of HCC in patients with [chronic hepatitis B],” the investigators wrote. “Our findings may be of help in future efforts to further improve the chemoprevention of HBV-related HCC, and a proof-of-concept study is thus warranted.”
The investigators described several mechanisms that may have contribute to the possible risk reduction provided by aspirin. For one, aspirin inhibits platelet activation, which is associated with development of HBV-related liver disease. Additional benefit may come from induction of HCC cell apoptosis, control of tumor growth, reduced liver fibrosis, and increased liver regeneration, all of which have been associated with aspirin in rodent models.
“Hepatitis B virus–related HCC is generally a consequence of chronic inflammation due to hepatitis, fibrosis, dysplasia, and tumor growth,” the investigators wrote, suggesting that aspirin-related reductions in inflammation could also explain reduced neoplastic activity.
To assess for increased risk of peptic ulcers secondary to aspirin, the investigators performed a subanalysis of peptic ulcer bleeding. These results showed that rates of peptic ulcer bleeding, at around 5%-6%, were similar between the aspirin group and the control group. Among other variables, cirrhosis didn’t significantly affect rates of peptic ulcer bleeding, and aspirin users had similar rates of peptic ulcer bleeding regardless of HBV status. Because of the study design, however, the investigators cautioned that these analyses could underestimate ulcer risk because patients who could not tolerate aspirin for at least 90 days were excluded from the study.
Although statins stood out as another possible risk reducer, the investigators noted that “randomized clinical trials are required to confirm the chemopreventive effect of statins.”
Similarly, the investigators suggested that a prospective trial is needed before aspirin can be adopted as an HCC preventive.
The study was funded by the Ministry of Science and Technology, National Health Research Institutes, and Taichung (Taiwan) Veterans General Hospital, Taiwan. One author reported financial compensation from Gilead and Bristol-Myers Squibb.
SOURCE: Lee T-Y et al. JAMA Intern Med. 2019 Mar 18. doi:10.1001/jamainternmed.2018.8342.
Sixteen years of data showed that daily aspirin therapy reduced the risk of HBV-related HCC by 29%, reported lead author Teng-Yu Lee, MD, PhD, of Taichung (Taiwan) Veterans General Hospital and his colleagues. Analysis also showed that antiviral nucleos(t)ide analogue therapy and statin use were independently associated with reduced risk of HCC, whereas older age, cirrhosis, and male sex increased risk.
“Therapy with [nucleos(t)ide analogues] is associated with reductions in HCC risk, but the risk is not erased,” the investigators wrote in JAMA Internal Medicine. “Therefore, using only [nucleos(t)ide analogue] therapy may not be enough for HCC prevention. Antiviral therapy is not indicated in most HBV carriers, so another effective way of reducing HCC risk needs to be developed.”
Previous studies have shown that aspirin can reduce the risk of colorectal cancer; however, data supporting aspirin for HCC prevention are limited to a few animal models and human studies, the latter of which are statistically unreliable.
“Therefore, we conducted a nationwide cohort study to evaluate the association of daily aspirin therapy with HBV-related HCC,” the investigators wrote.
They screened 204,507 patients with HBV included in the Taiwanese National Health Insurance Research Database (NHIRD) between 1997 and 2012, first excluding any with confounding conditions, such as hepatitis C infection or alcoholic liver disease. Next, 2,123 patients were identified who had taken aspirin for 90 days or longer. Finally, these cases were randomly matched with 8,492 control patients with HBV who had never received antiplatelet therapy. The main measured outcome was diagnosis with HCC. Patients were followed until this diagnosis was made, death occurred, or the end of the study period.
Analysis showed that most patients were male (72.4%) and took aspirin for about 4 years, usually prescribed for cardiovascular disease risk factors. Almost all patients in the treatment group (98%) received an aspirin dose of 100 mg or less.
After 5 years, the cumulative incidence of HCC in the aspirin group was 5.20% versus 7.87% in the control group (P less than .001). Multivariable analysis revealed that daily aspirin was associated with a significant risk reduction of 29% (HR 0.71; P less than .001), as were nucleos(t)ide analogues and statins, which lowered risk by 46% and 38%, respectively. In contrast, risk increased with older age at the rate of 1% per year, male sex carried an additional risk of 75%, and liver cirrhosis was associated with a 2.89-fold risk increase.
“In the present study, we report that daily aspirin therapy was associated with a reduced incidence of HCC in patients with [chronic hepatitis B],” the investigators wrote. “Our findings may be of help in future efforts to further improve the chemoprevention of HBV-related HCC, and a proof-of-concept study is thus warranted.”
The investigators described several mechanisms that may have contribute to the possible risk reduction provided by aspirin. For one, aspirin inhibits platelet activation, which is associated with development of HBV-related liver disease. Additional benefit may come from induction of HCC cell apoptosis, control of tumor growth, reduced liver fibrosis, and increased liver regeneration, all of which have been associated with aspirin in rodent models.
“Hepatitis B virus–related HCC is generally a consequence of chronic inflammation due to hepatitis, fibrosis, dysplasia, and tumor growth,” the investigators wrote, suggesting that aspirin-related reductions in inflammation could also explain reduced neoplastic activity.
To assess for increased risk of peptic ulcers secondary to aspirin, the investigators performed a subanalysis of peptic ulcer bleeding. These results showed that rates of peptic ulcer bleeding, at around 5%-6%, were similar between the aspirin group and the control group. Among other variables, cirrhosis didn’t significantly affect rates of peptic ulcer bleeding, and aspirin users had similar rates of peptic ulcer bleeding regardless of HBV status. Because of the study design, however, the investigators cautioned that these analyses could underestimate ulcer risk because patients who could not tolerate aspirin for at least 90 days were excluded from the study.
Although statins stood out as another possible risk reducer, the investigators noted that “randomized clinical trials are required to confirm the chemopreventive effect of statins.”
Similarly, the investigators suggested that a prospective trial is needed before aspirin can be adopted as an HCC preventive.
The study was funded by the Ministry of Science and Technology, National Health Research Institutes, and Taichung (Taiwan) Veterans General Hospital, Taiwan. One author reported financial compensation from Gilead and Bristol-Myers Squibb.
SOURCE: Lee T-Y et al. JAMA Intern Med. 2019 Mar 18. doi:10.1001/jamainternmed.2018.8342.
FROM JAMA INTERNAL MEDICINE
Brachytherapy access may mediate poor cervical cancer survival in blacks
HONOLULU – , according to a speaker at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.
Stephanie Alimena, MD, of Brigham and Women’s Hospital in Boston, presented a large, retrospective study showing that use of brachytherapy mediated survival differences by race.
In the absence of brachytherapy, black patients had a significantly higher risk of death than did non-black patients (P = .013). However, when brachytherapy was used, black and non-black patients had a similar risk of death (P = .83).
“[W]e know that use of a brachytherapy boost is associated with improved patient outcomes, including improved cancer-specific and overall survival,” Dr. Alimena said. “We also know that African-American women have one of the highest incidences of cervical cancer in the United States and also have worse mortality from cervical cancer.”
“Studies have reached varying conclusions about the impact of race on brachytherapy utilization, with several smaller studies suggesting that minority women may be less likely to receive brachytherapy services compared to white women. No studies have specifically examined the interaction between race, radiation, and survival.”
Dr. Alimena and her colleagues decided to examine the interaction using data from the National Cancer Database. The researchers evaluated 15,411 women diagnosed with cervical cancer from 2004 to 2014. The patients had stage IB2 to IVA disease, their mean age was 54 years (range, 19-90), 58% had received brachytherapy, and 19% were black.
“Race was defined as black or non-black race, given that previous data had shown similar and even increased survival rates for Hispanic and Asian-American women compared to white patients diagnosed with cervical cancer,” Dr. Alimena noted.
Differences by race
The researchers found that black patients were significantly less likely to receive brachytherapy than were non-black patients: 52.5% vs. 59.0%, respectively (P less than .001).
Black patients were significantly more likely to have stage III disease (42.7% vs. 37.6%; P less than .001) and less likely to have stage IVA disease (6.8% vs. 7.3%; P less than .001).
Black patients were significantly more likely to have government insurance (57.0% vs. 49.1%; P less than .001) and less likely to have private insurance (27.6% vs. 36.7%; P less than .001).
And black patients were significantly more likely to have annual incomes below $38,000 (49.4% vs. 22.6%; P less than .001).
Factors associated with brachytherapy
In a multivariate analysis, black race was significantly associated with a reduced likelihood of receiving brachytherapy. The odds ratio (OR) was 0.86 (P = .003).
Other factors significantly associated with a reduced likelihood of receiving brachytherapy were:
- Being older than 70 years (OR = 0.59; P less than .001)
- Having government insurance (OR = 0.89; P = .008) or no insurance/unknown insurance status (OR = 0.75; P less than .001)
- Having stage III disease (OR = 0.47; P less than .001) or stage IVA disease (OR = 0.20; P less than .001)
- Being treated in southern states (OR = 0.67; P less than .001) or western states (OR = 0.86; P = .02)
- Having a Charlson/Deyo score of 2 or more (OR = 0.73; P less than .001).
Race, brachytherapy, and survival
“Consistent with prior data, we found that black patients had a significant decrease in overall survival, compared to non-black women,” Dr. Alimena said. “Furthermore, we found survival differences by race were mediated by brachytherapy use.”
The median overall survival was 52.5 months among black patients and 65.3 months among non-black patients (P less than .001).
Among patients who did not receive brachytherapy, black patients had a significantly higher risk of death than non-black patients (adjusted hazard ratio = 1.11; P = .013).
However, among patients who did receive brachytherapy, black and non-black patients had a similar risk of death (adjusted hazard ratio = 1.01; P = .83). The interaction term comparing these survival curves was statistically significant (P = .043).
“This is the first study, to our knowledge, to show such an interaction between race and survival being mediated by one particular treatment modality,” Dr. Alimena said.
“While not directly tested in this study, the most likely hypothesis why black patients may be less likely to receive brachytherapy is having poor access to brachytherapy services. This suggests that reducing racial disparities in survival is possible by increasing access to brachytherapy for black patients.”
Dr. Alimena had no financial disclosures.
SOURCE: Alimena S et al. SGO 2019. Abstract 11.
HONOLULU – , according to a speaker at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.
Stephanie Alimena, MD, of Brigham and Women’s Hospital in Boston, presented a large, retrospective study showing that use of brachytherapy mediated survival differences by race.
In the absence of brachytherapy, black patients had a significantly higher risk of death than did non-black patients (P = .013). However, when brachytherapy was used, black and non-black patients had a similar risk of death (P = .83).
“[W]e know that use of a brachytherapy boost is associated with improved patient outcomes, including improved cancer-specific and overall survival,” Dr. Alimena said. “We also know that African-American women have one of the highest incidences of cervical cancer in the United States and also have worse mortality from cervical cancer.”
“Studies have reached varying conclusions about the impact of race on brachytherapy utilization, with several smaller studies suggesting that minority women may be less likely to receive brachytherapy services compared to white women. No studies have specifically examined the interaction between race, radiation, and survival.”
Dr. Alimena and her colleagues decided to examine the interaction using data from the National Cancer Database. The researchers evaluated 15,411 women diagnosed with cervical cancer from 2004 to 2014. The patients had stage IB2 to IVA disease, their mean age was 54 years (range, 19-90), 58% had received brachytherapy, and 19% were black.
“Race was defined as black or non-black race, given that previous data had shown similar and even increased survival rates for Hispanic and Asian-American women compared to white patients diagnosed with cervical cancer,” Dr. Alimena noted.
Differences by race
The researchers found that black patients were significantly less likely to receive brachytherapy than were non-black patients: 52.5% vs. 59.0%, respectively (P less than .001).
Black patients were significantly more likely to have stage III disease (42.7% vs. 37.6%; P less than .001) and less likely to have stage IVA disease (6.8% vs. 7.3%; P less than .001).
Black patients were significantly more likely to have government insurance (57.0% vs. 49.1%; P less than .001) and less likely to have private insurance (27.6% vs. 36.7%; P less than .001).
And black patients were significantly more likely to have annual incomes below $38,000 (49.4% vs. 22.6%; P less than .001).
Factors associated with brachytherapy
In a multivariate analysis, black race was significantly associated with a reduced likelihood of receiving brachytherapy. The odds ratio (OR) was 0.86 (P = .003).
Other factors significantly associated with a reduced likelihood of receiving brachytherapy were:
- Being older than 70 years (OR = 0.59; P less than .001)
- Having government insurance (OR = 0.89; P = .008) or no insurance/unknown insurance status (OR = 0.75; P less than .001)
- Having stage III disease (OR = 0.47; P less than .001) or stage IVA disease (OR = 0.20; P less than .001)
- Being treated in southern states (OR = 0.67; P less than .001) or western states (OR = 0.86; P = .02)
- Having a Charlson/Deyo score of 2 or more (OR = 0.73; P less than .001).
Race, brachytherapy, and survival
“Consistent with prior data, we found that black patients had a significant decrease in overall survival, compared to non-black women,” Dr. Alimena said. “Furthermore, we found survival differences by race were mediated by brachytherapy use.”
The median overall survival was 52.5 months among black patients and 65.3 months among non-black patients (P less than .001).
Among patients who did not receive brachytherapy, black patients had a significantly higher risk of death than non-black patients (adjusted hazard ratio = 1.11; P = .013).
However, among patients who did receive brachytherapy, black and non-black patients had a similar risk of death (adjusted hazard ratio = 1.01; P = .83). The interaction term comparing these survival curves was statistically significant (P = .043).
“This is the first study, to our knowledge, to show such an interaction between race and survival being mediated by one particular treatment modality,” Dr. Alimena said.
“While not directly tested in this study, the most likely hypothesis why black patients may be less likely to receive brachytherapy is having poor access to brachytherapy services. This suggests that reducing racial disparities in survival is possible by increasing access to brachytherapy for black patients.”
Dr. Alimena had no financial disclosures.
SOURCE: Alimena S et al. SGO 2019. Abstract 11.
HONOLULU – , according to a speaker at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.
Stephanie Alimena, MD, of Brigham and Women’s Hospital in Boston, presented a large, retrospective study showing that use of brachytherapy mediated survival differences by race.
In the absence of brachytherapy, black patients had a significantly higher risk of death than did non-black patients (P = .013). However, when brachytherapy was used, black and non-black patients had a similar risk of death (P = .83).
“[W]e know that use of a brachytherapy boost is associated with improved patient outcomes, including improved cancer-specific and overall survival,” Dr. Alimena said. “We also know that African-American women have one of the highest incidences of cervical cancer in the United States and also have worse mortality from cervical cancer.”
“Studies have reached varying conclusions about the impact of race on brachytherapy utilization, with several smaller studies suggesting that minority women may be less likely to receive brachytherapy services compared to white women. No studies have specifically examined the interaction between race, radiation, and survival.”
Dr. Alimena and her colleagues decided to examine the interaction using data from the National Cancer Database. The researchers evaluated 15,411 women diagnosed with cervical cancer from 2004 to 2014. The patients had stage IB2 to IVA disease, their mean age was 54 years (range, 19-90), 58% had received brachytherapy, and 19% were black.
“Race was defined as black or non-black race, given that previous data had shown similar and even increased survival rates for Hispanic and Asian-American women compared to white patients diagnosed with cervical cancer,” Dr. Alimena noted.
Differences by race
The researchers found that black patients were significantly less likely to receive brachytherapy than were non-black patients: 52.5% vs. 59.0%, respectively (P less than .001).
Black patients were significantly more likely to have stage III disease (42.7% vs. 37.6%; P less than .001) and less likely to have stage IVA disease (6.8% vs. 7.3%; P less than .001).
Black patients were significantly more likely to have government insurance (57.0% vs. 49.1%; P less than .001) and less likely to have private insurance (27.6% vs. 36.7%; P less than .001).
And black patients were significantly more likely to have annual incomes below $38,000 (49.4% vs. 22.6%; P less than .001).
Factors associated with brachytherapy
In a multivariate analysis, black race was significantly associated with a reduced likelihood of receiving brachytherapy. The odds ratio (OR) was 0.86 (P = .003).
Other factors significantly associated with a reduced likelihood of receiving brachytherapy were:
- Being older than 70 years (OR = 0.59; P less than .001)
- Having government insurance (OR = 0.89; P = .008) or no insurance/unknown insurance status (OR = 0.75; P less than .001)
- Having stage III disease (OR = 0.47; P less than .001) or stage IVA disease (OR = 0.20; P less than .001)
- Being treated in southern states (OR = 0.67; P less than .001) or western states (OR = 0.86; P = .02)
- Having a Charlson/Deyo score of 2 or more (OR = 0.73; P less than .001).
Race, brachytherapy, and survival
“Consistent with prior data, we found that black patients had a significant decrease in overall survival, compared to non-black women,” Dr. Alimena said. “Furthermore, we found survival differences by race were mediated by brachytherapy use.”
The median overall survival was 52.5 months among black patients and 65.3 months among non-black patients (P less than .001).
Among patients who did not receive brachytherapy, black patients had a significantly higher risk of death than non-black patients (adjusted hazard ratio = 1.11; P = .013).
However, among patients who did receive brachytherapy, black and non-black patients had a similar risk of death (adjusted hazard ratio = 1.01; P = .83). The interaction term comparing these survival curves was statistically significant (P = .043).
“This is the first study, to our knowledge, to show such an interaction between race and survival being mediated by one particular treatment modality,” Dr. Alimena said.
“While not directly tested in this study, the most likely hypothesis why black patients may be less likely to receive brachytherapy is having poor access to brachytherapy services. This suggests that reducing racial disparities in survival is possible by increasing access to brachytherapy for black patients.”
Dr. Alimena had no financial disclosures.
SOURCE: Alimena S et al. SGO 2019. Abstract 11.
REPORTING FROM SGO 2019
FDA halts enrollment in trial of venetoclax for multiple myeloma
The Food and Drug Administration has halted enrollment in trials of venetoclax (Venclexta) for multiple myeloma.
The move comes after a review of data from the phase 3 BELLINI trial, which pitted venetoclax against placebo in relapsed and refractory multiple myeloma patients on a background of bortezomib and low-dose dexamethasone. Venetoclax is not approved for the treatment of multiple myeloma; the agency said that patients using the drug for approved indications should continue use of the drug.
There were 41/194 deaths (21.1%) in the venetoclax arm, versus 11/97 (11.3%) in the placebo group; 13 of the deaths in the venetoclax arm (32%) and 1 death in the placebo arm (9%) were treatment related. Sepsis, pneumonia, and cardiac arrest were the most common treatment-related causes of death in the venetoclax group; 8 of the 13 deaths (62%) were due to infection.
The FDA estimated that the drug doubled the risk of death compared to placebo.
The agency warned against off-label use of venetoclax for multiple myeloma, and noted that the drug “is safe and effective for its approved uses,” which include second-line treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma in adults, as well as newly-diagnosed acute myeloid leukemia in adults age 75 years or older or who have contraindications to standard chemotherapy.
There are more than 10 trials in the United States of venetoclax for multiple myeloma, and most of them have been suspended, including BELLINI.
Patients already enrolled in the trial can remain on treatment, but they must re-consent to the trial. The FDA “will be working directly with sponsors of Venclexta, as well as other investigators conducting clinical trials in patients with multiple myeloma, to determine the extent of the safety issue,” the agency said in a statement.
Abbvie, which is developing venetoclax in partnership with Roche, noted in its own press release that the drug otherwise outperformed placebo in BELLINI, both in progression-free survival (22.4 months versus 11.5 months), and in overall (82% versus 68%) and partial (59% versus 36%) response rates.
Severe grade 3-5 toxicity and serious adverse event rates were similar in the two study arms, as was the overall incidence of infections (79.8% versus 77.1%). However, the incidence of pneumonia was 20.7% with venetoclax, versus 15.6% with placebo.
“We will continue working with the FDA and worldwide regulatory agencies to determine appropriate next steps for the multiple myeloma program,” Michael Severino, MD, AbbVie vice chairman and president, said in the press release.
Venetoclax binds and inhibits the B-cell lymphoma-2 protein, which prevents some blood cancer cells from undergoing programmed cell death.
The Food and Drug Administration has halted enrollment in trials of venetoclax (Venclexta) for multiple myeloma.
The move comes after a review of data from the phase 3 BELLINI trial, which pitted venetoclax against placebo in relapsed and refractory multiple myeloma patients on a background of bortezomib and low-dose dexamethasone. Venetoclax is not approved for the treatment of multiple myeloma; the agency said that patients using the drug for approved indications should continue use of the drug.
There were 41/194 deaths (21.1%) in the venetoclax arm, versus 11/97 (11.3%) in the placebo group; 13 of the deaths in the venetoclax arm (32%) and 1 death in the placebo arm (9%) were treatment related. Sepsis, pneumonia, and cardiac arrest were the most common treatment-related causes of death in the venetoclax group; 8 of the 13 deaths (62%) were due to infection.
The FDA estimated that the drug doubled the risk of death compared to placebo.
The agency warned against off-label use of venetoclax for multiple myeloma, and noted that the drug “is safe and effective for its approved uses,” which include second-line treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma in adults, as well as newly-diagnosed acute myeloid leukemia in adults age 75 years or older or who have contraindications to standard chemotherapy.
There are more than 10 trials in the United States of venetoclax for multiple myeloma, and most of them have been suspended, including BELLINI.
Patients already enrolled in the trial can remain on treatment, but they must re-consent to the trial. The FDA “will be working directly with sponsors of Venclexta, as well as other investigators conducting clinical trials in patients with multiple myeloma, to determine the extent of the safety issue,” the agency said in a statement.
Abbvie, which is developing venetoclax in partnership with Roche, noted in its own press release that the drug otherwise outperformed placebo in BELLINI, both in progression-free survival (22.4 months versus 11.5 months), and in overall (82% versus 68%) and partial (59% versus 36%) response rates.
Severe grade 3-5 toxicity and serious adverse event rates were similar in the two study arms, as was the overall incidence of infections (79.8% versus 77.1%). However, the incidence of pneumonia was 20.7% with venetoclax, versus 15.6% with placebo.
“We will continue working with the FDA and worldwide regulatory agencies to determine appropriate next steps for the multiple myeloma program,” Michael Severino, MD, AbbVie vice chairman and president, said in the press release.
Venetoclax binds and inhibits the B-cell lymphoma-2 protein, which prevents some blood cancer cells from undergoing programmed cell death.
The Food and Drug Administration has halted enrollment in trials of venetoclax (Venclexta) for multiple myeloma.
The move comes after a review of data from the phase 3 BELLINI trial, which pitted venetoclax against placebo in relapsed and refractory multiple myeloma patients on a background of bortezomib and low-dose dexamethasone. Venetoclax is not approved for the treatment of multiple myeloma; the agency said that patients using the drug for approved indications should continue use of the drug.
There were 41/194 deaths (21.1%) in the venetoclax arm, versus 11/97 (11.3%) in the placebo group; 13 of the deaths in the venetoclax arm (32%) and 1 death in the placebo arm (9%) were treatment related. Sepsis, pneumonia, and cardiac arrest were the most common treatment-related causes of death in the venetoclax group; 8 of the 13 deaths (62%) were due to infection.
The FDA estimated that the drug doubled the risk of death compared to placebo.
The agency warned against off-label use of venetoclax for multiple myeloma, and noted that the drug “is safe and effective for its approved uses,” which include second-line treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma in adults, as well as newly-diagnosed acute myeloid leukemia in adults age 75 years or older or who have contraindications to standard chemotherapy.
There are more than 10 trials in the United States of venetoclax for multiple myeloma, and most of them have been suspended, including BELLINI.
Patients already enrolled in the trial can remain on treatment, but they must re-consent to the trial. The FDA “will be working directly with sponsors of Venclexta, as well as other investigators conducting clinical trials in patients with multiple myeloma, to determine the extent of the safety issue,” the agency said in a statement.
Abbvie, which is developing venetoclax in partnership with Roche, noted in its own press release that the drug otherwise outperformed placebo in BELLINI, both in progression-free survival (22.4 months versus 11.5 months), and in overall (82% versus 68%) and partial (59% versus 36%) response rates.
Severe grade 3-5 toxicity and serious adverse event rates were similar in the two study arms, as was the overall incidence of infections (79.8% versus 77.1%). However, the incidence of pneumonia was 20.7% with venetoclax, versus 15.6% with placebo.
“We will continue working with the FDA and worldwide regulatory agencies to determine appropriate next steps for the multiple myeloma program,” Michael Severino, MD, AbbVie vice chairman and president, said in the press release.
Venetoclax binds and inhibits the B-cell lymphoma-2 protein, which prevents some blood cancer cells from undergoing programmed cell death.
MCL survival rates improve with novel agents
Survival outcomes for patients with mantle cell lymphoma (MCL) substantially improved from 1995 to 2013, particularly for those with advanced-stage tumors, according to a retrospective analysis.
The median overall survival for the study period was 52 months and 57 months in two cancer databases.
“Over the past 20 years, many novel agents and treatment regimens have been developed to treat MCL,” Shuangshuang Fu, PhD, of the University of Texas, Houston, and her colleagues wrote in Cancer Epidemiology.
The researchers retrospectively studied population-based data from two separate databases: the national Surveillance, Epidemiology and End Results (SEER) database and the Texas Cancer Registry (TCR). They identified all adult patients who received a new diagnosis of MCL between Jan. 1, 1995, and Dec. 31, 2013.
A total of 9,610 patients were included in the study: 7,555 patients from SEER and 2,055 from the TCR. The team collected data related to MCL diagnosis, mortality, and other variables, including age at diagnosis, marital status, sex, and tumor stage.
In total, 76.2% and 61.6% of patients from the SEER and TCR databases, respectively, had an advanced-stage tumor.
Dr. Fu and her colleagues found that all-cause mortality rates in both groups were significantly reduced from 1995 to 2013 (SEER, P less than .001; TCR, P = .03).
In addition, the team reported that the median overall survival time for all patients in the SEER database was 52 months, and it was 57 months for the TCR database.
“MCL patients with [an] advanced stage tumor benefitted most from the introduction of newly developed regimens,” they added.
The researchers acknowledged that a key limitation of the study was the inability to assess treatment regimen–specific survival, which could only be estimated with these data.
“The findings of our study further confirmed the impact of novel agents on improved survival over time that was shown in other studies,” they wrote.
The study was supported by grant funding from the Cancer Prevention Research Institute of Texas and the National Institutes of Health. The researchers reported having no conflicts of interest.
SOURCE: Fu S et al. Cancer Epidemiol. 2019 Feb;58:89-97.
Survival outcomes for patients with mantle cell lymphoma (MCL) substantially improved from 1995 to 2013, particularly for those with advanced-stage tumors, according to a retrospective analysis.
The median overall survival for the study period was 52 months and 57 months in two cancer databases.
“Over the past 20 years, many novel agents and treatment regimens have been developed to treat MCL,” Shuangshuang Fu, PhD, of the University of Texas, Houston, and her colleagues wrote in Cancer Epidemiology.
The researchers retrospectively studied population-based data from two separate databases: the national Surveillance, Epidemiology and End Results (SEER) database and the Texas Cancer Registry (TCR). They identified all adult patients who received a new diagnosis of MCL between Jan. 1, 1995, and Dec. 31, 2013.
A total of 9,610 patients were included in the study: 7,555 patients from SEER and 2,055 from the TCR. The team collected data related to MCL diagnosis, mortality, and other variables, including age at diagnosis, marital status, sex, and tumor stage.
In total, 76.2% and 61.6% of patients from the SEER and TCR databases, respectively, had an advanced-stage tumor.
Dr. Fu and her colleagues found that all-cause mortality rates in both groups were significantly reduced from 1995 to 2013 (SEER, P less than .001; TCR, P = .03).
In addition, the team reported that the median overall survival time for all patients in the SEER database was 52 months, and it was 57 months for the TCR database.
“MCL patients with [an] advanced stage tumor benefitted most from the introduction of newly developed regimens,” they added.
The researchers acknowledged that a key limitation of the study was the inability to assess treatment regimen–specific survival, which could only be estimated with these data.
“The findings of our study further confirmed the impact of novel agents on improved survival over time that was shown in other studies,” they wrote.
The study was supported by grant funding from the Cancer Prevention Research Institute of Texas and the National Institutes of Health. The researchers reported having no conflicts of interest.
SOURCE: Fu S et al. Cancer Epidemiol. 2019 Feb;58:89-97.
Survival outcomes for patients with mantle cell lymphoma (MCL) substantially improved from 1995 to 2013, particularly for those with advanced-stage tumors, according to a retrospective analysis.
The median overall survival for the study period was 52 months and 57 months in two cancer databases.
“Over the past 20 years, many novel agents and treatment regimens have been developed to treat MCL,” Shuangshuang Fu, PhD, of the University of Texas, Houston, and her colleagues wrote in Cancer Epidemiology.
The researchers retrospectively studied population-based data from two separate databases: the national Surveillance, Epidemiology and End Results (SEER) database and the Texas Cancer Registry (TCR). They identified all adult patients who received a new diagnosis of MCL between Jan. 1, 1995, and Dec. 31, 2013.
A total of 9,610 patients were included in the study: 7,555 patients from SEER and 2,055 from the TCR. The team collected data related to MCL diagnosis, mortality, and other variables, including age at diagnosis, marital status, sex, and tumor stage.
In total, 76.2% and 61.6% of patients from the SEER and TCR databases, respectively, had an advanced-stage tumor.
Dr. Fu and her colleagues found that all-cause mortality rates in both groups were significantly reduced from 1995 to 2013 (SEER, P less than .001; TCR, P = .03).
In addition, the team reported that the median overall survival time for all patients in the SEER database was 52 months, and it was 57 months for the TCR database.
“MCL patients with [an] advanced stage tumor benefitted most from the introduction of newly developed regimens,” they added.
The researchers acknowledged that a key limitation of the study was the inability to assess treatment regimen–specific survival, which could only be estimated with these data.
“The findings of our study further confirmed the impact of novel agents on improved survival over time that was shown in other studies,” they wrote.
The study was supported by grant funding from the Cancer Prevention Research Institute of Texas and the National Institutes of Health. The researchers reported having no conflicts of interest.
SOURCE: Fu S et al. Cancer Epidemiol. 2019 Feb;58:89-97.
FROM CANCER EPIDEMIOLOGY