Sarcoma & GIST

MILAN – The 2014 update to the European Society of Medical Oncology’s sarcoma-management guidelines put unprecedented emphasis on genetic assessment and using the data to guide treatment.

"Molecular diagnosis is recommended as standard care" for patients with gastrointestinal stromal tumors (GIST), Dr. Jean-Yves Blay said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology (ESMO). Identifying the genetic profile of a newly diagnosed GIST "is predictive and can guide treatment in the adjuvant setting and possibly also in the advanced phase," said Dr. Blay, professor and head of medical oncology at Claude Bernard University in Lyon, France. "Molecular characterization is increasingly an important diagnostic and prognostic tool and also helps select treatment."

The new update also strengthened the advice from past updates to centralize GIST and sarcoma management at reference centers. "What is clear from looking at past guidelines is that since 2008 we have moved toward increasingly stronger recommendations to centralize," although the panel remained unable to settle on a definition of a GIST and sarcoma reference center, Dr. Blay said.

The 2014 revision to ESMO’s guidelines for managing GIST and sarcomas is the fourth biannual revision since these guidelines first appeared in 2008. The new update will soon appear on ESMO’s website. A majority of the guidelines remain based on consensus opinion and not evidence, because the number of randomized controlled trials that have tested various aspects of management remains limited, Dr. Blay said. The lack of trials also leaves many questions unanswered, such as the best treatment for GIST that carry the D842V mutation in their PDGFRA gene or for the "wild-type" GIST that don’t have any of the described GIST mutations. "Everyone agrees we need more studies," he said.

For managing patients with advanced GIST, the new update noted that surgical removal of recurrent lesions has not been proven beneficial to patients, and that the benefit from monitoring trough levels of a tyrosine-kinase inhibitor drug also remains unproven. The new update also acknowledged a possible role for continued imatinib (Gleevec) treatment after relapse, based on results from the RIGHT (Resumption of Imatinib to Control Metastatic or Unresectable GIST After Failure of Imatinib and Sunitinib) trial (Lancet Oncol. 2013;14:1175-82). In addition, the update recognized the potential benefit of trying regorafenib (Stivarga) after patients progress on imatinib or sunitinib (Sutent) treatment, and strongly advised against treating patients with two or more tyrosine-kinase inhibitor drugs simultaneously, as this approach needs further study.

One other change to the GIST guidelines this year was a suggestion to increase the frequency of follow-up examinations during the 1-3 years following the end of adjuvant therapy, also based on consensus opinion and without firm evidence, Dr. Blay said.

The revised soft-tissue sarcoma (STS) guidelines included adoption of the bone and STS classification scheme issued by the World Health Organization last year, and endorsement of genetic analyses when the histologic diagnosis is uncertain or the tumor has an unusual presentation. The revision added stronger language promoting the need to individualize radiotherapy based on factors such as clinical presentation of the sarcoma, patient history, tumor site, and patient’s age. The revision panel could not reach a consensus on a recommended, standard adjuvant regimen.

This inability to recommend adjuvant therapies should be "no surprise because there are no data. We need to look at larger numbers of patients to identify those who would benefit from adjuvant therapy," Dr. Blay said.

For treatment of advanced STSs, the panel added pazopanib (Votrient) as a second-line treatment option, but not for patients with liposarcomas, who were not included in the trial that established pazopanib’s efficacy for metastatic STS (Lancet 2012;379:1879-86). The update also recommended identifying sarcoma subtypes genetically and matching drugs to these types using agents such as sunitinib, crizotinib (Xalkori), and cediranib (Recentin). In addition, the new update highlighted that a role for intensified follow-up of metastatic STS using computed tomography was not supported by the results of a recent randomized, controlled trial.

The 2014 guidelines also include sections for four specific STSs: retroperitoneal, uterine, desmoids, and breast. "The guidelines are expanding to organ-specific locations, something we will probably see more of" in future updates, Dr. Blay said.

Dr. Blay disclosed that he has received honoraria as a consultant to PharmaMar, and that he has received research grants from Roche, GlaxoSmithKline, and Novartis.

[email protected]

On Twitter @mitchelzoler

MILAN – The 2014 update to the European Society of Medical Oncology’s sarcoma-management guidelines put unprecedented emphasis on genetic assessment and using the data to guide treatment.

"Molecular diagnosis is recommended as standard care" for patients with gastrointestinal stromal tumors (GIST), Dr. Jean-Yves Blay said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology (ESMO). Identifying the genetic profile of a newly diagnosed GIST "is predictive and can guide treatment in the adjuvant setting and possibly also in the advanced phase," said Dr. Blay, professor and head of medical oncology at Claude Bernard University in Lyon, France. "Molecular characterization is increasingly an important diagnostic and prognostic tool and also helps select treatment."

The new update also strengthened the advice from past updates to centralize GIST and sarcoma management at reference centers. "What is clear from looking at past guidelines is that since 2008 we have moved toward increasingly stronger recommendations to centralize," although the panel remained unable to settle on a definition of a GIST and sarcoma reference center, Dr. Blay said.

The 2014 revision to ESMO’s guidelines for managing GIST and sarcomas is the fourth biannual revision since these guidelines first appeared in 2008. The new update will soon appear on ESMO’s website. A majority of the guidelines remain based on consensus opinion and not evidence, because the number of randomized controlled trials that have tested various aspects of management remains limited, Dr. Blay said. The lack of trials also leaves many questions unanswered, such as the best treatment for GIST that carry the D842V mutation in their PDGFRA gene or for the "wild-type" GIST that don’t have any of the described GIST mutations. "Everyone agrees we need more studies," he said.

For managing patients with advanced GIST, the new update noted that surgical removal of recurrent lesions has not been proven beneficial to patients, and that the benefit from monitoring trough levels of a tyrosine-kinase inhibitor drug also remains unproven. The new update also acknowledged a possible role for continued imatinib (Gleevec) treatment after relapse, based on results from the RIGHT (Resumption of Imatinib to Control Metastatic or Unresectable GIST After Failure of Imatinib and Sunitinib) trial (Lancet Oncol. 2013;14:1175-82). In addition, the update recognized the potential benefit of trying regorafenib (Stivarga) after patients progress on imatinib or sunitinib (Sutent) treatment, and strongly advised against treating patients with two or more tyrosine-kinase inhibitor drugs simultaneously, as this approach needs further study.

One other change to the GIST guidelines this year was a suggestion to increase the frequency of follow-up examinations during the 1-3 years following the end of adjuvant therapy, also based on consensus opinion and without firm evidence, Dr. Blay said.

The revised soft-tissue sarcoma (STS) guidelines included adoption of the bone and STS classification scheme issued by the World Health Organization last year, and endorsement of genetic analyses when the histologic diagnosis is uncertain or the tumor has an unusual presentation. The revision added stronger language promoting the need to individualize radiotherapy based on factors such as clinical presentation of the sarcoma, patient history, tumor site, and patient’s age. The revision panel could not reach a consensus on a recommended, standard adjuvant regimen.

This inability to recommend adjuvant therapies should be "no surprise because there are no data. We need to look at larger numbers of patients to identify those who would benefit from adjuvant therapy," Dr. Blay said.

For treatment of advanced STSs, the panel added pazopanib (Votrient) as a second-line treatment option, but not for patients with liposarcomas, who were not included in the trial that established pazopanib’s efficacy for metastatic STS (Lancet 2012;379:1879-86). The update also recommended identifying sarcoma subtypes genetically and matching drugs to these types using agents such as sunitinib, crizotinib (Xalkori), and cediranib (Recentin). In addition, the new update highlighted that a role for intensified follow-up of metastatic STS using computed tomography was not supported by the results of a recent randomized, controlled trial.

The 2014 guidelines also include sections for four specific STSs: retroperitoneal, uterine, desmoids, and breast. "The guidelines are expanding to organ-specific locations, something we will probably see more of" in future updates, Dr. Blay said.

Dr. Blay disclosed that he has received honoraria as a consultant to PharmaMar, and that he has received research grants from Roche, GlaxoSmithKline, and Novartis.

[email protected]

On Twitter @mitchelzoler

MILAN – The 2014 update to the European Society of Medical Oncology’s sarcoma-management guidelines put unprecedented emphasis on genetic assessment and using the data to guide treatment.

"Molecular diagnosis is recommended as standard care" for patients with gastrointestinal stromal tumors (GIST), Dr. Jean-Yves Blay said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology (ESMO). Identifying the genetic profile of a newly diagnosed GIST "is predictive and can guide treatment in the adjuvant setting and possibly also in the advanced phase," said Dr. Blay, professor and head of medical oncology at Claude Bernard University in Lyon, France. "Molecular characterization is increasingly an important diagnostic and prognostic tool and also helps select treatment."

The new update also strengthened the advice from past updates to centralize GIST and sarcoma management at reference centers. "What is clear from looking at past guidelines is that since 2008 we have moved toward increasingly stronger recommendations to centralize," although the panel remained unable to settle on a definition of a GIST and sarcoma reference center, Dr. Blay said.

The 2014 revision to ESMO’s guidelines for managing GIST and sarcomas is the fourth biannual revision since these guidelines first appeared in 2008. The new update will soon appear on ESMO’s website. A majority of the guidelines remain based on consensus opinion and not evidence, because the number of randomized controlled trials that have tested various aspects of management remains limited, Dr. Blay said. The lack of trials also leaves many questions unanswered, such as the best treatment for GIST that carry the D842V mutation in their PDGFRA gene or for the "wild-type" GIST that don’t have any of the described GIST mutations. "Everyone agrees we need more studies," he said.

For managing patients with advanced GIST, the new update noted that surgical removal of recurrent lesions has not been proven beneficial to patients, and that the benefit from monitoring trough levels of a tyrosine-kinase inhibitor drug also remains unproven. The new update also acknowledged a possible role for continued imatinib (Gleevec) treatment after relapse, based on results from the RIGHT (Resumption of Imatinib to Control Metastatic or Unresectable GIST After Failure of Imatinib and Sunitinib) trial (Lancet Oncol. 2013;14:1175-82). In addition, the update recognized the potential benefit of trying regorafenib (Stivarga) after patients progress on imatinib or sunitinib (Sutent) treatment, and strongly advised against treating patients with two or more tyrosine-kinase inhibitor drugs simultaneously, as this approach needs further study.

One other change to the GIST guidelines this year was a suggestion to increase the frequency of follow-up examinations during the 1-3 years following the end of adjuvant therapy, also based on consensus opinion and without firm evidence, Dr. Blay said.

The revised soft-tissue sarcoma (STS) guidelines included adoption of the bone and STS classification scheme issued by the World Health Organization last year, and endorsement of genetic analyses when the histologic diagnosis is uncertain or the tumor has an unusual presentation. The revision added stronger language promoting the need to individualize radiotherapy based on factors such as clinical presentation of the sarcoma, patient history, tumor site, and patient’s age. The revision panel could not reach a consensus on a recommended, standard adjuvant regimen.

This inability to recommend adjuvant therapies should be "no surprise because there are no data. We need to look at larger numbers of patients to identify those who would benefit from adjuvant therapy," Dr. Blay said.

For treatment of advanced STSs, the panel added pazopanib (Votrient) as a second-line treatment option, but not for patients with liposarcomas, who were not included in the trial that established pazopanib’s efficacy for metastatic STS (Lancet 2012;379:1879-86). The update also recommended identifying sarcoma subtypes genetically and matching drugs to these types using agents such as sunitinib, crizotinib (Xalkori), and cediranib (Recentin). In addition, the new update highlighted that a role for intensified follow-up of metastatic STS using computed tomography was not supported by the results of a recent randomized, controlled trial.

The 2014 guidelines also include sections for four specific STSs: retroperitoneal, uterine, desmoids, and breast. "The guidelines are expanding to organ-specific locations, something we will probably see more of" in future updates, Dr. Blay said.

Dr. Blay disclosed that he has received honoraria as a consultant to PharmaMar, and that he has received research grants from Roche, GlaxoSmithKline, and Novartis.

[email protected]

On Twitter @mitchelzoler

MILAN – Many U.S. patients with gastrointestinal stromal tumors today start on the wrong adjuvant treatment because their physicians don’t order genetic assessment of the cancer, said two American oncologists.

"Initial treatment for GIST [gastrointestinal stromal tumors] is enhanced by molecular decision making," Dr. Jonathan C. Trent said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"I’ve had patients referred to me from academic centers where the patient was treated with imatinib [Gleevec], which didn’t work, sunitinib [Sutent], which didn’t work, and regorafenib [Stivarga], which didn’t work. We did genetic testing, and it was a D842V mutation [in the PDGFRA gene]. This patient should never have been treated with these drugs," because GIST that carry this PDGFRA mutation are resistant to all three of these tyrosine kinase inhibitor [TKI] drugs, said Dr. Trent, professor of medicine and director of the bone and soft tissue program at the University of Miami.

"If you’re thinking of giving adjuvant therapy, you absolutely need molecular profiling because in the primary, resected-disease setting, a full 20% of patients will have a mutation that makes imatinib useless, the D842V mutation," said Dr. George D. Demetri, professor of medicine at Harvard University and director of the Center for Sarcoma and Bone Oncology at Dana Farber Cancer Institute, Boston. The potential consequence of not performing a genetic analysis is "you could overtreat 20% of patients with what is a still moderately expensive drug that will give them side effects for 3 years when they don’t need it. That is bad medicine," Dr. Demetri said in an interview. "I’m flabbergasted that more people are not getting molecular profiling for GIST patients being considered for adjuvant therapy. We have not communicated this well. Genetic testing is easily accessible at reference labs."

Dr. Demetri highlighted that identifying a D842V mutation in the PDGFRA gene of a GIST is good news for patients, because when this mutation appears in a primary tumor it flags a very indolent form of GIST. "The physician can tell patients that they don’t need to take this drug because it won’t do them any good, plus most patients with your mutation don’t have their tumor recur for many years and sometimes never."

In its most recent guidelines for GIST management, the National Comprehensive Cancer Network (NCCN) said: "If tyrosine kinase inhibitors are considered as part of the treatment plan, genetic analysis of the tumor should be considered since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA tyrosine kinase genes are correlated with response (or lack of a response) to specific tyrosine kinase inhibitors."

Similar language exists in the posted GIST management recommendations of the National Cancer Institute (NCI), which date from 2012: "KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs. However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS [overall survival]."

Dr. Trent took issue with these positions and said that the NCCN and NCI need to call genetic assessment of primary GIST necessary, especially for patients considered for adjuvant treatment. But others saw reason for equivocation.

"Since the mutational status of GIST can impact your use of adjuvant therapy or even therapy for metastatic disease, most sarcoma physicians prefer to see it done," noted Dr. Robert G. Maki, professor of medicine and director of the sarcoma program at Mount Sinai Medical Center in New York. "That said, we often do not have clinical trial data to support" this approach to management. For example, no trial results clearly show that GIST that carry a PDGFRA D842V mutation do not respond well to imatinib and have better outcomes when treated with some other drug. "I would like to have these data to discuss the options" with patients, Dr. Maki said in an interview. The relatively well-described patterns of genetic mutation and drug sensitivity seen in GIST make this tumor different from other adult sarcomas, he added.

"We had a patient with the PDGFRA D842V mutation who clearly responded to imatinib," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston.

"You use imatinib empirically because it is the most benign drug, especially at the 400-mg/day level," Dr. Benjamin said in an interview. "It’s well tolerated, and it usually works." But Dr. Benjamin acknowledged the added value of learning a tumor’s genetic profile. "It’s analogous to infectious disease," where you might start a patient on an empiric antibiotic but then reconsider once you receive antibiotic-sensitivity results. Genotyping complements the clinical findings made after starting a patient on imatinib, he said.

Based on current data for GIST sensitivity to TKIs, Dr. Trent and Dr. Demetri summarized the current GIST mutation and treatment landscape this way:

• About 60% of GIST have the most common tyrosine kinase mutation, in exon 11 of the KIT gene, and are sensitive to 400 mg/day of imatinib.

• About 7% of GIST have the exon 9 mutation of KIT and are sensitive to a higher dosage of imatinib, ideally 800 mg/day if that is tolerated.

• About 20% of GIST have the D842V mutation in the PDGFRA tyrosine kinase gene, and these patients are candidates for enrollment in a trial, as no regimens are known effective for these tumors.

• About 12% of GIST have a mutation in the SDF gene, which appears to make them resistant to imatinib and sunitinib but which may be sensitive to another TKI, regorafenib.

• The remaining GIST have other, rare mutations.

Dr. Trent said that he had no disclosures. Dr. Demetri said that he has been a consultant to Bayer, Novartis, and other companies. Dr. Maki said that he has been a consultant to Eisai/Morphotek, Bayer, and other companies, and has received research support from Eisai/Morphotek, Tracon, and Bayer. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Many U.S. patients with gastrointestinal stromal tumors today start on the wrong adjuvant treatment because their physicians don’t order genetic assessment of the cancer, said two American oncologists.

"Initial treatment for GIST [gastrointestinal stromal tumors] is enhanced by molecular decision making," Dr. Jonathan C. Trent said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"I’ve had patients referred to me from academic centers where the patient was treated with imatinib [Gleevec], which didn’t work, sunitinib [Sutent], which didn’t work, and regorafenib [Stivarga], which didn’t work. We did genetic testing, and it was a D842V mutation [in the PDGFRA gene]. This patient should never have been treated with these drugs," because GIST that carry this PDGFRA mutation are resistant to all three of these tyrosine kinase inhibitor [TKI] drugs, said Dr. Trent, professor of medicine and director of the bone and soft tissue program at the University of Miami.

"If you’re thinking of giving adjuvant therapy, you absolutely need molecular profiling because in the primary, resected-disease setting, a full 20% of patients will have a mutation that makes imatinib useless, the D842V mutation," said Dr. George D. Demetri, professor of medicine at Harvard University and director of the Center for Sarcoma and Bone Oncology at Dana Farber Cancer Institute, Boston. The potential consequence of not performing a genetic analysis is "you could overtreat 20% of patients with what is a still moderately expensive drug that will give them side effects for 3 years when they don’t need it. That is bad medicine," Dr. Demetri said in an interview. "I’m flabbergasted that more people are not getting molecular profiling for GIST patients being considered for adjuvant therapy. We have not communicated this well. Genetic testing is easily accessible at reference labs."

Dr. Demetri highlighted that identifying a D842V mutation in the PDGFRA gene of a GIST is good news for patients, because when this mutation appears in a primary tumor it flags a very indolent form of GIST. "The physician can tell patients that they don’t need to take this drug because it won’t do them any good, plus most patients with your mutation don’t have their tumor recur for many years and sometimes never."

In its most recent guidelines for GIST management, the National Comprehensive Cancer Network (NCCN) said: "If tyrosine kinase inhibitors are considered as part of the treatment plan, genetic analysis of the tumor should be considered since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA tyrosine kinase genes are correlated with response (or lack of a response) to specific tyrosine kinase inhibitors."

Similar language exists in the posted GIST management recommendations of the National Cancer Institute (NCI), which date from 2012: "KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs. However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS [overall survival]."

Dr. Trent took issue with these positions and said that the NCCN and NCI need to call genetic assessment of primary GIST necessary, especially for patients considered for adjuvant treatment. But others saw reason for equivocation.

"Since the mutational status of GIST can impact your use of adjuvant therapy or even therapy for metastatic disease, most sarcoma physicians prefer to see it done," noted Dr. Robert G. Maki, professor of medicine and director of the sarcoma program at Mount Sinai Medical Center in New York. "That said, we often do not have clinical trial data to support" this approach to management. For example, no trial results clearly show that GIST that carry a PDGFRA D842V mutation do not respond well to imatinib and have better outcomes when treated with some other drug. "I would like to have these data to discuss the options" with patients, Dr. Maki said in an interview. The relatively well-described patterns of genetic mutation and drug sensitivity seen in GIST make this tumor different from other adult sarcomas, he added.

"We had a patient with the PDGFRA D842V mutation who clearly responded to imatinib," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston.

"You use imatinib empirically because it is the most benign drug, especially at the 400-mg/day level," Dr. Benjamin said in an interview. "It’s well tolerated, and it usually works." But Dr. Benjamin acknowledged the added value of learning a tumor’s genetic profile. "It’s analogous to infectious disease," where you might start a patient on an empiric antibiotic but then reconsider once you receive antibiotic-sensitivity results. Genotyping complements the clinical findings made after starting a patient on imatinib, he said.

Based on current data for GIST sensitivity to TKIs, Dr. Trent and Dr. Demetri summarized the current GIST mutation and treatment landscape this way:

• About 60% of GIST have the most common tyrosine kinase mutation, in exon 11 of the KIT gene, and are sensitive to 400 mg/day of imatinib.

• About 7% of GIST have the exon 9 mutation of KIT and are sensitive to a higher dosage of imatinib, ideally 800 mg/day if that is tolerated.

• About 20% of GIST have the D842V mutation in the PDGFRA tyrosine kinase gene, and these patients are candidates for enrollment in a trial, as no regimens are known effective for these tumors.

• About 12% of GIST have a mutation in the SDF gene, which appears to make them resistant to imatinib and sunitinib but which may be sensitive to another TKI, regorafenib.

• The remaining GIST have other, rare mutations.

Dr. Trent said that he had no disclosures. Dr. Demetri said that he has been a consultant to Bayer, Novartis, and other companies. Dr. Maki said that he has been a consultant to Eisai/Morphotek, Bayer, and other companies, and has received research support from Eisai/Morphotek, Tracon, and Bayer. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Many U.S. patients with gastrointestinal stromal tumors today start on the wrong adjuvant treatment because their physicians don’t order genetic assessment of the cancer, said two American oncologists.

"Initial treatment for GIST [gastrointestinal stromal tumors] is enhanced by molecular decision making," Dr. Jonathan C. Trent said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"I’ve had patients referred to me from academic centers where the patient was treated with imatinib [Gleevec], which didn’t work, sunitinib [Sutent], which didn’t work, and regorafenib [Stivarga], which didn’t work. We did genetic testing, and it was a D842V mutation [in the PDGFRA gene]. This patient should never have been treated with these drugs," because GIST that carry this PDGFRA mutation are resistant to all three of these tyrosine kinase inhibitor [TKI] drugs, said Dr. Trent, professor of medicine and director of the bone and soft tissue program at the University of Miami.

"If you’re thinking of giving adjuvant therapy, you absolutely need molecular profiling because in the primary, resected-disease setting, a full 20% of patients will have a mutation that makes imatinib useless, the D842V mutation," said Dr. George D. Demetri, professor of medicine at Harvard University and director of the Center for Sarcoma and Bone Oncology at Dana Farber Cancer Institute, Boston. The potential consequence of not performing a genetic analysis is "you could overtreat 20% of patients with what is a still moderately expensive drug that will give them side effects for 3 years when they don’t need it. That is bad medicine," Dr. Demetri said in an interview. "I’m flabbergasted that more people are not getting molecular profiling for GIST patients being considered for adjuvant therapy. We have not communicated this well. Genetic testing is easily accessible at reference labs."

Dr. Demetri highlighted that identifying a D842V mutation in the PDGFRA gene of a GIST is good news for patients, because when this mutation appears in a primary tumor it flags a very indolent form of GIST. "The physician can tell patients that they don’t need to take this drug because it won’t do them any good, plus most patients with your mutation don’t have their tumor recur for many years and sometimes never."

In its most recent guidelines for GIST management, the National Comprehensive Cancer Network (NCCN) said: "If tyrosine kinase inhibitors are considered as part of the treatment plan, genetic analysis of the tumor should be considered since the presence of mutations (or absence of mutations) in specific regions of the KIT and PDGFRA tyrosine kinase genes are correlated with response (or lack of a response) to specific tyrosine kinase inhibitors."

Similar language exists in the posted GIST management recommendations of the National Cancer Institute (NCI), which date from 2012: "KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs. However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS [overall survival]."

Dr. Trent took issue with these positions and said that the NCCN and NCI need to call genetic assessment of primary GIST necessary, especially for patients considered for adjuvant treatment. But others saw reason for equivocation.

"Since the mutational status of GIST can impact your use of adjuvant therapy or even therapy for metastatic disease, most sarcoma physicians prefer to see it done," noted Dr. Robert G. Maki, professor of medicine and director of the sarcoma program at Mount Sinai Medical Center in New York. "That said, we often do not have clinical trial data to support" this approach to management. For example, no trial results clearly show that GIST that carry a PDGFRA D842V mutation do not respond well to imatinib and have better outcomes when treated with some other drug. "I would like to have these data to discuss the options" with patients, Dr. Maki said in an interview. The relatively well-described patterns of genetic mutation and drug sensitivity seen in GIST make this tumor different from other adult sarcomas, he added.

"We had a patient with the PDGFRA D842V mutation who clearly responded to imatinib," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston.

"You use imatinib empirically because it is the most benign drug, especially at the 400-mg/day level," Dr. Benjamin said in an interview. "It’s well tolerated, and it usually works." But Dr. Benjamin acknowledged the added value of learning a tumor’s genetic profile. "It’s analogous to infectious disease," where you might start a patient on an empiric antibiotic but then reconsider once you receive antibiotic-sensitivity results. Genotyping complements the clinical findings made after starting a patient on imatinib, he said.

Based on current data for GIST sensitivity to TKIs, Dr. Trent and Dr. Demetri summarized the current GIST mutation and treatment landscape this way:

• About 60% of GIST have the most common tyrosine kinase mutation, in exon 11 of the KIT gene, and are sensitive to 400 mg/day of imatinib.

• About 7% of GIST have the exon 9 mutation of KIT and are sensitive to a higher dosage of imatinib, ideally 800 mg/day if that is tolerated.

• About 20% of GIST have the D842V mutation in the PDGFRA tyrosine kinase gene, and these patients are candidates for enrollment in a trial, as no regimens are known effective for these tumors.

• About 12% of GIST have a mutation in the SDF gene, which appears to make them resistant to imatinib and sunitinib but which may be sensitive to another TKI, regorafenib.

• The remaining GIST have other, rare mutations.

Dr. Trent said that he had no disclosures. Dr. Demetri said that he has been a consultant to Bayer, Novartis, and other companies. Dr. Maki said that he has been a consultant to Eisai/Morphotek, Bayer, and other companies, and has received research support from Eisai/Morphotek, Tracon, and Bayer. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.

"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.

"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.

Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.

The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).

Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).

Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.

Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.

Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.

Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.

"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.

"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.

Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.

The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).

Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).

Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.

Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.

Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.

Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

MILAN – Although genetic analysis has become a key part of gastrointestinal-stromal tumor assessment before treating a primary tumor, its use at the time of recurrence remains problematic because of the heterogeneity of recurrent clones at the time of relapse, according to Dr. George D. Demetri.

"Liquid biopsy" is a new genetic assessment method with the potential to address the heterogeneity by sampling the complete spectrum of a patient’s tumor using free circulating tumor DNA in the patient’s plasma, rather than biopsying specific pieces of the tumor.

"The challenge from multiple, progressing tumors in a patient with GIST who is failing tyrosine-kinase inhibitor treatment is how to get around the limitation of tumor biopsy. How useful are biopsies when each corner of the tumor tells you something different" when a patient has recurrent GIST? said Dr. Demetri at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "Do you think you get a comprehensive look by biopsying the tumor? How many biopsies do you take?" asked Dr. Demetri, professor of medicine at Harvard Medical School and director of the center for sarcoma and bone oncology at Dana Farber Cancer Institute, both in Boston.

Dr. Demetri called for continued research to prove the efficacy and utility of liquid biopsies. "We need to develop liquid biopsies to get around the issue of tumor biopsies," he said.

The approach relies on the concept that tumor cells are constantly dying and releasing their DNA into a patient’s blood, and hence the free DNA circulating reflects the genetic profile, including all mutations and clones the patient’s tumor has at the time; this approach was pioneered by researchers at Johns Hopkins University (Sci. Transl. Med. 2012;4:162ra154).

Last year, researchers in Germany reported good correlations when assessing mutations in free circulating DNA in multiple plasma samples drawn from 38 patients with recurrent GIST and matching the results with the patients’ clinical state (Clin. Cancer Res. 2013;19:4854-67).

Dr. Demetri said his own laboratory recently compared mutational analyses in 32 patients with primary GIST and found that in 29 of 32 cases (91%), the mutational profile seen in the free circulating DNA matched that seen in biopsy specimens from each patient.

Currently, genetic assessment of free circulating DNA relies on looking for known mutations using specific amplification primers for those mutations, but next-generation sequencing could be used instead to search for any type of mutation, Dr. Demetri said.

Genetic analysis of GIST at the time of relapse is important, given today’s treatment options and the need to match the right treatment to the right genetic profile, but the challenge is how to perform this analysis in a meaningful way, commented Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at M.D. Anderson Cancer Center in Houston. "The idea of using free DNA in blood is very exciting," he said in an interview.

Dr. Demetri said he has been a consultant to Bayer, Novartis, Pfizer, Sanofi Oncology, Merck, GlaxoSmithKline, and Ariad. Dr. Benjamin said he has been a consultant to Johnson & Johnson, Merck, and Pfizer.

[email protected]

On Twitter @mitchelzoler

Pazopanib was well tolerated and appeared to be of clinical benefit in children with soft tissue sarcoma in a phase I study. Although the findings are preliminary, eight children in the trial achieved stable disease and two achieved a partial response.

"The clinical activity of pazopanib is encouraging in this heavily pretreated pediatric population," said Dr. Julia Glad Bender, of Columbia University Medical Center, New York, and her associates (J. Clin. Oncol. 2013;31:3034-43).

Pazopanib (Votrient) is approved by the Food and Drug Administration as a treatment for adult patients with soft tissue sarcoma and in those with advanced renal cell carcinoma. The drug inhibited cell proliferation, angiogenesis, and possibly tumor growth in pediatric xenografts, prompting the research team to evaluate pazopanib’s therapeutic potential in children.

The multicenter phase I study examined the pharmacokinetic and pharmacodynamic properties of two formulations of pazopanib in children with soft tissue sarcoma or other refractory solid tumors. Overall, 51 children with a median age of 12.9 years and recurrent or refractory solid or primary central nervous system tumors were evaluated in the trial.

For the first component of the trial, the maximum tolerated dose (MTD) of a tablet formulation of pazopanib was determined in 25 children who had a median age of 13.5 years. The starting dose of pazopanib was 275 mg/m² given every day in 28-day cycles for up to a maximum of 24 cycles. The MTD was found to be 450 mg/m².

The researchers next determined the MTD of a powder suspension formulation of the drug based on the tablet MTD in 16 children with a median age of 10.5 years. The suspension MTD was found to be 160 mg/m².

Finally, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used at the start of and after 15 days’ treatment in 10 children with a median age of 17.2 years. All received pazopanib tablets at the MTD of 450 mg/m². The aim was to see if there was any sign of a change in tumor angiogenesis in response to treatment.

The most common adverse effects seen with pazopanib treatment were gastrointestinal (diarrhea, nausea, and vomiting), fatigue, proteinuria, and hypertension. Grade 3-4 toxicities that limited dosing in the first cycle of treatment included elevations in lipase, amylase and alanine transaminase, proteinuria, and hypertension. There was a single (grade 4) case of intracranial hemorrhage in a child with occult brain metastases.

"Overall toxicity seemed to correlate with exposure rather than dose," the researchers wrote. The bioavailability of pazopanib appeared to be higher with the suspension than with the tablet formulation, so there might be a relationship between higher steady state plasma trough concentrations and the development of hypertension.

"In adults, elevated blood pressure has been suggested as a correlative marker for improved antitumor efficacy of VEGF [vascular endothelial growth factor] pathway inhibitors," the researchers wrote. "Additional studies are warranted to determine whether hypertension can be used to optimize dose or predict clinical benefit in children."

Eight patients in the trial had stable disease for 6 months or more, and seven of those children had soft tissue sarcomas. Partial responses were seen in two children – one with a desmoplastic small round cell tumor and one with a hepatoblastoma. The latter patient had to be removed from the study due to recurrent neutropenia after 12 cycles.

Results of the DCE-MRI analysis showed a decrease in tumor blood volume from a mean of 16% at the start of treatment to 7% at the end of pazopanib treatment (P = .004).

"To our knowledge, this is the first pediatric, multicenter trial to systematically evaluate DCE-MRI in soft tissue sarcoma, demonstrating the feasibility of performing such studies in a clinical trial network," Dr. Bender and team commented.

"Within the imaging stratum, all patients with interpretable studies had a decrease in tumor blood volume and permeability consistent with the antiangiogenic mechanism of pazopanib." Due to the small number of children evaluated, however, it is not possible to correlate the decrease in tumor blood volume with any clinical benefit.

A phase II trial is planned to further determine the pharmacokinetics and pharmacodynamic of pazopanib in children with soft tissue sarcomas and other refractory solid tumors.

The study was supported by grants from the Alex’s Lemonade Stand Foundation, Columbia University, GlaxoSmithKline, and the National Institutes of Health. Dr. Bender has acted as an unpaid advisor to GlaxoSmithKline. The other authors reported no conflicts of interest.

[email protected]

Pazopanib was well tolerated and appeared to be of clinical benefit in children with soft tissue sarcoma in a phase I study. Although the findings are preliminary, eight children in the trial achieved stable disease and two achieved a partial response.

"The clinical activity of pazopanib is encouraging in this heavily pretreated pediatric population," said Dr. Julia Glad Bender, of Columbia University Medical Center, New York, and her associates (J. Clin. Oncol. 2013;31:3034-43).

Pazopanib (Votrient) is approved by the Food and Drug Administration as a treatment for adult patients with soft tissue sarcoma and in those with advanced renal cell carcinoma. The drug inhibited cell proliferation, angiogenesis, and possibly tumor growth in pediatric xenografts, prompting the research team to evaluate pazopanib’s therapeutic potential in children.

The multicenter phase I study examined the pharmacokinetic and pharmacodynamic properties of two formulations of pazopanib in children with soft tissue sarcoma or other refractory solid tumors. Overall, 51 children with a median age of 12.9 years and recurrent or refractory solid or primary central nervous system tumors were evaluated in the trial.

For the first component of the trial, the maximum tolerated dose (MTD) of a tablet formulation of pazopanib was determined in 25 children who had a median age of 13.5 years. The starting dose of pazopanib was 275 mg/m² given every day in 28-day cycles for up to a maximum of 24 cycles. The MTD was found to be 450 mg/m².

The researchers next determined the MTD of a powder suspension formulation of the drug based on the tablet MTD in 16 children with a median age of 10.5 years. The suspension MTD was found to be 160 mg/m².

Finally, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used at the start of and after 15 days’ treatment in 10 children with a median age of 17.2 years. All received pazopanib tablets at the MTD of 450 mg/m². The aim was to see if there was any sign of a change in tumor angiogenesis in response to treatment.

The most common adverse effects seen with pazopanib treatment were gastrointestinal (diarrhea, nausea, and vomiting), fatigue, proteinuria, and hypertension. Grade 3-4 toxicities that limited dosing in the first cycle of treatment included elevations in lipase, amylase and alanine transaminase, proteinuria, and hypertension. There was a single (grade 4) case of intracranial hemorrhage in a child with occult brain metastases.

"Overall toxicity seemed to correlate with exposure rather than dose," the researchers wrote. The bioavailability of pazopanib appeared to be higher with the suspension than with the tablet formulation, so there might be a relationship between higher steady state plasma trough concentrations and the development of hypertension.

"In adults, elevated blood pressure has been suggested as a correlative marker for improved antitumor efficacy of VEGF [vascular endothelial growth factor] pathway inhibitors," the researchers wrote. "Additional studies are warranted to determine whether hypertension can be used to optimize dose or predict clinical benefit in children."

Eight patients in the trial had stable disease for 6 months or more, and seven of those children had soft tissue sarcomas. Partial responses were seen in two children – one with a desmoplastic small round cell tumor and one with a hepatoblastoma. The latter patient had to be removed from the study due to recurrent neutropenia after 12 cycles.

Results of the DCE-MRI analysis showed a decrease in tumor blood volume from a mean of 16% at the start of treatment to 7% at the end of pazopanib treatment (P = .004).

"To our knowledge, this is the first pediatric, multicenter trial to systematically evaluate DCE-MRI in soft tissue sarcoma, demonstrating the feasibility of performing such studies in a clinical trial network," Dr. Bender and team commented.

"Within the imaging stratum, all patients with interpretable studies had a decrease in tumor blood volume and permeability consistent with the antiangiogenic mechanism of pazopanib." Due to the small number of children evaluated, however, it is not possible to correlate the decrease in tumor blood volume with any clinical benefit.

A phase II trial is planned to further determine the pharmacokinetics and pharmacodynamic of pazopanib in children with soft tissue sarcomas and other refractory solid tumors.

The study was supported by grants from the Alex’s Lemonade Stand Foundation, Columbia University, GlaxoSmithKline, and the National Institutes of Health. Dr. Bender has acted as an unpaid advisor to GlaxoSmithKline. The other authors reported no conflicts of interest.

[email protected]

Pazopanib was well tolerated and appeared to be of clinical benefit in children with soft tissue sarcoma in a phase I study. Although the findings are preliminary, eight children in the trial achieved stable disease and two achieved a partial response.

"The clinical activity of pazopanib is encouraging in this heavily pretreated pediatric population," said Dr. Julia Glad Bender, of Columbia University Medical Center, New York, and her associates (J. Clin. Oncol. 2013;31:3034-43).

Pazopanib (Votrient) is approved by the Food and Drug Administration as a treatment for adult patients with soft tissue sarcoma and in those with advanced renal cell carcinoma. The drug inhibited cell proliferation, angiogenesis, and possibly tumor growth in pediatric xenografts, prompting the research team to evaluate pazopanib’s therapeutic potential in children.

The multicenter phase I study examined the pharmacokinetic and pharmacodynamic properties of two formulations of pazopanib in children with soft tissue sarcoma or other refractory solid tumors. Overall, 51 children with a median age of 12.9 years and recurrent or refractory solid or primary central nervous system tumors were evaluated in the trial.

For the first component of the trial, the maximum tolerated dose (MTD) of a tablet formulation of pazopanib was determined in 25 children who had a median age of 13.5 years. The starting dose of pazopanib was 275 mg/m² given every day in 28-day cycles for up to a maximum of 24 cycles. The MTD was found to be 450 mg/m².

The researchers next determined the MTD of a powder suspension formulation of the drug based on the tablet MTD in 16 children with a median age of 10.5 years. The suspension MTD was found to be 160 mg/m².

Finally, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used at the start of and after 15 days’ treatment in 10 children with a median age of 17.2 years. All received pazopanib tablets at the MTD of 450 mg/m². The aim was to see if there was any sign of a change in tumor angiogenesis in response to treatment.

The most common adverse effects seen with pazopanib treatment were gastrointestinal (diarrhea, nausea, and vomiting), fatigue, proteinuria, and hypertension. Grade 3-4 toxicities that limited dosing in the first cycle of treatment included elevations in lipase, amylase and alanine transaminase, proteinuria, and hypertension. There was a single (grade 4) case of intracranial hemorrhage in a child with occult brain metastases.

"Overall toxicity seemed to correlate with exposure rather than dose," the researchers wrote. The bioavailability of pazopanib appeared to be higher with the suspension than with the tablet formulation, so there might be a relationship between higher steady state plasma trough concentrations and the development of hypertension.

"In adults, elevated blood pressure has been suggested as a correlative marker for improved antitumor efficacy of VEGF [vascular endothelial growth factor] pathway inhibitors," the researchers wrote. "Additional studies are warranted to determine whether hypertension can be used to optimize dose or predict clinical benefit in children."

Eight patients in the trial had stable disease for 6 months or more, and seven of those children had soft tissue sarcomas. Partial responses were seen in two children – one with a desmoplastic small round cell tumor and one with a hepatoblastoma. The latter patient had to be removed from the study due to recurrent neutropenia after 12 cycles.

Results of the DCE-MRI analysis showed a decrease in tumor blood volume from a mean of 16% at the start of treatment to 7% at the end of pazopanib treatment (P = .004).

"To our knowledge, this is the first pediatric, multicenter trial to systematically evaluate DCE-MRI in soft tissue sarcoma, demonstrating the feasibility of performing such studies in a clinical trial network," Dr. Bender and team commented.

"Within the imaging stratum, all patients with interpretable studies had a decrease in tumor blood volume and permeability consistent with the antiangiogenic mechanism of pazopanib." Due to the small number of children evaluated, however, it is not possible to correlate the decrease in tumor blood volume with any clinical benefit.

A phase II trial is planned to further determine the pharmacokinetics and pharmacodynamic of pazopanib in children with soft tissue sarcomas and other refractory solid tumors.

The study was supported by grants from the Alex’s Lemonade Stand Foundation, Columbia University, GlaxoSmithKline, and the National Institutes of Health. Dr. Bender has acted as an unpaid advisor to GlaxoSmithKline. The other authors reported no conflicts of interest.

[email protected]

The investigational agent ridaforolimus reduced the risk for progression and death by 28% in previously treated patients with advanced sarcoma in a large phase III study.

Results of the SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) study showed that there was a small, but significant median progression-free survival (PFS) gain of 3.3 weeks vs. placebo (17.7 vs. 14.6 weeks, hazard ratio, 0.72; P less than .001) by independent review.

"The absolute magnitude of this statistically significant improvement in disease control was small because of the more rapid than expected progression in all patients in this study," said Dr. George D. Demetri of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, and his associates (J. Clin. Oncol. 2013;31:2485-92).

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy."

"To our knowledge, this is the first study demonstrating a statistically significant, although clinically small, impact on maintenance treatment on tumor progression in patients with sarcomas," the researchers said. "Future studies will build on these results in an effort to improve the outcomes of this rapidly progressive life-threatening disease."

The study was designed with the premise that the median time to progression would be around 6-9 months in the control arm. In fact, it was less than 4 months, and there was a 6-month PFS rate of 23% and average tumor growth of 10% in target lesions.

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy," the researchers said.

The SUCCEED trial was an international, randomized, double blind, placebo-controlled trial of 711 patients with advanced soft tissue or bone sarcomas who had achieved stable disease or a continued partial or complete response to immediately preceding cytotoxic chemotherapy Patients were randomized to receive either the mammalian target of rapamycin inhibitor ridaforolimus (n = 347), given at a dose of four 10 mg tablets/day for 5 days every week, or matching placebo tablets (n = 364).

Baseline patient characteristics were similar between the two study groups. The mean age of patients was 52 years in the ridaforolimus arm and 50 years in the placebo arm. The majority (89.3%) of patients had soft tissue sarcomas, with the remainder having bone sarcomas. Almost 75% of tumors were high grade, 66.6% of patients had metastatic disease involving the lung, 14.4% involving the liver, and 11.5% involving the bone. Around 40% of patients had received two or more prior cytotoxic chemotherapy regimens, and the best response to treatment had been stable disease in 74.4%, a partial response in 18.4%, and a complete response in 5.5%.

Investigator-assessed PFS showed slightly better median survival rates of 22.4 vs. 14.7 weeks (HR, 0.69; P less than .001). There was mean decrease in target lesion size of 1.3% in the ridaforolimus arm vs. a 10.3% increase in size in the placebo arm (P less than .001).

No overall survival benefit was observed in the trial. Based on 478 death events and a minimum of 2 years’ follow-up, median overall survival was 90.6 weeks vs. 85.3 weeks (HR, 0.93; P = .46). Dr. Demetri and his coworkers point out, however, that the study was not powered to determine an overall survival benefit.

Adverse effects of any grade occurred in 100% of ridaforolimus-treated and 93.6% of placebo-treated patients. Adverse effects of note that occurred to a greater extent in the active treatment arm included stomatitis, thrombocytopenia, infections, rash, hypertriglyceridemia, and anemia. Grade 3 or higher adverse events occurred in 64.1% of patients treated with ridaforolimus and 25.6% of those in the placebo arm.

This was an unselected patient population but no potential biomarkers or predictors for response have been identified. As ridaforolimus improved, the best target lesion response and the clinical benefit rate, it might contribute to tumor growth control, the researchers speculated. They therefore suggested that it might be better suited as an element of combination treatment with other tumor-signaling inhibitors.

The SUCCEED study was funded by Merck, Sharp, and Dohme. Dr. Demetri has received consultancy fees and research funding from Merck and ARIAD Pharmaceuticals. Several of his coauthors had also received honoraria from Merck or were employees of the company.

The investigational agent ridaforolimus reduced the risk for progression and death by 28% in previously treated patients with advanced sarcoma in a large phase III study.

Results of the SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) study showed that there was a small, but significant median progression-free survival (PFS) gain of 3.3 weeks vs. placebo (17.7 vs. 14.6 weeks, hazard ratio, 0.72; P less than .001) by independent review.

"The absolute magnitude of this statistically significant improvement in disease control was small because of the more rapid than expected progression in all patients in this study," said Dr. George D. Demetri of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, and his associates (J. Clin. Oncol. 2013;31:2485-92).

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy."

"To our knowledge, this is the first study demonstrating a statistically significant, although clinically small, impact on maintenance treatment on tumor progression in patients with sarcomas," the researchers said. "Future studies will build on these results in an effort to improve the outcomes of this rapidly progressive life-threatening disease."

The study was designed with the premise that the median time to progression would be around 6-9 months in the control arm. In fact, it was less than 4 months, and there was a 6-month PFS rate of 23% and average tumor growth of 10% in target lesions.

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy," the researchers said.

The SUCCEED trial was an international, randomized, double blind, placebo-controlled trial of 711 patients with advanced soft tissue or bone sarcomas who had achieved stable disease or a continued partial or complete response to immediately preceding cytotoxic chemotherapy Patients were randomized to receive either the mammalian target of rapamycin inhibitor ridaforolimus (n = 347), given at a dose of four 10 mg tablets/day for 5 days every week, or matching placebo tablets (n = 364).

Baseline patient characteristics were similar between the two study groups. The mean age of patients was 52 years in the ridaforolimus arm and 50 years in the placebo arm. The majority (89.3%) of patients had soft tissue sarcomas, with the remainder having bone sarcomas. Almost 75% of tumors were high grade, 66.6% of patients had metastatic disease involving the lung, 14.4% involving the liver, and 11.5% involving the bone. Around 40% of patients had received two or more prior cytotoxic chemotherapy regimens, and the best response to treatment had been stable disease in 74.4%, a partial response in 18.4%, and a complete response in 5.5%.

Investigator-assessed PFS showed slightly better median survival rates of 22.4 vs. 14.7 weeks (HR, 0.69; P less than .001). There was mean decrease in target lesion size of 1.3% in the ridaforolimus arm vs. a 10.3% increase in size in the placebo arm (P less than .001).

No overall survival benefit was observed in the trial. Based on 478 death events and a minimum of 2 years’ follow-up, median overall survival was 90.6 weeks vs. 85.3 weeks (HR, 0.93; P = .46). Dr. Demetri and his coworkers point out, however, that the study was not powered to determine an overall survival benefit.

Adverse effects of any grade occurred in 100% of ridaforolimus-treated and 93.6% of placebo-treated patients. Adverse effects of note that occurred to a greater extent in the active treatment arm included stomatitis, thrombocytopenia, infections, rash, hypertriglyceridemia, and anemia. Grade 3 or higher adverse events occurred in 64.1% of patients treated with ridaforolimus and 25.6% of those in the placebo arm.

This was an unselected patient population but no potential biomarkers or predictors for response have been identified. As ridaforolimus improved, the best target lesion response and the clinical benefit rate, it might contribute to tumor growth control, the researchers speculated. They therefore suggested that it might be better suited as an element of combination treatment with other tumor-signaling inhibitors.

The SUCCEED study was funded by Merck, Sharp, and Dohme. Dr. Demetri has received consultancy fees and research funding from Merck and ARIAD Pharmaceuticals. Several of his coauthors had also received honoraria from Merck or were employees of the company.

The investigational agent ridaforolimus reduced the risk for progression and death by 28% in previously treated patients with advanced sarcoma in a large phase III study.

Results of the SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) study showed that there was a small, but significant median progression-free survival (PFS) gain of 3.3 weeks vs. placebo (17.7 vs. 14.6 weeks, hazard ratio, 0.72; P less than .001) by independent review.

"The absolute magnitude of this statistically significant improvement in disease control was small because of the more rapid than expected progression in all patients in this study," said Dr. George D. Demetri of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, and his associates (J. Clin. Oncol. 2013;31:2485-92).

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy."

"To our knowledge, this is the first study demonstrating a statistically significant, although clinically small, impact on maintenance treatment on tumor progression in patients with sarcomas," the researchers said. "Future studies will build on these results in an effort to improve the outcomes of this rapidly progressive life-threatening disease."

The study was designed with the premise that the median time to progression would be around 6-9 months in the control arm. In fact, it was less than 4 months, and there was a 6-month PFS rate of 23% and average tumor growth of 10% in target lesions.

"This finding confirms the aggressive nature of advanced sarcomas and underscores the medical need of these patients to improve with available therapy," the researchers said.

The SUCCEED trial was an international, randomized, double blind, placebo-controlled trial of 711 patients with advanced soft tissue or bone sarcomas who had achieved stable disease or a continued partial or complete response to immediately preceding cytotoxic chemotherapy Patients were randomized to receive either the mammalian target of rapamycin inhibitor ridaforolimus (n = 347), given at a dose of four 10 mg tablets/day for 5 days every week, or matching placebo tablets (n = 364).

Baseline patient characteristics were similar between the two study groups. The mean age of patients was 52 years in the ridaforolimus arm and 50 years in the placebo arm. The majority (89.3%) of patients had soft tissue sarcomas, with the remainder having bone sarcomas. Almost 75% of tumors were high grade, 66.6% of patients had metastatic disease involving the lung, 14.4% involving the liver, and 11.5% involving the bone. Around 40% of patients had received two or more prior cytotoxic chemotherapy regimens, and the best response to treatment had been stable disease in 74.4%, a partial response in 18.4%, and a complete response in 5.5%.

Investigator-assessed PFS showed slightly better median survival rates of 22.4 vs. 14.7 weeks (HR, 0.69; P less than .001). There was mean decrease in target lesion size of 1.3% in the ridaforolimus arm vs. a 10.3% increase in size in the placebo arm (P less than .001).

No overall survival benefit was observed in the trial. Based on 478 death events and a minimum of 2 years’ follow-up, median overall survival was 90.6 weeks vs. 85.3 weeks (HR, 0.93; P = .46). Dr. Demetri and his coworkers point out, however, that the study was not powered to determine an overall survival benefit.

Adverse effects of any grade occurred in 100% of ridaforolimus-treated and 93.6% of placebo-treated patients. Adverse effects of note that occurred to a greater extent in the active treatment arm included stomatitis, thrombocytopenia, infections, rash, hypertriglyceridemia, and anemia. Grade 3 or higher adverse events occurred in 64.1% of patients treated with ridaforolimus and 25.6% of those in the placebo arm.

This was an unselected patient population but no potential biomarkers or predictors for response have been identified. As ridaforolimus improved, the best target lesion response and the clinical benefit rate, it might contribute to tumor growth control, the researchers speculated. They therefore suggested that it might be better suited as an element of combination treatment with other tumor-signaling inhibitors.

The SUCCEED study was funded by Merck, Sharp, and Dohme. Dr. Demetri has received consultancy fees and research funding from Merck and ARIAD Pharmaceuticals. Several of his coauthors had also received honoraria from Merck or were employees of the company.

ATLANTA – Intensity-modulated radiation therapy proved significantly better than conventional radiation for local control of soft-tissue sarcomas of the extremities, according to new study results, investigators reported at the annual meeting of the American Society for Radiation Oncology.

The 5-year local control rate with intensity-modulated radiation therapy (IMRT) was 92.4%, compared with 85% for external-beam radiation therapy (EBRT), said Dr. Kaled M. Alektiar, a radiation oncologist at Memorial Sloan-Kettering Cancer Center in New York.

The benefits of IMRT were seen despite a preponderance of higher risks in patients treated with IMRT. And, "the morbidity profile, especially for chronic lymphedema of grade 3 or higher, was significantly less," Dr. Alektiar said.

He and his coinvestigators looked at 320 patients who underwent definitive surgery and radiation therapy at Memorial Sloan-Kettering for primary, nonmetastatic soft-tissue sarcomas of the extremities. Of this group, 155 received EBRT with a conventional technique, usually three-dimensional conformal radiation, and 165 patients received IMRT.

Most of the tumors (74.7%) were in the lower extremity, 45.6% were at least 10 cm in diameter, 92.2% were in deep tissue, 82.5% were high grade, and 40% had close or positive surgical margins. The majority of patients (75.9%) received adjuvant chemotherapy.

There were significantly more patients with positive or close margins in the IMRT group than in the conventional EBRT group (47.9% vs. 31.6%; P = .003), and more patients treated with IMRT had high-grade histology tumors, although this difference had only borderline significance (86.7% vs. 78.1%; P =.055).

Additionally, significantly more patients in the IMRT group received preoperative radiation (21.2% vs. 3.2%; P less than .001). Otherwise, the groups were balanced in terms of demographics, tumor size, depth, and use of CT in treatment planning.

The median follow-up was 49.5 months (42 months for patients treated with IMRT, and 87 months for those treated with EBRT). The 5-year local recurrence rates were 7.6% for IMRT and 15% for conventional EBRT. The median time to local recurrence was 18 months in each group.

Eight patients required amputations for salvage, including three in the IMRT cohort and five in the conventional radiation cohort.

In multivariate analysis, three factors that were significantly prognostic for local failure were IMRT (hazard ratio, 0.46; P = .02), age less than 50 years (HR, 0.44; P = .04), and a tumor size of 10 cm or less in the longest dimension (HR, 0.53; P = .05).

Overall survival at 5 years was 69.1% for IMRT and 75.6% for EBRT, a difference that was not significant.

Rates of grade 3 or 4 acute toxicities, including infected and noninfected wound complications and radiation dermatitis, were similar between the groups. Patients treated with IMRT had significantly shorter treatment interruptions, at a mean of 0.8 days, compared with 2.2 days for patients treated with conventional EBRT. Chronic grade 3 or higher lymphedema did not occur in any patients treated with IMRT, compared with four patients treated with conventional EBRT (P = .053).

The study was supported by a grant from the Clinical and Translational Science Center at Weill Cornell Medical College, New York. Dr. Alektiar reported having no relevant financial disclosures.

ATLANTA – Intensity-modulated radiation therapy proved significantly better than conventional radiation for local control of soft-tissue sarcomas of the extremities, according to new study results, investigators reported at the annual meeting of the American Society for Radiation Oncology.

The 5-year local control rate with intensity-modulated radiation therapy (IMRT) was 92.4%, compared with 85% for external-beam radiation therapy (EBRT), said Dr. Kaled M. Alektiar, a radiation oncologist at Memorial Sloan-Kettering Cancer Center in New York.

The benefits of IMRT were seen despite a preponderance of higher risks in patients treated with IMRT. And, "the morbidity profile, especially for chronic lymphedema of grade 3 or higher, was significantly less," Dr. Alektiar said.

He and his coinvestigators looked at 320 patients who underwent definitive surgery and radiation therapy at Memorial Sloan-Kettering for primary, nonmetastatic soft-tissue sarcomas of the extremities. Of this group, 155 received EBRT with a conventional technique, usually three-dimensional conformal radiation, and 165 patients received IMRT.

Most of the tumors (74.7%) were in the lower extremity, 45.6% were at least 10 cm in diameter, 92.2% were in deep tissue, 82.5% were high grade, and 40% had close or positive surgical margins. The majority of patients (75.9%) received adjuvant chemotherapy.

There were significantly more patients with positive or close margins in the IMRT group than in the conventional EBRT group (47.9% vs. 31.6%; P = .003), and more patients treated with IMRT had high-grade histology tumors, although this difference had only borderline significance (86.7% vs. 78.1%; P =.055).

Additionally, significantly more patients in the IMRT group received preoperative radiation (21.2% vs. 3.2%; P less than .001). Otherwise, the groups were balanced in terms of demographics, tumor size, depth, and use of CT in treatment planning.

The median follow-up was 49.5 months (42 months for patients treated with IMRT, and 87 months for those treated with EBRT). The 5-year local recurrence rates were 7.6% for IMRT and 15% for conventional EBRT. The median time to local recurrence was 18 months in each group.

Eight patients required amputations for salvage, including three in the IMRT cohort and five in the conventional radiation cohort.

In multivariate analysis, three factors that were significantly prognostic for local failure were IMRT (hazard ratio, 0.46; P = .02), age less than 50 years (HR, 0.44; P = .04), and a tumor size of 10 cm or less in the longest dimension (HR, 0.53; P = .05).

Overall survival at 5 years was 69.1% for IMRT and 75.6% for EBRT, a difference that was not significant.

Rates of grade 3 or 4 acute toxicities, including infected and noninfected wound complications and radiation dermatitis, were similar between the groups. Patients treated with IMRT had significantly shorter treatment interruptions, at a mean of 0.8 days, compared with 2.2 days for patients treated with conventional EBRT. Chronic grade 3 or higher lymphedema did not occur in any patients treated with IMRT, compared with four patients treated with conventional EBRT (P = .053).

The study was supported by a grant from the Clinical and Translational Science Center at Weill Cornell Medical College, New York. Dr. Alektiar reported having no relevant financial disclosures.

ATLANTA – Intensity-modulated radiation therapy proved significantly better than conventional radiation for local control of soft-tissue sarcomas of the extremities, according to new study results, investigators reported at the annual meeting of the American Society for Radiation Oncology.

The 5-year local control rate with intensity-modulated radiation therapy (IMRT) was 92.4%, compared with 85% for external-beam radiation therapy (EBRT), said Dr. Kaled M. Alektiar, a radiation oncologist at Memorial Sloan-Kettering Cancer Center in New York.

The benefits of IMRT were seen despite a preponderance of higher risks in patients treated with IMRT. And, "the morbidity profile, especially for chronic lymphedema of grade 3 or higher, was significantly less," Dr. Alektiar said.

He and his coinvestigators looked at 320 patients who underwent definitive surgery and radiation therapy at Memorial Sloan-Kettering for primary, nonmetastatic soft-tissue sarcomas of the extremities. Of this group, 155 received EBRT with a conventional technique, usually three-dimensional conformal radiation, and 165 patients received IMRT.

Most of the tumors (74.7%) were in the lower extremity, 45.6% were at least 10 cm in diameter, 92.2% were in deep tissue, 82.5% were high grade, and 40% had close or positive surgical margins. The majority of patients (75.9%) received adjuvant chemotherapy.

There were significantly more patients with positive or close margins in the IMRT group than in the conventional EBRT group (47.9% vs. 31.6%; P = .003), and more patients treated with IMRT had high-grade histology tumors, although this difference had only borderline significance (86.7% vs. 78.1%; P =.055).

Additionally, significantly more patients in the IMRT group received preoperative radiation (21.2% vs. 3.2%; P less than .001). Otherwise, the groups were balanced in terms of demographics, tumor size, depth, and use of CT in treatment planning.

The median follow-up was 49.5 months (42 months for patients treated with IMRT, and 87 months for those treated with EBRT). The 5-year local recurrence rates were 7.6% for IMRT and 15% for conventional EBRT. The median time to local recurrence was 18 months in each group.

Eight patients required amputations for salvage, including three in the IMRT cohort and five in the conventional radiation cohort.

In multivariate analysis, three factors that were significantly prognostic for local failure were IMRT (hazard ratio, 0.46; P = .02), age less than 50 years (HR, 0.44; P = .04), and a tumor size of 10 cm or less in the longest dimension (HR, 0.53; P = .05).

Overall survival at 5 years was 69.1% for IMRT and 75.6% for EBRT, a difference that was not significant.

Rates of grade 3 or 4 acute toxicities, including infected and noninfected wound complications and radiation dermatitis, were similar between the groups. Patients treated with IMRT had significantly shorter treatment interruptions, at a mean of 0.8 days, compared with 2.2 days for patients treated with conventional EBRT. Chronic grade 3 or higher lymphedema did not occur in any patients treated with IMRT, compared with four patients treated with conventional EBRT (P = .053).

The study was supported by a grant from the Clinical and Translational Science Center at Weill Cornell Medical College, New York. Dr. Alektiar reported having no relevant financial disclosures.

Rhabdomyosarcomas are a rare group of soft tissue neoplasms of mesenchymal origin. RMS is common among childhood cancers, but it is among the rarest of adult tumors. They account for about 5% of all childhood cancers.1 Soft-tissue sarcomas account for less than 1% of adult malignancies, and RMS account for only 3% of those sarcomas.2 Here, we report a case of RMS in the neck, which led to dysphagia due to external compression of the esophagus.

Click on the PDF icon at the top of this introduction to read the full article.

Rhabdomyosarcomas are a rare group of soft tissue neoplasms of mesenchymal origin. RMS is common among childhood cancers, but it is among the rarest of adult tumors. They account for about 5% of all childhood cancers.1 Soft-tissue sarcomas account for less than 1% of adult malignancies, and RMS account for only 3% of those sarcomas.2 Here, we report a case of RMS in the neck, which led to dysphagia due to external compression of the esophagus.

Click on the PDF icon at the top of this introduction to read the full article.

Rhabdomyosarcomas are a rare group of soft tissue neoplasms of mesenchymal origin. RMS is common among childhood cancers, but it is among the rarest of adult tumors. They account for about 5% of all childhood cancers.1 Soft-tissue sarcomas account for less than 1% of adult malignancies, and RMS account for only 3% of those sarcomas.2 Here, we report a case of RMS in the neck, which led to dysphagia due to external compression of the esophagus.

Click on the PDF icon at the top of this introduction to read the full article.

CHICAGO – A novel technique for ferreting out DNA mutations in circulating plasma appears to be more sensitive than is conventional pathology at detecting drug-resistant mutations in patients with gastrointestinal stromal tumors, said an investigator at the annual meeting of the American Society of Clinical Oncology.

Secondary KIT mutations associated with resistance to tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec) were detected in 47% of plasma samples using "BEAMing" (beads, emulsions, amplification, magnetics) technology, compared with only 12% of tissue biopsy specimens, said Dr. George D. Demetri, director of the center for sarcoma and bone oncology at the Dana-Farber Cancer Institute in Boston.

"We know that tumor cells are constantly turning over, apoptosing, dying, and releasing free DNA into the bloodstream. I want to emphasize that this is not looking at circulating tumor cells; this is looking at free circulating DNA in the plasma, and by looking at that circulating DNA, we may be able to get a more comprehensive assessment of all the mutations from across all tumor burden in any given patient," Dr. Demetri said.

The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 in plasma, according to the American Association for Cancer Research.

Dr. Demetri and his colleagues used the technology to retrospectively study mutations from patient samples in the GRID (GIST-Regorafenib in Progressive Disease) phase III study. In that trial, regorafenib (Stivarga), a multikinase inhibitor, significantly improved progression-free survival (PFS) compared with placebo (hazard ratio, 0.27; P less than .0001) in patients with metastatic GIST after failure of both standard and targeted therapies, including imatinib and sunitinib (Sutent).

The investigators looked for primary and secondary mutations in KIT in both plasma samples (available for 163 of 199 patients in GRID) and tumor tissue (from 102 patients), and found that BEAMing detected mutations in 58% of plasma samples, compared with 66% of tumor samples analyzed by the Sanger DNA sequencing method.

In addition, BEAMing detected mutations in PDGFRA in 1% of samples, and in KRAS in one of two samples, compared with 3% and 1%, respectively, for sequencing. Neither analysis method detected any BRAF mutations, and the numbers of PDGFRA and KRAS mutations were too small for researchers to draw meaningful conclusions.

When it came to KIT, however, there was a high degree of concordance between the tests where both types of samples from individual patients were available, including 100% agreement for primary KIT exon 9 mutations, 79% for primary KIT exon 11 mutations, and 84% overall for primary KIT exon 9 and 11 mutations.

The BEAMing technology can help determine prognosis of patients with GIST, Dr. Demetri said, noting that in the GRID trial, patients in the placebo arm who had secondary KIT mutations had shorter PFS than did patients without KIT mutations (HR, 1.82; P = .05). Patients with KIT exon 9 mutations had received a shorter course of imatinib than did the rest of the study population (HR, 2.02; P = .002) and a longer course of sunitinib (HR, 0.54; P = .005).

BEAMing analysis also showed that patients with secondary KIT mutations who received regorafenib had significantly better PFS than did patients in the placebo arm (HR, 0.22; P less than .001).

The data Dr. Demetri presented were "very exciting," said invited discussant Dr. Shreyaskumar R. Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.

"The important take-home messages are that there is some very good concordance between the tumor tissue analysis and the plasma analysis," and that regorafenib "appears to be totally agnostic to any of the mutational subsets and seems to equally benefit all patients," Dr. Patel said.

The study was supported in part by Bayer HealthCare. Dr. Demetri disclosed serving as a scientific consultant to the company. Dr. Patel reported having no disclosures relevant to the study.

CHICAGO – A novel technique for ferreting out DNA mutations in circulating plasma appears to be more sensitive than is conventional pathology at detecting drug-resistant mutations in patients with gastrointestinal stromal tumors, said an investigator at the annual meeting of the American Society of Clinical Oncology.

Secondary KIT mutations associated with resistance to tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec) were detected in 47% of plasma samples using "BEAMing" (beads, emulsions, amplification, magnetics) technology, compared with only 12% of tissue biopsy specimens, said Dr. George D. Demetri, director of the center for sarcoma and bone oncology at the Dana-Farber Cancer Institute in Boston.

"We know that tumor cells are constantly turning over, apoptosing, dying, and releasing free DNA into the bloodstream. I want to emphasize that this is not looking at circulating tumor cells; this is looking at free circulating DNA in the plasma, and by looking at that circulating DNA, we may be able to get a more comprehensive assessment of all the mutations from across all tumor burden in any given patient," Dr. Demetri said.

The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 in plasma, according to the American Association for Cancer Research.

Dr. Demetri and his colleagues used the technology to retrospectively study mutations from patient samples in the GRID (GIST-Regorafenib in Progressive Disease) phase III study. In that trial, regorafenib (Stivarga), a multikinase inhibitor, significantly improved progression-free survival (PFS) compared with placebo (hazard ratio, 0.27; P less than .0001) in patients with metastatic GIST after failure of both standard and targeted therapies, including imatinib and sunitinib (Sutent).

The investigators looked for primary and secondary mutations in KIT in both plasma samples (available for 163 of 199 patients in GRID) and tumor tissue (from 102 patients), and found that BEAMing detected mutations in 58% of plasma samples, compared with 66% of tumor samples analyzed by the Sanger DNA sequencing method.

In addition, BEAMing detected mutations in PDGFRA in 1% of samples, and in KRAS in one of two samples, compared with 3% and 1%, respectively, for sequencing. Neither analysis method detected any BRAF mutations, and the numbers of PDGFRA and KRAS mutations were too small for researchers to draw meaningful conclusions.

When it came to KIT, however, there was a high degree of concordance between the tests where both types of samples from individual patients were available, including 100% agreement for primary KIT exon 9 mutations, 79% for primary KIT exon 11 mutations, and 84% overall for primary KIT exon 9 and 11 mutations.

The BEAMing technology can help determine prognosis of patients with GIST, Dr. Demetri said, noting that in the GRID trial, patients in the placebo arm who had secondary KIT mutations had shorter PFS than did patients without KIT mutations (HR, 1.82; P = .05). Patients with KIT exon 9 mutations had received a shorter course of imatinib than did the rest of the study population (HR, 2.02; P = .002) and a longer course of sunitinib (HR, 0.54; P = .005).

BEAMing analysis also showed that patients with secondary KIT mutations who received regorafenib had significantly better PFS than did patients in the placebo arm (HR, 0.22; P less than .001).

The data Dr. Demetri presented were "very exciting," said invited discussant Dr. Shreyaskumar R. Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.

"The important take-home messages are that there is some very good concordance between the tumor tissue analysis and the plasma analysis," and that regorafenib "appears to be totally agnostic to any of the mutational subsets and seems to equally benefit all patients," Dr. Patel said.

The study was supported in part by Bayer HealthCare. Dr. Demetri disclosed serving as a scientific consultant to the company. Dr. Patel reported having no disclosures relevant to the study.

CHICAGO – A novel technique for ferreting out DNA mutations in circulating plasma appears to be more sensitive than is conventional pathology at detecting drug-resistant mutations in patients with gastrointestinal stromal tumors, said an investigator at the annual meeting of the American Society of Clinical Oncology.

Secondary KIT mutations associated with resistance to tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec) were detected in 47% of plasma samples using "BEAMing" (beads, emulsions, amplification, magnetics) technology, compared with only 12% of tissue biopsy specimens, said Dr. George D. Demetri, director of the center for sarcoma and bone oncology at the Dana-Farber Cancer Institute in Boston.

"We know that tumor cells are constantly turning over, apoptosing, dying, and releasing free DNA into the bloodstream. I want to emphasize that this is not looking at circulating tumor cells; this is looking at free circulating DNA in the plasma, and by looking at that circulating DNA, we may be able to get a more comprehensive assessment of all the mutations from across all tumor burden in any given patient," Dr. Demetri said.

The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 in plasma, according to the American Association for Cancer Research.

Dr. Demetri and his colleagues used the technology to retrospectively study mutations from patient samples in the GRID (GIST-Regorafenib in Progressive Disease) phase III study. In that trial, regorafenib (Stivarga), a multikinase inhibitor, significantly improved progression-free survival (PFS) compared with placebo (hazard ratio, 0.27; P less than .0001) in patients with metastatic GIST after failure of both standard and targeted therapies, including imatinib and sunitinib (Sutent).

The investigators looked for primary and secondary mutations in KIT in both plasma samples (available for 163 of 199 patients in GRID) and tumor tissue (from 102 patients), and found that BEAMing detected mutations in 58% of plasma samples, compared with 66% of tumor samples analyzed by the Sanger DNA sequencing method.

In addition, BEAMing detected mutations in PDGFRA in 1% of samples, and in KRAS in one of two samples, compared with 3% and 1%, respectively, for sequencing. Neither analysis method detected any BRAF mutations, and the numbers of PDGFRA and KRAS mutations were too small for researchers to draw meaningful conclusions.

When it came to KIT, however, there was a high degree of concordance between the tests where both types of samples from individual patients were available, including 100% agreement for primary KIT exon 9 mutations, 79% for primary KIT exon 11 mutations, and 84% overall for primary KIT exon 9 and 11 mutations.

The BEAMing technology can help determine prognosis of patients with GIST, Dr. Demetri said, noting that in the GRID trial, patients in the placebo arm who had secondary KIT mutations had shorter PFS than did patients without KIT mutations (HR, 1.82; P = .05). Patients with KIT exon 9 mutations had received a shorter course of imatinib than did the rest of the study population (HR, 2.02; P = .002) and a longer course of sunitinib (HR, 0.54; P = .005).

BEAMing analysis also showed that patients with secondary KIT mutations who received regorafenib had significantly better PFS than did patients in the placebo arm (HR, 0.22; P less than .001).

The data Dr. Demetri presented were "very exciting," said invited discussant Dr. Shreyaskumar R. Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.

"The important take-home messages are that there is some very good concordance between the tumor tissue analysis and the plasma analysis," and that regorafenib "appears to be totally agnostic to any of the mutational subsets and seems to equally benefit all patients," Dr. Patel said.

The study was supported in part by Bayer HealthCare. Dr. Demetri disclosed serving as a scientific consultant to the company. Dr. Patel reported having no disclosures relevant to the study.

Regorafenib, a multikinase inhibitor, has been approved as a treatment for locally advanced, unresectable, or metastatic gastrointestinal stromal tumor in people who have been treated with imatinib and sunitinib, the other two treatments approved for GIST, the Food and Drug Administration announced on Feb. 26.

Regorafenib was first approved in September as a treatment for metastatic colorectal cancer, and "provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. The recommended dose is 160 mg orally once a day for the first 21 days of each 28-day cycle, according to the prescribing information for regorafenib, which is marketed as Stivarga by Bayer HealthCare Pharmaceuticals.

Approval was based on the interim results of the phase III GRID (GIST – Regorafenib In Progressive Disease) study, comparing placebo plus best supportive care (BSC) to regorafenib plus BSC in 199 patients with locally advanced, unresectable, or metastatic GIST, previously treated with imatinib and sunitinib, according to the FDA statement, as well as the statement issued by the manufacturer. The median progression-free survival (the primary endpoint) was 4.8 months among those on regorafenib, compared with 0.8 months among those on placebo, a statistically significant difference (Lancet 381;9863:295-302). At the time of the planned interim analysis, there was no statistically significant difference in overall survival.

The most common adverse events associated with treatment, reported by at least 30% of those treated, included hand-foot syndrome, diarrhea, mucositis, dysphonia, asthenia/fatigue, hypertension, reduced appetite and food intake, and rash. Serious adverse events, affecting less than 1% of patients, included hepatotoxicity, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks, and intestinal perforations. The regorafenib label includes a boxed warning about the risk of hepatotoxicity associated with treatment, noting that severe and sometimes fatal hepatotoxicity has been reported in clinical trials, and that hepatic function should be monitored before and during treatment.

Regorafenib inhibits multiple kinases that are involved in normal cellular functions, as well as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment, according to the manufacturer.

Regorafenib was the focus of the FDA’s priority review program, which evaluates the drug in 6 months instead of the usual 12 months, and is designated for products "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," according to the FDA statement.

The FDA cites a National Cancer Institute estimate that 3,300-6,000 new cases of GIST are diagnosed every year in the United States, affecting mostly older adults. The previously approved colorectal cancer indication is for people who have metastatic colorectal cancer, who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

Imatinib (Gleevec) and sunitinib (Sutent) are both orally administered kinase inhibitors.

[email protected]

Regorafenib, a multikinase inhibitor, has been approved as a treatment for locally advanced, unresectable, or metastatic gastrointestinal stromal tumor in people who have been treated with imatinib and sunitinib, the other two treatments approved for GIST, the Food and Drug Administration announced on Feb. 26.

Regorafenib was first approved in September as a treatment for metastatic colorectal cancer, and "provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. The recommended dose is 160 mg orally once a day for the first 21 days of each 28-day cycle, according to the prescribing information for regorafenib, which is marketed as Stivarga by Bayer HealthCare Pharmaceuticals.

Approval was based on the interim results of the phase III GRID (GIST – Regorafenib In Progressive Disease) study, comparing placebo plus best supportive care (BSC) to regorafenib plus BSC in 199 patients with locally advanced, unresectable, or metastatic GIST, previously treated with imatinib and sunitinib, according to the FDA statement, as well as the statement issued by the manufacturer. The median progression-free survival (the primary endpoint) was 4.8 months among those on regorafenib, compared with 0.8 months among those on placebo, a statistically significant difference (Lancet 381;9863:295-302). At the time of the planned interim analysis, there was no statistically significant difference in overall survival.

The most common adverse events associated with treatment, reported by at least 30% of those treated, included hand-foot syndrome, diarrhea, mucositis, dysphonia, asthenia/fatigue, hypertension, reduced appetite and food intake, and rash. Serious adverse events, affecting less than 1% of patients, included hepatotoxicity, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks, and intestinal perforations. The regorafenib label includes a boxed warning about the risk of hepatotoxicity associated with treatment, noting that severe and sometimes fatal hepatotoxicity has been reported in clinical trials, and that hepatic function should be monitored before and during treatment.

Regorafenib inhibits multiple kinases that are involved in normal cellular functions, as well as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment, according to the manufacturer.

Regorafenib was the focus of the FDA’s priority review program, which evaluates the drug in 6 months instead of the usual 12 months, and is designated for products "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," according to the FDA statement.

The FDA cites a National Cancer Institute estimate that 3,300-6,000 new cases of GIST are diagnosed every year in the United States, affecting mostly older adults. The previously approved colorectal cancer indication is for people who have metastatic colorectal cancer, who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

Imatinib (Gleevec) and sunitinib (Sutent) are both orally administered kinase inhibitors.

[email protected]

Regorafenib, a multikinase inhibitor, has been approved as a treatment for locally advanced, unresectable, or metastatic gastrointestinal stromal tumor in people who have been treated with imatinib and sunitinib, the other two treatments approved for GIST, the Food and Drug Administration announced on Feb. 26.

Regorafenib was first approved in September as a treatment for metastatic colorectal cancer, and "provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. The recommended dose is 160 mg orally once a day for the first 21 days of each 28-day cycle, according to the prescribing information for regorafenib, which is marketed as Stivarga by Bayer HealthCare Pharmaceuticals.

Approval was based on the interim results of the phase III GRID (GIST – Regorafenib In Progressive Disease) study, comparing placebo plus best supportive care (BSC) to regorafenib plus BSC in 199 patients with locally advanced, unresectable, or metastatic GIST, previously treated with imatinib and sunitinib, according to the FDA statement, as well as the statement issued by the manufacturer. The median progression-free survival (the primary endpoint) was 4.8 months among those on regorafenib, compared with 0.8 months among those on placebo, a statistically significant difference (Lancet 381;9863:295-302). At the time of the planned interim analysis, there was no statistically significant difference in overall survival.

The most common adverse events associated with treatment, reported by at least 30% of those treated, included hand-foot syndrome, diarrhea, mucositis, dysphonia, asthenia/fatigue, hypertension, reduced appetite and food intake, and rash. Serious adverse events, affecting less than 1% of patients, included hepatotoxicity, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks, and intestinal perforations. The regorafenib label includes a boxed warning about the risk of hepatotoxicity associated with treatment, noting that severe and sometimes fatal hepatotoxicity has been reported in clinical trials, and that hepatic function should be monitored before and during treatment.

Regorafenib inhibits multiple kinases that are involved in normal cellular functions, as well as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment, according to the manufacturer.

Regorafenib was the focus of the FDA’s priority review program, which evaluates the drug in 6 months instead of the usual 12 months, and is designated for products "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," according to the FDA statement.

The FDA cites a National Cancer Institute estimate that 3,300-6,000 new cases of GIST are diagnosed every year in the United States, affecting mostly older adults. The previously approved colorectal cancer indication is for people who have metastatic colorectal cancer, who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

Imatinib (Gleevec) and sunitinib (Sutent) are both orally administered kinase inhibitors.

[email protected]

SAN FRANCISCO – Surgically removing residual gastrointestinal stromal tumors in patients who respond to imatinib therapy significantly increased time to tumor progression to 88 months, compared with 43 months using imatinib alone, based on findings from a retrospective study of 134 patients.

After controlling for the effects of other risk factors, the surgery decreased threefold the likelihood of disease progression and decreased fivefold the risk of death, Dr. Seong Joon Park reported in a press briefing sponsored by the American Society of Clinical Oncology (ASCO). The press conference was held in advance of at a meeting on gastrointestinal cancers sponsored by ASCO and three other cancer organizations.

The findings support the widely adopted practice of removing residual tumors in these patients, despite the retrospective and observational design of the study, Dr. Park said. A prospective European study of similar design to this one terminated early due to poor patient enrollment. "It’s really hard to conduct a prospective study of this design," said Dr. Park of Asan Medical Center, Seoul, South Korea.

He and his associates reviewed the records of patients who showed at least 6 months of disease stabilization or response to imatinib (Gleevec) treatment, 92 of whom got the drug treatment alone and 42 of whom underwent surgery to remove residual tumors after a median of 19 months of imatinib therapy. The imatinib therapy was restarted after surgery. Median follow-up for the cohort as a whole was 59 months.

"This treatment strategy is worth trying as a clinical practice if the medical center is large enough to have an experienced multidisciplinary team and to have low morbidity and mortality associated with surgery," he said.

Each year, approximately 5,000 new cases of gastrointestinal stromal tumors are diagnosed in the United States, most often in the stomach and small intestine, though they can occur anywhere in or near the GI tract. Imatinib typically is first-line therapy, and 80%-85% of patients will respond to the treatment, he said. A majority of patients who respond to imatinib will have residual tumors, however, which are believed to contribute to the development of drug resistance, leading to the hypothesis that removing the residual tumors would improve survival.

In general, one-third of patients are candidates for surgical removal of residual lesions, depending on the tumor size and other tumor and patient characteristics, Dr. Park said.

The two patient groups in the study were similar except that the surgery group was significantly younger (51 vs. 58 years) and was less likely to have metastases in the peritoneum (41% in the surgery group vs. 61% in the control group).

As it is an aggressive and difficult treatment, surgery is more likely to be considered and recommended to younger patients who have a good performance status and, thus, less likely to be recommended in patients with multiple peritoneal metastases.

Factors associated with longer progression-free and overall survival included surgery and having an initial tumor size less than 150 mm, multivariate analyses showed. Female sex and having the KIT exon 11 mutation also were associated with longer progression-free survival. The researchers used propensity scores and inverse-probability-weighting adjustments to account for the effects of factors other than surgery.

The gastrointestinal cancers meeting, where Dr. Park will present the results, is cosponsored by ASCO, the American Gastroenterological Association Institute, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Dr. Park reported having no financial disclosures.

On Twitter @sherryboschert

SAN FRANCISCO – Surgically removing residual gastrointestinal stromal tumors in patients who respond to imatinib therapy significantly increased time to tumor progression to 88 months, compared with 43 months using imatinib alone, based on findings from a retrospective study of 134 patients.

After controlling for the effects of other risk factors, the surgery decreased threefold the likelihood of disease progression and decreased fivefold the risk of death, Dr. Seong Joon Park reported in a press briefing sponsored by the American Society of Clinical Oncology (ASCO). The press conference was held in advance of at a meeting on gastrointestinal cancers sponsored by ASCO and three other cancer organizations.

The findings support the widely adopted practice of removing residual tumors in these patients, despite the retrospective and observational design of the study, Dr. Park said. A prospective European study of similar design to this one terminated early due to poor patient enrollment. "It’s really hard to conduct a prospective study of this design," said Dr. Park of Asan Medical Center, Seoul, South Korea.

He and his associates reviewed the records of patients who showed at least 6 months of disease stabilization or response to imatinib (Gleevec) treatment, 92 of whom got the drug treatment alone and 42 of whom underwent surgery to remove residual tumors after a median of 19 months of imatinib therapy. The imatinib therapy was restarted after surgery. Median follow-up for the cohort as a whole was 59 months.

"This treatment strategy is worth trying as a clinical practice if the medical center is large enough to have an experienced multidisciplinary team and to have low morbidity and mortality associated with surgery," he said.

Each year, approximately 5,000 new cases of gastrointestinal stromal tumors are diagnosed in the United States, most often in the stomach and small intestine, though they can occur anywhere in or near the GI tract. Imatinib typically is first-line therapy, and 80%-85% of patients will respond to the treatment, he said. A majority of patients who respond to imatinib will have residual tumors, however, which are believed to contribute to the development of drug resistance, leading to the hypothesis that removing the residual tumors would improve survival.

In general, one-third of patients are candidates for surgical removal of residual lesions, depending on the tumor size and other tumor and patient characteristics, Dr. Park said.

The two patient groups in the study were similar except that the surgery group was significantly younger (51 vs. 58 years) and was less likely to have metastases in the peritoneum (41% in the surgery group vs. 61% in the control group).

As it is an aggressive and difficult treatment, surgery is more likely to be considered and recommended to younger patients who have a good performance status and, thus, less likely to be recommended in patients with multiple peritoneal metastases.

Factors associated with longer progression-free and overall survival included surgery and having an initial tumor size less than 150 mm, multivariate analyses showed. Female sex and having the KIT exon 11 mutation also were associated with longer progression-free survival. The researchers used propensity scores and inverse-probability-weighting adjustments to account for the effects of factors other than surgery.

The gastrointestinal cancers meeting, where Dr. Park will present the results, is cosponsored by ASCO, the American Gastroenterological Association Institute, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Dr. Park reported having no financial disclosures.

On Twitter @sherryboschert

SAN FRANCISCO – Surgically removing residual gastrointestinal stromal tumors in patients who respond to imatinib therapy significantly increased time to tumor progression to 88 months, compared with 43 months using imatinib alone, based on findings from a retrospective study of 134 patients.

After controlling for the effects of other risk factors, the surgery decreased threefold the likelihood of disease progression and decreased fivefold the risk of death, Dr. Seong Joon Park reported in a press briefing sponsored by the American Society of Clinical Oncology (ASCO). The press conference was held in advance of at a meeting on gastrointestinal cancers sponsored by ASCO and three other cancer organizations.

The findings support the widely adopted practice of removing residual tumors in these patients, despite the retrospective and observational design of the study, Dr. Park said. A prospective European study of similar design to this one terminated early due to poor patient enrollment. "It’s really hard to conduct a prospective study of this design," said Dr. Park of Asan Medical Center, Seoul, South Korea.

He and his associates reviewed the records of patients who showed at least 6 months of disease stabilization or response to imatinib (Gleevec) treatment, 92 of whom got the drug treatment alone and 42 of whom underwent surgery to remove residual tumors after a median of 19 months of imatinib therapy. The imatinib therapy was restarted after surgery. Median follow-up for the cohort as a whole was 59 months.

"This treatment strategy is worth trying as a clinical practice if the medical center is large enough to have an experienced multidisciplinary team and to have low morbidity and mortality associated with surgery," he said.

Each year, approximately 5,000 new cases of gastrointestinal stromal tumors are diagnosed in the United States, most often in the stomach and small intestine, though they can occur anywhere in or near the GI tract. Imatinib typically is first-line therapy, and 80%-85% of patients will respond to the treatment, he said. A majority of patients who respond to imatinib will have residual tumors, however, which are believed to contribute to the development of drug resistance, leading to the hypothesis that removing the residual tumors would improve survival.

In general, one-third of patients are candidates for surgical removal of residual lesions, depending on the tumor size and other tumor and patient characteristics, Dr. Park said.

The two patient groups in the study were similar except that the surgery group was significantly younger (51 vs. 58 years) and was less likely to have metastases in the peritoneum (41% in the surgery group vs. 61% in the control group).

As it is an aggressive and difficult treatment, surgery is more likely to be considered and recommended to younger patients who have a good performance status and, thus, less likely to be recommended in patients with multiple peritoneal metastases.

Factors associated with longer progression-free and overall survival included surgery and having an initial tumor size less than 150 mm, multivariate analyses showed. Female sex and having the KIT exon 11 mutation also were associated with longer progression-free survival. The researchers used propensity scores and inverse-probability-weighting adjustments to account for the effects of factors other than surgery.

The gastrointestinal cancers meeting, where Dr. Park will present the results, is cosponsored by ASCO, the American Gastroenterological Association Institute, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Dr. Park reported having no financial disclosures.

On Twitter @sherryboschert