Neil Osterweil

What appears at first glance to be a renal vascular tumor may in fact be a rare type of renal cell carcinoma (RCC), authors of a case study cautioned.

A tumor recovered from a 62-year old woman who underwent a partial nephrectomy for an incidentally discovered asymptomatic left renal mass contained arborizing vessels that mimicked hemangioma. Immunohistochemical staining of the tumor highlighted the vascular component but masked epithelial cells, a situation that, in the absence of other clues, might cause a misdiagnosis, reported Kanika Taneja, MD, from the Henry Ford Cancer Institute in Detroit, and her colleagues.

The authors were tipped off to an unusual presentation, however, by mixed signals from immunohistochemical staining, leading them to an admittedly fuzzy diagnosis of “unclassified hemangioma-like RCC.”

“This case highlights that renal cell carcinoma must be strongly considered in the differential diagnosis of renal vascular tumors, and broadens the spectrum of histologies that may mimic hemangioma,” they wrote in Human Pathology.

Although there are a few recent reports in the medical literature of clear cell RCC tumors that mimic hemangiomas, the authors noted that, “to our knowledge, non–clear cell hemangioma-like renal cell carcinoma has not been previously reported.”

The tumor in question was removed from the patient with clear surgical margins during a partial nephrectomy.

Gross examination showed a 2.6 by 2.5 by 2.5 cm, well-circumscribed, tan-brown hemorrhagic mass. On microscopic examination the tumor had hemangioma-like features and lacked typical clear cell morphology, and immunohistochemical staining did little to clarify the picture.

Specifically, although staining highlighted the epithelial component of the tumor, the investigators saw what they described as “an abnormal combination of positive markers” that are normally used to distinguish clear cell from papillary histologies, effectively throwing a monkey wrench into the diagnostic works.

The marker profile in this case included cytokeratin 7, high molecular weight cytokeratin, and carbonic anhydrase IX, but only minimal labeling for alpha-methylacyl-CoA racemase and absence of GATA3.

To add to the confusion, fluorescent in situ hybridization “revealed negative studies for chromosome 3p, trisomy 7 or 17, and MITF family translocations, failing to further place this unique neoplasm into a definitive category,” Dr. Taneja and her colleagues wrote, adding that further study of the tumor may help to clarify whether it represents a distinct tumor type or is simply an unusual pattern caused by degeneration and involution of a known tumor type.

The authors did not disclose a study funding source, but reported having no conflicts of interest.

SOURCE: Taneja K et al. Hum Pathol. 2017 Nov 2. doi: 10.1016/j.humpath.2017.09.015.

What appears at first glance to be a renal vascular tumor may in fact be a rare type of renal cell carcinoma (RCC), authors of a case study cautioned.

A tumor recovered from a 62-year old woman who underwent a partial nephrectomy for an incidentally discovered asymptomatic left renal mass contained arborizing vessels that mimicked hemangioma. Immunohistochemical staining of the tumor highlighted the vascular component but masked epithelial cells, a situation that, in the absence of other clues, might cause a misdiagnosis, reported Kanika Taneja, MD, from the Henry Ford Cancer Institute in Detroit, and her colleagues.

The authors were tipped off to an unusual presentation, however, by mixed signals from immunohistochemical staining, leading them to an admittedly fuzzy diagnosis of “unclassified hemangioma-like RCC.”

“This case highlights that renal cell carcinoma must be strongly considered in the differential diagnosis of renal vascular tumors, and broadens the spectrum of histologies that may mimic hemangioma,” they wrote in Human Pathology.

Although there are a few recent reports in the medical literature of clear cell RCC tumors that mimic hemangiomas, the authors noted that, “to our knowledge, non–clear cell hemangioma-like renal cell carcinoma has not been previously reported.”

The tumor in question was removed from the patient with clear surgical margins during a partial nephrectomy.

Gross examination showed a 2.6 by 2.5 by 2.5 cm, well-circumscribed, tan-brown hemorrhagic mass. On microscopic examination the tumor had hemangioma-like features and lacked typical clear cell morphology, and immunohistochemical staining did little to clarify the picture.

Specifically, although staining highlighted the epithelial component of the tumor, the investigators saw what they described as “an abnormal combination of positive markers” that are normally used to distinguish clear cell from papillary histologies, effectively throwing a monkey wrench into the diagnostic works.

The marker profile in this case included cytokeratin 7, high molecular weight cytokeratin, and carbonic anhydrase IX, but only minimal labeling for alpha-methylacyl-CoA racemase and absence of GATA3.

To add to the confusion, fluorescent in situ hybridization “revealed negative studies for chromosome 3p, trisomy 7 or 17, and MITF family translocations, failing to further place this unique neoplasm into a definitive category,” Dr. Taneja and her colleagues wrote, adding that further study of the tumor may help to clarify whether it represents a distinct tumor type or is simply an unusual pattern caused by degeneration and involution of a known tumor type.

The authors did not disclose a study funding source, but reported having no conflicts of interest.

SOURCE: Taneja K et al. Hum Pathol. 2017 Nov 2. doi: 10.1016/j.humpath.2017.09.015.

What appears at first glance to be a renal vascular tumor may in fact be a rare type of renal cell carcinoma (RCC), authors of a case study cautioned.

A tumor recovered from a 62-year old woman who underwent a partial nephrectomy for an incidentally discovered asymptomatic left renal mass contained arborizing vessels that mimicked hemangioma. Immunohistochemical staining of the tumor highlighted the vascular component but masked epithelial cells, a situation that, in the absence of other clues, might cause a misdiagnosis, reported Kanika Taneja, MD, from the Henry Ford Cancer Institute in Detroit, and her colleagues.

The authors were tipped off to an unusual presentation, however, by mixed signals from immunohistochemical staining, leading them to an admittedly fuzzy diagnosis of “unclassified hemangioma-like RCC.”

“This case highlights that renal cell carcinoma must be strongly considered in the differential diagnosis of renal vascular tumors, and broadens the spectrum of histologies that may mimic hemangioma,” they wrote in Human Pathology.

Although there are a few recent reports in the medical literature of clear cell RCC tumors that mimic hemangiomas, the authors noted that, “to our knowledge, non–clear cell hemangioma-like renal cell carcinoma has not been previously reported.”

The tumor in question was removed from the patient with clear surgical margins during a partial nephrectomy.

Gross examination showed a 2.6 by 2.5 by 2.5 cm, well-circumscribed, tan-brown hemorrhagic mass. On microscopic examination the tumor had hemangioma-like features and lacked typical clear cell morphology, and immunohistochemical staining did little to clarify the picture.

Specifically, although staining highlighted the epithelial component of the tumor, the investigators saw what they described as “an abnormal combination of positive markers” that are normally used to distinguish clear cell from papillary histologies, effectively throwing a monkey wrench into the diagnostic works.

The marker profile in this case included cytokeratin 7, high molecular weight cytokeratin, and carbonic anhydrase IX, but only minimal labeling for alpha-methylacyl-CoA racemase and absence of GATA3.

To add to the confusion, fluorescent in situ hybridization “revealed negative studies for chromosome 3p, trisomy 7 or 17, and MITF family translocations, failing to further place this unique neoplasm into a definitive category,” Dr. Taneja and her colleagues wrote, adding that further study of the tumor may help to clarify whether it represents a distinct tumor type or is simply an unusual pattern caused by degeneration and involution of a known tumor type.

The authors did not disclose a study funding source, but reported having no conflicts of interest.

SOURCE: Taneja K et al. Hum Pathol. 2017 Nov 2. doi: 10.1016/j.humpath.2017.09.015.

The National Comprehensive Cancer Network (NCCN) has issued its first-ever clinical practice guidelines for the treatment of gestational trophoblastic neoplasia (GTN), a rare, serious complication of pregnancy that can often be cured, but can have devastating consequences if mismanaged or if treatment is needlessly delayed.

David Mutch, MD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, who heads the NCCN Clinical Practice Guidelines in Oncology Committee for GTN, explained the critical importance of the GTN guidelines.

“It’s a rare disease, people weren’t that familiar with it, and they often are patients treated with single-agent therapy when they should be treated with multi-agent therapy,” he said in an interview.

“There wasn’t a clear understanding of what to do except by those people who treated these patients regularly. The only thing most people knew was that it was very chemosensitive and should be curable, but it’s only curable if you follow the appropriate algorithms,” he continued.

The algorithms he referred to were established by a handful of centers with expertise and experience in diagnosing and treating these rare conditions, including noninvasive hydatidiform mole, invasive mole, and choriocarcinoma, the most aggressive form of GTN.

Neil Horowitz, MD, director of clinical research in gynecologic oncology at the Dana-Farber Cancer Institute in Boston, works with colleagues in one of those referral centers, the New England Trophoblastic Disease Center, and is familiar with the new guidelines. As with other rare malignancies, there are data to suggest that patients with GTN who are treated in centers of excellence with higher patient volumes have better outcomes than do similar patients treated in a community setting, he said in an interview.
 

Placental origins

GTNs arise from placental rather than maternal tissue. They most commonly present with vaginal bleeding and a rapidly enlarging uterus, and may be accompanied by pelvic pain or pressure, anemia, severe nausea/vomiting (hyperemesis gravidarum), hyperthyroidism, or early-pregnancy preeclampsia.

The overall reported incidence of GTN in the United States, including hydatidiform mole, is approximately 110 to 120 per 100,000 pregnancies, and the reported incidence of choriocarcinoma is about 2 to 7 per 100,000, according to the National Cancer Institute.

The GTN guidelines provide evidence-based recommendations about optimal approaches to GTN in all of its known forms. For example, the section on noninvasive hydatidiform mole recommends the tests that should be routinely performed during workup, followed by surgery with either suction, dilation and curettage – preferably under ultrasound guidance – or hysterectomy for women who are older or who do not wish to preserve fertility.

The guidelines also specify steps that should be taken for diagnosis and staging of GTN as well as risk-based therapeutic approaches.

For example, the guidelines recommend therapy with either methotrexate alone or alternating with leucovorin, or dactinomycin alone for patients with confirmed low risk GTN, defined as a prognostic score less than 7.

The prognostic scoring index, also included in the guidelines, considers risk factors such as age, prior pregnancies, interval from an index pregnancy, pretreatment human chorionic gonadotropin (hCG) levels, site and number of metastases, largest tumor size, and previous chemotherapy failure.

For patients with high-risk GTN, defined as FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stages II-III with a prognostic score of 7 or greater, or FIGO stage IV, chemotherapy with the EMA/CO regimen is recommended. This aggressive regimen consists of etoposide, methotrexate, dactinomycin (the “EMA “component) plus cyclophosphamide and vincristine (the “CO” component).

“In my mind, the most important part of the guidelines is reiterating how the diagnosis of GTN should be made, and importantly, how the score should be calculated so that women are put in the appropriate low-risk or high-risk category, so they get the right treatment,” Dr. Horowitz said.
 

Reassuring insurers

Dr. Mutch said that he and his colleagues in GTN centers sometimes treat patients with intermediate or high-risk disease who were started on single-agent therapy or suboptimal therapies and present with advanced, drug-resistant disease.

“These guidelines were established so that people could see exactly what needs to be done when,” he said.

The guidelines also are critical for convincing third-party payers about the need for specific treatments, he added.

“I had a high-risk patient who needed EMA/CO, and the insurance company said ‘well, there’s no NCCN guidelines – we won’t approve it.’ So then I had to wait 3 days while it went through peer review. Meanwhile, the tumor doubled in size, and then the nurse who was reviewing it declined the ‘CO’ part, so that was delayed a week, and it really jeopardized this patient’s survival,” Dr. Mutch said.

The guidelines also include recommendations for patients with special clinical situations, such as women with clinical responses to EMA/CO who continue to have plateauing low levels of hCG or have a re-elevation of hCG levels after having a complete response to EMA/CO.

There are also specific recommendations for treatment of two even rarer intermediate trophoblastic tumor types: placental-site trophoblastic tumor and epithelioid trophoblastic tumor.

The guidelines are supported by the NCCN. Dr. Mutch reported consulting/advisory board participation for Clovis. Dr. Horowitz reported having no relationships to disclose.

SOURCE: Gestational Trophoblastic Neoplasia. NCCN.org, Version 1.2019, published Aug. 9, 2018.

The National Comprehensive Cancer Network (NCCN) has issued its first-ever clinical practice guidelines for the treatment of gestational trophoblastic neoplasia (GTN), a rare, serious complication of pregnancy that can often be cured, but can have devastating consequences if mismanaged or if treatment is needlessly delayed.

David Mutch, MD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, who heads the NCCN Clinical Practice Guidelines in Oncology Committee for GTN, explained the critical importance of the GTN guidelines.

“It’s a rare disease, people weren’t that familiar with it, and they often are patients treated with single-agent therapy when they should be treated with multi-agent therapy,” he said in an interview.

“There wasn’t a clear understanding of what to do except by those people who treated these patients regularly. The only thing most people knew was that it was very chemosensitive and should be curable, but it’s only curable if you follow the appropriate algorithms,” he continued.

The algorithms he referred to were established by a handful of centers with expertise and experience in diagnosing and treating these rare conditions, including noninvasive hydatidiform mole, invasive mole, and choriocarcinoma, the most aggressive form of GTN.

Neil Horowitz, MD, director of clinical research in gynecologic oncology at the Dana-Farber Cancer Institute in Boston, works with colleagues in one of those referral centers, the New England Trophoblastic Disease Center, and is familiar with the new guidelines. As with other rare malignancies, there are data to suggest that patients with GTN who are treated in centers of excellence with higher patient volumes have better outcomes than do similar patients treated in a community setting, he said in an interview.
 

Placental origins

GTNs arise from placental rather than maternal tissue. They most commonly present with vaginal bleeding and a rapidly enlarging uterus, and may be accompanied by pelvic pain or pressure, anemia, severe nausea/vomiting (hyperemesis gravidarum), hyperthyroidism, or early-pregnancy preeclampsia.

The overall reported incidence of GTN in the United States, including hydatidiform mole, is approximately 110 to 120 per 100,000 pregnancies, and the reported incidence of choriocarcinoma is about 2 to 7 per 100,000, according to the National Cancer Institute.

The GTN guidelines provide evidence-based recommendations about optimal approaches to GTN in all of its known forms. For example, the section on noninvasive hydatidiform mole recommends the tests that should be routinely performed during workup, followed by surgery with either suction, dilation and curettage – preferably under ultrasound guidance – or hysterectomy for women who are older or who do not wish to preserve fertility.

The guidelines also specify steps that should be taken for diagnosis and staging of GTN as well as risk-based therapeutic approaches.

For example, the guidelines recommend therapy with either methotrexate alone or alternating with leucovorin, or dactinomycin alone for patients with confirmed low risk GTN, defined as a prognostic score less than 7.

The prognostic scoring index, also included in the guidelines, considers risk factors such as age, prior pregnancies, interval from an index pregnancy, pretreatment human chorionic gonadotropin (hCG) levels, site and number of metastases, largest tumor size, and previous chemotherapy failure.

For patients with high-risk GTN, defined as FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stages II-III with a prognostic score of 7 or greater, or FIGO stage IV, chemotherapy with the EMA/CO regimen is recommended. This aggressive regimen consists of etoposide, methotrexate, dactinomycin (the “EMA “component) plus cyclophosphamide and vincristine (the “CO” component).

“In my mind, the most important part of the guidelines is reiterating how the diagnosis of GTN should be made, and importantly, how the score should be calculated so that women are put in the appropriate low-risk or high-risk category, so they get the right treatment,” Dr. Horowitz said.
 

Reassuring insurers

Dr. Mutch said that he and his colleagues in GTN centers sometimes treat patients with intermediate or high-risk disease who were started on single-agent therapy or suboptimal therapies and present with advanced, drug-resistant disease.

“These guidelines were established so that people could see exactly what needs to be done when,” he said.

The guidelines also are critical for convincing third-party payers about the need for specific treatments, he added.

“I had a high-risk patient who needed EMA/CO, and the insurance company said ‘well, there’s no NCCN guidelines – we won’t approve it.’ So then I had to wait 3 days while it went through peer review. Meanwhile, the tumor doubled in size, and then the nurse who was reviewing it declined the ‘CO’ part, so that was delayed a week, and it really jeopardized this patient’s survival,” Dr. Mutch said.

The guidelines also include recommendations for patients with special clinical situations, such as women with clinical responses to EMA/CO who continue to have plateauing low levels of hCG or have a re-elevation of hCG levels after having a complete response to EMA/CO.

There are also specific recommendations for treatment of two even rarer intermediate trophoblastic tumor types: placental-site trophoblastic tumor and epithelioid trophoblastic tumor.

The guidelines are supported by the NCCN. Dr. Mutch reported consulting/advisory board participation for Clovis. Dr. Horowitz reported having no relationships to disclose.

SOURCE: Gestational Trophoblastic Neoplasia. NCCN.org, Version 1.2019, published Aug. 9, 2018.

The National Comprehensive Cancer Network (NCCN) has issued its first-ever clinical practice guidelines for the treatment of gestational trophoblastic neoplasia (GTN), a rare, serious complication of pregnancy that can often be cured, but can have devastating consequences if mismanaged or if treatment is needlessly delayed.

David Mutch, MD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, who heads the NCCN Clinical Practice Guidelines in Oncology Committee for GTN, explained the critical importance of the GTN guidelines.

“It’s a rare disease, people weren’t that familiar with it, and they often are patients treated with single-agent therapy when they should be treated with multi-agent therapy,” he said in an interview.

“There wasn’t a clear understanding of what to do except by those people who treated these patients regularly. The only thing most people knew was that it was very chemosensitive and should be curable, but it’s only curable if you follow the appropriate algorithms,” he continued.

The algorithms he referred to were established by a handful of centers with expertise and experience in diagnosing and treating these rare conditions, including noninvasive hydatidiform mole, invasive mole, and choriocarcinoma, the most aggressive form of GTN.

Neil Horowitz, MD, director of clinical research in gynecologic oncology at the Dana-Farber Cancer Institute in Boston, works with colleagues in one of those referral centers, the New England Trophoblastic Disease Center, and is familiar with the new guidelines. As with other rare malignancies, there are data to suggest that patients with GTN who are treated in centers of excellence with higher patient volumes have better outcomes than do similar patients treated in a community setting, he said in an interview.
 

Placental origins

GTNs arise from placental rather than maternal tissue. They most commonly present with vaginal bleeding and a rapidly enlarging uterus, and may be accompanied by pelvic pain or pressure, anemia, severe nausea/vomiting (hyperemesis gravidarum), hyperthyroidism, or early-pregnancy preeclampsia.

The overall reported incidence of GTN in the United States, including hydatidiform mole, is approximately 110 to 120 per 100,000 pregnancies, and the reported incidence of choriocarcinoma is about 2 to 7 per 100,000, according to the National Cancer Institute.

The GTN guidelines provide evidence-based recommendations about optimal approaches to GTN in all of its known forms. For example, the section on noninvasive hydatidiform mole recommends the tests that should be routinely performed during workup, followed by surgery with either suction, dilation and curettage – preferably under ultrasound guidance – or hysterectomy for women who are older or who do not wish to preserve fertility.

The guidelines also specify steps that should be taken for diagnosis and staging of GTN as well as risk-based therapeutic approaches.

For example, the guidelines recommend therapy with either methotrexate alone or alternating with leucovorin, or dactinomycin alone for patients with confirmed low risk GTN, defined as a prognostic score less than 7.

The prognostic scoring index, also included in the guidelines, considers risk factors such as age, prior pregnancies, interval from an index pregnancy, pretreatment human chorionic gonadotropin (hCG) levels, site and number of metastases, largest tumor size, and previous chemotherapy failure.

For patients with high-risk GTN, defined as FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stages II-III with a prognostic score of 7 or greater, or FIGO stage IV, chemotherapy with the EMA/CO regimen is recommended. This aggressive regimen consists of etoposide, methotrexate, dactinomycin (the “EMA “component) plus cyclophosphamide and vincristine (the “CO” component).

“In my mind, the most important part of the guidelines is reiterating how the diagnosis of GTN should be made, and importantly, how the score should be calculated so that women are put in the appropriate low-risk or high-risk category, so they get the right treatment,” Dr. Horowitz said.
 

Reassuring insurers

Dr. Mutch said that he and his colleagues in GTN centers sometimes treat patients with intermediate or high-risk disease who were started on single-agent therapy or suboptimal therapies and present with advanced, drug-resistant disease.

“These guidelines were established so that people could see exactly what needs to be done when,” he said.

The guidelines also are critical for convincing third-party payers about the need for specific treatments, he added.

“I had a high-risk patient who needed EMA/CO, and the insurance company said ‘well, there’s no NCCN guidelines – we won’t approve it.’ So then I had to wait 3 days while it went through peer review. Meanwhile, the tumor doubled in size, and then the nurse who was reviewing it declined the ‘CO’ part, so that was delayed a week, and it really jeopardized this patient’s survival,” Dr. Mutch said.

The guidelines also include recommendations for patients with special clinical situations, such as women with clinical responses to EMA/CO who continue to have plateauing low levels of hCG or have a re-elevation of hCG levels after having a complete response to EMA/CO.

There are also specific recommendations for treatment of two even rarer intermediate trophoblastic tumor types: placental-site trophoblastic tumor and epithelioid trophoblastic tumor.

The guidelines are supported by the NCCN. Dr. Mutch reported consulting/advisory board participation for Clovis. Dr. Horowitz reported having no relationships to disclose.

SOURCE: Gestational Trophoblastic Neoplasia. NCCN.org, Version 1.2019, published Aug. 9, 2018.

Women with germline pathogenic variants in five genes are at high risk for developing triple-negative breast cancer, and have a greater than 20% lifetime risk for breast cancer in general, results of a large study suggest.

Multigene testing of nearly 11,000 women with triple-negative breast cancer (TNBC; lacking estrogen, progesterone, and human epidermal growth factor receptors) showed that germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with risk for clinical TNBC ranging from nearly sixfold to more than 16-fold higher than that of women without the genetic variants, reported Fergus J. Couch, PhD, of the Mayo Clinic, Rochester, Minn., and his colleagues.

“The results suggest that all TNBC patients should undergo multigene panel testing, regardless of age at diagnosis or family history of cancer, for improved cancer risk assessment and because of the ongoing development of targeted therapeutic approaches for TNBC patients with mutations in predisposition genes,” they wrote. Their report is in the Journal of the National Cancer Institute.

Although National Comprehensive Cancer Network guidelines recommend testing for the cancer predisposition genes BRCA1 and BRCA2 in women with a TNBC diagnosis at age 60 or younger or those with a family history of breast and/or ovarian cancer, the picture is less clear regarding genetic predisposition to TNBC, the authors noted.

“[R]ecommendations for testing of other genes are not fully established because the risks of TNBC associated with mutations in cancer predisposition genes have not been established. Thus, a better understanding of gene-specific risks for TNBC is needed to identify the genes that should be tested in the setting of TNBC,” they wrote.

The investigators looked for associations between deleterious mutations in cancer predisposition genes and TNBC among 8,753 patients with TNBC testing with a 21-gene assay, and among 2,148 women tested for 17 genes in studies conducted by the Triple Negative Breast Cancer Consortium.

They found that among white women, germline pathogenic variants were associated with the following odds ratios (OR) for TNBC (all P values less than .0001):
 

• BRCA2 = 5.42
• BARD1 = 5.92
• RAD51D = 6.97
• PALB2 = 14.41
• BRCA1 = 16.27

Although there were insufficient data on the risks for African American women, an exploratory analysis showed that risks for TNBC associated with specific pathogenic variants were similar to those for white women, the authors said.

The pathogenic variants were detected in 12% of all patients in the study.

“Continued study of gene-specific risks for breast cancer subtypes may lead to tailored medical management recommendations for PV [pathogenic variant] carriers. Consistent with this hypothesis, initial studies evaluating intensified screening in high-risk women have suggested that a decrease in mortality from TNBC can be achieved,” they wrote.

The study was supported in part by the National Institutes of Health and the Breast Cancer Research Foundation, and was sponsored by Ambry Genetics Inc. The authors reported having no conflicts of interest.

SOURCE: Shimelis H et al. J Natl Cancer Inst. 2018 Aug 7. doi: 10.1093/jnci/djy106.

Women with germline pathogenic variants in five genes are at high risk for developing triple-negative breast cancer, and have a greater than 20% lifetime risk for breast cancer in general, results of a large study suggest.

Multigene testing of nearly 11,000 women with triple-negative breast cancer (TNBC; lacking estrogen, progesterone, and human epidermal growth factor receptors) showed that germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with risk for clinical TNBC ranging from nearly sixfold to more than 16-fold higher than that of women without the genetic variants, reported Fergus J. Couch, PhD, of the Mayo Clinic, Rochester, Minn., and his colleagues.

“The results suggest that all TNBC patients should undergo multigene panel testing, regardless of age at diagnosis or family history of cancer, for improved cancer risk assessment and because of the ongoing development of targeted therapeutic approaches for TNBC patients with mutations in predisposition genes,” they wrote. Their report is in the Journal of the National Cancer Institute.

Although National Comprehensive Cancer Network guidelines recommend testing for the cancer predisposition genes BRCA1 and BRCA2 in women with a TNBC diagnosis at age 60 or younger or those with a family history of breast and/or ovarian cancer, the picture is less clear regarding genetic predisposition to TNBC, the authors noted.

“[R]ecommendations for testing of other genes are not fully established because the risks of TNBC associated with mutations in cancer predisposition genes have not been established. Thus, a better understanding of gene-specific risks for TNBC is needed to identify the genes that should be tested in the setting of TNBC,” they wrote.

The investigators looked for associations between deleterious mutations in cancer predisposition genes and TNBC among 8,753 patients with TNBC testing with a 21-gene assay, and among 2,148 women tested for 17 genes in studies conducted by the Triple Negative Breast Cancer Consortium.

They found that among white women, germline pathogenic variants were associated with the following odds ratios (OR) for TNBC (all P values less than .0001):
 

• BRCA2 = 5.42
• BARD1 = 5.92
• RAD51D = 6.97
• PALB2 = 14.41
• BRCA1 = 16.27

Although there were insufficient data on the risks for African American women, an exploratory analysis showed that risks for TNBC associated with specific pathogenic variants were similar to those for white women, the authors said.

The pathogenic variants were detected in 12% of all patients in the study.

“Continued study of gene-specific risks for breast cancer subtypes may lead to tailored medical management recommendations for PV [pathogenic variant] carriers. Consistent with this hypothesis, initial studies evaluating intensified screening in high-risk women have suggested that a decrease in mortality from TNBC can be achieved,” they wrote.

The study was supported in part by the National Institutes of Health and the Breast Cancer Research Foundation, and was sponsored by Ambry Genetics Inc. The authors reported having no conflicts of interest.

SOURCE: Shimelis H et al. J Natl Cancer Inst. 2018 Aug 7. doi: 10.1093/jnci/djy106.

Women with germline pathogenic variants in five genes are at high risk for developing triple-negative breast cancer, and have a greater than 20% lifetime risk for breast cancer in general, results of a large study suggest.

Multigene testing of nearly 11,000 women with triple-negative breast cancer (TNBC; lacking estrogen, progesterone, and human epidermal growth factor receptors) showed that germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with risk for clinical TNBC ranging from nearly sixfold to more than 16-fold higher than that of women without the genetic variants, reported Fergus J. Couch, PhD, of the Mayo Clinic, Rochester, Minn., and his colleagues.

“The results suggest that all TNBC patients should undergo multigene panel testing, regardless of age at diagnosis or family history of cancer, for improved cancer risk assessment and because of the ongoing development of targeted therapeutic approaches for TNBC patients with mutations in predisposition genes,” they wrote. Their report is in the Journal of the National Cancer Institute.

Although National Comprehensive Cancer Network guidelines recommend testing for the cancer predisposition genes BRCA1 and BRCA2 in women with a TNBC diagnosis at age 60 or younger or those with a family history of breast and/or ovarian cancer, the picture is less clear regarding genetic predisposition to TNBC, the authors noted.

“[R]ecommendations for testing of other genes are not fully established because the risks of TNBC associated with mutations in cancer predisposition genes have not been established. Thus, a better understanding of gene-specific risks for TNBC is needed to identify the genes that should be tested in the setting of TNBC,” they wrote.

The investigators looked for associations between deleterious mutations in cancer predisposition genes and TNBC among 8,753 patients with TNBC testing with a 21-gene assay, and among 2,148 women tested for 17 genes in studies conducted by the Triple Negative Breast Cancer Consortium.

They found that among white women, germline pathogenic variants were associated with the following odds ratios (OR) for TNBC (all P values less than .0001):
 

• BRCA2 = 5.42
• BARD1 = 5.92
• RAD51D = 6.97
• PALB2 = 14.41
• BRCA1 = 16.27

Although there were insufficient data on the risks for African American women, an exploratory analysis showed that risks for TNBC associated with specific pathogenic variants were similar to those for white women, the authors said.

The pathogenic variants were detected in 12% of all patients in the study.

“Continued study of gene-specific risks for breast cancer subtypes may lead to tailored medical management recommendations for PV [pathogenic variant] carriers. Consistent with this hypothesis, initial studies evaluating intensified screening in high-risk women have suggested that a decrease in mortality from TNBC can be achieved,” they wrote.

The study was supported in part by the National Institutes of Health and the Breast Cancer Research Foundation, and was sponsored by Ambry Genetics Inc. The authors reported having no conflicts of interest.

SOURCE: Shimelis H et al. J Natl Cancer Inst. 2018 Aug 7. doi: 10.1093/jnci/djy106.

In patients with clear cell renal cell carcinoma (ccRCC), radiogenomic analysis can reveal associations between specific features on CT imaging and messenger RNA-based tumor subtyping, authors of a preliminary analysis contend.

Among 177 patients with ccRCC for whom CT data and molecular subtyping information were available, well-defined vs. poorly-defined tumor margins were significantly associated with messenger RNA (mRNA) subtype m1 tumors, and a combination of margin definition and other qualitative tumor features was significantly associated with m3 subtype, reported Lan Bowen, MD, and Li Xiaojing, MD, from Huizhou (China) Central People’s Hospital.

“We demonstrated m1-subtype is positively associated with well-defined margin while m3-subtype is positively associated with ill-defined margin, renal vein invasion, and collecting-system invasion. These findings should be further investigated and validated in other cohorts,” they wrote. The report was published in Academic Radiology.

Radiogenomic analysis is a method for identifying associations between imaging features and gene expression profiles to provide information that can be used for clinical decision making.

The investigators used the technique to retrospectively explore associations between ccRCC mRNA-based subtyping and CT features.

They identified data on a total of 177 patients with ccRCC from The Cancer Genome Atlas for whom complete CT imaging, including contrast-enhanced images, and mRNA-based subtyping were available.

CT features studied included calcifications, margin definition, renal vein invasion, collecting-system invasion, multicystic tumors, nodular tumor enhancement, and intratumoral vasculature.

In univariate logistic regression analysis, well-defined tumor margins (vs. poorly-defined margins) were significant associated with m1 subtype (odd ratio [OR] 2.104, P = .041).

Similarly, a combination of well-defined tumor margins (OR 2.104, P = .013), no collecting system invasion (OR 0.421, P = .028), and renal vein invasion (OR 2.164, P = .026) were significantly associated with the m3 subtype.

They were no significant associations between CT imaging features and either the m2 or m4 subtypes, the authors found.

The authors did not report study funding sources or potential conflicts of interest.

SOURCE: Bowen L, Xiaojing L. Acad Radiol. doi: 10.1016/j.acra.2018.05.002.

In patients with clear cell renal cell carcinoma (ccRCC), radiogenomic analysis can reveal associations between specific features on CT imaging and messenger RNA-based tumor subtyping, authors of a preliminary analysis contend.

Among 177 patients with ccRCC for whom CT data and molecular subtyping information were available, well-defined vs. poorly-defined tumor margins were significantly associated with messenger RNA (mRNA) subtype m1 tumors, and a combination of margin definition and other qualitative tumor features was significantly associated with m3 subtype, reported Lan Bowen, MD, and Li Xiaojing, MD, from Huizhou (China) Central People’s Hospital.

“We demonstrated m1-subtype is positively associated with well-defined margin while m3-subtype is positively associated with ill-defined margin, renal vein invasion, and collecting-system invasion. These findings should be further investigated and validated in other cohorts,” they wrote. The report was published in Academic Radiology.

Radiogenomic analysis is a method for identifying associations between imaging features and gene expression profiles to provide information that can be used for clinical decision making.

The investigators used the technique to retrospectively explore associations between ccRCC mRNA-based subtyping and CT features.

They identified data on a total of 177 patients with ccRCC from The Cancer Genome Atlas for whom complete CT imaging, including contrast-enhanced images, and mRNA-based subtyping were available.

CT features studied included calcifications, margin definition, renal vein invasion, collecting-system invasion, multicystic tumors, nodular tumor enhancement, and intratumoral vasculature.

In univariate logistic regression analysis, well-defined tumor margins (vs. poorly-defined margins) were significant associated with m1 subtype (odd ratio [OR] 2.104, P = .041).

Similarly, a combination of well-defined tumor margins (OR 2.104, P = .013), no collecting system invasion (OR 0.421, P = .028), and renal vein invasion (OR 2.164, P = .026) were significantly associated with the m3 subtype.

They were no significant associations between CT imaging features and either the m2 or m4 subtypes, the authors found.

The authors did not report study funding sources or potential conflicts of interest.

SOURCE: Bowen L, Xiaojing L. Acad Radiol. doi: 10.1016/j.acra.2018.05.002.

In patients with clear cell renal cell carcinoma (ccRCC), radiogenomic analysis can reveal associations between specific features on CT imaging and messenger RNA-based tumor subtyping, authors of a preliminary analysis contend.

Among 177 patients with ccRCC for whom CT data and molecular subtyping information were available, well-defined vs. poorly-defined tumor margins were significantly associated with messenger RNA (mRNA) subtype m1 tumors, and a combination of margin definition and other qualitative tumor features was significantly associated with m3 subtype, reported Lan Bowen, MD, and Li Xiaojing, MD, from Huizhou (China) Central People’s Hospital.

“We demonstrated m1-subtype is positively associated with well-defined margin while m3-subtype is positively associated with ill-defined margin, renal vein invasion, and collecting-system invasion. These findings should be further investigated and validated in other cohorts,” they wrote. The report was published in Academic Radiology.

Radiogenomic analysis is a method for identifying associations between imaging features and gene expression profiles to provide information that can be used for clinical decision making.

The investigators used the technique to retrospectively explore associations between ccRCC mRNA-based subtyping and CT features.

They identified data on a total of 177 patients with ccRCC from The Cancer Genome Atlas for whom complete CT imaging, including contrast-enhanced images, and mRNA-based subtyping were available.

CT features studied included calcifications, margin definition, renal vein invasion, collecting-system invasion, multicystic tumors, nodular tumor enhancement, and intratumoral vasculature.

In univariate logistic regression analysis, well-defined tumor margins (vs. poorly-defined margins) were significant associated with m1 subtype (odd ratio [OR] 2.104, P = .041).

Similarly, a combination of well-defined tumor margins (OR 2.104, P = .013), no collecting system invasion (OR 0.421, P = .028), and renal vein invasion (OR 2.164, P = .026) were significantly associated with the m3 subtype.

They were no significant associations between CT imaging features and either the m2 or m4 subtypes, the authors found.

The authors did not report study funding sources or potential conflicts of interest.

SOURCE: Bowen L, Xiaojing L. Acad Radiol. doi: 10.1016/j.acra.2018.05.002.

Photo courtesy of the CDC

Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.

The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.

A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).

“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.

“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”

Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.

To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.

The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.

Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.

However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).

Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.

The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).

“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.

The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.

Photo courtesy of the CDC

Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.

The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.

A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).

“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.

“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”

Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.

To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.

The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.

Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.

However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).

Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.

The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).

“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.

The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.

Photo courtesy of the CDC

Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.

The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.

A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).

“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.

“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”

Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.

To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.

The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.

Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.

However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).

Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.

The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).

“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.

The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.

CHICAGO – Patients with high-risk soft-tissue sarcomas identified by patient data and a risk calculator had significantly better overall and disease-free survival when they were treated with adjuvant doxorubicin and ifosfamide, a retrospective analysis from a randomized clinical trial showed.

The findings suggest that future clinical trials for sarcoma therapies may need to focus on specific risk categories, investigators said.

Among 290 patients with soft tissues sarcomas (STS) of the trunk wall or extremities, adjuvant chemotherapy with doxorubicin, ifosfamide, mesna, and lenograstim more than halved the risk of death for patients determined by the nomogram to have a low probability of 10-year overall survival, reported Sandro Pasquali, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and his colleagues.

“These findings interpret conflicting results of randomized controlled trials on perioperative chemotherapy in STS showing that inclusion of low-risk tumors have diluted the effect of chemotherapy leading to negative results and small study effect in meta-analysis,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The clinical trial in question, EORTC-STBSG 62931, results of which were published in 2012 in The Lancet Oncology, was technically a failure, because it did not show a significant benefit of adjuvant chemotherapy vs. observation in patients with STS.

To see whether adjuvant chemotherapy may have benefited select patients, the investigators calculated 10-year probabilities of overall survival (P-OS) for 290 patients with STS of the trunk wall or extremities out of the total trial cohort of 351 patients. The P-OS for each of three categories – low (51% or less), intermediate (52%-66%), and high (67% or greater) – was calculated using individual patient data and the freely available smartphone-based nomogram Sarculator (available in the Apple App Store and Google Play).

They calculated disease-free survival at the study median follow-up of 8 years.

The tumor histologies included malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and others.

A total of 52 patients were in the low P-OS group, including 24 treated with observation, and 28 with adjuvant chemotherapy. Respective numbers for the intermediate and high P-OS categories were 34/34, and 90/80.

The investigators found that for patients in the low P-OS group, adjuvant chemotherapy cut the risk of death by slightly more than half, with a hazard ratio of 0.46 (P = .033). In contrast, there were no significant differences in the risk of death for patients at either intermediate or high probability of 10 year OS (HR, 1.00 and 1.08, respectively; P values not significant).

Similarly, adjuvant chemotherapy cut the risk of disease progression by the same amount, with an HR of 0.46 (P = .021), whereas there was no additional benefit among patients at either intermediate or high probability of 10-year OS (HR 0.74 and 0.90; P values were not significant).

The absolute risk reduction for adjuvant chemotherapy was 21% (8-yr disease-free survival of 34% for adjuvant chemotherapy vs. 13% for observation), with a number needed to treated of 4.76.

The study was supported by the European Organization for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
 

SOURCE: Pasquali S et al. ASCO 2018, Abstract 115118.
 

CHICAGO – Patients with high-risk soft-tissue sarcomas identified by patient data and a risk calculator had significantly better overall and disease-free survival when they were treated with adjuvant doxorubicin and ifosfamide, a retrospective analysis from a randomized clinical trial showed.

The findings suggest that future clinical trials for sarcoma therapies may need to focus on specific risk categories, investigators said.

Among 290 patients with soft tissues sarcomas (STS) of the trunk wall or extremities, adjuvant chemotherapy with doxorubicin, ifosfamide, mesna, and lenograstim more than halved the risk of death for patients determined by the nomogram to have a low probability of 10-year overall survival, reported Sandro Pasquali, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and his colleagues.

“These findings interpret conflicting results of randomized controlled trials on perioperative chemotherapy in STS showing that inclusion of low-risk tumors have diluted the effect of chemotherapy leading to negative results and small study effect in meta-analysis,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The clinical trial in question, EORTC-STBSG 62931, results of which were published in 2012 in The Lancet Oncology, was technically a failure, because it did not show a significant benefit of adjuvant chemotherapy vs. observation in patients with STS.

To see whether adjuvant chemotherapy may have benefited select patients, the investigators calculated 10-year probabilities of overall survival (P-OS) for 290 patients with STS of the trunk wall or extremities out of the total trial cohort of 351 patients. The P-OS for each of three categories – low (51% or less), intermediate (52%-66%), and high (67% or greater) – was calculated using individual patient data and the freely available smartphone-based nomogram Sarculator (available in the Apple App Store and Google Play).

They calculated disease-free survival at the study median follow-up of 8 years.

The tumor histologies included malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and others.

A total of 52 patients were in the low P-OS group, including 24 treated with observation, and 28 with adjuvant chemotherapy. Respective numbers for the intermediate and high P-OS categories were 34/34, and 90/80.

The investigators found that for patients in the low P-OS group, adjuvant chemotherapy cut the risk of death by slightly more than half, with a hazard ratio of 0.46 (P = .033). In contrast, there were no significant differences in the risk of death for patients at either intermediate or high probability of 10 year OS (HR, 1.00 and 1.08, respectively; P values not significant).

Similarly, adjuvant chemotherapy cut the risk of disease progression by the same amount, with an HR of 0.46 (P = .021), whereas there was no additional benefit among patients at either intermediate or high probability of 10-year OS (HR 0.74 and 0.90; P values were not significant).

The absolute risk reduction for adjuvant chemotherapy was 21% (8-yr disease-free survival of 34% for adjuvant chemotherapy vs. 13% for observation), with a number needed to treated of 4.76.

The study was supported by the European Organization for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
 

SOURCE: Pasquali S et al. ASCO 2018, Abstract 115118.
 

CHICAGO – Patients with high-risk soft-tissue sarcomas identified by patient data and a risk calculator had significantly better overall and disease-free survival when they were treated with adjuvant doxorubicin and ifosfamide, a retrospective analysis from a randomized clinical trial showed.

The findings suggest that future clinical trials for sarcoma therapies may need to focus on specific risk categories, investigators said.

Among 290 patients with soft tissues sarcomas (STS) of the trunk wall or extremities, adjuvant chemotherapy with doxorubicin, ifosfamide, mesna, and lenograstim more than halved the risk of death for patients determined by the nomogram to have a low probability of 10-year overall survival, reported Sandro Pasquali, MD, from the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, and his colleagues.

“These findings interpret conflicting results of randomized controlled trials on perioperative chemotherapy in STS showing that inclusion of low-risk tumors have diluted the effect of chemotherapy leading to negative results and small study effect in meta-analysis,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The clinical trial in question, EORTC-STBSG 62931, results of which were published in 2012 in The Lancet Oncology, was technically a failure, because it did not show a significant benefit of adjuvant chemotherapy vs. observation in patients with STS.

To see whether adjuvant chemotherapy may have benefited select patients, the investigators calculated 10-year probabilities of overall survival (P-OS) for 290 patients with STS of the trunk wall or extremities out of the total trial cohort of 351 patients. The P-OS for each of three categories – low (51% or less), intermediate (52%-66%), and high (67% or greater) – was calculated using individual patient data and the freely available smartphone-based nomogram Sarculator (available in the Apple App Store and Google Play).

They calculated disease-free survival at the study median follow-up of 8 years.

The tumor histologies included malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and others.

A total of 52 patients were in the low P-OS group, including 24 treated with observation, and 28 with adjuvant chemotherapy. Respective numbers for the intermediate and high P-OS categories were 34/34, and 90/80.

The investigators found that for patients in the low P-OS group, adjuvant chemotherapy cut the risk of death by slightly more than half, with a hazard ratio of 0.46 (P = .033). In contrast, there were no significant differences in the risk of death for patients at either intermediate or high probability of 10 year OS (HR, 1.00 and 1.08, respectively; P values not significant).

Similarly, adjuvant chemotherapy cut the risk of disease progression by the same amount, with an HR of 0.46 (P = .021), whereas there was no additional benefit among patients at either intermediate or high probability of 10-year OS (HR 0.74 and 0.90; P values were not significant).

The absolute risk reduction for adjuvant chemotherapy was 21% (8-yr disease-free survival of 34% for adjuvant chemotherapy vs. 13% for observation), with a number needed to treated of 4.76.

The study was supported by the European Organization for Research and Treatment of Cancer. Dr. Pasquali reported having no conflicts of interest.
 

SOURCE: Pasquali S et al. ASCO 2018, Abstract 115118.
 

For patients with locally advanced or metastatic basal cell carcinoma, Sonic hedgehog inhibitors (SSHi) are effective but are associated with primarily partial responses, and the two Food and Drug Administration–approved agents have significant toxicities, results of a systematic review and meta-analysis indicated.

Data on patients with metastatic or locally advanced basal cell carcinoma (BCC) treated with either vismodegib (Erivedge) or sonidegib (Odomzo) showed that the two agents had roughly similar overall response rates (ORR). Vismodegib, however, had a significantly higher rate of complete responses (CR) in patients with locally advanced disease, reported Pingxing Xie, MD, PhD, and Philippe Lefrançois, MD, PhD, from McGill University, Montreal.

“Common side effects of SHHi therapy tend to incapacitate patients, leading to high discontinuation rates. Over 25% of patients stopped treatment due to side effects. Most side effects are reversible after therapy cessation, except cases of persistent alopecia have been reported,” they wrote in the Journal of the American Academy of Dermatology.

The authors conducted the review to evaluate SHHi as a class and to get a better idea of the efficacy and safety of each agent in the class. They searched the literature to identify all studies using SHHi to treat BCC with vismodegib, sonidegib, itraconazole, or the investigational compound TAK-441, and identified 14 studies focused on vismodegib, 2 on sonidegib, and 1 each on itraconazole and TAK-441.

Of the 18 studies, data from 16 were pooled in fixed-effects linear models to analyze efficacy. The pooled ORR for all patients was 59.6%, “indicating that most patients receiving SHHi achieve at least a partial response.”

Combined ORR results showed a rate of 61.9% for vismodegib, 55.2% for sonidegib, 50% for itraconazole, and 20% for TAK-441, although data for the latter two agents were limited.

In studies looking at locally advanced and metastatic BCC separately, vismodegib was numerically better but statistically similar to sonidegib for locally advanced disease (ORR, 68.8% vs. 56.6%). However, vismodegib was significantly superior to sonidegib for patients with metastatic BCC (ORR, 39.7% vs. 14.7%; P = .007).

The pooled CR for all patients was 23.5%, and there were no CRs with either itraconazole or TAK-441. The combined CR rate for vismodegib was 28% (P = .012). The combined CR rate for sonidegib was just 8.9% and was not statistically significant, the investigators found.

In subgroup analyses for locally advanced BCC, the CR rate for vismodegib was 30.9% for vismodegib (P = .012), “meaning that many patients can expect cure.” In contrast, only 3% of patients treated for locally advanced disease had a CR with sonidegib. The difference between the drugs in this subpopulation was significant (P less than .0001).

Neither drug produced significant CRs in patients with metastatic melanoma, and the pooled clinical benefit rate (all patients with stable disease or better) was 94.9%, with rates similar among all four drugs.

Pooled prevalences of adverse events showed a 67.1% prevalence of muscle spasms, 54.1% prevalence of dysgeusia, and a 57.7% prevalence of alopecia. The proportions of side effects were similar between vismodegib and sonidegib, but sonidegib was associated with a higher prevalence of upper gastrointestinal tract distress than vismodegib.

The study was partially funded by the Canadian Dermatology Foundation. The authors reported having no conflicts of interest.

SOURCE: Xie P et al. J Am Acad Dermatol. 2018 Jul 9. doi: 10.1016/j.jaad.2018.07.004.

For patients with locally advanced or metastatic basal cell carcinoma, Sonic hedgehog inhibitors (SSHi) are effective but are associated with primarily partial responses, and the two Food and Drug Administration–approved agents have significant toxicities, results of a systematic review and meta-analysis indicated.

Data on patients with metastatic or locally advanced basal cell carcinoma (BCC) treated with either vismodegib (Erivedge) or sonidegib (Odomzo) showed that the two agents had roughly similar overall response rates (ORR). Vismodegib, however, had a significantly higher rate of complete responses (CR) in patients with locally advanced disease, reported Pingxing Xie, MD, PhD, and Philippe Lefrançois, MD, PhD, from McGill University, Montreal.

“Common side effects of SHHi therapy tend to incapacitate patients, leading to high discontinuation rates. Over 25% of patients stopped treatment due to side effects. Most side effects are reversible after therapy cessation, except cases of persistent alopecia have been reported,” they wrote in the Journal of the American Academy of Dermatology.

The authors conducted the review to evaluate SHHi as a class and to get a better idea of the efficacy and safety of each agent in the class. They searched the literature to identify all studies using SHHi to treat BCC with vismodegib, sonidegib, itraconazole, or the investigational compound TAK-441, and identified 14 studies focused on vismodegib, 2 on sonidegib, and 1 each on itraconazole and TAK-441.

Of the 18 studies, data from 16 were pooled in fixed-effects linear models to analyze efficacy. The pooled ORR for all patients was 59.6%, “indicating that most patients receiving SHHi achieve at least a partial response.”

Combined ORR results showed a rate of 61.9% for vismodegib, 55.2% for sonidegib, 50% for itraconazole, and 20% for TAK-441, although data for the latter two agents were limited.

In studies looking at locally advanced and metastatic BCC separately, vismodegib was numerically better but statistically similar to sonidegib for locally advanced disease (ORR, 68.8% vs. 56.6%). However, vismodegib was significantly superior to sonidegib for patients with metastatic BCC (ORR, 39.7% vs. 14.7%; P = .007).

The pooled CR for all patients was 23.5%, and there were no CRs with either itraconazole or TAK-441. The combined CR rate for vismodegib was 28% (P = .012). The combined CR rate for sonidegib was just 8.9% and was not statistically significant, the investigators found.

In subgroup analyses for locally advanced BCC, the CR rate for vismodegib was 30.9% for vismodegib (P = .012), “meaning that many patients can expect cure.” In contrast, only 3% of patients treated for locally advanced disease had a CR with sonidegib. The difference between the drugs in this subpopulation was significant (P less than .0001).

Neither drug produced significant CRs in patients with metastatic melanoma, and the pooled clinical benefit rate (all patients with stable disease or better) was 94.9%, with rates similar among all four drugs.

Pooled prevalences of adverse events showed a 67.1% prevalence of muscle spasms, 54.1% prevalence of dysgeusia, and a 57.7% prevalence of alopecia. The proportions of side effects were similar between vismodegib and sonidegib, but sonidegib was associated with a higher prevalence of upper gastrointestinal tract distress than vismodegib.

The study was partially funded by the Canadian Dermatology Foundation. The authors reported having no conflicts of interest.

SOURCE: Xie P et al. J Am Acad Dermatol. 2018 Jul 9. doi: 10.1016/j.jaad.2018.07.004.

For patients with locally advanced or metastatic basal cell carcinoma, Sonic hedgehog inhibitors (SSHi) are effective but are associated with primarily partial responses, and the two Food and Drug Administration–approved agents have significant toxicities, results of a systematic review and meta-analysis indicated.

Data on patients with metastatic or locally advanced basal cell carcinoma (BCC) treated with either vismodegib (Erivedge) or sonidegib (Odomzo) showed that the two agents had roughly similar overall response rates (ORR). Vismodegib, however, had a significantly higher rate of complete responses (CR) in patients with locally advanced disease, reported Pingxing Xie, MD, PhD, and Philippe Lefrançois, MD, PhD, from McGill University, Montreal.

“Common side effects of SHHi therapy tend to incapacitate patients, leading to high discontinuation rates. Over 25% of patients stopped treatment due to side effects. Most side effects are reversible after therapy cessation, except cases of persistent alopecia have been reported,” they wrote in the Journal of the American Academy of Dermatology.

The authors conducted the review to evaluate SHHi as a class and to get a better idea of the efficacy and safety of each agent in the class. They searched the literature to identify all studies using SHHi to treat BCC with vismodegib, sonidegib, itraconazole, or the investigational compound TAK-441, and identified 14 studies focused on vismodegib, 2 on sonidegib, and 1 each on itraconazole and TAK-441.

Of the 18 studies, data from 16 were pooled in fixed-effects linear models to analyze efficacy. The pooled ORR for all patients was 59.6%, “indicating that most patients receiving SHHi achieve at least a partial response.”

Combined ORR results showed a rate of 61.9% for vismodegib, 55.2% for sonidegib, 50% for itraconazole, and 20% for TAK-441, although data for the latter two agents were limited.

In studies looking at locally advanced and metastatic BCC separately, vismodegib was numerically better but statistically similar to sonidegib for locally advanced disease (ORR, 68.8% vs. 56.6%). However, vismodegib was significantly superior to sonidegib for patients with metastatic BCC (ORR, 39.7% vs. 14.7%; P = .007).

The pooled CR for all patients was 23.5%, and there were no CRs with either itraconazole or TAK-441. The combined CR rate for vismodegib was 28% (P = .012). The combined CR rate for sonidegib was just 8.9% and was not statistically significant, the investigators found.

In subgroup analyses for locally advanced BCC, the CR rate for vismodegib was 30.9% for vismodegib (P = .012), “meaning that many patients can expect cure.” In contrast, only 3% of patients treated for locally advanced disease had a CR with sonidegib. The difference between the drugs in this subpopulation was significant (P less than .0001).

Neither drug produced significant CRs in patients with metastatic melanoma, and the pooled clinical benefit rate (all patients with stable disease or better) was 94.9%, with rates similar among all four drugs.

Pooled prevalences of adverse events showed a 67.1% prevalence of muscle spasms, 54.1% prevalence of dysgeusia, and a 57.7% prevalence of alopecia. The proportions of side effects were similar between vismodegib and sonidegib, but sonidegib was associated with a higher prevalence of upper gastrointestinal tract distress than vismodegib.

The study was partially funded by the Canadian Dermatology Foundation. The authors reported having no conflicts of interest.

SOURCE: Xie P et al. J Am Acad Dermatol. 2018 Jul 9. doi: 10.1016/j.jaad.2018.07.004.

CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.

There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.

“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.

Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.

They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.

The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.

The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.

Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).

The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.

Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.

A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.

The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.

As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.

“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.

The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.

SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.

CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.

There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.

“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.

Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.

They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.

The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.

The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.

Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).

The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.

Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.

A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.

The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.

As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.

“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.

The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.

SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.

CHICAGO – For patients with gastrointestinal stromal tumor (GIST) with KIT mutations conferring resistance to imatinib, a strategy of rapid alteration of drugs with complementary activity against KIT mutations is feasible but has thus far failed to yield significant clinical benefits, investigators said.

There were no objective responses among 12 patients treated continuously with 3 days of sunitinib (Sutent) followed by 4 days of regorafenib (Stivarga), and although 4 patients had stable disease in the short term, in each case the disease progressed within 16 weeks, reported Cesar Serrano-Garcia, MD, from the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and his colleagues.

“Drug exposure is critical to effectively target specific resistant subpopulations and low exposure may have contributed to the lack of efficacy in this cohort,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The investigators noted that the main mechanism of resistance to imatinib (Gleevec) in GIST is polyclonal emergence of KIT secondary mutations. They then theorized that rapid alteration of sunitinib with regorafenib, which both have complementary activity against different KIT resistance mutations, could be a novel therapeutic strategy for controlling imatinib-resistant disease.

Both agents are active against KIT and platelet-derived growth factor receptor alpha (PDGFR-alpha). Sunitinib has stronger activity against ATP-binding pocket mutations, and regorafenib is more effective against activation loop oncoproteins, the investigators explained.

They conducted a phase Ib trial to evaluate the safety and preliminary efficacy of the strategy in patients with metastatic GIST that had advanced on therapy with all established protocols. The trial had a standard 3+3 design to determine the recommended phase 2 dose; a total of 14 patients were enrolled, but only 12 received one or more complete cycles.

The median patient age was 63.5%. Nine patients had Eastern Cooperative Oncology Group performance status of 0, and five had an ECOG status of 1. The patients had received a median of four prior lines of therapy, and all had received at least three lines.

The primary mutations were at KIT exon 11 in eight patients, exon 9 in five patients, and a KIT/PDGFR-alpha wild type in one patient.

Of the 12 patients who received one or more complete cycles, 7 were treated with sunitinib 37.5 mg daily for 3 days, followed by regorafenib 120 mg daily for 4 days. There were no dose-limiting toxicities in this group. The median number of cycles delivered was 2 (range 1-4).

The other five patients were treated with sunitinib at the same 37.5 mg daily dose for 3 days, followed immediately by regorafenib 160 mg daily for 4 days. There were two dose-limiting toxicities in this group, both grade 3 hypophosphatemia, one of which was refractory to phosphorous replacement.

Antitumor activity according to Response Evaluation Criteria in Solid Tumors version 1.1 included four cases of stable disease at the time of the efficacy analysis, and eight cases of disease progression. The median progression-free survival was 1.9 months. As noted before, there were no complete or partial responses among the 12 patients.

A pharmacokinetic profile at cycle 1 showed that neither drug reached its reported active blood drug levels.

The patients appeared to tolerate the treatment well, with grade 1 or 2 fatigue in all patients being the most common adverse events. Grade 3 or 4 events included hand-foot syndrome, hypertension, and hypophosphatemia in two patients each.

As noted, the authors acknowledged that low drug exposure levels may explain the lack of any responses in this cohort.

“Therapeutic strategies based on KIT inhibition remain crucial in GIST patients progressing to multiple lines,” they wrote.

The study was supported by an ASCO Young Investigator Award, Pfizer, and Bayer. Dr. Serrano-Garcia disclosed honoraria from Bayer, a consulting or advisory role for Deciphera, research funding from Bayer and Deciphera, and travel accommodations and expenses from Pfizer.

SOURCE: Serrano-Garcia C et al. ASCO 2018, Abstract 11510.

CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.

In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.

“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.

Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.

An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).

Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.

The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.

There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.

“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.

The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.

SOURCE: George S et al. ASCO 2018. Abstract 11511.

CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.

In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.

“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.

Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.

An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).

Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.

The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.

There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.

“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.

The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.

SOURCE: George S et al. ASCO 2018. Abstract 11511.

CHICAGO – Detection of circulating tumor DNA (ctDNA), aka “liquid biopsy,” may serve as a noninvasive marker for disease heterogeneity and aid in the assessment of clinical responses to therapy for patients with gastrointestinal stromal tumors (GIST), according to investigators.

In a phase 1 trial of the investigational agent DCC-2618, a pan-KIT/platelet-derived growth factor receptor alpha (PDGFRA) switch control inhibitor, identification of ctDNA by next-generation sequencing (NGS) was accomplished in the majority of patients, with findings that support the need for a broad-spectrum KIT inhibitor for patients with GIST resistant to imatinib (Gleevec), reported Suzanne George, MD, of Dana-Farber Cancer Institute in Boston, and her colleagues.

“This data demonstrates for the first time that the distribution of resistance mutations in KIT across exons 13, 14, 17, and 18 or a combination thereof is similar in 2nd, 3rd, and 4th-line patients,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

The dose-finding and escalation trial included baseline evaluations of KIT/PDGFRA mutations with both ctDNA and fresh tumor biopsy, and ctDNA measurements during treatment.

Biopsy detected 68 KIT mutations at baseline in 81 patients, and ctDNA detected 75 mutations in 95 patients. Some patients had multiple mutations within one exon.

An analysis of mutations by response showed that of 73 patients with detectable KIT mutations by ctDNA at baseline, 35 became KIT ctDNA negative during at least one treatment time point. Of this group, 8 had a partial response (PR) and 27 had stable disease (SD). In all, 57 of the 73 patients had a more than 50% reduction in KIT mutation allele frequency (MAF).

Some patients with stable disease remained KIT negative out to 60 weeks following the first DCC-2618 dose.

The investigators also looked at ctDNA at baseline (21 patients) and post treatment (20 patients) in those who had a PR as their best response. Ten of these patients had KIT mutations detected at baseline, and of this group, eight became KIT negative after treatment; one had no detectable mutations in one exon and one exon with an MAF less than .1%. No posttreatment samples were available for the remaining patient.

There were preliminary data suggesting that DCC-2618 in the second line could be more efficacious than sunitinib (Sutent) in the same setting, and that in KIT-driven GIST DCC-2618 may provide more benefit in the second line compared with the fourth or subsequent lines of therapy, the authors stated.

“The mutational profile of KIT in tumors and plasma at baseline in GIST patients supports the need for a broad spectrum KIT inhibitor in all post-imatinib lines of therapy,” they wrote.

The trial is supported by Deciphera Pharmaceuticals. Dr. George disclosed stock or other ownership in Abbott Laboratories and Abbvie, consulting/advising for AstraZeneca, Blueprint Medicines, and Deciphera, and institutional research funding from Ariad, Bayer, Blueprint Medicine, Deciphera, Novartis, and Pfizer.

SOURCE: George S et al. ASCO 2018. Abstract 11511.

CHICAGO – A combination of the investigational agent PLX9486 with another novel tyrosine kinase inhibitor (TKI) showed some efficacy against a range of primary and secondary KIT mutations in patients with gastrointestinal stromal tumor (GIST), the results of a phase 1 dose escalation study have suggested.

Among 39 patients with GIST who had progressed on imatinib and other TKIs, the rates of clinical benefit at 16 weeks were 64% for 11 patients treated with PLX8486 monotherapy at a dose of 1,000 mg daily and 67% for 9 patients treated with PLX9486 and the investigational TKI pexidartinib.

One patient in the 1,000 mg monotherapy group had a partial response on interim analysis. The median progression-free survival in this dose group was 6 months, which was “significantly better than at lower doses,” reported Andrew J. Wagner, MD, PhD, from the Dana-Farber Cancer Institute in Boston and his colleagues.

“The combination of PLX9486 with either pexidartinib or sunitinib is generally well tolerated and toxicities are typically grade 1 or 2 in nature and reversible,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

PLX9486 is an inhibitor of KIT primary mutations in exons 9 and 11 and secondary resistance mutations in exons 17 and 18. Compared with other KIT-targeted TKIs, PLX9486 has complementary selectivity for mutant forms of KIT with a greater than 150-fold selectivity for mutant versus wild-type KIT, the investigators explained.

“Combinations of PLX9486 with either pexidartinib (PLX3397) or sunitinib potentially inhibit and address all common primary and secondary KIT mutations,” they wrote.

The investigators conducted a phase 1, open-label, dose-escalation study with two parts. The first part was designed to study the safety and pharmacokinetics of single-agent PLX9486 and established a maximum tolerated dose (MTD) for phase 2 studies. The second part was designed to study the drug as a single agent at the recommended phase 2 dose in GIST and other solid tumors with KIT mutations and also in combination with either pexidartinib or sunitinib in patients with GIST.

They found that single-agent PLX9486 was well tolerated at all doses tested (250, 300, 350, 500, and 1,000 mg daily) and that it selectively inhibited a spectrum of KIT mutations, “including difficult to treat exon 17/18 activation loop variants.”

The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67%, with a PFS on interim analysis of 6 months.

The efficacy of single agent PLX9486 was suggested by circulating tumor DNA studies, which showed reductions in circulating tumor DNA levels of exons 11 and 17/18, which reflected the selectivity profile of the TKI.

In the PLX9486 dose escalation phase, there were three cases of grade 3 or 4 toxicities, including one case each of fatigue, creatinine phosphokinase increase, and hypophosphatemia.

The combination of PLX9486 and pexidartinib was associated with grade 1 or 2 adverse events, including hair color changes in five patients; fatigue and decreased appetite in four patients each; anemia, diarrhea, nausea, alanine aminotransferase increase, and aspartate aminotransferase increase in three patients each; and weight loss, maculopapular rash, and hypertension in two patients each.

At the time of the poster presentation, the sunitinib cohort was still accruing, and interim efficacy data were not available.

“Given these interim results, it is anticipated that the selectivity profile and potency of PLX9486 + sunitinib combination will achieve broader and more durable coverage of primary and secondary KIT mutations,” Dr. Wagner and his associates wrote.

SOURCE: Wagner AJ et al. ASCO 2018, Abstract 11509.
 

CHICAGO – A combination of the investigational agent PLX9486 with another novel tyrosine kinase inhibitor (TKI) showed some efficacy against a range of primary and secondary KIT mutations in patients with gastrointestinal stromal tumor (GIST), the results of a phase 1 dose escalation study have suggested.

Among 39 patients with GIST who had progressed on imatinib and other TKIs, the rates of clinical benefit at 16 weeks were 64% for 11 patients treated with PLX8486 monotherapy at a dose of 1,000 mg daily and 67% for 9 patients treated with PLX9486 and the investigational TKI pexidartinib.

One patient in the 1,000 mg monotherapy group had a partial response on interim analysis. The median progression-free survival in this dose group was 6 months, which was “significantly better than at lower doses,” reported Andrew J. Wagner, MD, PhD, from the Dana-Farber Cancer Institute in Boston and his colleagues.

“The combination of PLX9486 with either pexidartinib or sunitinib is generally well tolerated and toxicities are typically grade 1 or 2 in nature and reversible,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

PLX9486 is an inhibitor of KIT primary mutations in exons 9 and 11 and secondary resistance mutations in exons 17 and 18. Compared with other KIT-targeted TKIs, PLX9486 has complementary selectivity for mutant forms of KIT with a greater than 150-fold selectivity for mutant versus wild-type KIT, the investigators explained.

“Combinations of PLX9486 with either pexidartinib (PLX3397) or sunitinib potentially inhibit and address all common primary and secondary KIT mutations,” they wrote.

The investigators conducted a phase 1, open-label, dose-escalation study with two parts. The first part was designed to study the safety and pharmacokinetics of single-agent PLX9486 and established a maximum tolerated dose (MTD) for phase 2 studies. The second part was designed to study the drug as a single agent at the recommended phase 2 dose in GIST and other solid tumors with KIT mutations and also in combination with either pexidartinib or sunitinib in patients with GIST.

They found that single-agent PLX9486 was well tolerated at all doses tested (250, 300, 350, 500, and 1,000 mg daily) and that it selectively inhibited a spectrum of KIT mutations, “including difficult to treat exon 17/18 activation loop variants.”

The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67%, with a PFS on interim analysis of 6 months.

The efficacy of single agent PLX9486 was suggested by circulating tumor DNA studies, which showed reductions in circulating tumor DNA levels of exons 11 and 17/18, which reflected the selectivity profile of the TKI.

In the PLX9486 dose escalation phase, there were three cases of grade 3 or 4 toxicities, including one case each of fatigue, creatinine phosphokinase increase, and hypophosphatemia.

The combination of PLX9486 and pexidartinib was associated with grade 1 or 2 adverse events, including hair color changes in five patients; fatigue and decreased appetite in four patients each; anemia, diarrhea, nausea, alanine aminotransferase increase, and aspartate aminotransferase increase in three patients each; and weight loss, maculopapular rash, and hypertension in two patients each.

At the time of the poster presentation, the sunitinib cohort was still accruing, and interim efficacy data were not available.

“Given these interim results, it is anticipated that the selectivity profile and potency of PLX9486 + sunitinib combination will achieve broader and more durable coverage of primary and secondary KIT mutations,” Dr. Wagner and his associates wrote.

SOURCE: Wagner AJ et al. ASCO 2018, Abstract 11509.
 

CHICAGO – A combination of the investigational agent PLX9486 with another novel tyrosine kinase inhibitor (TKI) showed some efficacy against a range of primary and secondary KIT mutations in patients with gastrointestinal stromal tumor (GIST), the results of a phase 1 dose escalation study have suggested.

Among 39 patients with GIST who had progressed on imatinib and other TKIs, the rates of clinical benefit at 16 weeks were 64% for 11 patients treated with PLX8486 monotherapy at a dose of 1,000 mg daily and 67% for 9 patients treated with PLX9486 and the investigational TKI pexidartinib.

One patient in the 1,000 mg monotherapy group had a partial response on interim analysis. The median progression-free survival in this dose group was 6 months, which was “significantly better than at lower doses,” reported Andrew J. Wagner, MD, PhD, from the Dana-Farber Cancer Institute in Boston and his colleagues.

“The combination of PLX9486 with either pexidartinib or sunitinib is generally well tolerated and toxicities are typically grade 1 or 2 in nature and reversible,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.

PLX9486 is an inhibitor of KIT primary mutations in exons 9 and 11 and secondary resistance mutations in exons 17 and 18. Compared with other KIT-targeted TKIs, PLX9486 has complementary selectivity for mutant forms of KIT with a greater than 150-fold selectivity for mutant versus wild-type KIT, the investigators explained.

“Combinations of PLX9486 with either pexidartinib (PLX3397) or sunitinib potentially inhibit and address all common primary and secondary KIT mutations,” they wrote.

The investigators conducted a phase 1, open-label, dose-escalation study with two parts. The first part was designed to study the safety and pharmacokinetics of single-agent PLX9486 and established a maximum tolerated dose (MTD) for phase 2 studies. The second part was designed to study the drug as a single agent at the recommended phase 2 dose in GIST and other solid tumors with KIT mutations and also in combination with either pexidartinib or sunitinib in patients with GIST.

They found that single-agent PLX9486 was well tolerated at all doses tested (250, 300, 350, 500, and 1,000 mg daily) and that it selectively inhibited a spectrum of KIT mutations, “including difficult to treat exon 17/18 activation loop variants.”

The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67%, with a PFS on interim analysis of 6 months.

The efficacy of single agent PLX9486 was suggested by circulating tumor DNA studies, which showed reductions in circulating tumor DNA levels of exons 11 and 17/18, which reflected the selectivity profile of the TKI.

In the PLX9486 dose escalation phase, there were three cases of grade 3 or 4 toxicities, including one case each of fatigue, creatinine phosphokinase increase, and hypophosphatemia.

The combination of PLX9486 and pexidartinib was associated with grade 1 or 2 adverse events, including hair color changes in five patients; fatigue and decreased appetite in four patients each; anemia, diarrhea, nausea, alanine aminotransferase increase, and aspartate aminotransferase increase in three patients each; and weight loss, maculopapular rash, and hypertension in two patients each.

At the time of the poster presentation, the sunitinib cohort was still accruing, and interim efficacy data were not available.

“Given these interim results, it is anticipated that the selectivity profile and potency of PLX9486 + sunitinib combination will achieve broader and more durable coverage of primary and secondary KIT mutations,” Dr. Wagner and his associates wrote.

SOURCE: Wagner AJ et al. ASCO 2018, Abstract 11509.