Journal Club

For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.

After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported Mrinal M. Gounder, MD, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.

“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the New England Journal of Medicine.

There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).

Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.

They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.

The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.

As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.

Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.

The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”

The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.

The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.

The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.

SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.

For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.

After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported Mrinal M. Gounder, MD, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.

“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the New England Journal of Medicine.

There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).

Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.

They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.

The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.

As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.

Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.

The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”

The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.

The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.

The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.

SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.

For patients with progressive, refractory, or symptomatic desmoid tumors – also known as aggressive fibromatosis – treatment with daily sorafenib (Nexavar) was associated with durable responses and a significant improvement in progression-free survival.

After a median follow-up of 27.2 months, the 2-year progression-free survival (PFS) rate for patients randomly assigned to receive 400 mg sorafenib daily was 81%, compared with 36% for patients assigned to placebo (P less than .001), reported Mrinal M. Gounder, MD, from Memorial Sloan Kettering Cancer Center in New York City, and his colleagues.

“Other agents that are used to treat these tumors include anthracyclines [e.g., pegylated liposomal doxorubicin], vinca alkaloids, and pazopanib. On the basis of the predictable toxic-effects profile and substantial progression-free survival advantage conferred by sorafenib, the drug has antitumor activity as first-line therapy or as subsequent therapy for desmoid tumors,” they wrote in the New England Journal of Medicine.

There is no accepted standard of care for the systemic treatment for desmoid tumors, with options ranging from hormonal blockade, cytotoxic chemotherapy, and targeted agents such as tyrosine kinase inhibitors (TKIs).

Based on a retrospective study showing that the multitargeting oral TKI sorafenib was associated with a 25% response rate and acceptable safety in patients with desmoid tumors, the investigators initiated a phase 3, randomized trial to evaluate the efficacy and safety of sorafenib in this population.

They enrolled 87 patients aged 18 years or older with a histologically documented desmoid tumor that showed clinical and radiographic progression of at least 10% in maximum unidimensional measurement within the last 6 months, symptomatic disease, or recurrent or primary disease that was either inoperable or deemed to require extensive surgery.

The patients were randomized in double-blinded fashion on a 2:1 basis to receive either sorafenib 400 mg daily or placebo until progression. Crossover to sorafenib was allowed for patients assigned to placebo who experienced disease progressions.

As noted before, investigator-assessed PFS, the primary endpoint, clearly favored sorafenib.

Objective response rates before crossover were 33% in the sorafenib arm, consisting of 1 complete and 15 partial responses, and 20% in the placebo arm, consisting of 7 partial responses. The respective median times to objective response were 9.6 months versus 13.3 months. The earliest response, defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, occurred at 2.2 months in the sorafenib arm versus 8.8 months in the placebo arm.

The authors also performed an exploratory analysis looking at MRI as a measure of response evaluation and found that “changes in T2-weighted signal intensity and volumetric measurements may be better measures of treatment effect than RECIST. This is particularly evident when the best response according to RECIST is stable disease.”

The most frequently reported adverse events among patients treated with sorafenib were grade 1 or 2 rash in 73%, fatigue in 67%, hypertension in 55%, and diarrhea in 51%. The most frequent treatment-emergent adverse events in the placebo group were rash of any kind in 42% and palmar-plantar erythrodysesthesia syndrome in 22%.

The investigators acknowledged that the mechanism of action of sorafenib in desmoid tumors is unknown, but noted that they are looking for clues in 25 sets of paired biopsy samples.

The study was supported by grants from the National Cancer Institute, Bayer, Memorial Sloan Kettering Cancer Center, the American Society of Clinical Oncology, Desmoid Tumor Research Foundation, and an Orphan Products Clinical Trials Grant from the Food and Drug Administration. Dr. Gounder reported fees for advisory board activities/consulting for Bayer, Epizyme, Karyopharm Therapeutics, Daiichi Sankyo, TRACON Pharmaceuticals, and Amgen, and travel expenses from Epizyme.

SOURCE: Gounder MM et al. N Engl J Med. 2018 Dec 19. doi: 10.1056/NEJMoa1805052.

Alveolar soft part sarcoma (ASPS) has often proven to be resistant to conventional doxorubicin-based chemotherapy, but tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) may provide new treatment strategies for this rare type of sarcoma, according to a literature review.

A rare, translocation-driven sarcoma of the soft tissues, ASPS often affects young adults and is characterized by indolent behavior and early metastasis. Despite its resistance to chemotherapy, studies indicate that survival is often prolonged in patients with metastatic disease. The literature has shown 5-year survival rates at about 60%, and this percentage has remained fairly consistent for the past 3 decades.

Luca Paoluzzi, MD, of New York University, and Robert G. Maki, MD, PhD, of Hofstra University, Hempstead, N.Y., reviewed the literature from 1952 to March 2018, in order to gain a better understanding of ASPS and the opportunities “for the translation of such knowledge into clinical practice,” they wrote in JAMA.

From a therapeutic standpoint, ASPS is characterized by sensitivity to vascular endothelial growth factor receptor–predominant TKIs, compared with other soft tissue sarcomas (STS), and recent data have emphasized that it is responsive to new immunotherapy regimens including ICIs. Pazopanib is currently the only agent that has received regulatory approval for use in STS refractory to other treatments and it appears to have consistent activity in metastatic ASPS. Management of ASPS generally also involves surgical resection and/or systemic treatment for metastatic disease. Conventional agents such as anthracycline-based chemotherapy have demonstrated a poor response rate lower than 10%, and while a complete resection may be curative, metastases are common and can occur years after resection of the primary tumor.

Conversely, ICIs “represent a promising area of drug development in ASPS; the data to date are limited but encouraging,” wrote Dr. Paoluzzi and Dr. Maki.

They pointed to one study that included 50 patients with sarcoma with 14 different subtypes of STS who were enrolled in immunotherapy trials conducted at the University of Texas MD Anderson Cancer Center, Houston. There were two pretreated patients with ASPS (two to four prior lines) in the cohort who received antiprogrammed death-ligand 1–based therapy, and achieved a partial response bordering on a complete response that lasted 8 and 12 months. An additional two patients achieved stable disease.

Another paper, presented at the 2017 Connective Tissue Oncology Society annual meeting, presented preliminary data from a phase 2 study that showed four of nine evaluable patients with ASPS treated with the TKI axitinib, combined with pembrolizumab, achieved a partial response. Three others had stable disease.

“Pathway-driven basket trials facilitate the enrollment of patients with such uncommon cancers and should provide valuable information regarding a second type of immune responsiveness to ICIs, one that is not a function of high tumor mutational burden,” the authors concluded.

No outside funding sources were reported. Dr. Maki reported receiving consultant fees from numerous sources and research support to New York University from Immune Design, Immunocore, Eli Lilly, Presage Biosciences, TRACON Pharmaceuticals, SARC, Regeneron, and Genentech. No other conflicts were reported.

SOURCE: Paoluzzi L et al. JAMA Oncol. 2018 Oct 18. doi: 10.1001/jamaoncol.2018.4490.

Alveolar soft part sarcoma (ASPS) has often proven to be resistant to conventional doxorubicin-based chemotherapy, but tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) may provide new treatment strategies for this rare type of sarcoma, according to a literature review.

A rare, translocation-driven sarcoma of the soft tissues, ASPS often affects young adults and is characterized by indolent behavior and early metastasis. Despite its resistance to chemotherapy, studies indicate that survival is often prolonged in patients with metastatic disease. The literature has shown 5-year survival rates at about 60%, and this percentage has remained fairly consistent for the past 3 decades.

Luca Paoluzzi, MD, of New York University, and Robert G. Maki, MD, PhD, of Hofstra University, Hempstead, N.Y., reviewed the literature from 1952 to March 2018, in order to gain a better understanding of ASPS and the opportunities “for the translation of such knowledge into clinical practice,” they wrote in JAMA.

From a therapeutic standpoint, ASPS is characterized by sensitivity to vascular endothelial growth factor receptor–predominant TKIs, compared with other soft tissue sarcomas (STS), and recent data have emphasized that it is responsive to new immunotherapy regimens including ICIs. Pazopanib is currently the only agent that has received regulatory approval for use in STS refractory to other treatments and it appears to have consistent activity in metastatic ASPS. Management of ASPS generally also involves surgical resection and/or systemic treatment for metastatic disease. Conventional agents such as anthracycline-based chemotherapy have demonstrated a poor response rate lower than 10%, and while a complete resection may be curative, metastases are common and can occur years after resection of the primary tumor.

Conversely, ICIs “represent a promising area of drug development in ASPS; the data to date are limited but encouraging,” wrote Dr. Paoluzzi and Dr. Maki.

They pointed to one study that included 50 patients with sarcoma with 14 different subtypes of STS who were enrolled in immunotherapy trials conducted at the University of Texas MD Anderson Cancer Center, Houston. There were two pretreated patients with ASPS (two to four prior lines) in the cohort who received antiprogrammed death-ligand 1–based therapy, and achieved a partial response bordering on a complete response that lasted 8 and 12 months. An additional two patients achieved stable disease.

Another paper, presented at the 2017 Connective Tissue Oncology Society annual meeting, presented preliminary data from a phase 2 study that showed four of nine evaluable patients with ASPS treated with the TKI axitinib, combined with pembrolizumab, achieved a partial response. Three others had stable disease.

“Pathway-driven basket trials facilitate the enrollment of patients with such uncommon cancers and should provide valuable information regarding a second type of immune responsiveness to ICIs, one that is not a function of high tumor mutational burden,” the authors concluded.

No outside funding sources were reported. Dr. Maki reported receiving consultant fees from numerous sources and research support to New York University from Immune Design, Immunocore, Eli Lilly, Presage Biosciences, TRACON Pharmaceuticals, SARC, Regeneron, and Genentech. No other conflicts were reported.

SOURCE: Paoluzzi L et al. JAMA Oncol. 2018 Oct 18. doi: 10.1001/jamaoncol.2018.4490.

Alveolar soft part sarcoma (ASPS) has often proven to be resistant to conventional doxorubicin-based chemotherapy, but tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) may provide new treatment strategies for this rare type of sarcoma, according to a literature review.

A rare, translocation-driven sarcoma of the soft tissues, ASPS often affects young adults and is characterized by indolent behavior and early metastasis. Despite its resistance to chemotherapy, studies indicate that survival is often prolonged in patients with metastatic disease. The literature has shown 5-year survival rates at about 60%, and this percentage has remained fairly consistent for the past 3 decades.

Luca Paoluzzi, MD, of New York University, and Robert G. Maki, MD, PhD, of Hofstra University, Hempstead, N.Y., reviewed the literature from 1952 to March 2018, in order to gain a better understanding of ASPS and the opportunities “for the translation of such knowledge into clinical practice,” they wrote in JAMA.

From a therapeutic standpoint, ASPS is characterized by sensitivity to vascular endothelial growth factor receptor–predominant TKIs, compared with other soft tissue sarcomas (STS), and recent data have emphasized that it is responsive to new immunotherapy regimens including ICIs. Pazopanib is currently the only agent that has received regulatory approval for use in STS refractory to other treatments and it appears to have consistent activity in metastatic ASPS. Management of ASPS generally also involves surgical resection and/or systemic treatment for metastatic disease. Conventional agents such as anthracycline-based chemotherapy have demonstrated a poor response rate lower than 10%, and while a complete resection may be curative, metastases are common and can occur years after resection of the primary tumor.

Conversely, ICIs “represent a promising area of drug development in ASPS; the data to date are limited but encouraging,” wrote Dr. Paoluzzi and Dr. Maki.

They pointed to one study that included 50 patients with sarcoma with 14 different subtypes of STS who were enrolled in immunotherapy trials conducted at the University of Texas MD Anderson Cancer Center, Houston. There were two pretreated patients with ASPS (two to four prior lines) in the cohort who received antiprogrammed death-ligand 1–based therapy, and achieved a partial response bordering on a complete response that lasted 8 and 12 months. An additional two patients achieved stable disease.

Another paper, presented at the 2017 Connective Tissue Oncology Society annual meeting, presented preliminary data from a phase 2 study that showed four of nine evaluable patients with ASPS treated with the TKI axitinib, combined with pembrolizumab, achieved a partial response. Three others had stable disease.

“Pathway-driven basket trials facilitate the enrollment of patients with such uncommon cancers and should provide valuable information regarding a second type of immune responsiveness to ICIs, one that is not a function of high tumor mutational burden,” the authors concluded.

No outside funding sources were reported. Dr. Maki reported receiving consultant fees from numerous sources and research support to New York University from Immune Design, Immunocore, Eli Lilly, Presage Biosciences, TRACON Pharmaceuticals, SARC, Regeneron, and Genentech. No other conflicts were reported.

SOURCE: Paoluzzi L et al. JAMA Oncol. 2018 Oct 18. doi: 10.1001/jamaoncol.2018.4490.

A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.

High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.

PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.

“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.

The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.

Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m² every 3 weeks.

“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”

Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).

“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.

They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”

The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.

SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.

A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.

High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.

PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.

“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.

The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.

Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m² every 3 weeks.

“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”

Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).

“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.

They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”

The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.

SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.

A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.

High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.

PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.

“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.

The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.

Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m² every 3 weeks.

“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”

Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).

“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.

They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”

The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.

SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.

A novel method for detection of translocations appears to be superior to conventional molecular assays in the evaluation of bone and soft tissue tumor samples, according to researchers.

The technique of anchored multiplex polymerase chain reaction (AMP)–based targeted next-generation sequencing (NGS) had a failure rate of 14% but, nonetheless, worked favorably when compared with conventional techniques, which were associated with several false positives in this study, the researchers reported in the Journal of Molecular Diagnostics.

Two new fusion partners for the USP6 gene were found using AMP-based targeted NGS in this study, which thus contributed to the “further unraveling of the molecular landscape” for these tumors, added corresponding author Judith V.M.G. Bovée, MD, PhD, of the department of pathology at Leiden (the Netherlands) University Medical Center and her colleagues.

While the genetics of bone and soft tissue tumors have diagnostic value in clinical practice, standard fluorescence in situ hybridization (FISH) and reverse transcriptase PCR are associated with several drawbacks, such as a high false negative rate in the case of FISH, Dr. Bovée and her coauthors wrote.

Accordingly, the researchers evaluated the applicability of a targeted sequencing assay (Archer FusionPlex Sarcoma kit, which was developed by ArcherDX) aimed at 26 genes relevant to bone and soft tissue tumor diagnostics.

Besides allowing for assessment of multiple target genes in a single assay, this technique circumvents the need to know both fusion partners for translocation detection, which opens up the possibility of identifying novel or rare fusion partners, investigators noted.

AMP-based targeted NGS was used to evaluate 81 bone and soft tissue tumor samples, and of those, 48 cases showed a fusion. For the remaining 33 cases in which no fusion was detected, 22 were considered truly negative because samples met all criteria for good quality, while the remaining 11 (14%) were considered not reliable because of insufficient quality, investigators reported.

The samples were also evaluated through use of FISH, reverse transcriptase PCR, or both in 58 cases and use of immunohistochemistry in 16 cases; for the remaining seven cases, no assay or immunohistochemistry could be applied because of a lack of availability, according to investigators.

Among the 48 entities that were fusion-positive according to AMP-based targeted NGS, 29 were validated using standard molecular assays, and of those, 25 had concordant results. Further analysis of the four discordant cases with a third independent technique confirmed the AMP-based targeted NGS findings, according to the published report.

Among the 22 fusion-negative high-quality samples, 19 were validated using FISH, and one case was found to be discordant; however, despite use of a third independent technique, this discrepancy could not be resolved, investigators said.

The AMP-based targeted NGS technique identified COL1A1 and SEC31A as novel fusion partners for USP6 in two cases of nodular fasciitis. Those fusion partners had been previously described in aneurysmal bone cysts, according to investigators.

Despite the promising results for the novel assay, conventional methods were sufficient in this study to confirm translocations in straightforward cases and ordinary rearrangements, according to the investigators.

“Both reverse transcription PCR and FISH are not only quick and easy to conduct but are also of low cost and high analytical validity and accuracy, which make them attractive methods,” they wrote.

The work by Dr. Bovée and her colleagues was supported by Leiden University Medical Center. The department of pathology and the department of cell and chemical biology at the medical center receive royalty payments from Kreatech/Leica, which provided a COL1A1/PDGFB fusion probe used in the research.

SOURCE: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.

A novel method for detection of translocations appears to be superior to conventional molecular assays in the evaluation of bone and soft tissue tumor samples, according to researchers.

The technique of anchored multiplex polymerase chain reaction (AMP)–based targeted next-generation sequencing (NGS) had a failure rate of 14% but, nonetheless, worked favorably when compared with conventional techniques, which were associated with several false positives in this study, the researchers reported in the Journal of Molecular Diagnostics.

Two new fusion partners for the USP6 gene were found using AMP-based targeted NGS in this study, which thus contributed to the “further unraveling of the molecular landscape” for these tumors, added corresponding author Judith V.M.G. Bovée, MD, PhD, of the department of pathology at Leiden (the Netherlands) University Medical Center and her colleagues.

While the genetics of bone and soft tissue tumors have diagnostic value in clinical practice, standard fluorescence in situ hybridization (FISH) and reverse transcriptase PCR are associated with several drawbacks, such as a high false negative rate in the case of FISH, Dr. Bovée and her coauthors wrote.

Accordingly, the researchers evaluated the applicability of a targeted sequencing assay (Archer FusionPlex Sarcoma kit, which was developed by ArcherDX) aimed at 26 genes relevant to bone and soft tissue tumor diagnostics.

Besides allowing for assessment of multiple target genes in a single assay, this technique circumvents the need to know both fusion partners for translocation detection, which opens up the possibility of identifying novel or rare fusion partners, investigators noted.

AMP-based targeted NGS was used to evaluate 81 bone and soft tissue tumor samples, and of those, 48 cases showed a fusion. For the remaining 33 cases in which no fusion was detected, 22 were considered truly negative because samples met all criteria for good quality, while the remaining 11 (14%) were considered not reliable because of insufficient quality, investigators reported.

The samples were also evaluated through use of FISH, reverse transcriptase PCR, or both in 58 cases and use of immunohistochemistry in 16 cases; for the remaining seven cases, no assay or immunohistochemistry could be applied because of a lack of availability, according to investigators.

Among the 48 entities that were fusion-positive according to AMP-based targeted NGS, 29 were validated using standard molecular assays, and of those, 25 had concordant results. Further analysis of the four discordant cases with a third independent technique confirmed the AMP-based targeted NGS findings, according to the published report.

Among the 22 fusion-negative high-quality samples, 19 were validated using FISH, and one case was found to be discordant; however, despite use of a third independent technique, this discrepancy could not be resolved, investigators said.

The AMP-based targeted NGS technique identified COL1A1 and SEC31A as novel fusion partners for USP6 in two cases of nodular fasciitis. Those fusion partners had been previously described in aneurysmal bone cysts, according to investigators.

Despite the promising results for the novel assay, conventional methods were sufficient in this study to confirm translocations in straightforward cases and ordinary rearrangements, according to the investigators.

“Both reverse transcription PCR and FISH are not only quick and easy to conduct but are also of low cost and high analytical validity and accuracy, which make them attractive methods,” they wrote.

The work by Dr. Bovée and her colleagues was supported by Leiden University Medical Center. The department of pathology and the department of cell and chemical biology at the medical center receive royalty payments from Kreatech/Leica, which provided a COL1A1/PDGFB fusion probe used in the research.

SOURCE: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.

A novel method for detection of translocations appears to be superior to conventional molecular assays in the evaluation of bone and soft tissue tumor samples, according to researchers.

The technique of anchored multiplex polymerase chain reaction (AMP)–based targeted next-generation sequencing (NGS) had a failure rate of 14% but, nonetheless, worked favorably when compared with conventional techniques, which were associated with several false positives in this study, the researchers reported in the Journal of Molecular Diagnostics.

Two new fusion partners for the USP6 gene were found using AMP-based targeted NGS in this study, which thus contributed to the “further unraveling of the molecular landscape” for these tumors, added corresponding author Judith V.M.G. Bovée, MD, PhD, of the department of pathology at Leiden (the Netherlands) University Medical Center and her colleagues.

While the genetics of bone and soft tissue tumors have diagnostic value in clinical practice, standard fluorescence in situ hybridization (FISH) and reverse transcriptase PCR are associated with several drawbacks, such as a high false negative rate in the case of FISH, Dr. Bovée and her coauthors wrote.

Accordingly, the researchers evaluated the applicability of a targeted sequencing assay (Archer FusionPlex Sarcoma kit, which was developed by ArcherDX) aimed at 26 genes relevant to bone and soft tissue tumor diagnostics.

Besides allowing for assessment of multiple target genes in a single assay, this technique circumvents the need to know both fusion partners for translocation detection, which opens up the possibility of identifying novel or rare fusion partners, investigators noted.

AMP-based targeted NGS was used to evaluate 81 bone and soft tissue tumor samples, and of those, 48 cases showed a fusion. For the remaining 33 cases in which no fusion was detected, 22 were considered truly negative because samples met all criteria for good quality, while the remaining 11 (14%) were considered not reliable because of insufficient quality, investigators reported.

The samples were also evaluated through use of FISH, reverse transcriptase PCR, or both in 58 cases and use of immunohistochemistry in 16 cases; for the remaining seven cases, no assay or immunohistochemistry could be applied because of a lack of availability, according to investigators.

Among the 48 entities that were fusion-positive according to AMP-based targeted NGS, 29 were validated using standard molecular assays, and of those, 25 had concordant results. Further analysis of the four discordant cases with a third independent technique confirmed the AMP-based targeted NGS findings, according to the published report.

Among the 22 fusion-negative high-quality samples, 19 were validated using FISH, and one case was found to be discordant; however, despite use of a third independent technique, this discrepancy could not be resolved, investigators said.

The AMP-based targeted NGS technique identified COL1A1 and SEC31A as novel fusion partners for USP6 in two cases of nodular fasciitis. Those fusion partners had been previously described in aneurysmal bone cysts, according to investigators.

Despite the promising results for the novel assay, conventional methods were sufficient in this study to confirm translocations in straightforward cases and ordinary rearrangements, according to the investigators.

“Both reverse transcription PCR and FISH are not only quick and easy to conduct but are also of low cost and high analytical validity and accuracy, which make them attractive methods,” they wrote.

The work by Dr. Bovée and her colleagues was supported by Leiden University Medical Center. The department of pathology and the department of cell and chemical biology at the medical center receive royalty payments from Kreatech/Leica, which provided a COL1A1/PDGFB fusion probe used in the research.

SOURCE: Lam SW et al. J Mol Diagn. 2018 Aug 20;20(5):653-63.

Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.

Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.

In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.

“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.

Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage

The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.

They found similar loops forming canonical fusions in three other sarcoma types.

“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.

The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.

About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.

mdales@mdedge.com

SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.

Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.

Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.

In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.

“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.

Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage

The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.

They found similar loops forming canonical fusions in three other sarcoma types.

“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.

The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.

About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.

mdales@mdedge.com

SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.

Chromoplexy, a sudden burst of complex, loop-like gene rearrangements that gives rise to a fusion gene, appears to be associated with aggressive Ewing sarcomas, based on a study of 124 tumors reported in Science.

Ewing sarcomas with complex karyotypes are associated with a poorer prognosis compared with those with simpler karyotypes. The new findings show that these complex karyotypes are the product of chromoplexy, and that chromoplexy-generated fusions arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

Analysis of the sequence context surrounding chromoplexy breaks may provide clues and potentially point to a therapeutic vulnerability that could be used to treat Ewing sarcomas. Further, given the preference of chromoplexy events for transcriptionally active regions, Ewing sarcomas arising from chromoplexy may be responsive to immune checkpoint inhibition.

In a study of the whole genomes of 124 Ewing sarcomas, chromoplexy rather than simple reciprocal translocations defined the gene fusions seen in 52 tumors (42%). Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors.

“Our analyses reveal rearrangement bursts (chromoplectic loops) as a source of gene fusion in human bone and soft tissue tumors. Ewing sarcomas with complex karyotypes are associated with a poorer prognosis than those with simpler karyotypes, and here we show chromoplexy as the mechanism in 42% of tumors. It is possible that the chromoplectic tumor’s additional gene disruptions and fusions contribute to the difference in patient survival,” wrote Nathaniel D. Anderson of the Hospital for Sick Children, Toronto, and the University of Toronto, and his colleagues.

Standard reciprocal translocations involve DNA breaks in two fusion partners. Chromoplexy involves three or more breakpoints in the genome. A loop pattern emerges as these three or more broken chromosome ends are forced to find a new partner. The result is the formation of functional EWSR1-FLI1 or EWSR1-ERG fusions that, upon expression, provide a selective growth or survival advantage

The researchers found that the loop rearrangements always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions.

They found similar loops forming canonical fusions in three other sarcoma types.

“Our whole-genome sequence data support a model in which there is an early clone of (Ewing sarcoma), containing EWSR1-ETS and chromoplexy, arising at least 1 year before diagnosis, which gives rise to both the primary and metastatic or relapse tumors. Whether the bursts ... are chance events or driven by specific mutational processes, akin to the RAG machinery operative in leukemia, remains to be established. As an increasing and diverse number of tumor genome sequences become available, we may be able to define further rearrangement processes that underlie fusion genes and thus unravel the causes of fusion-driven human cancers,” the researchers wrote.

The clinical features and demographics of the study patients were typical of Ewing sarcoma patients. Average patient age at diagnosis was 14.8 years (2.8 to 36.6 years); the male to female ratio was 1.38:1; and 14 patients had relapsed, with 13 having died from their disease.

About half of fusions between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 arose via chromoplexy.

mdales@mdedge.com

SOURCE: Anderson et al. Science 2018 Aug 31. doi: 10.1126/science.aam8419.

Sarcoma dominance in uterine carcinosarcomas was associated with decreased survival among women with stages I-IV uterine carcinosarcomas who underwent primary surgery, according to Dr Koji Matsuo, MD, PhD, of the Keck School of Medicine, University of Southern California, Los Angeles, and his colleagues.

The researchers additionally found that adding radiotherapy to chemotherapy may be an effective postoperative strategy for these patients.

Uterine carcinosarcomas are rare, high-grade endometrial cancers that represent 5% of all endometrial cancers. Sarcoma dominance was defined as having more than a 50% sarcoma component in the uterine tumor. In this study, the sarcoma component was grouped as homologous (endometrial stromal sarcoma, leiomyosarcoma, fibrosarcoma, and undifferentiated sarcoma) or heterologous (rhabdomyosarcoma, osteosarcoma, chondrosarcoma, and liposarcoma) types

Among 1,192 cases of uterine carcinosarcomas identified in a secondary analysis of a multicenter retrospective study, 906 cases were available for histopathology slide review. Of those, 889 cases had evaluation for sarcoma dominance. The most common group was homologous sarcoma without sarcoma dominance (39.5%), followed by heterologous sarcoma with sarcoma dominance (21.3%), homologous sarcoma with sarcoma dominance (19.7%) and heterologous sarcoma with sarcoma non-dominance (19.6%), they reported in a study published online in Surgical Oncology https://doi.org/10.1016/j.suronc.2018.05.017

On univariate analysis, sarcoma dominance was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (P less than 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homologous/dominance 1.35-1.69, and heterologous/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homologous/non-dominance (all, P less than 0.05).

In women with stage I-III disease, and tumors with sarcoma dominance, adding radiotherapy to chemotherapy was associated with improved PFS (adjusted-HR: homologous/dominance 0.49, and heterologous/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P less than 0.05); This association was not observed in women with tumors that lacked sarcoma dominance (all, P greater than 0.05), the researchers said.

Sarcoma dominance in uterine carcinosarcomas was associated with decreased survival among women with stages I-IV uterine carcinosarcomas who underwent primary surgery, according to Dr Koji Matsuo, MD, PhD, of the Keck School of Medicine, University of Southern California, Los Angeles, and his colleagues.

The researchers additionally found that adding radiotherapy to chemotherapy may be an effective postoperative strategy for these patients.

Uterine carcinosarcomas are rare, high-grade endometrial cancers that represent 5% of all endometrial cancers. Sarcoma dominance was defined as having more than a 50% sarcoma component in the uterine tumor. In this study, the sarcoma component was grouped as homologous (endometrial stromal sarcoma, leiomyosarcoma, fibrosarcoma, and undifferentiated sarcoma) or heterologous (rhabdomyosarcoma, osteosarcoma, chondrosarcoma, and liposarcoma) types

Among 1,192 cases of uterine carcinosarcomas identified in a secondary analysis of a multicenter retrospective study, 906 cases were available for histopathology slide review. Of those, 889 cases had evaluation for sarcoma dominance. The most common group was homologous sarcoma without sarcoma dominance (39.5%), followed by heterologous sarcoma with sarcoma dominance (21.3%), homologous sarcoma with sarcoma dominance (19.7%) and heterologous sarcoma with sarcoma non-dominance (19.6%), they reported in a study published online in Surgical Oncology https://doi.org/10.1016/j.suronc.2018.05.017

On univariate analysis, sarcoma dominance was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (P less than 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homologous/dominance 1.35-1.69, and heterologous/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homologous/non-dominance (all, P less than 0.05).

In women with stage I-III disease, and tumors with sarcoma dominance, adding radiotherapy to chemotherapy was associated with improved PFS (adjusted-HR: homologous/dominance 0.49, and heterologous/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P less than 0.05); This association was not observed in women with tumors that lacked sarcoma dominance (all, P greater than 0.05), the researchers said.

Sarcoma dominance in uterine carcinosarcomas was associated with decreased survival among women with stages I-IV uterine carcinosarcomas who underwent primary surgery, according to Dr Koji Matsuo, MD, PhD, of the Keck School of Medicine, University of Southern California, Los Angeles, and his colleagues.

The researchers additionally found that adding radiotherapy to chemotherapy may be an effective postoperative strategy for these patients.

Uterine carcinosarcomas are rare, high-grade endometrial cancers that represent 5% of all endometrial cancers. Sarcoma dominance was defined as having more than a 50% sarcoma component in the uterine tumor. In this study, the sarcoma component was grouped as homologous (endometrial stromal sarcoma, leiomyosarcoma, fibrosarcoma, and undifferentiated sarcoma) or heterologous (rhabdomyosarcoma, osteosarcoma, chondrosarcoma, and liposarcoma) types

Among 1,192 cases of uterine carcinosarcomas identified in a secondary analysis of a multicenter retrospective study, 906 cases were available for histopathology slide review. Of those, 889 cases had evaluation for sarcoma dominance. The most common group was homologous sarcoma without sarcoma dominance (39.5%), followed by heterologous sarcoma with sarcoma dominance (21.3%), homologous sarcoma with sarcoma dominance (19.7%) and heterologous sarcoma with sarcoma non-dominance (19.6%), they reported in a study published online in Surgical Oncology https://doi.org/10.1016/j.suronc.2018.05.017

On univariate analysis, sarcoma dominance was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (P less than 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homologous/dominance 1.35-1.69, and heterologous/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homologous/non-dominance (all, P less than 0.05).

In women with stage I-III disease, and tumors with sarcoma dominance, adding radiotherapy to chemotherapy was associated with improved PFS (adjusted-HR: homologous/dominance 0.49, and heterologous/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P less than 0.05); This association was not observed in women with tumors that lacked sarcoma dominance (all, P greater than 0.05), the researchers said.

Genomic profiling of soft tissue sarcomas detected mutations that could guide the use of targeted therapies in over 41% of patients, reported Carlo Lucchesi, PhD, of Institut Bergonié in Bordeaux, France, and his associates.

In a cross-sectional study of next-generation sequencing results from 584 patients with soft tissue sarcomas in the American Association for Cancer Research’s GENIE Database, 57% of patients had complex genomics sarcomas (sarcomas with multiple, complex karyotypic abnormalities with no specific pattern), 25% had translocation-related sarcomas (sarcomas with specific reciprocal translocations resulting in oncogenic fusion transcripts), and 18% had simple amplicon sarcomas or sarcomas with inactivating mutations.

A total of 2,697 alterations (1,154 substitutions, 765 gene amplifications, 364 short indels and splicing variants, 346 gene homozygous deletions, and 68 gene rearrangements) were identified in 451 genes. A median of four alterations per case were detected, the researchers wrote in a study published online May 3 in JAMA Oncology.

The researchers identified the 20 genes that were most often altered. The top 5 were TP53, MDM2, CDK4, RB1, and ATRX.

Among these 584 samples, 85% had at least one alteration. The proportions of affected patients in each sarcoma group varied significantly among groups, with the other sarcomas group being the most altered (90.8%) and translocation-related sarcomas being the least mutated (77.8%).

At least one relevant gene alteration that could potentially be used to guide targeted therapy was found in 239 cases (41%) with a statistically significant higher number in other sarcomas (89 cases) and complex genomics sarcomas (131 cases) than in translocation-related sarcomas (19 cases).

This finding of an “unexpectedly high frequency” of clinically relevant genetic alterations supports the premise of the soon-to-be-launched MULTISARC trial, which posits that next-generation sequencing results can be used to guide and improve the treatment outcomes of patients with advanced soft tissue sarcomas. For MULTISARC, such patients will be randomized either to an experimental group that will undergo exome and RNA sequencing – and their results will be discussed in a molecular tumor board to tailor the treatment – or to a control group that will not undergo molecular profiling and will receive conventional therapy. The program will include 16 targeted therapies.

The researchers reported having no relevant financial conflicts of interest.

mdales@mdedge.com

SOURCE: Lucchesi C et al. JAMA Oncol. doi: 10.1001/jamaoncol.2018.0723.

Genomic profiling of soft tissue sarcomas detected mutations that could guide the use of targeted therapies in over 41% of patients, reported Carlo Lucchesi, PhD, of Institut Bergonié in Bordeaux, France, and his associates.

In a cross-sectional study of next-generation sequencing results from 584 patients with soft tissue sarcomas in the American Association for Cancer Research’s GENIE Database, 57% of patients had complex genomics sarcomas (sarcomas with multiple, complex karyotypic abnormalities with no specific pattern), 25% had translocation-related sarcomas (sarcomas with specific reciprocal translocations resulting in oncogenic fusion transcripts), and 18% had simple amplicon sarcomas or sarcomas with inactivating mutations.

A total of 2,697 alterations (1,154 substitutions, 765 gene amplifications, 364 short indels and splicing variants, 346 gene homozygous deletions, and 68 gene rearrangements) were identified in 451 genes. A median of four alterations per case were detected, the researchers wrote in a study published online May 3 in JAMA Oncology.

The researchers identified the 20 genes that were most often altered. The top 5 were TP53, MDM2, CDK4, RB1, and ATRX.

Among these 584 samples, 85% had at least one alteration. The proportions of affected patients in each sarcoma group varied significantly among groups, with the other sarcomas group being the most altered (90.8%) and translocation-related sarcomas being the least mutated (77.8%).

At least one relevant gene alteration that could potentially be used to guide targeted therapy was found in 239 cases (41%) with a statistically significant higher number in other sarcomas (89 cases) and complex genomics sarcomas (131 cases) than in translocation-related sarcomas (19 cases).

This finding of an “unexpectedly high frequency” of clinically relevant genetic alterations supports the premise of the soon-to-be-launched MULTISARC trial, which posits that next-generation sequencing results can be used to guide and improve the treatment outcomes of patients with advanced soft tissue sarcomas. For MULTISARC, such patients will be randomized either to an experimental group that will undergo exome and RNA sequencing – and their results will be discussed in a molecular tumor board to tailor the treatment – or to a control group that will not undergo molecular profiling and will receive conventional therapy. The program will include 16 targeted therapies.

The researchers reported having no relevant financial conflicts of interest.

mdales@mdedge.com

SOURCE: Lucchesi C et al. JAMA Oncol. doi: 10.1001/jamaoncol.2018.0723.

Genomic profiling of soft tissue sarcomas detected mutations that could guide the use of targeted therapies in over 41% of patients, reported Carlo Lucchesi, PhD, of Institut Bergonié in Bordeaux, France, and his associates.

In a cross-sectional study of next-generation sequencing results from 584 patients with soft tissue sarcomas in the American Association for Cancer Research’s GENIE Database, 57% of patients had complex genomics sarcomas (sarcomas with multiple, complex karyotypic abnormalities with no specific pattern), 25% had translocation-related sarcomas (sarcomas with specific reciprocal translocations resulting in oncogenic fusion transcripts), and 18% had simple amplicon sarcomas or sarcomas with inactivating mutations.

A total of 2,697 alterations (1,154 substitutions, 765 gene amplifications, 364 short indels and splicing variants, 346 gene homozygous deletions, and 68 gene rearrangements) were identified in 451 genes. A median of four alterations per case were detected, the researchers wrote in a study published online May 3 in JAMA Oncology.

The researchers identified the 20 genes that were most often altered. The top 5 were TP53, MDM2, CDK4, RB1, and ATRX.

Among these 584 samples, 85% had at least one alteration. The proportions of affected patients in each sarcoma group varied significantly among groups, with the other sarcomas group being the most altered (90.8%) and translocation-related sarcomas being the least mutated (77.8%).

At least one relevant gene alteration that could potentially be used to guide targeted therapy was found in 239 cases (41%) with a statistically significant higher number in other sarcomas (89 cases) and complex genomics sarcomas (131 cases) than in translocation-related sarcomas (19 cases).

This finding of an “unexpectedly high frequency” of clinically relevant genetic alterations supports the premise of the soon-to-be-launched MULTISARC trial, which posits that next-generation sequencing results can be used to guide and improve the treatment outcomes of patients with advanced soft tissue sarcomas. For MULTISARC, such patients will be randomized either to an experimental group that will undergo exome and RNA sequencing – and their results will be discussed in a molecular tumor board to tailor the treatment – or to a control group that will not undergo molecular profiling and will receive conventional therapy. The program will include 16 targeted therapies.

The researchers reported having no relevant financial conflicts of interest.

mdales@mdedge.com

SOURCE: Lucchesi C et al. JAMA Oncol. doi: 10.1001/jamaoncol.2018.0723.