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Uterine cancer low in myomectomy with power morcellation
The prevalence of uterine cancer was 0.09% among women who underwent myomectomy with electric power morcellation, according to the results of a large database study, lower than for women who underwent myomectomy without power morcellation.
But the prevalence of uterine cancer increased with age, the researchers reported on Feb. 19 in JAMA Oncology.
“Given that older women are at the greatest risk for pathologic abnormalities, electric power morcellation should be approached with caution in patients older than 50 years undergoing myomectomy,” Dr. Jason D. Wright and his colleagues at Columbia University, New York, wrote (JAMA Oncol. 2015 Feb.19).
Electric power morcellation facilitates the excision of uterine leiomyoma in minimally invasive surgery. Its use has received increased scrutiny after a patient underwent hysterectomy with electric power morcellation for presumed benign leiomyoma that was, in fact, a uterine sarcoma, which was disseminated. The case has prompted an evaluation of electric power morcellation safety in performance of hysterectomy and myomectomy.
The Food and Drug Administration also entered the debate last year, issuing a safety alert for electric power morcellators in November and warning “against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids.”
The Columbia University researchers examined the prevalence of cancers and precancerous abnormalities of the uterus in women who underwent myomectomy from 2006 to 2012 using administrative data from the Perspective database.
Among 38,557 women who underwent myomectomy without electric power morcellation, uterine cancer prevalence was 0.19% or 1 in 528, and prevalence of any pathologic abnormality was 0.67% or 1 in 150.
For women who underwent the procedure with electric power morcellation, uterine cancer prevalence was 0.09% or 1 in 1,073, and prevalence of any pathologic abnormality was 0.43% or 1 in 230.
Age was the strongest risk factor for uterine cancer and other abnormalities.
Comparing women aged 50-59 years to women 60 years and older who had myomectomy without morcellation, the prevalence of uterine cancer increased from 0.62% to 3.40%. In women who had power morcellation, the prevalence of uterine cancer was 0.97% in women aged 50-59 years and 0% in those 60 years or older.
The researchers reported similar trends for endometrial hyperplasia and overall adverse pathologic findings.
The researchers reported having no financial disclosures.
Most systematic literature reviews and large studies have focused on hysterectomy patients, overlooking myomectomy patients, according to a commentary by Dr. Ceana Nezhat. Worldwide, thousands of myomectomies are performed in reproductive-age women to preserve and enhance fertility. The impact of tissue disruption at the time of myomectomy by any method carries a small risk of intraperitoneal dissemination of occult malignant tissue. Studies on the prevalence of malignant and premalignant uterine lesions in younger patients are needed to better understand the risks tumor dissemination during myomectomy by any method, he wrote.
“The FDA black box warning on power morcellators must not cause a reversal to laparotomy or increase in the number of hysterectomies for uterine tumors,” Dr. Nezhat wrote.
“The report by Wright et al. opens the door to the use of administrative data. However, there are significant differences between administrative data and clinical registries to measure outcome and surgical quality,” Dr. Nezhat wrote. An earlier report based on clinical data found that electric power morcellation was associated with substantially higher risk of abdominopelvic recurrence and lower disease-free survival than suggested by the Wright study, he wrote.
Using administrative data is much less expensive than maintaining prospective registries. Developing strategies to combine clinical data, including final pathology reports and long-term results, with administrative data will help in improving surgical quality, as well as aid in counseling patients based on scientific research, according to Dr. Nezhat.
Dr. Ceana Nezhat is a minimally invasive surgeon at the Atlanta Center for Minimally Invasive Surgery and Reproductive Medicine. These remarks were part of an editorial accompanying the report (JAMA Oncol. 2015 Feb. 19). Dr. Nezhat is a consultant for Karl Storz Endoscopy, a medical adviser to Plasma Surgical, and serves on the Scientific Advisory Board of SurgiQuest.
Most systematic literature reviews and large studies have focused on hysterectomy patients, overlooking myomectomy patients, according to a commentary by Dr. Ceana Nezhat. Worldwide, thousands of myomectomies are performed in reproductive-age women to preserve and enhance fertility. The impact of tissue disruption at the time of myomectomy by any method carries a small risk of intraperitoneal dissemination of occult malignant tissue. Studies on the prevalence of malignant and premalignant uterine lesions in younger patients are needed to better understand the risks tumor dissemination during myomectomy by any method, he wrote.
“The FDA black box warning on power morcellators must not cause a reversal to laparotomy or increase in the number of hysterectomies for uterine tumors,” Dr. Nezhat wrote.
“The report by Wright et al. opens the door to the use of administrative data. However, there are significant differences between administrative data and clinical registries to measure outcome and surgical quality,” Dr. Nezhat wrote. An earlier report based on clinical data found that electric power morcellation was associated with substantially higher risk of abdominopelvic recurrence and lower disease-free survival than suggested by the Wright study, he wrote.
Using administrative data is much less expensive than maintaining prospective registries. Developing strategies to combine clinical data, including final pathology reports and long-term results, with administrative data will help in improving surgical quality, as well as aid in counseling patients based on scientific research, according to Dr. Nezhat.
Dr. Ceana Nezhat is a minimally invasive surgeon at the Atlanta Center for Minimally Invasive Surgery and Reproductive Medicine. These remarks were part of an editorial accompanying the report (JAMA Oncol. 2015 Feb. 19). Dr. Nezhat is a consultant for Karl Storz Endoscopy, a medical adviser to Plasma Surgical, and serves on the Scientific Advisory Board of SurgiQuest.
Most systematic literature reviews and large studies have focused on hysterectomy patients, overlooking myomectomy patients, according to a commentary by Dr. Ceana Nezhat. Worldwide, thousands of myomectomies are performed in reproductive-age women to preserve and enhance fertility. The impact of tissue disruption at the time of myomectomy by any method carries a small risk of intraperitoneal dissemination of occult malignant tissue. Studies on the prevalence of malignant and premalignant uterine lesions in younger patients are needed to better understand the risks tumor dissemination during myomectomy by any method, he wrote.
“The FDA black box warning on power morcellators must not cause a reversal to laparotomy or increase in the number of hysterectomies for uterine tumors,” Dr. Nezhat wrote.
“The report by Wright et al. opens the door to the use of administrative data. However, there are significant differences between administrative data and clinical registries to measure outcome and surgical quality,” Dr. Nezhat wrote. An earlier report based on clinical data found that electric power morcellation was associated with substantially higher risk of abdominopelvic recurrence and lower disease-free survival than suggested by the Wright study, he wrote.
Using administrative data is much less expensive than maintaining prospective registries. Developing strategies to combine clinical data, including final pathology reports and long-term results, with administrative data will help in improving surgical quality, as well as aid in counseling patients based on scientific research, according to Dr. Nezhat.
Dr. Ceana Nezhat is a minimally invasive surgeon at the Atlanta Center for Minimally Invasive Surgery and Reproductive Medicine. These remarks were part of an editorial accompanying the report (JAMA Oncol. 2015 Feb. 19). Dr. Nezhat is a consultant for Karl Storz Endoscopy, a medical adviser to Plasma Surgical, and serves on the Scientific Advisory Board of SurgiQuest.
The prevalence of uterine cancer was 0.09% among women who underwent myomectomy with electric power morcellation, according to the results of a large database study, lower than for women who underwent myomectomy without power morcellation.
But the prevalence of uterine cancer increased with age, the researchers reported on Feb. 19 in JAMA Oncology.
“Given that older women are at the greatest risk for pathologic abnormalities, electric power morcellation should be approached with caution in patients older than 50 years undergoing myomectomy,” Dr. Jason D. Wright and his colleagues at Columbia University, New York, wrote (JAMA Oncol. 2015 Feb.19).
Electric power morcellation facilitates the excision of uterine leiomyoma in minimally invasive surgery. Its use has received increased scrutiny after a patient underwent hysterectomy with electric power morcellation for presumed benign leiomyoma that was, in fact, a uterine sarcoma, which was disseminated. The case has prompted an evaluation of electric power morcellation safety in performance of hysterectomy and myomectomy.
The Food and Drug Administration also entered the debate last year, issuing a safety alert for electric power morcellators in November and warning “against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids.”
The Columbia University researchers examined the prevalence of cancers and precancerous abnormalities of the uterus in women who underwent myomectomy from 2006 to 2012 using administrative data from the Perspective database.
Among 38,557 women who underwent myomectomy without electric power morcellation, uterine cancer prevalence was 0.19% or 1 in 528, and prevalence of any pathologic abnormality was 0.67% or 1 in 150.
For women who underwent the procedure with electric power morcellation, uterine cancer prevalence was 0.09% or 1 in 1,073, and prevalence of any pathologic abnormality was 0.43% or 1 in 230.
Age was the strongest risk factor for uterine cancer and other abnormalities.
Comparing women aged 50-59 years to women 60 years and older who had myomectomy without morcellation, the prevalence of uterine cancer increased from 0.62% to 3.40%. In women who had power morcellation, the prevalence of uterine cancer was 0.97% in women aged 50-59 years and 0% in those 60 years or older.
The researchers reported similar trends for endometrial hyperplasia and overall adverse pathologic findings.
The researchers reported having no financial disclosures.
The prevalence of uterine cancer was 0.09% among women who underwent myomectomy with electric power morcellation, according to the results of a large database study, lower than for women who underwent myomectomy without power morcellation.
But the prevalence of uterine cancer increased with age, the researchers reported on Feb. 19 in JAMA Oncology.
“Given that older women are at the greatest risk for pathologic abnormalities, electric power morcellation should be approached with caution in patients older than 50 years undergoing myomectomy,” Dr. Jason D. Wright and his colleagues at Columbia University, New York, wrote (JAMA Oncol. 2015 Feb.19).
Electric power morcellation facilitates the excision of uterine leiomyoma in minimally invasive surgery. Its use has received increased scrutiny after a patient underwent hysterectomy with electric power morcellation for presumed benign leiomyoma that was, in fact, a uterine sarcoma, which was disseminated. The case has prompted an evaluation of electric power morcellation safety in performance of hysterectomy and myomectomy.
The Food and Drug Administration also entered the debate last year, issuing a safety alert for electric power morcellators in November and warning “against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids.”
The Columbia University researchers examined the prevalence of cancers and precancerous abnormalities of the uterus in women who underwent myomectomy from 2006 to 2012 using administrative data from the Perspective database.
Among 38,557 women who underwent myomectomy without electric power morcellation, uterine cancer prevalence was 0.19% or 1 in 528, and prevalence of any pathologic abnormality was 0.67% or 1 in 150.
For women who underwent the procedure with electric power morcellation, uterine cancer prevalence was 0.09% or 1 in 1,073, and prevalence of any pathologic abnormality was 0.43% or 1 in 230.
Age was the strongest risk factor for uterine cancer and other abnormalities.
Comparing women aged 50-59 years to women 60 years and older who had myomectomy without morcellation, the prevalence of uterine cancer increased from 0.62% to 3.40%. In women who had power morcellation, the prevalence of uterine cancer was 0.97% in women aged 50-59 years and 0% in those 60 years or older.
The researchers reported similar trends for endometrial hyperplasia and overall adverse pathologic findings.
The researchers reported having no financial disclosures.
FROM JAMA ONCOLOGY
Key clinical point: Among women who underwent myomectomy, the prevalence of cancers was low but increased with age.
Major finding: Rates of uterine cancers for women who underwent myomectomy with and without electric power morcellation were 0.09% and 0.19%, respectively.
Data source: The nationwide database study retrospectively analyzed 41,777 women who underwent myomectomy in 496 U.S. hospitals.
Disclosures: The researchers reported having no financial disclosures.
Bevacizumab plus ET failed to improve PFS in HER2-negative, HR-positive BC
First-line treatment with endocrine therapy plus bevacizumab did not significantly improve PFS compared with endocrine therapy alone for postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer, according to results from a multicenter phase III trial published online Feb. 17 in Journal of Clinical Oncology.
Furthermore, patients taking endocrine therapy plus bevacizumab (ET-B) had significantly more adverse events.
“On the basis of this particular trial and in light of the higher toxicity, ET-B should not be recommended in the treatment of advanced hormone receptor-positive/HER2-negative breast cancer,” wrote Dr. Miguel Martín of Universidad Complutense de Madrid and his associates (J. Clin. Oncol. 2015 Feb. 17 [doi:10.1200/JCO.2014.57.2388]).
Previous studies have shown overexpression of VEGF in breast cancer and that high VEGF levels are associated with early recurrence and resistance to hormone therapy. The Letrozole/Fulvestrant and Avastin (LEA) Study evaluated whether anti-VEGF bevacizumab in combination with ET would improve outcomes. After a median follow up of 23.7 months, patients in the ET-B arm had a median PFS of 19.3 months (95% CI, 16.5-22.1) vs. 14.4 months (11.4-17.5) for patients taking ET alone (P = .125). Compared with the ET alone arm, patients in the ET-B arm had improved ORR (40.8% vs 21.9%, P < .001) and CBR (76.8% vs 67.4%, P = .041). Grade 3-4 adverse events were significantly more frequent in the ET-B arm, including hypertension (15.0% vs 3.0%, P < .001), aminotransferase elevation (3.7% vs 1.0%, P = .068), and proteinuria (7.0% vs 0.0%, P < .001). In the ET-B arm, 39 patients (20.5%) discontinued treatment, including 8 patients who died. There were no toxicity-related deaths in the ET arm.
“Although the potential impact of age and comorbidities should not be discounted in the mortality outcomes of the LEA study, we observed an unexpectedly high rate of toxicity-related deaths among patients receiving ET-B. In addition, adverse events were significantly higher in the ET-B arm. Therefore, a toxicity interaction between these agents cannot be ruled out and should be carefully monitored in ongoing studies with this combination,” wrote Dr. Martin and colleagues.
First-line treatment with endocrine therapy plus bevacizumab did not significantly improve PFS compared with endocrine therapy alone for postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer, according to results from a multicenter phase III trial published online Feb. 17 in Journal of Clinical Oncology.
Furthermore, patients taking endocrine therapy plus bevacizumab (ET-B) had significantly more adverse events.
“On the basis of this particular trial and in light of the higher toxicity, ET-B should not be recommended in the treatment of advanced hormone receptor-positive/HER2-negative breast cancer,” wrote Dr. Miguel Martín of Universidad Complutense de Madrid and his associates (J. Clin. Oncol. 2015 Feb. 17 [doi:10.1200/JCO.2014.57.2388]).
Previous studies have shown overexpression of VEGF in breast cancer and that high VEGF levels are associated with early recurrence and resistance to hormone therapy. The Letrozole/Fulvestrant and Avastin (LEA) Study evaluated whether anti-VEGF bevacizumab in combination with ET would improve outcomes. After a median follow up of 23.7 months, patients in the ET-B arm had a median PFS of 19.3 months (95% CI, 16.5-22.1) vs. 14.4 months (11.4-17.5) for patients taking ET alone (P = .125). Compared with the ET alone arm, patients in the ET-B arm had improved ORR (40.8% vs 21.9%, P < .001) and CBR (76.8% vs 67.4%, P = .041). Grade 3-4 adverse events were significantly more frequent in the ET-B arm, including hypertension (15.0% vs 3.0%, P < .001), aminotransferase elevation (3.7% vs 1.0%, P = .068), and proteinuria (7.0% vs 0.0%, P < .001). In the ET-B arm, 39 patients (20.5%) discontinued treatment, including 8 patients who died. There were no toxicity-related deaths in the ET arm.
“Although the potential impact of age and comorbidities should not be discounted in the mortality outcomes of the LEA study, we observed an unexpectedly high rate of toxicity-related deaths among patients receiving ET-B. In addition, adverse events were significantly higher in the ET-B arm. Therefore, a toxicity interaction between these agents cannot be ruled out and should be carefully monitored in ongoing studies with this combination,” wrote Dr. Martin and colleagues.
First-line treatment with endocrine therapy plus bevacizumab did not significantly improve PFS compared with endocrine therapy alone for postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer, according to results from a multicenter phase III trial published online Feb. 17 in Journal of Clinical Oncology.
Furthermore, patients taking endocrine therapy plus bevacizumab (ET-B) had significantly more adverse events.
“On the basis of this particular trial and in light of the higher toxicity, ET-B should not be recommended in the treatment of advanced hormone receptor-positive/HER2-negative breast cancer,” wrote Dr. Miguel Martín of Universidad Complutense de Madrid and his associates (J. Clin. Oncol. 2015 Feb. 17 [doi:10.1200/JCO.2014.57.2388]).
Previous studies have shown overexpression of VEGF in breast cancer and that high VEGF levels are associated with early recurrence and resistance to hormone therapy. The Letrozole/Fulvestrant and Avastin (LEA) Study evaluated whether anti-VEGF bevacizumab in combination with ET would improve outcomes. After a median follow up of 23.7 months, patients in the ET-B arm had a median PFS of 19.3 months (95% CI, 16.5-22.1) vs. 14.4 months (11.4-17.5) for patients taking ET alone (P = .125). Compared with the ET alone arm, patients in the ET-B arm had improved ORR (40.8% vs 21.9%, P < .001) and CBR (76.8% vs 67.4%, P = .041). Grade 3-4 adverse events were significantly more frequent in the ET-B arm, including hypertension (15.0% vs 3.0%, P < .001), aminotransferase elevation (3.7% vs 1.0%, P = .068), and proteinuria (7.0% vs 0.0%, P < .001). In the ET-B arm, 39 patients (20.5%) discontinued treatment, including 8 patients who died. There were no toxicity-related deaths in the ET arm.
“Although the potential impact of age and comorbidities should not be discounted in the mortality outcomes of the LEA study, we observed an unexpectedly high rate of toxicity-related deaths among patients receiving ET-B. In addition, adverse events were significantly higher in the ET-B arm. Therefore, a toxicity interaction between these agents cannot be ruled out and should be carefully monitored in ongoing studies with this combination,” wrote Dr. Martin and colleagues.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: In women with HER2-negative, hormone receptor–positive breast cancer, the addition of bevacizumab to endocrine therapy did not significantly improve PFS or OS.
Major finding: Median PFS for ET alone vs ET-B was 14.4 months vs 19.3 months; patients taking ET-B had significantly more adverse events.
Data source: The open-label phase III Letrozole/Fulvestrant and Avastin Study that randomized 374 patients to receive fulvestrant or letrozole alone (n = 184) or ET plus bevacizumab (n = 190).
Disclosures: Dr. Martín disclosed that he is a consultant for Roche/Genentech.
Time and money spent locating unknown primary tumor site might be better spent on genomic analyses
A genomic analysis of 200 carcinoma of unknown primary site, or CUP samples found that nearly all (96%) contained at least one genetic alteration, and most (85%) had one or more clinically relevant mutation. Adenocarcinomas of unknown primary site, or ACUPs accounted for 63% of the total and non-ACUP cases comprised 38%.
Investigators analyzed tumor samples that had no confirmed primary site, based on analyses by diagnostic imaging, immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), serum biomarkers, mRNA transcriptional profiles, and/or prior surgery.
“Some oncologists have hypothesized that a test that can guide targeted therapy selection for patients with CUP ‘up front’ would have utility in clinical management and could help avert the expensive and potentially futile search for the primary lesion that is often pursued,” Dr. Jeffrey Ross and his colleagues wrote (JAMA Oncol. 2015 Feb. 12 [doi:10.1001/jamaoncol.2014.216]).
Clinically relevant genetic alterations (GAs) were defined as those genes targeted by drugs currently on the market or in clinical trials. Out of 169 CUP samples that contained relevant GAs, 113 were in the ACUP group, and 90 (72%) of these were in the receptor tyrosine kinase (RTK)/Ras signaling pathway. Non-ACUP samples had a much smaller proportion in this pathway, 39% of the relevant GAs.
The most common clinically relevant GAs that could potentially affect treatment decisions included KRAS (20%), CDKN2A (19%), MCL1 (10%), PTEN (7%), PIK3CA (9%), ERBB2 (8%), RICTOR (6%), BRAF (6%), and NF1 (4%).
The authors suggest that comprehensive genomic profiling (CGP) analysis may offer cost savings. A CUP diagnostic work-up might include imaging procedures, IHC panels, serum tumor marker panels, and mRNA profiling, and often costs over $10,000. In about one-quarter of cases, the primary site remains unknown, and therapies considered are off label.
The need to locate the primary tumor site when a patient presents with metastatic disease is called into question by a clinical outcome study that reports the impact of therapy selection based on knowledge of the primary site is estimated to be at most several months. Dr. Ross and his associates did not seek to identify the primary site, but rather to identify a treatment option specific to the tumor. Use of CGP at time of diagnosis may enable identification of targeted treatment options to improve response rates, progression-free survival, and overall survival without searching for the primary site.
Clinical trials are needed to compare front-line use of CGP to identify targeted regimens with conventional use of nonspecific cytotoxic chemotherapy in patients with CUP.
“Only by routinely investigating the genomic landscape of a tumor can we realize the full clinical impact of refocusing diagnostic testing away from costly laboratory and imaging studies,” wrote Dr. Ross and associates.
The study by Ross et al. on comprehensive genomic profiling to aid in CUP treatment reflects the broader push toward personalized medicine that aims to identify driver mutations that can be targeted specifically in cancer treatment. Because a proportion of CUP cases entail nonspecific chemotherapy treatment, it is a natural fit for targeted therapies independent of tumor site.
A CUP diagnosis requires a search using imaging and pathological analyses for the primary tumor. IHC analysis provides useful information because expression profiles of the primary and metastatic cancers show concordance. Some patients with CUP and with site-specific IHC and select mutations have well-defined therapy options. Until site-specific therapies for known cancers are replaced by GA-based targeted therapies, some basic IHC analysis should not be abandoned. What is urgently needed is a tiered, uniform set of IHC markers to promptly determine diagnostic patterns.
Among the roughly 75% of patients for whom first-level IHC fails to indicate a primary site, alternative diagnostic procedures include additional IH, molecular tissue of origin (ToO) profiling, or next-generation sequencing (NGS) tools.
Imaging and pathology information are essential to arrive at a better understanding of CGP results. Most CUP tumors likely have multiple mutations, and determining the oncogenic drivers is easier when approached from a cellular context. A KRAS mutation in a patient with a “lung profile” may have different implications than in a patient with a “colorectal profile.”
A traditional randomized trial to evaluate NGS tools presents challenges given the heterogeneity of CUP. A prospective randomized trial design might require more than 500 patients to achieve unambiguous results. Piggybacking on established trials may present a more efficient way forward. The Molecular Profiling-Based Assignment of Cancer Therapeutics (M-PACT) from the National Cancer Institute examines whether treatment based on specific genetic mutations improves overall response rate and/or 4-month progression-free survival in patients with advanced solid tumors.
Moving forward with better diagnosis and treatments requires a selective diagnostic approach that leverages proteomics and genomics tools as well as careful selection of the types of research trials that will deliver validated results.
Dr. Gauri Varadhachary is a professor in the department of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston. These comments were taken from an editorial accompanying the article (JAMA Oncol. 2015 Feb. 12 [doi:10.1001/jamaoncol.2014.277]).
The study by Ross et al. on comprehensive genomic profiling to aid in CUP treatment reflects the broader push toward personalized medicine that aims to identify driver mutations that can be targeted specifically in cancer treatment. Because a proportion of CUP cases entail nonspecific chemotherapy treatment, it is a natural fit for targeted therapies independent of tumor site.
A CUP diagnosis requires a search using imaging and pathological analyses for the primary tumor. IHC analysis provides useful information because expression profiles of the primary and metastatic cancers show concordance. Some patients with CUP and with site-specific IHC and select mutations have well-defined therapy options. Until site-specific therapies for known cancers are replaced by GA-based targeted therapies, some basic IHC analysis should not be abandoned. What is urgently needed is a tiered, uniform set of IHC markers to promptly determine diagnostic patterns.
Among the roughly 75% of patients for whom first-level IHC fails to indicate a primary site, alternative diagnostic procedures include additional IH, molecular tissue of origin (ToO) profiling, or next-generation sequencing (NGS) tools.
Imaging and pathology information are essential to arrive at a better understanding of CGP results. Most CUP tumors likely have multiple mutations, and determining the oncogenic drivers is easier when approached from a cellular context. A KRAS mutation in a patient with a “lung profile” may have different implications than in a patient with a “colorectal profile.”
A traditional randomized trial to evaluate NGS tools presents challenges given the heterogeneity of CUP. A prospective randomized trial design might require more than 500 patients to achieve unambiguous results. Piggybacking on established trials may present a more efficient way forward. The Molecular Profiling-Based Assignment of Cancer Therapeutics (M-PACT) from the National Cancer Institute examines whether treatment based on specific genetic mutations improves overall response rate and/or 4-month progression-free survival in patients with advanced solid tumors.
Moving forward with better diagnosis and treatments requires a selective diagnostic approach that leverages proteomics and genomics tools as well as careful selection of the types of research trials that will deliver validated results.
Dr. Gauri Varadhachary is a professor in the department of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston. These comments were taken from an editorial accompanying the article (JAMA Oncol. 2015 Feb. 12 [doi:10.1001/jamaoncol.2014.277]).
The study by Ross et al. on comprehensive genomic profiling to aid in CUP treatment reflects the broader push toward personalized medicine that aims to identify driver mutations that can be targeted specifically in cancer treatment. Because a proportion of CUP cases entail nonspecific chemotherapy treatment, it is a natural fit for targeted therapies independent of tumor site.
A CUP diagnosis requires a search using imaging and pathological analyses for the primary tumor. IHC analysis provides useful information because expression profiles of the primary and metastatic cancers show concordance. Some patients with CUP and with site-specific IHC and select mutations have well-defined therapy options. Until site-specific therapies for known cancers are replaced by GA-based targeted therapies, some basic IHC analysis should not be abandoned. What is urgently needed is a tiered, uniform set of IHC markers to promptly determine diagnostic patterns.
Among the roughly 75% of patients for whom first-level IHC fails to indicate a primary site, alternative diagnostic procedures include additional IH, molecular tissue of origin (ToO) profiling, or next-generation sequencing (NGS) tools.
Imaging and pathology information are essential to arrive at a better understanding of CGP results. Most CUP tumors likely have multiple mutations, and determining the oncogenic drivers is easier when approached from a cellular context. A KRAS mutation in a patient with a “lung profile” may have different implications than in a patient with a “colorectal profile.”
A traditional randomized trial to evaluate NGS tools presents challenges given the heterogeneity of CUP. A prospective randomized trial design might require more than 500 patients to achieve unambiguous results. Piggybacking on established trials may present a more efficient way forward. The Molecular Profiling-Based Assignment of Cancer Therapeutics (M-PACT) from the National Cancer Institute examines whether treatment based on specific genetic mutations improves overall response rate and/or 4-month progression-free survival in patients with advanced solid tumors.
Moving forward with better diagnosis and treatments requires a selective diagnostic approach that leverages proteomics and genomics tools as well as careful selection of the types of research trials that will deliver validated results.
Dr. Gauri Varadhachary is a professor in the department of gastrointestinal medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston. These comments were taken from an editorial accompanying the article (JAMA Oncol. 2015 Feb. 12 [doi:10.1001/jamaoncol.2014.277]).
A genomic analysis of 200 carcinoma of unknown primary site, or CUP samples found that nearly all (96%) contained at least one genetic alteration, and most (85%) had one or more clinically relevant mutation. Adenocarcinomas of unknown primary site, or ACUPs accounted for 63% of the total and non-ACUP cases comprised 38%.
Investigators analyzed tumor samples that had no confirmed primary site, based on analyses by diagnostic imaging, immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), serum biomarkers, mRNA transcriptional profiles, and/or prior surgery.
“Some oncologists have hypothesized that a test that can guide targeted therapy selection for patients with CUP ‘up front’ would have utility in clinical management and could help avert the expensive and potentially futile search for the primary lesion that is often pursued,” Dr. Jeffrey Ross and his colleagues wrote (JAMA Oncol. 2015 Feb. 12 [doi:10.1001/jamaoncol.2014.216]).
Clinically relevant genetic alterations (GAs) were defined as those genes targeted by drugs currently on the market or in clinical trials. Out of 169 CUP samples that contained relevant GAs, 113 were in the ACUP group, and 90 (72%) of these were in the receptor tyrosine kinase (RTK)/Ras signaling pathway. Non-ACUP samples had a much smaller proportion in this pathway, 39% of the relevant GAs.
The most common clinically relevant GAs that could potentially affect treatment decisions included KRAS (20%), CDKN2A (19%), MCL1 (10%), PTEN (7%), PIK3CA (9%), ERBB2 (8%), RICTOR (6%), BRAF (6%), and NF1 (4%).
The authors suggest that comprehensive genomic profiling (CGP) analysis may offer cost savings. A CUP diagnostic work-up might include imaging procedures, IHC panels, serum tumor marker panels, and mRNA profiling, and often costs over $10,000. In about one-quarter of cases, the primary site remains unknown, and therapies considered are off label.
The need to locate the primary tumor site when a patient presents with metastatic disease is called into question by a clinical outcome study that reports the impact of therapy selection based on knowledge of the primary site is estimated to be at most several months. Dr. Ross and his associates did not seek to identify the primary site, but rather to identify a treatment option specific to the tumor. Use of CGP at time of diagnosis may enable identification of targeted treatment options to improve response rates, progression-free survival, and overall survival without searching for the primary site.
Clinical trials are needed to compare front-line use of CGP to identify targeted regimens with conventional use of nonspecific cytotoxic chemotherapy in patients with CUP.
“Only by routinely investigating the genomic landscape of a tumor can we realize the full clinical impact of refocusing diagnostic testing away from costly laboratory and imaging studies,” wrote Dr. Ross and associates.
A genomic analysis of 200 carcinoma of unknown primary site, or CUP samples found that nearly all (96%) contained at least one genetic alteration, and most (85%) had one or more clinically relevant mutation. Adenocarcinomas of unknown primary site, or ACUPs accounted for 63% of the total and non-ACUP cases comprised 38%.
Investigators analyzed tumor samples that had no confirmed primary site, based on analyses by diagnostic imaging, immunohistochemical (IHC) staining, fluorescence in situ hybridization (FISH), serum biomarkers, mRNA transcriptional profiles, and/or prior surgery.
“Some oncologists have hypothesized that a test that can guide targeted therapy selection for patients with CUP ‘up front’ would have utility in clinical management and could help avert the expensive and potentially futile search for the primary lesion that is often pursued,” Dr. Jeffrey Ross and his colleagues wrote (JAMA Oncol. 2015 Feb. 12 [doi:10.1001/jamaoncol.2014.216]).
Clinically relevant genetic alterations (GAs) were defined as those genes targeted by drugs currently on the market or in clinical trials. Out of 169 CUP samples that contained relevant GAs, 113 were in the ACUP group, and 90 (72%) of these were in the receptor tyrosine kinase (RTK)/Ras signaling pathway. Non-ACUP samples had a much smaller proportion in this pathway, 39% of the relevant GAs.
The most common clinically relevant GAs that could potentially affect treatment decisions included KRAS (20%), CDKN2A (19%), MCL1 (10%), PTEN (7%), PIK3CA (9%), ERBB2 (8%), RICTOR (6%), BRAF (6%), and NF1 (4%).
The authors suggest that comprehensive genomic profiling (CGP) analysis may offer cost savings. A CUP diagnostic work-up might include imaging procedures, IHC panels, serum tumor marker panels, and mRNA profiling, and often costs over $10,000. In about one-quarter of cases, the primary site remains unknown, and therapies considered are off label.
The need to locate the primary tumor site when a patient presents with metastatic disease is called into question by a clinical outcome study that reports the impact of therapy selection based on knowledge of the primary site is estimated to be at most several months. Dr. Ross and his associates did not seek to identify the primary site, but rather to identify a treatment option specific to the tumor. Use of CGP at time of diagnosis may enable identification of targeted treatment options to improve response rates, progression-free survival, and overall survival without searching for the primary site.
Clinical trials are needed to compare front-line use of CGP to identify targeted regimens with conventional use of nonspecific cytotoxic chemotherapy in patients with CUP.
“Only by routinely investigating the genomic landscape of a tumor can we realize the full clinical impact of refocusing diagnostic testing away from costly laboratory and imaging studies,” wrote Dr. Ross and associates.
FROM JAMA ONCOLOGY
Key clinical point: The resources and time spent to locate the primary tumor site in patients with metastatic unknown primary cancer might be better allocated to a genomic analysis of the metastases to guide treatment.
Major finding: Among 200 samples of metastatic carcinoma of unknown primary site evaluated, genomic profiling identified ≥ 1 clinically relevant genetic alteration in 186 (85%).
Data source: The prospective trial evaluated CUP tumor samples by comprehensive genomic profiling using the hybrid-capture FoundationOne assay on the Illumina HiSeq 2500 instrument.
Disclosures: Dr. Ross is affiliated with Foundation Medicine Inc.
Overall survival plateaus at 3 years for ipilimumab-treated melanoma patients
Among patients with advanced melanoma who were treated with ipilimumab, about 20%-26% survived to 3 years, and these patients are likely to have a good long-term outcome, according to a pooled analysis of survival data published online Feb. 9 in the Journal of Clinical Oncology.
Investigators pooled data from ten prospective (including two phase III trials) and two retrospective studies with a total of 1,257 previously treated and 604 treatment-naive patients. At least 3 years after receiving ipilimumab, 254 patients were still alive, with a median follow up for this subset of 69 months. Around year 3, the Kaplan-Meier overall survival (OS) curve began to plateau and extended to 9.9 years for the longest survival follow-up.
“These results suggest that the majority of patients who reached this milestone time point had a low risk of death thereafter,” wrote Dr. Dirk Schadendorf and his associates (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]).
Compared with patients who were previously treated, treatment-naive patients had a higher median overall survival (13.5 months [95% confidence interval, 11.9-15.4] vs. 10.7 months [9.6-11.4]) and higher 3-year-survival rates (26% [21%-30%] vs. 20% [18%-23%]). No definitive conclusion could be drawn from this observation, however, since nonrandomized subsets were used for this analysis. Subset analysis by dose showed similar median OS and 3-year survival rates for ipilimumab 3 mg/kg, 10 mg/kg, and other dosing regimens.
The researchers expanded the study to include overall survival (OS) data from 2,985 patients enrolled in a U.S. multicenter, open-label, expanded-access treatment protocol (EAP). This group included patients with poorer prognostic factors, some of whom were ineligible for clinical trials. The expanded group showed a lower median OS of 9.5 months and 3 year–survival rate of 21%, with the familiar OS curve plateau around 3 years that extended up to 10 years in some patients.
While this analysis only examined overall survival rates, individual ipilimumab studies that tracked patient responses to the drug have shown that some proportion of long-term survivors did not achieve a response. Identifying the specific disease characteristics of the long-term survivors will require further study.
“Considering the historic median OS of approximately 8-10 months and a 5-year survival rate of approximately 10% in advanced melanoma, the results presented herein are encouraging for patients diagnosed with this aggressive disease,” the authors wrote.
Dr. Schadendorf and his associates demonstrate a plateau in the survival curve of ipilimumab-treated patients beginning at about 3 years and representing about 21% of the treatment group. The curve suggests that those who survive to 3 years are highly likely to have a good long-term outcome, which provides a strong motivating factor in the decision to consider ipilimumab treatment. While pooled data adds information far beyond individual trials, a major drawback lies in the loss of control data necessary to isolate the added benefit of the study drug.
An indirect comparison using historic control series, in this case a large cohort documented in the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, can substitute for missing control data in the pooled analysis. Reviewing data for stage IIIc and IV patients, the overall survival Kaplan-Meier curves in this population also show a plateau, but much later than that reported for ipilimumab, at beyond 8 years.
The AJCC melanoma classification gives survival rates at 3, 5, and 10 years of 19%, 13%, and 9%, respectively. Comparison with ipilimumab data suggests that survival at 3 years is similar, but thereafter improves with ipilimumab by 10% over other treatments that were available at the time. This difference is similar to the percentage of patients who achieved objective responses with ipilimumab. Although assessing response rate and progression-free survival in patients treated with ipilimumab presents challenges, the long-term benefits of ipilimumab could be better ascertained if information on the number of patients in the 21% plateau who were disease free or stably maintaining response had been collected.
Evaluation of long-term benefits of ipilimumab should consider toxicities and costs, as it is one of the most costly systemic therapies used for cancer treatment. The phase III trial using the drug at 3 mg/kg demonstrated that the large majority of patients had no serious adverse effects. If older patients and those with advanced disease are candidates, then the 10%-15% of grade 3 or 4 adverse events may translate to hospitalization and added expense, putting health regulatory systems in the position to deny widespread use of the agent despite proven benefit.
As the first agent to benefit overall survival of patients with advanced melanoma, ipilimumab may pave the way to broader improvements in a larger proportion of patients by combining with targeted therapies, such as BRAF and MEK inhibitors, and other new immunotherapies, such as anti-PD-1 antibodies.
Dr. Antoni Ribas is an oncologist with the Jonsson Comprehensive Cancer Center, Los Angles, and Dr. Keith T. Flaherty is an oncologist with Massachusetts General Hospital Cancer Center, Boston. These remarks were part of an editorial accompanying the report (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]). Dr. Ribas has an advisory role with Merck, Amgen, Novartis, GlaxoSmithKline, and Genentech/Roche. Dr. Flaherty has an advisory role with GlaxoSmithKline, Genentech/Roche, Novartis, and Merck.
Dr. Schadendorf and his associates demonstrate a plateau in the survival curve of ipilimumab-treated patients beginning at about 3 years and representing about 21% of the treatment group. The curve suggests that those who survive to 3 years are highly likely to have a good long-term outcome, which provides a strong motivating factor in the decision to consider ipilimumab treatment. While pooled data adds information far beyond individual trials, a major drawback lies in the loss of control data necessary to isolate the added benefit of the study drug.
An indirect comparison using historic control series, in this case a large cohort documented in the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, can substitute for missing control data in the pooled analysis. Reviewing data for stage IIIc and IV patients, the overall survival Kaplan-Meier curves in this population also show a plateau, but much later than that reported for ipilimumab, at beyond 8 years.
The AJCC melanoma classification gives survival rates at 3, 5, and 10 years of 19%, 13%, and 9%, respectively. Comparison with ipilimumab data suggests that survival at 3 years is similar, but thereafter improves with ipilimumab by 10% over other treatments that were available at the time. This difference is similar to the percentage of patients who achieved objective responses with ipilimumab. Although assessing response rate and progression-free survival in patients treated with ipilimumab presents challenges, the long-term benefits of ipilimumab could be better ascertained if information on the number of patients in the 21% plateau who were disease free or stably maintaining response had been collected.
Evaluation of long-term benefits of ipilimumab should consider toxicities and costs, as it is one of the most costly systemic therapies used for cancer treatment. The phase III trial using the drug at 3 mg/kg demonstrated that the large majority of patients had no serious adverse effects. If older patients and those with advanced disease are candidates, then the 10%-15% of grade 3 or 4 adverse events may translate to hospitalization and added expense, putting health regulatory systems in the position to deny widespread use of the agent despite proven benefit.
As the first agent to benefit overall survival of patients with advanced melanoma, ipilimumab may pave the way to broader improvements in a larger proportion of patients by combining with targeted therapies, such as BRAF and MEK inhibitors, and other new immunotherapies, such as anti-PD-1 antibodies.
Dr. Antoni Ribas is an oncologist with the Jonsson Comprehensive Cancer Center, Los Angles, and Dr. Keith T. Flaherty is an oncologist with Massachusetts General Hospital Cancer Center, Boston. These remarks were part of an editorial accompanying the report (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]). Dr. Ribas has an advisory role with Merck, Amgen, Novartis, GlaxoSmithKline, and Genentech/Roche. Dr. Flaherty has an advisory role with GlaxoSmithKline, Genentech/Roche, Novartis, and Merck.
Dr. Schadendorf and his associates demonstrate a plateau in the survival curve of ipilimumab-treated patients beginning at about 3 years and representing about 21% of the treatment group. The curve suggests that those who survive to 3 years are highly likely to have a good long-term outcome, which provides a strong motivating factor in the decision to consider ipilimumab treatment. While pooled data adds information far beyond individual trials, a major drawback lies in the loss of control data necessary to isolate the added benefit of the study drug.
An indirect comparison using historic control series, in this case a large cohort documented in the American Joint Committee on Cancer (AJCC) Melanoma Staging Database, can substitute for missing control data in the pooled analysis. Reviewing data for stage IIIc and IV patients, the overall survival Kaplan-Meier curves in this population also show a plateau, but much later than that reported for ipilimumab, at beyond 8 years.
The AJCC melanoma classification gives survival rates at 3, 5, and 10 years of 19%, 13%, and 9%, respectively. Comparison with ipilimumab data suggests that survival at 3 years is similar, but thereafter improves with ipilimumab by 10% over other treatments that were available at the time. This difference is similar to the percentage of patients who achieved objective responses with ipilimumab. Although assessing response rate and progression-free survival in patients treated with ipilimumab presents challenges, the long-term benefits of ipilimumab could be better ascertained if information on the number of patients in the 21% plateau who were disease free or stably maintaining response had been collected.
Evaluation of long-term benefits of ipilimumab should consider toxicities and costs, as it is one of the most costly systemic therapies used for cancer treatment. The phase III trial using the drug at 3 mg/kg demonstrated that the large majority of patients had no serious adverse effects. If older patients and those with advanced disease are candidates, then the 10%-15% of grade 3 or 4 adverse events may translate to hospitalization and added expense, putting health regulatory systems in the position to deny widespread use of the agent despite proven benefit.
As the first agent to benefit overall survival of patients with advanced melanoma, ipilimumab may pave the way to broader improvements in a larger proportion of patients by combining with targeted therapies, such as BRAF and MEK inhibitors, and other new immunotherapies, such as anti-PD-1 antibodies.
Dr. Antoni Ribas is an oncologist with the Jonsson Comprehensive Cancer Center, Los Angles, and Dr. Keith T. Flaherty is an oncologist with Massachusetts General Hospital Cancer Center, Boston. These remarks were part of an editorial accompanying the report (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]). Dr. Ribas has an advisory role with Merck, Amgen, Novartis, GlaxoSmithKline, and Genentech/Roche. Dr. Flaherty has an advisory role with GlaxoSmithKline, Genentech/Roche, Novartis, and Merck.
Among patients with advanced melanoma who were treated with ipilimumab, about 20%-26% survived to 3 years, and these patients are likely to have a good long-term outcome, according to a pooled analysis of survival data published online Feb. 9 in the Journal of Clinical Oncology.
Investigators pooled data from ten prospective (including two phase III trials) and two retrospective studies with a total of 1,257 previously treated and 604 treatment-naive patients. At least 3 years after receiving ipilimumab, 254 patients were still alive, with a median follow up for this subset of 69 months. Around year 3, the Kaplan-Meier overall survival (OS) curve began to plateau and extended to 9.9 years for the longest survival follow-up.
“These results suggest that the majority of patients who reached this milestone time point had a low risk of death thereafter,” wrote Dr. Dirk Schadendorf and his associates (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]).
Compared with patients who were previously treated, treatment-naive patients had a higher median overall survival (13.5 months [95% confidence interval, 11.9-15.4] vs. 10.7 months [9.6-11.4]) and higher 3-year-survival rates (26% [21%-30%] vs. 20% [18%-23%]). No definitive conclusion could be drawn from this observation, however, since nonrandomized subsets were used for this analysis. Subset analysis by dose showed similar median OS and 3-year survival rates for ipilimumab 3 mg/kg, 10 mg/kg, and other dosing regimens.
The researchers expanded the study to include overall survival (OS) data from 2,985 patients enrolled in a U.S. multicenter, open-label, expanded-access treatment protocol (EAP). This group included patients with poorer prognostic factors, some of whom were ineligible for clinical trials. The expanded group showed a lower median OS of 9.5 months and 3 year–survival rate of 21%, with the familiar OS curve plateau around 3 years that extended up to 10 years in some patients.
While this analysis only examined overall survival rates, individual ipilimumab studies that tracked patient responses to the drug have shown that some proportion of long-term survivors did not achieve a response. Identifying the specific disease characteristics of the long-term survivors will require further study.
“Considering the historic median OS of approximately 8-10 months and a 5-year survival rate of approximately 10% in advanced melanoma, the results presented herein are encouraging for patients diagnosed with this aggressive disease,” the authors wrote.
Among patients with advanced melanoma who were treated with ipilimumab, about 20%-26% survived to 3 years, and these patients are likely to have a good long-term outcome, according to a pooled analysis of survival data published online Feb. 9 in the Journal of Clinical Oncology.
Investigators pooled data from ten prospective (including two phase III trials) and two retrospective studies with a total of 1,257 previously treated and 604 treatment-naive patients. At least 3 years after receiving ipilimumab, 254 patients were still alive, with a median follow up for this subset of 69 months. Around year 3, the Kaplan-Meier overall survival (OS) curve began to plateau and extended to 9.9 years for the longest survival follow-up.
“These results suggest that the majority of patients who reached this milestone time point had a low risk of death thereafter,” wrote Dr. Dirk Schadendorf and his associates (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.56.2736]).
Compared with patients who were previously treated, treatment-naive patients had a higher median overall survival (13.5 months [95% confidence interval, 11.9-15.4] vs. 10.7 months [9.6-11.4]) and higher 3-year-survival rates (26% [21%-30%] vs. 20% [18%-23%]). No definitive conclusion could be drawn from this observation, however, since nonrandomized subsets were used for this analysis. Subset analysis by dose showed similar median OS and 3-year survival rates for ipilimumab 3 mg/kg, 10 mg/kg, and other dosing regimens.
The researchers expanded the study to include overall survival (OS) data from 2,985 patients enrolled in a U.S. multicenter, open-label, expanded-access treatment protocol (EAP). This group included patients with poorer prognostic factors, some of whom were ineligible for clinical trials. The expanded group showed a lower median OS of 9.5 months and 3 year–survival rate of 21%, with the familiar OS curve plateau around 3 years that extended up to 10 years in some patients.
While this analysis only examined overall survival rates, individual ipilimumab studies that tracked patient responses to the drug have shown that some proportion of long-term survivors did not achieve a response. Identifying the specific disease characteristics of the long-term survivors will require further study.
“Considering the historic median OS of approximately 8-10 months and a 5-year survival rate of approximately 10% in advanced melanoma, the results presented herein are encouraging for patients diagnosed with this aggressive disease,” the authors wrote.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Ipilimumab-treated advanced melanoma patients alive at 3 years tend to have good long-term outcomes.
Major finding: Around year 3, the Kaplan-Meier OS curve began to plateau and extended to 9.9 years for the longest survival follow-up.
Data source: Pooled overall survival data from 12 studies including 1,861 ipilimumab-treated patients with advanced melanoma.
Disclosures: Dr. Schadendorf disclosed that he is a consultant for Bristol-Myers Squibb. Bristol-Myers Squibb sponsored this study.