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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.
