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Sarcoma Patients Should Receive Genomic Profiling More Often, Research Suggests


NEW YORK – Research analyzing genomic sequencing data from more than 7,000 soft tissue and bone sarcoma tumor samples found about one-third of these patients harbor potentially actionable mutations, but less than 6 percent of patients were eligible for US Food and Drug Administration-approved drugs.

Over six years, the researchers performed next-generation sequencing using Foundation Medicine's FoundationOne Heme platform on nearly 7,500 adult and pediatric sarcoma patients representing 44 sarcoma subtypes, in the study published in Nature Communications this month.

Lead author Mrinal Gounder, a medical oncologist specializing in sarcomas at Memorial Sloan Kettering, and colleagues from cancer centers across the US aimed to determine the utility of clinical genomic sequencing in patients with these rare malignancies that arise in the bones and connective tissues. In Gounder's view, his group's research supports broader use of NGS testing in sarcoma patients to improve diagnosis and help match them to clinical trials, especially since there are few biomarker-informed treatment options approved by the FDA in this setting.

NGS panels like FoundationOne Heme have been FDA approved to identify patients who harbor specific biomarkers and may benefit from certain drugs, but Gounder noted that none of the companion diagnostic indications in these panels are specifically for personalizing treatment for sarcoma patients. This leads to inconsistent use of NGS for sarcoma patients.

"In sarcomas, these [tests] are not FDA approved for any indication, and it's very variable who gets it done," he said. "People in clinics across the world are ordering these tests in a sporadic way, but we don't have a good sense of whether it really helps the patient and how it helps."

This not only limits patients' opportunities to receive precision care, but can also lead to inaccurate diagnoses. Sarcoma is a heterogeneous disease, and Gounder's study specifically showed that sequencing could be used to home in on specific subtypes. The researchers found that 10.5 percent of patients were misdiagnosed after looking at the NGS results.

Gounder said many sarcomas have been molecularly characterized. For instance, Ewing sarcoma, a bone tumor often seen in children, is characterized by EWSR1 gene fusions. The tumors most frequently reclassified based on NGS results in this dataset were sarcomas not otherwise specified (NOS), liposarcomas NOS, chondrosarcomas, Ewing sarcomas, and synovial sarcomas.

"For these patients, the opportunity was missed to get a proper diagnosis, so they may have been overtreated, undertreated, or inappropriately treated," Gounder said, noting that the rarity of some sarcomas makes it difficult for experts to make an accurate diagnosis. Other studies have found that diagnostic errors occur often in sarcoma, leading precision oncology proponents to encourage the use of genetic testing for accurate diagnosis.

"Molecular genetic testing should be mandatory for diagnostic accuracy of sarcoma and appropriate clinical management, even when histological diagnosis is made by pathologist experts in this field," insisted a group of researchers in a 2016 paper, in which they described using molecular testing to correct diagnostic errors in sarcoma patients treated at multiple European institutions.

Gounder's research provided further evidence of the same. "We showed that by doing NGS you can get the right diagnosis," he said.

While this study did not include clinical data from patients, the researchers did analyze the NGS results to determine the frequency of potentially actionable genetic mutations. They defined actionable mutations using MSK's OncoKB genetic variant database that includes information about the treatment implications of certain mutations.

OncoKB has four levels of actionable biomarkers, ranging from level 1, denoting biomarkers that have an FDA-approved drug for a patient's specific tumor type, to level 4, denoting biomarkers that have some biological evidence suggesting they may be associated with response to a drug.

Researchers found that around one-third (31.7 percent) of sarcoma patients in their study harbored at least one potentially actionable mutation. Most of these biomarkers had level 3 status in OncoKB, denoting that there was evidence they can predict whether patients with cancers other than sarcomas can benefit from certain drugs. "This means that they could now be triaged into a clinical trial for a drug that exists," Gounder said.

Across all sarcomas, nearly half of patients had alterations in the p53 pathway, which regulates genomic stability, with 47.8 percent harboring alterations in TP53, MDM2, and MDM4. Close to half of patients, 46.8 percent, also harbored alterations in the Rb pathway that regulates the cell cycle and includes alterations in RB1, CDKN2A/B, CDK4/6, CCND1/2/3, and CCNE1.

The researchers also identified that 2.6 percent of patients had potentially actionable kinase fusions, including ALK, BRAF, FGFR1-4, NTRK1-3, RET, and ROS1 kinase fusions, across a range of sarcoma subtypes.

These patients may be eligible for studies exploring biomarker-informed treatments, or they could try to get compassionate use access to drugs that aren't yet on the market but have shown benefit for their specific type of biomarker-defined sarcoma. For example, in MDM2-amplified sarcoma, Rain Therapeutics' milademetan has shown anti-tumor activity in a small cohort of intimal sarcoma patients.

Meanwhile, only 5.9 percent of sarcoma patients in the study had OncoKB level 1 biomarkers for which there was an FDA-approved drug for their sarcoma subtype. These top-tier biomarkers are more frequent among gastrointestinal stromal tumors (GIST), with 64.4 percent of GIST patients harboring level 1 alterations. There are several targeted therapies approved for GIST, including Novartis' Gleevec (imatinib) for patients with KIT (CD117)-positive GIST and Blueprint Medicines' Ayvakit (avapritinib) for GISTs harboring a PDGFRA exon 18 mutation.

However, GIST patients made up less than 2 percent of the population (104 patients) in Gounder's study, and level 1 biomarkers were identified in a total of 439 patients across sarcoma subtypes.

Other FDA-approved biomarker-defined drugs that sarcoma patients are eligible for are Bayer's Vitrakvi (larotrectinib) and Genentech's Rozlytrek (entrectinib), which are both tissue-agnostic treatments for patients with advanced, refractory solid tumors harboring NTRK gene fusions.

The researchers also looked for tissue-agnostic biomarkers that would make sarcoma patients eligible for immunotherapies, such as microsatellite instability, mismatch repair deficiency, and tumor mutation burden. They found that 2.1 percent of sarcoma patients had mismatch repair deficiency, but microsatellite instability was very rare, only found in 18 cases in this study.

TMB greater than 10 mutations/mega base, which would make cancer patients eligible for Merck's Keytruda (pembrolizumab), was found in 3.9 percent of sarcoma patients, and the subtypes with the highest frequency of TMB greater than 10 were patients with angiosarcoma, undifferentiated pleomorphic sarcoma, malignant peripheral nerve sheath tumors, and ossifying fibromyxoid tumor.

"There are some diseases where the tumor mutation burden, for example, is extremely low, but even in that disease there are outliers," Gounder said. "If you just looked at the histology alone and you didn't look at the genomics, you would miss that. If you did genomic sequencing and you incidentally found this one patient, maybe it's just one patient out of 50 patients, but if you can even change that one life with a drug that's already available, it's worth doing a test like this."

There are some ongoing trials of immunotherapies in certain sarcomas. One trial is exploring Pfizer's Ibrance (palbociclib) in advanced soft tissue sarcomas that overexpress CDK4 and underexpress CDKN2A. In results presented from that study at the American Society of Clinical Oncology's annual meeting this month, Ibrance showed activity across a variety of sarcoma subtypes with these alterations.

Other precision medicine development programs include Salarius Pharmaceuticals' LSD1 inhibitor seclidemstat, which the firm is evaluating as a treatment for Ewing sarcomas and other types of sarcomas with translocations involving the FET family of proteins.

The researchers have made the data from their study available to other oncologists and investigators worldwide in the hopes of jumpstarting more precision oncology trials for sarcoma. Gounder noted there may be opportunities for umbrella trials in sarcoma based on the presence of certain kinase fusions or other genomic biomarkers that can occur across subtypes.

He acknowledged sarcoma patients may face more insurance barriers when it comes to genomic profiling, particularly because there are no approved NGS tests for guiding sarcoma treatments. "If the Center for Medicaid & Medicare Services and [commercial] insurance companies saw the value of this and then they decided to cover this testing, that would be the best thing one can do for all this work that was done so that it serves patients who are affected," he said.