In Partnership With City of Hope and Allegheny Health Network

With over 100 histological subtypes of sarcomas, understanding the genomics of sarcomas and how molecular testing can be useful in this space is of the utmost importance.

Lisa B. Ercolano, MD

According to Lisa B. Ercolano, MD, molecular testing can be beneficial in the sarcoma space because it aids in diagnosing and treating patients across histologies. Getting a greater understanding of the molecular characteristics of a patient’s disease is a process that has evolved over time.

This testing is important to identifying molecular drivers that could make patients eligible for clinical trial enrollment. It also helps determine whether there are any FDA-approved therapies that a patient can receive.

“We definitely have learned a lot in terms of being able to sequence these tumors and get down to the molecular level,” Ercolano, orthopedic oncologist and chief of musculoskeletal oncology at Allegheny Health Network, told Targeted Oncology^TM in an interview. “I'd say that that's been most helpful in diagnosis thus far. There's a number of types of bone sarcomas—there's actually hundreds of types of soft tissue sarcomas, and that number keeps getting longer and longer as we continue to subdivide some of these out. That's where a lot of the molecular work has helped us.”

Molecular Testing in Sarcoma

In the sarcoma space, molecular testing helps confirm the diagnosis for many tumors. Some of the molecular diagnostic methods used for sarcomas include targeted gene-level assays, copy number arrays, and newer techniques.¹

Mark Agulnik, MD

“There are genetics that we're born with and genetics that we acquire over time. There are some patients whereby there is a genetic component with respect to the genes that are passed to them, and then there are acquired mutations that cause the tumors. Those are the ones that often we are searching for using different platforms like next-generation sequencing [NGS] platforms,” said Mark Agulnik, MD, in an interview with Targeted Oncology.

Specifically, fluorescence in situ hybridization (FISH) is widely used targeted gene-level assays as it effectively identifies translocations and amplifications. FISH typically targets 1 gene, which means the pathologist must recognize the suspected tumor subtype in the differential diagnosis.²

Another clinical molecular diagnostic test is polymerase chain reaction (PCR) where primers are designed to work against specific sarcoma fusion breakpoints.³ However, a risk with this method is that it may miss alternative fusion partners that are not in the prespecified fusion breakpoints.¹ Similar to PCR, a newer method called multiplex fluorescent color-coded probes uses DNA probes with fluorescent molecular barcodes and directly binds target RNA. While this method has the ability to multiplex hundreds of targets, a weakness, like with PCR, is that the probes are designed against specific fusion breakpoints and cannot identify novel fusion partners.

Comparative genomic hybridization (CGH) or single nucleotide (SNP) arrays are another method that works by identifying copy number alterations of a broad range of sizes. One of the complications with this method is its limited ability to identify balanced rearrangements and small coding sequence mutations.

As Agulnik mentioned, a prevalent approach is NGS, which is able to capture many fusions and can identify fusions and/or fusion partners. However, there is a high cost associated with this method, as well as greater complexity compared with commonly used techniques.

“We are looking at different factors to see whether or not they would benefit from immunotherapy. All of those are reasons that we would do sequencing of our patients who have metastatic disease to specifically look for what is driving their tumor. If we're able to find the driver, we're able to find and tailor a therapy that's more unique to their tumor vs a therapy that would be for every patient walking in the door with the same diagnosis,” added Agulnik, section chief of Sarcoma Medical Oncology, Department of Medical Oncology & Therapeutics, and research professor, Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center.

As more research is done on molecular testing, experts are hopeful they will be more common globally, especially as NGS costs decrease. Utilizing molecular methods continues to demonstrate potential for improving and diagnosing these rare cancers. Not only will this help pathologists with diagnostic guidelines for soft tissue and bone tumors, but it will also help push forward the era of individualized treatment.

“We've been able to do that with an understanding of the molecular differences between these different tumor types. Obviously, the goal is that that can turn into targeted treatments for each of these. That's definitely in the works, that's occurred, we have drugs that target these specific mutations that come about,” said Ercolano.

Other Advances to the Sarcoma Treatment Landscape

In recent years, there has been a great increase in the number of therapies for the treatment of sarcoma, including CDK4 inhibitors and MDM2 inhibitors for patients with liposarcomas and desmoid sarcomas, gamma secretase inhibitors for Kaposi sarcoma, and FGFR and IDH mutations as potential targets in some soft tissue and bone sarcomas.

Previously, treatments like pazopanib (Votrient) and olaratumab (Lartruvo) were studied in sarcomas. However, progression-free survival results were not robust enough compared with placebo for the patient group studied.

According to Agulnik, new therapies are being investigated, including regorafenib (Stivarga), entrectinib (Rozlytrek), and larotrectinib (Vitrakvi), each of which have shown better outcomes in this patient population. Additional therapies, including cabozantinib (Cabometyx) and immunotherapies, are being explored for the treatment of sarcomas.

Targeted Therapies

Past National Comprehensive Cancer Network guidelines for soft tissue sarcomas had little, if any, immunotherapy options recommended and very few targeted agents. With recent advances, the entire guidelines have changed over time to incorporate these immunotherapy options.⁴

“There is an FDA approval for atezolizumab [Tecentriq] for alveolar soft part sarcomas, which would be the first approved for sarcomas. We also have possible recommendations for use of pembrolizumab [Keytruda] or nivolumab [Opdivo] for patients with certain types of soft tissue sarcomas, such as an undifferentiated pleomorphic sarcoma, or cutaneous angiosarcoma. So we know from the phase 2 clinical trials [NCT02834013, NCT02301039, NCT02888665, NCT02636725] that we've done that we are able to impact patients' care with the use of immunotherapy—not for everyone, but certainly for a large subset,” Agulnik explained.^5,6,7

Agulnik also noted that there is a role for CDK4/6 inhibitors in this space, as supported by research that has been done at City of Hope, with respect to the drugs like regorafenib.

“There is an ability for [CDK4/6 inhibitors] to have an impact on patients with angiosarcomas and certainly other targeted agents for those diseases,” said Agulnik. “What's important for patients with soft tissue sarcomas and bone sarcomas is to look at: Do they have a subtype or histology that potentially is amenable to a therapy like a tyrosine kinase inhibitor or immunotherapy? Because the toxicity profiles of these drugs are traditionally going to be better than the toxicity profile of a standard chemotherapy.”

Individualized Treatments

The current standard for treating many types of sarcomas is surgery. However, radiation and other therapies play a role. Due to the many varieties of sarcomas and subtypes, there is not 1 specific combination of drugs or standard of care for treating these patients.

According to experts like Agulnik and Ercolano, determining which drug to use against different forms of sarcoma depends on data from clinical trials. This is especially true for targeted therapies, which seek to alter the molecular drivers of the tumor.

“With respect to individualization of treatment, I break it down into different elements. What we want to do is take sarcoma, then break it down further to the histology, so leiomyosarcoma, liposarcoma, etc, look at other aspects of it, see if one could [find] the fusion, amplification, or alteration on a genomic sequencing. If I was a patient and had leiomyosarcoma, do I care what 99% of other patients have with respect to that leiomyosarcoma? Probably not. I would love for you to find me a therapy that works for me, that is individualized to me, and will produce an outcome that is going to be beneficial. Can we do that for everybody? No, but it is our goal to do it for everybody,” said Agulnik.

While some sarcomas may benefit from the use of tyrosine kinase inhibitors or gamma secretase inhibitors, others may only derive benefit from targeted drugs. Currently, there is only 1 targeted drug that has been FDA approved for the treatment of patients with sarcoma.

“Each of these [subtypes] are so different. We have tumors that have 1 name and if you take 10 patients with the same diagnosis, the disease can behave quite differently. [While] that's the case probably for all cancers, we see that a lot in sarcoma,” said Ercolano.

Experts remain optimistic and look to further their understanding of when to utilize immunotherapy for this patient population.

“For rare diseases, the way of the future is not cookie cutter, it's going to be tailored to the individual,” added Ercolano.

Looking Ahead in Sarcoma

While there are now several molecular modalities used to evaluate tumors and treatments showing encouraging outcomes, there is still a lot that needs to be done.

“Unfortunately, unlike some other types of cancers, we've not really hit the jackpot yet, in terms of finding drugs that drastically improve outcomes. There are some that we think help with prolonging disease-free survival and things like that, but we haven't had any total breakthroughs yet,” said Ercolano.

This speaks to the fact that more research, funding, and clinical trials are needed in the field of sarcoma. While this is a rare disease, there is a large unmet need that still exists and more can be done to improve the quality-of-life and outcomes for patients.

“We haven't cured the disease. I think that all of us in the realm of sarcoma care come to it with a passion and a dedication to improving outcomes for patients. I think that the average patient with metastatic disease still has a prognosis that we are not envious of and a prognosis that we would like to change. I certainly hope that over time, we're able to push things further so that we end up with less toxic therapies that are more effective, and that the prognosis improves over time,” said Agulnik.

REFERENCES

1. Wang XQ, Goytain A, Dickson BC, Nielsen TO. Advances in sarcoma molecular diagnostics. Genes Chromosomes Cancer. Published online January 21, 2022. doi:10.1002/gcc.23025

2. Matthew H. Molecular Diagnostics in Sarcoma Pathology. College of American Pathologists. Accessed July 13, 2023. https://www.cap.org/member-resources/articles/molecular-diagnostics-in-sarcoma-pathology

3. Rottmann D, Abdulfatah E, Pantanowitz L. Molecular testing of soft tissue tumors. Diagn Cytopathol. 2023;51(1):12-25. doi:10.1002/dc.25013

4. von Mehren M, Kane JM, Agulnik M, et al. Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(7):815-833. doi:10.6004/jnccn.2022.0035

5. Wagner MJ, Othus M, Patel SP, et al. Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). J Immunother Cancer. 2021;9(8):e002990. doi:10.1136/jitc-2021-002990

6. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial [published correction appears in Lancet Oncol. 2017 Dec;18(12 ):e711] [published correction appears in Lancet Oncol. 2018 Jan;19(1):e8]. Lancet Oncol. 2017;18(11):1493-1501. doi:10.1016/S1470-2045(17)30624-1

7. Birdi HK, Jirovec A, Cortés-Kaplan S, et al. Immunotherapy for sarcomas: new frontiers and unveiled opportunities [published correction appears in J Immunother Cancer. 2022 Apr;10(4):]. J Immunother Cancer. 2021;9(2):e001580. doi:10.1136/jitc-2020-001580