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Sarcoma describes a broad group of cancers that originate in the bones and soft or connective tissues, forming in the blood vessels, nerves, muscle, fat, tendons and the lining of the joints. With over 70 types of sarcomas, treatment for this unique cancer depends on the sarcoma type, its location and a multitude of other factors.

For the latest updates in soft tissue sarcoma treatment, we spoke with , an associate professor who is a discussant and heavily featured in presentations on the latest sarcoma research at this month¡¯s annual American Society of Clinical Oncology (ASCO) Annual Meeting. Somaiah is proud of the research that will be presented by her colleagues and is excited to present on clinical trials concerning combination therapies. These trials show promising results regarding angiosarcoma, a sarcoma that forms in the lining of the blood vessels and lymph vessels. Liposarcomas and leiomyosarcomas are the topics of two posters.

We asked Somaiah about these recent trials and research.

There¡¯s innovative research happening in the world of sarcoma. Tell us about the exciting sarcoma advances that you will discuss at ASCO.

At the sarcoma oral abstract session,? I¡¯ll discuss initial results from a first-in-human dose escalation trial of a novel immune-stimulating oncolytic adenovirus, AdAPT-001TGF-? Trap will be presented by , and colleagues. This novel immunotherapy approach is showing promise in some sarcoma subtypes.

Dr. Nakazawa is presenting research under the mentorship of and ,?looking at the loss of the DNA repair gene RNaseH2 and a unique subset of DDR-deficient leiomyosarcomas (LMS). This exciting translational biomarker work evaluating RNAseH2 loss in uterine LMS is the basis of a biomarker-selected clinical trial of ATR +/- PARP inhibition in uterine LMS that is currently under development by Dr. Nakazawa and his mentors.

Dr. Thirasastr, one of my mentees, will be presenting clinical correlations of recurring mutations in myxoid liposarcoma. These are interesting trends in chemotherapy response in myxoid liposarcoma patients. It needs further validation in a larger sample set, which could help with determining the best treatment selection for individual patients.

Your research points to success in combining therapies to treat sarcoma. Tell us about this research.

During my oral abstract session,?I¡¯ll be discussing the success of three combination trials, which concern a tyrosine kinase inhibitor called cabozantinib, which is currently gaining prominence in the sarcoma world. These clinical trial results highlight the need for optimal combination strategies based on the sarcoma subtype to help improve outcomes. Cabozantinib has been combined with immunotherapy showing high response rates and disease control in angiosarcoma patients, and cabozantinib combined with temozolomide appears to have higher response and disease control compared to what has been previously reported with either agent alone.

Tell us about the new research looking at the clinical implications of recurring mutations in myxoid liposarcoma (MLS).

Liposarcomas are the most common type of soft tissue sarcoma in adults. Myxoid liposarcomas are a subtype of liposarcoma typified by tumors that arise in the body's fat tissue, usually in the lower extremities.

Prapassorn Thirasastr, M.D., a postdoctoral fellow in Sarcoma Medical Oncology, is presenting findings from a study of recurring mutation in myxoid liposarcomas in a poster session at ASCO (abstract 11577, poster board 511). Thirasastr says he and his colleagues were generally aware that MLS is characterized by gene translocation resulting in the fusion protein, particularly involving the DDIT3 gene. Translocation means a genetic change in which a piece of one chromosome breaks off and attaches to another. Fusion proteins are created when pieces from two or more different genes join together through this chromosomal rearrangement and are then turned into a single protein. This fusion protein is considered one of the main drivers of MLS, but the exact mechanisms of how this happens are only partially understood.

However, there are two other noteworthy conclusions from the study.

One result showed that over 83% of patients tested with DNA sequencing called next-generation sequencing showed a somatic mutation, a genetic condition known to lead to cancer. Thirasastr says most of these mutations were found in the promoter region of the Telomerase reverse transcriptase (TERT) gene (TERTp), a gene involved in maintaining chromosomal stability. The recurring mutation in this hotspot was also identified in 19% of all cancers.

In cancer research, doctors and researchers can connect the genetic alterations in cancer cells with signaling pathways that control processes associated with the formation of tumors, which helps them piece together the signaling networks involved in fueling cancer progression.

¡°44% percent of MLS patients have the mutation that leads to PTEN-PI3K-AKT-mTOR pathway activation. This pathway is potentially targetable with inhibitors that are available and have been approved in other cancers,¡± Thirasastr explains.?

Next, he said they found patients having dual mutations of PIK3CA and TERTp mutation suggests worse progression-free survival from chemotherapies.

Thirasastr says the next steps involve testing a larger population for these specific mutations to obtain larger data sets.

Another poster highlights the loss of the DNA repair gene RNase H2 and a unique subset of DDR-deficient leiomyosarcomas. Tell us about that.

Structural changes in DNA such as genetic mutations or deletions can severely interfere with its functionality, including the ability to replicate and play a significant role in both age-related diseases and cancer. Tumors that have a disruption in the DNA damage repair (DDR) gene, termed DDR-deficient, can trigger an immune response that could make them more susceptible to DNA-damaging therapies. Leiomyosarcoma, a rare cancer that grows in the smooth muscles, can occur throughout the body, including the intestines, bladder, blood vessels, skin and uterus. ?

Michael Nakazawa, M.D., Ph.D., a third-year Hematology and Oncology fellow who will be joining the faculty later this year, says there¡¯s been recent interest in DDR-deficiency in leiomyosarcoma, particularly uterine leiomyosarcoma, as this general class of genetic mutations and/or deletions can sensitize tumors to targeted therapies, including PARP and ATR inhibitors. ¡°This area is of particular interest, as currently there are no FDA-approved targeted agents for the treatment of leiomyosarcomas,¡± says Nakazawa, first author of a poster on this topic for ASCO (abstract 11549, poster board 483).

RNase H2 is a specific cancer-related gene not typically tested in current clinical sequencing panels. Its loss may make certain cancers susceptible to treatment with DDR-targeted therapies that are currently being tested in clinical trials.

¡°Our study found that RNase H2 loss is common, with up to a 30% prevalence specifically in uterine leiomyosarcoma patients, so screening could potentially broaden the number of patients who can benefit from these treatments,¡± says Nakazawa.

Ultimately, screening for RNase H2 deficiency may be a useful biomarker for future clinical trials of these classes of agents in uterine leiomyosarcoma patients.

at MD Anderson.

After a Mardi Gras parade in February 2019, Taylor Fradella-Doucet noticed some soreness in her thigh, but she chalked it up to evidence of good time and kept going. A few days later, the 23-year-old noticed a lump on the same thigh. As a first-year medical student, Taylor knew a painless lump was something to get checked out.

She had some MRIs and met with a local orthopedic surgeon, who said it may be a fibroid.

¡°He gave me the option of getting a fine needle aspiration biopsy to determine what the lump was, but I was scared and wanted it out right then,¡± says Taylor.

After surgically removing the lump, the doctor sent it to a local pathologist, but the results were inconclusive. They then sent it to two larger hospitals, one being MD Anderson. The pathology results from MD Anderson showed that Taylor¡¯s lump was malignant. It was leiomyosarcoma, a rare type of soft tissue sarcoma that grows in the smooth muscles of the body.?

Taylor chose to follow up with MD Anderson for her cancer treatment because of how quickly she got her results, and it was close to her hometown of New Orleans.

Finding success with radiation therapy clinical trial

When Taylor first arrived with her parents at MD Anderson, she was overwhelmed by the size of the campus. But she appreciated how kind and helpful everyone was.

Her care team immediately went to work developing a treatment plan for the soft tissue sarcoma. This included radiation therapy, then surgery.

Taylor¡¯s radiation oncologist, , told her about a clinical trial in which patients received higher daily doses, but a lower total dose of radiation, for three weeks rather than receiving lower daily doses of radiation for five weeks, resulting in a higher total dose. The trial was investigating safely condensing the dose of radiation therapy to a shorter course while maintaining a dose known to be effective for the longer course.

¡°It was, in part, based on a breast cancer study, in which both methods were shown to have the same efficacy,¡± says Taylor. ¡°They were trying to see if it was the same for sarcomas, and MD Anderson was very confident that it would be, based on their data with other cancers.¡±

The trial has since been published in with early results confirming that this shorter course of radiation therapy is safe and effective for soft tissue sarcoma.

Since she was in medical school in New Orleans at the time, Taylor joined the clinical trial to limit the amount of time she¡¯d be away from home.

She received radiation treatments every day for three weeks.

¡°It was kind of fun living in Houston,¡± she says. ¡°I even got to go to some Astros games.¡±

Surgery for soft tissue sarcoma

A month after Taylor completed radiation, orthopedic oncologist , performed a radical tumor bed resection. Taylor¡¯s tumor was in her vastus lateralis muscle, so Satcher removed that entire muscle.

¡°Because the area was contaminated by the first surgery, they had to take all of the skin on top,¡± says Taylor. ¡°The plastic surgeon gave me the option of doing a skin graft, which would require them to remove skin from my other leg, but I didn¡¯t want to do that.¡±

Instead, the plastic surgeon just pulled the skin really tight.

¡°I really appreciate them giving me a say in that procedure,¡± she says.

Taylor returned to New Orleans with a drain in her leg for two weeks, then came back to MD Anderson to have the drain removed.

She now only comes to MD Anderson every six months for follow-ups, and she¡¯s happy that she has had no evidence of disease for three-and-a-half years.

Learning from her experience and sharing with others

During her treatment at MD Anderson, Taylor tried to focus on medical school and trust that her care team was working hard to help her get better.

¡°As a medical student, I already had a trust in medicine,¡± says Taylor. ¡°And after talking to Dr. Satcher and his physician assistant, Chris Mehring, I saw they had a plan. I was confident that they knew what they were doing.¡±

Now a resident physician in Louisiana State University¡¯s neurology program, Taylor is expecting her first baby with her husband this August. She says her experience with soft tissue sarcoma has helped her connect with her patients. When a patient became frustrated waiting on pathology results, Taylor reassured her that knowing exactly what kind of cancer they were dealing with would help them provide her with the best care.

¡°Had I moved more slowly and gotten pathology results before my first surgery, I could have avoided a second surgery,¡± says Taylor. ¡°It¡¯s in our nature to want things done right away because cancer is a scary diagnosis, but coming up with a strategy before beginning treatment is a wiser choice.¡±?

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