Rare Sarcomas Pose Significant Hurdles, But Foster Collaboration

Damon Reed, MD

With advancements in molecular diagnostics continuing to demonstrate that cancers such as breast, lung, and melanoma are more heterogeneous than previously thought, individualized therapy may soon become the norm.

As that happens, oncologists in those fields may want to turn to sarcoma specialists, who are used to dealing with over 70 different subtypes, says Damon Reed, MD.

“I hope that we can really lead the field of oncology in how we handle rare cancers,” says Reed, director of the Adolescent and Young Adult Program and medical director of the Department of Sarcoma at Moffitt Cancer Center.

“There are things we really do well for our patients that others can learn from and can continue to learn from as the breakdown of common cancers into baskets and molecularly defied entities continues. We don’t have all the answers, but we understand the struggle inherently.”

OncLive: What are you most excited about in sarcoma right now?

In an interview with OncLive, Reed discusses the challenges associated with treating rare sarcomas, the importance of collaboration, advancements in the field, and the potential for immunotherapy in the disease.Reed: I am hopeful that advances in sequencing trickle down to these rare tumors and, with better collaboration, I am definitely hoping that we will be able to make significant differences in these ultra-rare subtypes of sarcoma.

What I am most excited about is targeting the translocation-defined sarcomas with epigenetic small molecules. There is a pretty healthy race in Ewing sarcoma to try and find small molecule inhibitors that will target that fusion protein or its partners.

What are the challenges with treating rare sarcomas?

Epigenetic modifiers are being considered now in other areas, including malignant peripheral nerve sheath tumors. This ever-growing list of translocation-derived sarcomas will eventually be treated much differently than they are now. We do give doxorubicin to a lot of patients, regardless of their biology, and so we will have more specific agents than that to offer patients.There are a lot of different sarcomas and I wish we had 20 different studies. However, 20 different studies with 1 or 2 patients each are just unmanageable in every aspect. Models for improved collaboration or lowering barriers in cost are really things that I hope the sarcoma community will continue to work on.

There are wonderful opportunities for pharmaceutical companies to work with patients who have sarcoma. We don’t have tens of thousands of patients—that is for sure. However, for subtypes with 200 to 300 patients, the biology of their disease is much more homogeneous than breast cancer or lung cancer. I do think the way patients get very rare sarcomas is very similar, biologically.

Collaboration is also key. I have patients who have extremely rare types of sarcoma; however, the sarcoma community is so friendly and collaborative. I can send an email to someone at Memorial Sloan Kettering Cancer Center or another major institution, and I will hear back within 1 hour regarding the clinical trial I am trying to enroll the patient on.

What are the biggest questions that you would like to see answered in sarcoma?

In the sarcoma community, there is not that same inherent competition as there is in other cancers. When someone has a promising trial, we try not to open a competing study but, rather, just send the patient there. It is a forced collaboration because the disease is so rare, but it does draw a certain type of physician to it—one who enjoys sharing data and networking. I love that.I think of it almost like an onion. I just hope we can peel off some sarcomas that we would like to make major differences in, 1 at a time. GIST is the best example of this. If you would have asked someone in 1998 what the outcomes are for patients with GIST, people would have said that it is a hopeless condition.

Then, in 2002, it becomes a chronic condition and imatinib (Gleevec) was the fix. We have all been waiting for that second, third, and fourth “GIST story.” This is one of the more common sarcomas; there are thousands of patients who have it. I can’t wait to see more successes in the rarer cancers.

The major problem is that we are faced with patients who have really large tumors and, if it’s metastatic, we don’t have curative options. We need better agents for metastatic disease.

Do you see a role for immunotherapy in sarcoma?

There are also challenges with stage III patients with localized disease. After resection, it is often difficult to have confidence that you are adding benefit with adjuvant chemotherapy. It is a highly contentious area. If patients go on to get 2 or 3 opinions, they often get 2 or 3 different opinions. It still causes a lot of stress. Even though there are studies, there is not truly a solid consensus. There are a lot of different factors to consider, including age, patient enthusiasm for chemotherapy, tumor size, tumor grade, and more. There are so many variables. That is a real challenge.I am optimistic about immunotherapy, but it doesn’t seem like it is going to take off right away like it has with melanoma or non—small cell lung cancer. There needs to be more of an effort put into how we can harness immunotherapy in sarcomas.

There are 2 ways to get sarcoma. About half of the sarcomas are p53 mutations, have many mutations, and a lot of structural variations; it’s a messy genome. Those are the osteosarcomas, leiomyosarcomas, and many others. There is a hope that immunotherapy may work for them. They are biologically complex with a lot of neoantigens, sort of like melanoma or lung cancer.

The other side of the coin is these very simple sarcomas, such as Ewing sarcoma, alveolar rhabdomyosarcoma, and myxofibrosarcoma. These are characterized by 1 DNA break in a translocation of 2 chromosomes. In that area, at this moment, I am not optimistic about immunotherapy—at least not checkpoint inhibitors.

I do think immunotherapy might help some patients with sarcoma; however, I don’t think it is going to be PD-1 or CTLA-4 right now. I am hopeful that someone will figure out if there are different immune checkpoints that will matter in this disease.