Liposarcoma Advances and Challenges – Sarcoma Talk #9 with Vinayak Venkataraman

In this edition of Sarcoma Talk on OncoDaily, Dr. Vinayak Venkataraman, a medical oncologist from Dana-Farber Cancer Institute‘s Sarcoma Center, joins host Shushan Hovsepyan. Dr. Vinayak discusses the unique nature of liposarcomas, including their various subtypes, challenges in management, and current standard treatments. He also highlights recent advancements in therapies and shares insights from his personal journey into oncology.

Vinayak Venkataraman, MD is a board-certified medical oncologist. He specializesvwith caring for patients with bone and soft tissue sarcomas.  He is also board-certified in internal medicine and pediatrics. He earned his BSE in Electrical Engineering from Princeton University, received an MD from Duke University School of Medicine. He is an Instructor in Medicine at Harvard Medical School. He completed his residency Massachusetts General Hospital, Internal Medicine-Pediatrics. He is a sarcoma pathways director at the Danna – Farber Cancer Institute.

Shushan Hovsepyan is a pediatric oncologist and adjunct assistant professor at the Yerevan State Medical University. Currently, she is the Editor-in-Chief of OncoDaily Medical Journal.

She completed her clinical fellowship at the National Institute of Cancer in Milan, Italy and at the St. Anna Children’s Research Hospital in Austria. Furthermore, she held a research fellowship position at the European Organisation for Research and Treatment of Cancer in Brussels, Belgium.

She is a former co-chair of the SIOP Global Health Network Education and Training Working Group.

00:16 Introduction
01:00 Liposarcoma Subtypes Overview
03:30 Challenges in Recurrence and Treatment
05:06 Multidisciplinary Care and Treatment Approaches
08:18 Preoperative Pembrolizumab Synergy
11:50 Career Path to Oncology

Shushan Hovsepyan: Hello everyone and welcome to this edition of the five-minute sarcoma talk on Oncodaily. I’m back with you as your host Shushan Hovsepyan and today I’m thrilled to be joined by an expert in the field of sarcoma Dr. Vinayak Venkataraman. Dr. Venkatraman is a medical oncologist working at Dana-Farber Cancer Institute where he works in the sarcoma center. Thank you Dr. Venkatraman for joining us and hello.

Vinayak Venkataraman: Hello, thanks so much for having me. I’m really excited to talk with you.

Shushan Hovsepyan: Thank you. So let’s start by exploring the unique nature of liposarcomas in adults. We know that they are rare tumors representing a small percentage of all cancers.
Could you please tell us more about what makes liposarcoma particularly unique compared to other malignancies?

Vinayak Venkataraman: Sure, yes. So as you in the audience probably know, sarcomas are very rare. They affect less than one percent of all adults.

They’re basically a group of different cancers that connect your body together and give you form and function. And among those less than one percent, liposarcomas in adults are probably the most common that we see, roughly about 20 percent. You know, I think what makes them really unique is that there are various different subtypes of liposarcoma and each of those subtypes is very biologically and clinically distinct.

You know, we’ll probably spend the most time talking about the most common subtype, which is called well-differentiated liposarcoma and de-differentiated liposarcoma. They’re sort of cousins of each other. They have similar biology.
They’re both characterized by high levels of a couple proteins, MDM2 and CDK4. However, clinically they behave in slightly different ways, well-differentiated being more like an indolent, almost benign tumor, de-differentiated being slightly more aggressive, more like a high-grade sarcoma. And you can actually have tumors that have components of both within them.

More rare subtypes that are also biologically distinct, one is called mixoid round cell liposarcoma. That’s characterized by a specific chromosomal translocation, so similar to other types of sarcoma in that regard. It’s the DDIT3 FUS or TLS are the most common.

And those ones tend to be a little bit more aggressive. I see them in younger patients, typically soft tissue. They like to spread to the spine and bone marrow, so it makes them unique and managed very, very differently than the first subtype.
And then finally, the most uncommon subtype is pleomorphic liposarcoma. We won’t probably spend as much time on them. It resembles more high-grade sarcomas like EPS, and so we manage them in that sort of way.
But yeah, all three are very distinct and sort of managed differently, and I’m looking forward to talking more about that.

Shushan Hovsepyan: Thank you very much for breaking down the unique aspects of liposarcomas, especially the distinct biological subtypes. And building on that, given the uniqueness, given the rarity, I imagine that there are a lot of challenges that come with it. So what are some of the most significant challenges you face in managing liposarcoma cases, and how these challenges influence your approach to both early diagnosis and long-term management?

Vinayak Venkataraman: Yeah, so I think the biggest challenge with liposarcoma, similar to other types of sarcoma, is that even if you find it in one place and you do everything you can to remove it in that one place, there still is a high chance of it coming back, both either in the same place or local recurrence, or at another site, typically the lungs, which is called distant recurrence.

And so a lot of the efforts in terms of how we improve our treatment is how do we, for localized disease, reduce the risk of it coming back either in the same place or in other parts of your body. For metastatic disease, the challenge is really finding biologically informed treatments to better control the disease in a way that gets us away from chemotherapy, which is traditionally what most commonly use, and trying to find ways that we can target the biology either with targeted treatments or use the immune system to our advantage to fight the cancer.

And so I’d say the biggest challenge in the metastatic disease is just that our current armament of tools, they work, but they sort of don’t work as well as we’d like, and they’re not really sustained in their durability. And so if we can find ways to better treat them going forward, I think that’s the greatest challenge and opportunity.

Shushan Hovsepyan: Yeah. The challenges you have highlighted, particularly regarding the recurrence, the difficulty in treating metastatic disease, emphasize the complexity of management. So to continue on that, let’s discuss also the treatment.
It is, of course, a critical aspect, and could you elaborate more on the current standard treatment options for liposarcomas?

Vinayak Venkataraman: Yeah. So liposarcomas, because they’re rare, they’re best treated in a multidisciplinary sarcoma center with specialized radiologists, surgeons, and medical oncologists taking care of the patients. And for localized disease, we’ll focus mostly, I think, on D-diff and well-diff liposarcoma.
For well-differentiated liposarcoma, the standard of care is trying to do the maximum tumor reduction with the minimum harm, because we know if all of the tumor is well-diff, then the chance of it coming back is fairly low. And if it comes back, it typically comes back in the same place. And we actually call well-differentiated liposarcomas in the limbs, atypical lipomatous tumors, or ALT.

And in those cases, unlike other sarcomas, we actually will do a marginal excision rather than a radical excision, because we want to preserve as much limb as we can, knowing that the chance of it coming back is relatively low. For D-differentiated liposarcoma, the standard of care really is the use of radiation either before and after surgery, because we know that if all we did was surgery, there’s a high chance for those higher-grade tumors of it coming back in the limbs. And so you can either do radiation before or after.

They sort of have different pros and cons. Same outcomes, but we at Dana-Farber, we typically do preoperative radiation because it’s a lower dose and a lower amount of field of treatment. We acknowledge that there’s a higher risk of wound complications after surgery, but we think that the lower dose is better in the long run.

In the abdomen, it’s a little bit more complicated. There was a large trial STRASS that looked at using preoperative radiation for retroperitoneal sarcomas, including liposarcomas, and there wasn’t a benefit seen. So we commonly don’t use that in our practice.

The use of systemic treatments in localized disease is controversial, and it sort of depends on the provider and the patient and the risk of recurrence, whether or not that’s used. To that point, we are participating in STRASS2, which is looking at the use of neoadjuvant chemotherapy for localized receptible liposarcomas in the retroperitoneum to see if that can reduce the chance of distant recurrence. But I’d say by and large for WELL-DIF and D-DIF, if it’s in the limbs, D-DIF, you do radiation and surgery.

And if it’s in the abdomen, you typically do a surgical resection followed by surveillance. Mixoid liposarcoma and pleomorphic, we don’t talk as much about. They’re sort of more managed, similar to D-DIF liposarcoma if they’re localized.
And then for metastatic disease, similar. For all of them, we, you know, our first-line agents are chemotherapy, but for D-DIF liposarcoma, we’re starting to be able to use off-label targeted therapies like CDK4 inhibitors, as well as immune therapies are also something that we’ve seen some response in. So those are being used in the metastatic setting.

Shushan Hovsepyan: Yeah. Thanks a lot for sharing that. And of course, standard of care is the first choice, but sometimes it’s not enough.

And what are the recent advancements in any new breakthrough therapies in liposarcomas that you find particularly promising?

Vinayak Venkataraman: Yeah, yeah. So for localized D-DIF liposarcoma, actually this past ASCO 2024, there was a major abstract that was presented looking at, you know, in addition to preoperative radiation and surgery for these extremity or domino wall liposarcomas, can we use pembrolizumab in the preoperative setting concurrently and synergistically with radiation, and then also after surgery to improve our outcomes. So the study, which we were a participating study, did show that in this phase two trial, there was a benefit in terms of disease-free survival for high grade tumors, specifically.

It’s still premature for overall survival. So that’s what we’re waiting on in terms of longer follow-up and also larger clinical trials, such as a phase three trial. But I think that’s the most exciting thing in localized liposarcoma at present.

And then for metastatic disease, you know, I’d say it’s in the realm of trying to improve how our targeted approach to the underlying biology of the tumor, as well as, you know, trying to see if we can use the immune system to our advantage. And so for D-DIF liposarcoma, you know, we have trials looking at, you know, for example, is abemaciclib a better agent than palbociclib? So we have a trial of abema versus placebo and seeing if we can add that to our toolkit.

That’s exciting to us. It’s a national trial. Another one is looking at palbociclib compared to palbociclib plus cemiplimab, an immune therapy to see if there’s some synergy that we can see by using both a targeted therapy and an immunotherapy for metastatic disease.

And then we do have a couple newer agents that we’re testing in liposarcoma. One is a DNA-PK inhibitor, peposertib, with low dose Doxil. And then another one is called BTX-A51.

And so both of those are, and that’s a CK1a and CDK7-9 inhibitor. And so basically, are there better ways that we can target the underlying biology? And I think the most exciting thing for us is really an international collaboration.

Data Farber runs the David Liposarcoma Research Initiative, which brings together scientists from across the country and world to really see if, can we under, can we understand the underlying biology of liposarcoma in a way that allows us to improve our targeting of the underlying disease? And then finally, I’ll just end with myxoid liposarcoma. You know, there’s been a lot of excitement in synovial sarcoma because of an engineered T-cell product that targets MAGE-A4 hyperexpressed in synovial sarcoma.

And we know that myxoid liposarcoma are also, do have hyperexpression of MAGE-A4 and NY-ES0-1, which are two cancer testes antigens. And so there’s a lot of interest in, can we see the same response we saw in synovial sarcoma? Can we see it in myxoid liposarcoma, both for engineered T-cell products, as well as by specific T-cell engagers?
So that’s all very exciting to us in the field.

Shushan Hovsepyan: Thank you so much for the comprehensive overview. It was very helpful. And even though the tumors are very rare and challenging, it is very exciting to see that a lot of research is ongoing.
And I would like to change the subject a little bit. And before we wrap up, I would love to hear about your personal journey. What inspired you to specialize in sarcomas in this challenging and unique field?

Vinayak Venkataraman: Yeah. Yeah. So depending on how far you want to go back, for example, I didn’t go to college thinking I’d be a doctor.
I was actually an electrical engineer. And I did an internship at Bausch and Lohm in my hometown of Rochester, New York. And that sort of opened my eyes to the idea of, can you solve problems and challenges for people in a more actionable way and sort of leverage the ideas of engineering and technology to do that?

And so that’s really the initial inspiration for medicine as a field. And then I sort of popped around to different fields within medicine. I thought I’d be a neurologist or cardiologist.

I did some work in telemedicine with Parkinson’s disease. And then the medical school is when I really realized that actually, I thought I’d only want to take care of adults, but I actually really loved taking care of kids and found a lot of meaning in taking care of kids with cancer specifically. But there was sort of an age group that I really resonated the most with, which were young adults teenagers and young adults.

And so that led me to train in med peds. And so I’m both an internist and pediatrician, but really with a focus and interest in young adults, you know, facing chronic illness. But then it was only in residency that I realized that oncology was was the sort of application of the population of need was young adults with cancer was the one that I really wanted to focus my life, my life’s work in.

And it’s been really rewarding and meaningful to support young adults through their journey and understanding that, you know, taking attendance, you know, pediatrics, where we think about the whole person and whole body and, you know, the emotional, social and economic needs of our patients and their families, bringing that approach to adult medicine has been really rewarding.

And that’s how we try to approach the care of young adults. It’s sort of not just their disease, but also all the things in their life that are gone awry by their cancer diagnosis and how best we can support them to help them thrive.

Shushan Hovsepyan: Yeah, I completely agree. That was very interesting. And thank you for sharing your insights on liposarcoma today and also your personal journey.
It’s clear that while there are challenges in managing this rare cancers, there are also incredible progress being made in research and treatment. So thanks a lot for joining us. Stay tuned and stay healthy until our next episode.Thank you.

Vinayak Venkataraman: Thanks so much. Great to chat.

Previous episodes of  5 min Sarcoma Talk with Shushan Hovsepyan

Episode 1: Leo Kager

Episode 2: Rajkumar Venkatramani

Episode 3: Aaron Weiss

Episode 4: Leo Mascarenhas

Episode 5: Andrea Ferrari

Episode 6: Sandra D’Angelo

Episode 7: Roger Wilson

Episode 8: Joe McNeill