Advancements in Breast Cancer Treatments with Dr. Fred Dirbas

On this episode of Scrubcast, we speak with Dr. Fred Dirbas, the John and Ann Doerr Faculty Scholar of Breast Surgery and chair of the breast disease site working group for the Society for Surgical Oncology. 

Rather than ascribing to a particular set of screening recommendations, Dr. Dirbas advocates for personalized screening strategies, particularly for women with a family history of breast cancer.  

He discusses his innovative work in FLASH radiotherapy, which aims to minimize side effects typically associated with traditional radiation, and his research on triple-negative breast cancer (TNBC), focusing on identifying subpopulations of TNBC stem cells through molecular profiling.

Rachel Baker : [00:00:00] Welcome to Scrubcast, where we take a closer look at the research happening at Stanford University's Department of Surgery. I'm your host, Rachel Baker. Today we're speaking with Dr. Fred Dirbas. Welcome to the show.

Dr. Fred Dirbas: Thank you for having me. It's a pleasure to be here, Rachel.

Rachel Baker : Thank you for joining us. It is so nice to have you here.

Dr. Dirbas, you are an associate professor in our division of general surgery and the John and Ann Doerr Faculty Scholar of Breast Surgery. Why did you choose breast surgery?

Dr. Fred Dirbas: Well, it was a little bit of a securities path. When I was an undergraduate at Stanford, I worked in cardiovascular, uh, surgery labs, actually in Norman Shumway's transplant lab.

I joined just after they had done the first successful animal heart lung transplant. And one of my jobs was to inject this immunosuppressive agent that Phil [00:01:00] Oyer was bringing over from Switzerland, I believe later turned out to be Cyclosporine. So I got to take care of those animals, helped out with some of the operations, and, um, was interested in cardiac surgery after that for a long time.

And, and then I went to the NIH for two years. To do a clinical and research fellowship, nine months of which were clinical, 12 months of which I was doing heterotopic heart transplants and monkeys and rats, which was great because it was really nice experience in vascular surgical techniques and also would essentially immunotherapy because we were giving antibodies conjugated to our radioligand atrium 90 and using that to attack the T cells that were causing rejection.

That resulted in a few publications. Then became a little disillusioned with cardiac surgery. What people were publishing at the time were mostly papers on how long does a certain valve last before it fails? Or how long do vein bypass grafts last before they fail? And to me, that [00:02:00] wasn't, I know, it just wasn't as exciting as I felt it could be.

So, when I came back from that experience, I sort of mentally drifted for a while in terms of what I was interested in. And then John Niederhuber came to Stanford as the chair. And while we always have had surgeons who were doing surgical oncology, he really was the first one who fit the mold of what one today would consider a true surgical oncologist very, very multidisciplinary.

It was not only your job to be able to take out a big tumor, it was also your job to understand where systemic therapy fit in, where radiotherapy fit in the imaging component, how to work up patients. The pathology and at the time, for example, there were a lot of what we would, you know, refer to as peak and shriek operations for things like pancreatic cancer.

I ultimately ended up doing a surgical oncology fellowship, so I did two fellowships overall, but the one in surgical [00:03:00] oncology, because of the transition in leadership, there were only three chief residents. The year after I finished, we finished five, but the next year there were only three. So he asked me to stay on as kind of a super fellow.

And I got to do Whipples and liver resections and, and a lot of breast surgery with John. I think there was one patient the entire year that we took to the operating room where we actually didn't do the resection because it hadn't been worked up properly. So, I really liked that because it, it made it sort of like a chest match.

You know, you gotta be very deliberate in your thinking and very careful in your planning. You have to go outside your own discipline to make things work and. Especially with breast cancer, you were kind of in the driver's seat. A lot of other things like cardiac surgery, you rely on referrals from cardiologists and GI.

You refer on referrals sometimes from gastroenterologist, but when somebody has a breast mass or a new cancer, it's like, when can I get into to see the surgeon? So, I like that part of it. [00:04:00] I came from a medical school, Columbia, where the tyrannosaurus rexes, so to speak, of the surgeons did breast surgery.

So, I was very comfortable with that. And at the time, no one at Stanford really wanted to do breast surgery. So, I was over at the VA for a little while and all the faculty said, well get Durbis back over here. He's good. And, and I came back over and I really, I really enjoyed it. I had a lot of empathy for women dealing with breast cancer.

We're seeing women in their twenties and thirties and forties and fifties, never did anything to hurt themselves, you know, and. I also felt a great deal of empathy for the women because they either worked or they worked and had families, or they just had young families. So, seeing someone come in who's in their thirties with breast cancer on multiple involved nodes and three kids, or a woman who's working and you know, cruising at a high altitude at, you know, [00:05:00] 40 years old, just assuming they're gonna meet Mr. Right and then have their kids and wham. All of a sudden, they've got breast cancer, and it's chemotherapy, and there go the ovaries and then you have the women who work and have kids and they feel they're doing a terrible job at both. So, I just really felt like I could help, and I think the patients sensed that when, with some of the folks who had, uh, gone on sabbaticals came back.

The patients actually asked that I stay and, uh, join the faculty.

Rachel Baker : Awesome. Well, it is Breast Cancer Awareness Month and one of the things I try to do on this show is remind people about preventative care. What is the current advice around breast cancer prevention? How often should women be performing breast exams and home, and how often should they be coming in for professional screening?

Dr. Fred Dirbas: So, quite honestly, one could go on Google or ChatGPT and get the official recommendations from the various [00:06:00] societies about what age is optimal for screening? I think they're all generally okay. You know, most of them start at age 40 or 45. Some of the recommendations are get annual mammograms or get mammograms every two years.

I think that one of the difficulties I've always had with the recommendations. That come out of these very large, uh, epidemiological studies is that they focus on endpoints mortality, which I understand is a very important thing. But what they don't really dive into is the pathway. So somebody who has a breast cancer diagnosed at age 40, for example, and has a four-centimeter tumor and multiple positive nodes, may end up still as a cure.

Even though they got their mammograms every two years, but that's gonna be a very different pathway than somebody who had their mammogram at age 40 and had something picked up when it [00:07:00] was 15 millimeters and the lymph nodes were negative and maybe they didn't need chemotherapy. So, you know, you see enough patients go through this and surgery is not easy.

I would argue as a surgeon that the chemotherapy is harder for most folks. If you can minimize the extent of treatment, which is a big, big topic now in breast cancer surgery, it's often referred to as de-escalation. If you can save someone the experience of a sentinel node biopsy where they've gotta a worry about going around telling everybody, “don't touch my arm 'cause I can't get lymphedema” or save them radiotherapy or chemotherapy because you know, the tumor was detected at a size below, which chemotherapy isn't recommended.

I think you've done that individual a favor. Granted, all of these imaging studies have false positives. That's a big issue. You hear a lot of frustration from patients who [00:08:00] come in and they haven't had their mammograms in a few years and the tumor's been picked up at a late stage. Um, you also hear a lot of concerns and complaints about women who go through procedures that they don't really need.

So I don't know what the right answer is, but I think. Length of life is super important mortality, but I think quality of life is also really important. And that's why if you ask most breast cancer specialists, they're typically going to recommend more on the side of getting annual screening, starting at age 40 for someone who doesn't have a family background.

And just to sort of, this is a nice segue for women who do have a family background. The importance of genetic testing, which some organizations like the American Society of Breast Surgeons is very supportive of all women who are diagnosed getting genetic testing, although that's not what insurance companies I think are all recognizing at this point.

We do look to primary care doctors to [00:09:00] be aware of these things, and I always think that it's greater to raise awareness among individuals who have a family background of breast cancer, and it's always not obvious. Some individuals still think it's just gotta be on the mother's side of the family when it could just as easily be on the father's side of the family.

They might not recognize the associations between ovarian cancer and breast cancer. And these are the patients that are the most, in a way disappointing to see that nobody had mentioned genetic testing to them along the way. I think physical exams, if one has a primary care doctor and a gynecologist, and getting a breast exam twice a year is not unreasonable.

And as far as women doing their own exams, there are some very prominent individuals who have pointed out that no one's ever proven that doing a breast self-exam improves survival. But again, it gets to the point of the journey, not necessarily the outcome. I think what most [00:10:00] don't understand is that.

It's very helpful for a clinician to have a patient who knows what their typical breast exam is like, and that we're not expecting a woman to come in and tell us they have breast cancer. We are simply expecting them to come in and just say, you know what? I felt this lump, and this is not me. This is new.

You know, there's really no bad time to start checking. For women who have a family history, the consensus is to start really looking in earnest, including things like MRI and mammography. Years before the youngest relative was diagnosed.

Rachel Baker : Mm-hmm. Interesting. What I've learned from being at Stanford Surgery is that there is no “One size fits all” model. So, I think that makes a lot of sense of doing what is right for you based on your family history. But actually I was stalking you as part of my research as, as I always do with my guests. And I found one thing really interesting and that is flash [00:11:00] radiotherapy. I don't think I have heard of anyone else doing this.

It's. Ultra-high dose radiotherapy. What's the difference between flash and conventional dose?

Dr. Fred Dirbas: Yeah. Great. Thanks for asking. So it's definitely, um, something that's under the radar. I was asked to speak at a conference last week and one of the program committee chairs. Around. I said, have you guys heard about Flash Dirbas is doing? And they're all like, no, I don’t know what you're talking about.

Rachel Baker : I feel better then.

Dr. Fred Dirbas: Yeah. Where Flash differs is it's ultra-high dose rate. The ultimate dose doesn't differ. Oh,

Rachel Baker : it's just faster.

Dr. Fred Dirbas: Yeah. Typically, for a woman having breast radiotherapy, the radiotherapy is delivered at a dose of 0.03 or 0.04 gram per second.

Okay, [00:12:00] so a woman receiving radiotherapy will lay on what's referred to within radiation oncology as a couch. It's not the couch you have at home, but that's what they call it. And the radiation takes approximately two minutes to deliver. Flash radiotherapy was described actually several decades ago in bacteria.

Mm-hmm. Its ultra-high dose rate, and the current definition is a dose rate over 40 gray per second, even up to a hundred or more gray per second. So if you were to take a typical dose that a woman receiving conventional breast radiotherapy, 1.8 gray a day, that dose would take, you know, two minutes or maybe a bit less.

That dose is now delivered in, in about 600 milliseconds.

Rachel Baker : Wow.

Dr. Fred Dirbas: It's like giving radiotherapy through a fire hose rather than a garden hose. One might think doing something like [00:13:00] that would just destroy normal tissue, everything. But in fact, in all the preclinical studies that are done, and there are now clinical trials that are starting in Europe, the skin and tissue holds up well.

What we've seen in our experiments is. A tremendous difference early on where literally the mice had have received flash radiotherapy to the entire left chest, and this is what some of the work we're about to publish on. The mice lose all their hair and you just see their chest wall. When you look at the mice have received flash, it's like nothing happened.

Rachel Baker : Whoa.

Dr. Fred Dirbas: There's some question whether the same benefits hold up long term, although some have shown that under the right conditions it will hold up long term.

Radiation oncology is very interesting in that nobody has ever fully understood radiation oncology to begin with. We know that it causes hydroxyl radicals and DNA damage, there are immunologic effects that have been shown, uh, but nobody's ever really dissected all the pathways fully into how it [00:14:00] works.

Part of the work we're doing is looking at normal tissue toxicity and what the, what the benefit is of that, and part of the work that we're doing. Is trying to understand tumor cell kill and how we can augment that with immunotherapy. And a lot of it comes down to radiation physics in terms of beam parameters.

Things that again, nobody ever really thinks about. Like flash is delivered in pulses of a certain amount of gray. Mm-hmm. And there are really sort of minute details about how long is the pulse, what's the time set, and, and we're talking like milliseconds now. Between the delivery of the pulse, how much energy is in each pulse to try to dissect out what are the optimal conditions that one can use to translate this into something that will work for humans.

But now that I've seen it with my own eyes, just how beneficial it is. I think it's something that just absolutely has to be pursued because. Radiotherapy is very effective, but it does have some side effects. [00:15:00] If we could find a way to deliver radiotherapy where women didn't get the typical sunburn or maybe found a way to avoid some of the late toxicity.

So these are the things that I think we can improve. And the nice thing about flash is that it appears to work on a variety of tumors. So it's not just breast, it could be applied to virtually everything. And where a lot of the research is being directed right now are some of the tumors that have been typically.

Avoided or where there's been a lot of toxicity like neoblastoma or ovarian cancer in places where you really couldn't give radiotherapy. So people weren't as excited about doing it for breast because there's always this attitude. Yeah, well, you know, it works okay for breasts, so we got other things we should focus on, but women who have breast cancer need attention to.

So we've got a lot of people working in the lab now on it. We have two PhDs in cancer biology. I just hired a postdoc in radiation physics and then James Agolia is working with us also [00:16:00] Nice in splitting his time between our lab and Dan Delitto's lab because of the experience he has with single cell sequencing and some of the very new techniques that are available to try to elucidate the mechanisms, uh, with single cell sequencing and spatial transcriptomics to see.

What's going on at the cellular level in terms of pathways and how you can tell cells that may be 10 microns apart, what they may be behaving differently, where otherwise they would just stay the same.

Rachel Baker : Very cool. You have another project you're working on concurrently that is a little harder to understand at, at least for me.

Mm-hmm. It's with doctors Aaron Newman and Michael Clark. You're looking at triple negative breast cancer, um, acronym, TNBC. Apparently, it's super deadly.

Dr. Fred Dirbas: It's a problem. It's a problem because there's no expression of the estrogen receptor or [00:17:00] progesterone receptor or HER2 receptor, so you rely on straight up chemotherapy now with various forms of immunotherapy.

Which work in roughly 20 to 30% of patients and have non-trivial toxicity, but there's just no easy target for it. So that's why it's a problem. So Mike Clark is a stem cell biologist.

Rachel Baker : Mm-hmm.

Dr. Fred Dirbas: Mike is best known for being the first individual to identify cancer stem cells in a solid tumor. Oh, he did when he was at Michigan in 2004.

Aaron Newman is an amazing bioinformatics specialist who has developed these incredible tools for being able to separate out the different cell types within a tumor. He uses single cell sequencing to be able to identify which are the cancer stem cells. So the purpose of that study [00:18:00] was to try to identify whether there were different subtypes.

Of cancer stem cells within that triple negative breast cancer lineage. So samples have been collected and Aaron is working his way through those. And my contribution to that has been some of the background about the clinical treatment for patients with triple negative breast cancer and how that information might be used clinically.

So if we're able to find that, we may be able to find pathways that. Show why some are more aggressive than others, much like the molecular profiling studies from the Brown-Botstein lab decades ago. Can you identify subpopulations of these triple negative breast cancer, uh, stem cells that will help determine what type of treatment may work better, or whether one's more aggressive than another, or what pathway drives them.

So that's the hope with that project.

Rachel Baker : Awesome. I mean, it's so [00:19:00] inspiring to hear all of the different things that you have going on, even though I feel like we've made so much progress with breast cancer, there's still, this is still a problem, as you mentioned.

Dr. Fred Dirbas: Yeah. Well, one of the things that's been very inspirational for me is getting back to that experience.

When I worked in Dr. Shumway's lab, watching heart lung transplants go from experiments in, you know, initially there were dogs and then monkeys. Then going to humans, and now it's done worldwide. Watching the work come out of the Brown-Botstein lab and who knew where that was gonna go? And now that's an everyday part of how we care for patients.

I was the principal investigator for Stanford's investigator initiated clinical trial and partial breast or aviation at the time. People were saying, why do we need to change breast radiotherapy? It's just fine the way it is. It's six weeks now. Partial breast radiation is something we do every day. So I've seen this series of experiments go from, you know, a lab experiment to routine clinical [00:20:00] use, so I know it can be done, so it can be done again.

Rachel Baker : Well, we've talked about your clinical side. We've spoken about your research side. Let's talk a little bit about your leadership side. You are the chair of the breast disease site working group for the Society for Surgical Oncology. What does that job entail?

Dr. Fred Dirbas: Yeah, so it's been a great undertaking.

It's something I wish I had pursued earlier in my career, and it's been really a wonderful outlet to interact regularly. A lot of the folks are from MD Anderson, Sloan Kettering, Dana-Farber. And it's a very, very, very active group. There are emails every day on this stuff. Not to plug us, but I will a little bit, I suppose.

There's a surgeon academy where we have webinars on different aspects of breast cancer. We just did one a few months ago, was a collaborative effort on breast cancer in [00:21:00] adolescents and young adults. That was done in conjunction with the Taiwanese and Korean breast cancer societies.

We have separate podcasts. Those are available on Spotify or through Apple. Anyone can listen to those. Uh, and those are on a variety of topics. We just did one last week on male breast cancer and we're constantly writing papers, whether it's editorials or commentaries or helping with guidelines. We're now looking at updating what are referred to as the Choosing Wisely Guidelines for how can we de-escalate some aspects of breast cancer surgery.

Literally this morning I was on a call where we're working on setting up next year's program for the SSOs annual meeting, which will be in Phoenix in March, and being involved in these discussions. And I think working with these individuals who are very motivated to do these educational seminars and help establish guidelines and provide education has been a wonderful, wonderful, though very time intensive aspect of work.

But it's been a lot of fun. And I'll be the chair through [00:22:00] 2027. Providing I don't do anything to offend anyone.

Rachel Baker : Well, that sound means that it is time for our lightning round. On each episode of Scrubcast, we ask each of our guests the same three questions. The first one is, who is a surgeon you admire and why?

Dr. Fred Dirbas: So, I've been doing surgery for a while, so it would be hard for me to get through this by just saying one surgeon.

My father was a colorectal surgeon. I probably. I wouldn't have gone into surgery if it wasn't for him. I dunno why, but it was just like I was gonna be, I, I actually wanted to be an Air Force pilot, but I needed glasses in eighth grade, so that was out. Um, but um, you know, I didn't really appreciate it at the time, but my father was a board-certified colorectal surgeon.

He did a fellowship in 1956 at Temple. Um, I was like, you know, too clueless as a teenager to really have any idea what that meant. He used to do his own endoscopies. [00:23:00] Everything you would expect a front runner in colorectal surgery to be doing so he is a great inspiration. Robert Birch was a wonderful surgeon at Columbia who just totally had my back in a way that probably no one ever had before or has had since.

Just in help of looking out for me, uh, Bruce Reitz, who took me into Shumway's laboratory and who did the heart lung transplantation work. Watching Bruce do surgery was like listening to James Taylor sing. It's just so beautiful and so effortless that it's almost criminal to watch that, to think that just anybody can do that.

Craig Miller was another brilliant is he's now retired, but was, I had the great exposure to him. Uh, cardiovascular surgery. Umberto Veronesi was a visionary, some would say the greatest living breast surgeon. He passed away a few years ago, going back to 1968. He pointed out that in order for breast conservation to work, one needed to do mammography, one needed to resect to [00:24:00] clean margins, one needed to have good pathology and one needed radiotherapy, and he just articulated what was just way ahead of his time.

He built them wonderful sites in Italy that did these amazing clinical trials, sometimes actually beating the US to the punch in terms of results that nobody really talks about 'em just 'cause it's across the pond, so to speak. But the one who I probably would say that I have to admire the most is Norman Shumway, who, you know, I, I had a great opportunity to interact with him, even though I was an undergraduate, and then later on as a resident, see him and be able to scrub on cases, harvesting veins where he was working on.

I didn't want to diminish the importance of it, but it was almost like listening to Yoda when he'd be taking an experienced cardiac surgeon through a case. They'd be summing a valve in and he would say, don't you know, don't put the stitch there 'cause you're gonna catch the coronary sinus. And then the resident would go somewhere else to put the stitch in and he literally would, uh, [00:25:00] I mean I recall the operation: he said don't put the stitch there, the valve will leak in two months. The resident was, went to put the stitch somewhere else and he goes, good chance you're gonna cause some conduction abnormalities if you put it there. It's like he had just seen everything. And you know, he's actually quoted as saying, I may not be the world's best surgeon, but I'm the world's best first assistant.

And it was just, um, it was just really amazing to watch him. But he also was brilliant in terms of setting up a parallel laboratory that doing the immunotherapy research and then having the vision to set up a program that was two years of general surgery, then cardiac way before anybody accepted that concept.

And creating a cadre of cardiac surgeons who all went out and became chairs of cardiac surgery around the country, one of whom operated on my father emergently when he needed bypass surgery. Um, between the research and, uh, his clinical ability and his ability to administer a great program, he's probably at the top of the list there.[00:26:00]

Rachel Baker : The second question is, what is the best advice you have received in 10 words or fewer?

Dr. Fred Dirbas: Well, first I'll share two pieces of advice that I have on my own. Then I'll share the best advice I received. The two pieces of advice that I would give out, and I think this is true, whether it's a relationship, whether it's work, whether it's a business relationship, whatever.

And this is something that it took me four decades to learn, is that if there's something that isn't working out for you and you're thinking about it all the time, it's probably a sign that you should be out of it. The second thing, and this applies really to research, is that you can make up for lost money, but you can never make up for lost time.

Rachel Baker : Oh yeah.

Dr. Fred Dirbas: So it's really important to be on top of the stuff you're doing and making sure you're not repeating something that somebody else has proven doesn't work or does work. The one piece of advice that I got, and it's very short, is that the cream always rises to the top. [00:27:00]

Rachel Baker : How did you, um, put that into surgery?

Dr. Fred Dirbas: Well, if there's ever a time where you're feeling like things aren't going well or you know that there aren't folks that believe in you, that you just gotta believe in yourself.

Rachel Baker : Love that. The final question, what is your preferred OR music?

Dr. Fred Dirbas: Well, I think anyone who's scrubbed with me would probably could answer that question.

That's gotta be Bruce Springsteen hands down. Although the Beach Boys are coming in a close second lately.

Rachel Baker : Quality choices. Thank you. Well, it has been such a pleasure chatting to you. Before we go, I wanna ask one final question. Sure. And that is what is next for Dr. Dirbas?

Dr. Fred Dirbas: Keep helping women who have breast cancer and uh, keep trying to move research along so that we're finding better ways to treat individuals and keep enjoying and hoping for good health with my daughters and wife.

[00:28:00] And, uh, just trying to keep it all together.

Rachel Baker : Absolutely. That's all we can, any of us can do. Well, I look forward to reading, uh, all of the amazing stuff you come out with. I'm gonna have to go over to the SSO and listen to some of your podcasts. Maybe check out one of your webinars. Thank you so much for being on the show.

Dr. Fred Dirbas: Thanks for the invitation. It's a pleasure. And I appreciate your time.

Rachel Baker : And thank you to our listeners for tuning in to this episode of Scrubcast. Until next time, stay sharp.

And that brings us to the end of another episode. If you like Scrubcast, we hope you'll tell your friends and subscribe wherever you get your podcasts. Scrubcast is a production of Stanford University's Department of Surgery. Today's episode was produced by Rachel Baker. The music is by Midnight Rounds, and our chair is Dr. Mary [00:29:00] Hawn.