Dr. Kendal Williams (Host): Welcome, everyone, to the Penn Primary Care podcast. I'm your host, Dr. Kendal Williams. So, we've been doing a short series here on the podcast focused on women's health. And you can't talk about women's health without talking about breast cancer. One of the most common malignancies in America and around the world, one in eight women are going to experience breast cancer in their lifetime. We see a lot of breast cancer in primary care. We co-manage with our colleagues, both surgeons and oncologists, our patients who have breast cancer. They often come back to us with questions about treatment modalities, surgical options, and all kinds of different questions. And so, we've done this in the past, but I wanted to bring back, and do another podcast on breast cancer treatment with two experts at Penn. And for that, I've invited two experts on. Dr. Ashley Newman is a surgical oncologist based at Penn/Princeton, and Dr. Ramy Sedhom is a medical-oncologist, who treats breast cancer and is the clinical Director of Medical Oncology at Princeton Penn Med.

Ashley and Rami, thanks for coming on.

Dr. Ashley Newman: Thanks for having us.

Host: So, first off, I just wanted, because we actually haven't had an expert, a Penn expert from Princeton on the podcast. I just want to ask a little bit about the program out there. The two of you work pretty closely together, I imagine.

Dr. Ashley Newman: Rami and I work very closely together. When I first actually started in Princeton, I was in private practice. And one of the reasons that I made the jump to join Penn Medicine was to build a more integrated program with medical oncology and surgical oncology. I think our program is really special. It's different. There's a lot of multidisciplinary care that's focused on heavily. Rami started the geriatric oncology program at Princeton, which is a really unique system set up for older adults who are struggling with cancer diagnoses and how to navigate that journey.

Over the last year since I've come onto Penn, we've started a high-risk program at Penn/Princeton for women who are at high-risk or aren't sure what their risk is of breast cancer and want to discuss that as well as screening options for them. We work very closely with our colleagues in physical therapy and PMNR. They really help my patients deal with the consequences of surgery, discomfort after surgery, lymphedema, or really just early monitoring. And unfortunately, if necessary, early treatment thereof of lymphedema, very integrated with radiation-oncology as well.

We have a lovely program here, and a lot of really good teammates that work with both of us on all of these endeavors. So, it's a nice program. We're building it into something really special. And the goal here is to be able to get the same kind of care that you would receive going downtown that you would have in Princeton and be closer to home for a lot of folks.

Dr. Ramy Sedhom: And I just wanted to maybe share one last point. Bob Vonderheide, as many may know, is the Cancer Center Director down in Philadelphia. I love his vision, which is he wants to make sure that whether you walk into Princeton, Lancaster General, Radnor, Chester, that you're walking into Penn Medicine. And I think the quality of care, the physicians that people see at Princeton do represent that.

Many of us trained at very good institutions. Our plastic surgeon, for example, came from Penn, Philadelphia. Our PMNR doc came from Penn, Philadelphia. Many of our radiation-oncologist trained at Penn back in their day. Dr. Newman came from a pretty good health system called Harvard Health System. So, it's really nice that people have quality care close to home. The one gap that we're trying to build is having treatment trials close to home, and that's been our next horizon.

Host: That's terrific. So, really, I think when a patient is diagnosed with breast cancer, there's sort of an algorithm, right? And I want to take us through that algorithm as to how you treat various stages. Ashley, I'm going to ask you a lot of questions about surgical options, because I know little about that.

So, I'll tell you how this happens on our end, right? We send a patient for a mammogram. We order a mammogram, our gynecology colleagues have ordered a mammogram. We get a result back. There's this potentially suspicious finding. We're asked to order another diagnostic study. Patients then go for that. If that's positive or suggestive, an ultrasound is done. And then, usually, a patient is referred to a biopsy or directly to a surgeon.

So, Ashley, I'm actually going to ask you because, I think, in this paradigm, the modern paradigm for the management of breast cancer through breast cancer centers, surgeons are really at the center of it in many ways.

Now, that's kind of different from other fields, right? I mean, lot of times a surgeon comes in and does their thing and then they're gone. But oftentimes, the surgeon is the first point of contact and they're really the one from whom all the spokes go out, right?

Dr. Ashley Newman: Yes, that's exactly the model. I love being the ringleader, because it means that I can control how things go. And I meet patients at all steps along with this journey, whether at their initial screening mammogram after something's come back as abnormal and they're not sure what other imaging is necessary, or if it's after biopsy results have already been received and a diagnosis has been made.

But I think what's really important to me is that when patients come in, they leave with their questions answered, that they know the next step in their care plan, and that they have a vision of how this is going to move forward. Whether that means surgery, whether that means meeting other doctors. In modern care for breast cancer, a lot of my patients meet criteria for neoadjuvant therapy or some sort of systemic treatment prior to surgery. And so, a lot of the time if I see a patient pop up on the schedule, Rami and I will coordinate our schedule so that he's available to see the patient thereafter, just to give some brief overview and answer some questions from his standpoint about some of the things that will be considered as part of their treatment paradigm.

But it is, it's a different system for breast surgeons, I think, than for other surgical disease sites. I love it. That's why I chose to go into breast surgery. I like having that relationship with my patients. I think it's really, really important. And I think we do a really good job of taking care of the whole person that comes in to see us. Whatever needs that there are, we're happy to address and really take that as a team approach.

Host: So when a patient comes to you, Ashley, let's say, have most of them already had some form of biopsy or are you the one that's often coordinating that biopsy?

Dr. Ashley Newman: I usually coordinate the biopsy or I'll order the biopsy. We try to get this done as efficiently as possible so that, if a patient is referred to see me, sometimes just because of my schedule or their schedule, it just is more efficient for the patient to go ahead and have the biopsy before they come in and speak with me.

If that's the case and a positive result is found on that biopsy, the benefit then is that I can expedite their care thereafter. Like, I get that result in my inbox. I can call them, I can have my staff call them. We can set them up usually within 24 hours to see me, and go through all the details of that. And that visit when I meet with patients for the first time is usually about an hour long. It's a long visit. I always encourage people to bring friends, family, any other set of ears that can come, because it's a ton of information that I go through.

But I'd say, a lot of the time, even without a positive diagnosis of a breast cancer, sometimes the visit before or after the biopsy is so important for me to coordinate and understand what their exam findings are in the setting of whatever imaging that we're looking at. I do review all of my own imaging, whether that's mammogram, ultrasound, or MRI. And I usually review it with the patient so that they can see what we're talking about and understand what we're worried about, what we're looking at.

So even in the benign setting, I've disagreed sometimes with their reads on some of these scans, or I've had a radiologist give me a second opinion and just see if they also think that there's something out of line or of a concern. And it allows me to start that conversation with the patient, build that rapport, build that relationship so they don't feel like that they're in the dark through that whole phase.

Because I think that's what creates the most anxiety. If they don't know what's going on or what we're talking about, it creates a lot of questions. And then everybody, of course, goes to the worst case scenario every time. And usually, I spend the first part of my cancer consultations talking everybody off the ledge because they're not in the worst case scenario. The good thing about breast cancer care is most patients do absolutely excellent throughout their treatment, and they go on to live completely normal lives.

Host: So, let's talk about the pathology that you'll get back from the biopsy, right? And we don't have to go into great detail on this, but obviously there's a category of DCIS, which is stage zero. This is a tumor that is still in situ. It has not invaded yet, but my understanding is that 40% of DCIS can go on to invasive and we treat that then as a breast cancer nowadays. We didn't always do this, but now we do. And then, of course, you have stage I, stage II, stage III, which we'll go over in a bit, but both the stages and the pathology classification in some way starts with DCIS at the most basic level. And then, you have invasive ductal cancer, right? Then, you have lobular cancers that start in the breast lobule.

LCIS, from what I understand, is not considered a malignant condition, but invasive lobular cancer is. And then, there are some other subtypes that are less common, but is there anything that, Rami, you and Ashley want to say about these subtypes that really drive, that you're really looking for? In some ways, I wonder, beyond DCIS, does it even matter so much from a treatment paradigm which one of these It is?

Dr. Ashley Newman: Definitely.

Dr. Ramy Sedhom: Sure. I'll start by sharing that I think the most important initial distinction, is it invasive disease or is it not? So as you had shared, there are hosts of pre-cancerous lesions that we often will still co-manage together, along with radiation-oncology. And aside from the pathologic subtype, there's a lot of different risk calculators or historical or family history that may also help decide on what's the best way to risk-reduce cancer. So oftentimes, for any of these stage 0 histologies, the conversation we're often having Is, "Here's what we can do to lower your lifetime risk of developing an invasive cancer."

And I think like invasive cancer, even in this precancerous situation, a lot of it really depends on patient values, their fears, what matters most, what has their been experience been with other family or other friends. Because aside from the risk reduction, there's a lot of patient preferences around how often do they want to continue to get these equivocal findings on imaging and get biopsies and re-biopsies. The pendulum does swing. And I think data has suggested, in recent years, people are more prone to do risk reduction surgeries than they have been in the past. We've been seeing prop ups of some prophylactic mastectomy clinics that have come up in large academic centers because of all the fear that has come from abnormal mammograms and the fear of biopsies. And was the biopsy a false negative? So, I'd maybe start with there's so much here around patient context and goals.

Dr. Newman, was there anything that you wanted to add around just histological subtypes, at least in the preinvasive scenario?

Dr. Ashley Newman: I think there's a spectrum of DCIS, there's a spectrum of invasive disease. And I know that you'll totally agree with me. You really cannot beat bad biology. Biology drives all of it, drives what we recommend in terms of surgical medical management, radiation management. There's a lot of data out there now about deescalating care. And we do that based on the biology of what we're seeing and treating.

So, I think that's become the biggest shift in terms of treatment for breast cancer, is that this is a very different disease process in every patient. And treatment plans are highly personalized, because we take into account these personal wishes and other risk factors that a patient may or may not have to help them make decisions about their treatment, but also to help them understand the risk because it's not the same. A 35-year-old being diagnosed with DCIS and an 85-year old being diagnosed with DCIS, that's two totally different disease processes. You have to think about why it happened in the first place, what their risk factors are, what strategies do you have to offer them risk reduction in the future. It's a very nuanced conversation. So, I think that's where this gets really complicated.

Host: Yeah. So when we get beyond DCIS—which I want come back to—we;re going to focus very specifically on the treatment in a minute, but just to kind of get the overall context for our audience, basically I think from what I understand, breast cancer breaks down into four basic categories. So, you have in situ, that's DCIS. You have early invasive, right? It still remains in the breast, right, I suppose? And then, you have locally advanced, which has gone to the lymph nodes, is outside, but it still stayed local. And then, of course, you have metastatic. And it seems that a lot of the treatment, the major differences are between the three categories of those four categories.

And so, you know, going back to the DCIS piece, Ashley, what are you offering? And you said it's contextualized to the patient scenario and so forth, whether or not you're offering surgery. But what are you offering?

Dr. Ashley Newman: So, there's three options with DCIS you can choose to monitor. The COMET trial was really designed to help us understand which versions of DCIS are safest to monitor and which needs some treatment. And that was very helpful to help us, especially older patients who have very low risk DCIS, so hormone positive, low to intermediate grade, less than two centimeters in extent. Those are the patients who have the option to do anything. They can watch it, they can simply remove it, or they can remove it, and then take steps to reduce risk if it were to come back.

The problem with DCIS is that when it does recur, about half the time, it comes back as DCIS, which is not a problem, and half the time it comes back as invasive cancer. And so, our goal is to really find those patients that benefit most from surgery and then risk reduction strategies, whether that's endocrine therapy to reduce the risk of a hormone-positive DCIS recurring and/or discussing radiation therapy to the breast depending on the surgical approach.

But there's really only two surgeries that we do for any type of breast cancer. There's is either a mastectomy where we remove the entire breast or a lumpectomy where we only remove the area of concern as well as some normal tissue surrounding it to ensure clear margins. With DCIS, the trick is that you need larger margins than you actually do for invasive disease. And what all that really equates to is that for those who undergo a lumpectomy, there's a slightly higher chance you may need to go back to clear a margin for a re-excision, which is a separate surgery. It's not nothing, you know, if a patients holding anticoagulation or they have other medical comorbidities, sometimes the second surgery is a big deal. So, those are really the two surgical options that patients have.

Oftentimes, my recommendations really depend on the extent of what I think is going on locally. So, do I think it's something small? Can I realistically remove this or attempt to remove this with lumpectomy and expect a reasonable chance of clear margins and complete excision? Or do I think that the size or extent of this is larger and would require a mastectomy in order to clear all of the disease?

So, it's pretty straightforward from a surgery standpoint. There's really only two types that we do. The lymph node piece of it, again, a little bit more nuanced. But in pure DCIS, the only time that we sample lymph nodes would be during a mastectomy, because it does allow me to do more of a targeted lymph node excision and decrease surgical morbidity in that way.

Host: And if you do just a lumpectomy, you would follow that up with XRT with radiation. And would you do that if you did a mastectomy? Would you follow it up with XRT?

Dr. Ashley Newman: So usually, no radiation after a mastectomy, sometimes radiation after a lumpectomy. So, this is, again, where it gets really patient-centric. So for good-risk DCIS, we can say that you can choose to take it out and do no radiation. That is an option if you're willing to accept a local recurrence risk that's slightly higher. In the invasive setting, we estimate about 1% per year, so similar in this setting. But again, 1% per year that it recurs as something DCIS or invasive cancer.

Host: So, I failed to do at the beginning, something I wanted to do, and that is to sort of lay out all the tools that you have in your armamentarium for treating breast cancer. Because we jumped into DCIS, which jumps into surgery and XRT and radiation therapy. And then, also, I'm going to ask you about endocrine therapy for DCIS in a minute. But then, it reminded me that we hadn't actually sort of laid out those tools.

So, to treat breast cancer, we have surgery as we've been discussing. And then, we have radiation therapy, we have endocrine therapy, right? So, hormonal therapy, blocking therapy for patients that have the appropriate biology. We have chemotherapy traditional sort of taxane and other based chemotherapy. There's now newer immunotherapy. And there may be other things even beyond what I've just said. So, I wanted to kind of lay that out, and maybe have you guys—Rami, you can comment. Is there anything I'm missing in that? Are those the tools in your toolbox for the most part?

Dr. Ramy Sedhom: Essentially, I would maybe add that under each of those umbrellas, there are more and more advancing therapies. And a lot of it comes from our understanding of biology. For example, in the endocrine therapy space, we're really understanding how much ovarian suppression can also contribute to good long-term outcomes. So much so that there's a national trial now challenging if chemotherapy is even needed in certain situations or can ovarian suppression plus anastrozole or letrozole or tamoxifen have a similar outcome. Similarly, newer modalities for how we deliver cytotoxic chemotherapy, like antibody drug conjugates. But yes, I would say those are the big umbrella pieces.

Host: And that's very helpful by the way. We're going to get into the hormonal therapy piece and talk about ovarian suppression. But okay, going back to the DCIS folks, we talked about the lumpectomy or mastectomy, potentially XRT. Now, there is still an endocrine aspect of that, a hormonal aspect, right? So if a patient is estrogen receptor-positive, I assume either estrogen or progesterone, they get tamoxifen. If they're postmenopausal, they can get an aromatase inhibitor if they're postmenopausal, but they could also get tamoxifen. Is that right?

Dr. Ramy Sedhom: Yeah, that's exactly right. And I would maybe say for pre-invasive disease, the caveat is that they would need breast tissue to have a benefit. So, there's a lot of data that if they had a double mastectomy. There's much lower role for adjuvant endocrine therapy. And I actually love the term that used to be in UpToDate—I know no one uses UpToDate anymore, but it's chemoprevention. So, these strategies are a way to try to lower the risk of needing chemotherapy for an invasive cancer in the future.

So, the way I often frame this for people is they've done a lot already with their surgical intervention, as Dr. Newman mentioned, radiation may offer risk reduction for local control. I think the caveat that's important to highlight it is there's no overall survival benefit for radiation in the DCIS space. And then, endocrine therapy reduces the risk of future breast cancer. In premenopausal patients, historically, we'd often use tamoxifen. In postmenopausal, it could be tamoxifen or one of the other hormone therapies like anastrozole, letrozole, exemestane.

However, I think a prevailing problem, which we know our primary care docs share with us, is the patient experience on these therapies. Nationally, if you follow adherence to therapy for the recommended five years, almost 40% of patients stop therapy early. There's so many different reasons why. But ultimately, there can be toxic drugs. While they are not chemotherapy, having a symptom every single day can really add up for people.

So, I would add that one recent trial that got all of us excited, oncologists, surgeons, patients alike, was what we often frame as the Baby TAM trial. So, this was a trial that was done in Italy. I guess a lot of people don't leave their small town in Italy when they live there. So, they were able to actually follow patients for 15 years. And what was really novel about this trial is they actually lowered the dose of tamoxifen from 20 milligrams to 5 milligrams. They also cut the duration of therapy from five years to three years. And they actually randomized the placebo. So, it was actually really nice to know how did this low-dose actually compare to doing nothing at all.

And what really caught people by surprise was a risk reduction. So, a hazard ratio or an effect size essentially that was similar to full dose from historic studies. And what I often show patients in the room is that if you pull up table two, which was the adverse event profile, there was not a significant finding for any toxicity compared to placebo.

So, I would say for a lot of patients who are risk-averse or are really worried about how they will feel on these therapies or the risk of osteoporosis or endometrial toxicity, I often will start and recommend Baby TAM as a good option for them.

Host: That's interesting. So yeah, this comes up a lot in primary care. So, you do have that option now. That's great. So, I think that ends our DCIS discussion. So, these are not yet invasive tumors, lumpectomy, mastectomy, XRT as we noted, and then endocrine therapy does apply. And then, let's just skip down and say, "Okay, now, you get pathology back, and it actually appears to be early invasive." Ashley, how does that change how you approach this patient?

Dr. Ashley Newman: A lot of the time, the surgical approach is the same. It depends on the tumor size and patient preference. We also offer a lot of genetic testing options at Penn/Princeton. Both Rami and myself do point-of-care testing. So if a patient meets criteria for genetic testing, I can just order it and have the blood drawn done while they're still in the office to expedite that, because it does take a couple of weeks to come back. And in younger patients, it does change management. Oftentimes, you know, if we find a genetic mutation, I counsel differently in terms of recurrence risk, in terms of secondary malignancy risk, or developing a contralateral breast cancer, it's different. So, that's one piece that sometimes will affect our decision-making.

Host: And can I just ask you something? So by genetics, you're talking about the genetics of the patient, right? In terms of their individual risk for breast cancer, if they're identified as being BRCA, for instance, or something else, that's going to change how you think about the other breast, right, and their risk? But you don't mean genetics of the tumor itself, right? Markers the tumor?

Dr. Ashley Newman: Not yet.

Host: Not yet. Okay.

Dr. Ashley Newman: That comes later. Yeah, that comes usually after surgery. That's for Rami to help them to make decisions about treatment and what's going to be most beneficial. But they're like somatic genetic testing is what we're looking at. And really, we're trying to see if the risk of them getting a second breast cancer over the course of their lifetime is elevated. Especially in younger folks like Rami alluded to, there is a huge trend to just removing both breasts. It's not a nothing thing to do. There are long-term permanent consequences of that type of surgery.

Something that I don't think most patients understand until they talk with a surgeon is that you're permanently numb after a mastectomy. Even if you do preserve your nipple–areolar complex, it's not functional. It's truly cosmetic at that point. I remember as a fellow having a patient tell me she wished she knew that before. Because when she went to hug her son, she couldn't feel him the same way. That's a big deal. And it has a lot of side effects in terms of sexual health, in terms of health of a relationship at home. These are big adjustments that people make. So, it's not nothing to remove both breasts. If it's something that will reduce your risk of developing additional cancers or potentially have any type of survival advantage, then absolutely it makes sense for most. But they're long surgeries, recovery time is not nothing. It's usually at least four to six weeks. If you remove both breasts, I usually say closer to eight weeks. Surgical recovery after that procedure too is not super straightforward for all. It's usually additional surgeries required if they choose to do reconstruction with implants.

So, having that sense of where they're going to go with their care upfront is really helpful. Most patients only want to see me with a new cancer diagnosis once in their lifetime. They're not looking to be coming back and finding these things over and over again. So if I do find that they carry like a pathogenic BRCA1 mutation, I can tell them, "Well, your risk of a second breast cancer is really, really high." So, it may be at that point worth considering removing both breasts as part of treatment, but also risk reduction in the future.

Host: This is one of the main reasons for this podcast, because we wanted to get into this, because we're seeing differences in this in our practices. I think more and more patients coming back, both with bilateral mastectomies for reasons you outlined, but also are being taken through a process of breast reconstruction.

So, I actually want to sort of opt out of our discussion by stage and talk a little bit more about surgical stuff right now and just ask you some more specific questions. So, we talked about lumpectomy, which does not architecturally distort the breast that much, right? Mastectomy is mastectomy. The breast gets removed. And then, there's bilateral mastectomy, right? So, what happens? And I assume it's the same pretty much for bilateral or unilateral, what's the process? So, a person has their breasts removed. And then, you said that, it's a six-week recovery from that. And then, what are they looking at in terms of breast reconstruction in the modern day? What are their options?

Dr. Ashley Newman: So in general, there are two basic options. It's either implant-based or autologous, meaning using their own tissue. I can also tell you there's a third option in there, besides just straightforward lumpectomy and mastectomy, there's also oncoplastic reduction. This is something we do a lot here at Princeton, because we have excellent plastic surgeons that we work with and who are available to us to come and help us with these cases.

So, it's not uncommon that I meet a woman who has a very large breast and even if she has a large tumor, would benefit from a large lumpectomy, which can also be combined with a breast reduction, ends up essentially being a mastopexy on the one side. And then, the plastic surgeon can do a contralateral symmetry procedure on the other side to make the match. And this does get covered by insurance. It's a way to have a breast reduction covered by insurance with no questions asked for the most part.

The benefit of that approach is there's no implant, there's no foreign tissue. And when we talk about reconstruction after mastectomy, whether that's using implant or your own tissue, there's recovery associated with that, where I think with the oncoplastic reductions, while there's definitely still surgical recovery, it's a lot less. If there are drains, there's one drain, not two drains, so that cuts the drain time down by half as they're recovering. I'll tell you, that's the part everybody hates the most. They still have the benefit of doing these large tissue rearrangements with plastic surgery so that they look and feel normal when they're recovering and healing from their surgery.

If they do a mastectomy, it's usually two procedures. The first is the mastectomy removal of the breast tissue, often sampling of the lymph nodes. And during that same operation, once the breast is removed, the plastic surgeon comes in and puts a temporary implant in place called a tissue expander. The tissue expander is silicone on the outside. And inside, they'll either fill with air or nothing. They put that in immediately after the breast is removed. They usually check blood supply of the skin. And if we've preserved the nipple, they'll check blood supply of that as well. And then, the patient recovers from that initial operation. Assuming that there's no indication for chemotherapy or radiation therapy after their surgery, approximately three months later, they undergo usually exchange of the temporary implant or tissue expander with a permanent implant.

At that point, they'll be able to decide the overall size that they want to be. The benefit of the tissue expander is that it can be inflated or deflated to match the size needs of the patient. It also allows us to slowly expand the tissue expander so that there isn't so much pressure on that skin immediately after a mastectomy, which already takes a hit from a perfusion standpoint. So, it does allow better wound healing, less complications. And then once they're at the size that they prefer to be, that's usually assuming, like I said, there's no other pieces to their cancer care that needs to be done first as a priority, then they can go on and do the cosmetic piece where they do the tissue expander exchange. At that point is really when patients make the decision between implant-based reconstruction and autologous reconstruction.

For autologous reconstruction, there's two flaps that I see done more commonly. That would be deep flap where you harvest from the abdominal wall and latissimus flap, which is a rotational flap, where we take skin and muscle and tissue from the back and rotate that in to help recreate the breast. Any type of flap surgery will also have donor site morbidity, which is another thing that I think is not well understood.

One of the biggest concerns and criticisms of abdominal wall flaps has been the hernia risk over time. And that's not small and can create many complications, as all of us know who've treated patients with hernias. That risk doesn't exist with the latissimus flap, which is a benefit of that flap. But the size of the recreated breasts that you'll be able to make using a latisimus donor flap is smaller. So, it's not uncommon that I've seen plastic surgeons employ both a latisimus flap and a smaller implant in order to create the size breast that the patient desires.

I find that most often, when we're doing flaps, it's because a patient has been previously radiated on that breast within the last five to 10 years. If radiation was delivered many years ago, like over 10 years ago, and there's not extensive damage to the remaining tissue, it's not impossible to perform another lumpectomy with radiation, they can be reradiated in certain cases. But if not, if we're electing for mastectomy or they require one, oftentimes the plastic surgeon will employ a latisimus flap to support the blood supply to the remaining tissue or the skin that would cover the reconstructed breast so that this way we know there's such small vessel changes that happen after radiation and these changes are longstanding. So, we decrease the risk of flap loss or of reconstruction loss being needed to be taken down because of ischemia. So, it can be a little bit of both. But usually, especially around here, it is an implant-based reconstruction and patients do very, very well with it.

Host: When you said implant-based, do you mean the temporary implant or a permanent?

Dr. Ashley Newman: Permanent implant.

Host: Okay. Yeah. So, after describing the flaps and other options, most people are still getting implants now. Is that right?

Dr. Ashley Newman: Well, and I'll tell you too, we are very fortunate, we see a lot of healthy people in Princeton. And you need a lot of tissue to rebuild a breast. I don't think people realize just how much abdominal fat you need in order to reconstruct a breast. And like I said, the latissimus flap usually is not enough on its own unless the patient wants a smaller reconstructed breast.

Host: Yeah, I would imagine, you kind of need your latisimus. I always wondered about these surgical things. You know, you guys take things from one place and put it in another. And I said, "Well, the lattismus is still pretty important."

Dr. Ashley Newman: Yep.

Host: You won't be able to do pullups.

Dr. Ashley Newman: No pullups. No pullups. I'll tell you, it's rare. They do a bilateral latissimus flap reconstruction, because of the morbidity of that. But unilateral is usually well-tolerated.

Host: I had thought, just in my experience with my own practice, that it had seemed that more patients were choosing for autologous. I was seeing less and less implants. But you're telling me the implants are still pretty popular, huh?

Dr. Ashley Newman: I still think they're the most popular. They're also lower risk in general. Imagine going through a 16-hour surgery for a bilateral deep flap. And then, the flap going down two days later. And you're still left with an implant and now you have no other donor tissue to use to reconstruct. These things happen. Thankfully, they're not common because we work with such excellent plastic surgeons, but these are major surgeries. They involve microsurgery to reconstruct vessels. It's not a small thing, and there are definitely complications.

Host: Do patients with implants need to have those revised in time?

Dr. Ashley Newman: Nope, not unless there's a problem with them. That's sort of old dogma that they need to be swapped out every 10 or 20 years. I'll say too, it's not uncommon that I order an MRI on a patient who's had a bilateral mastectomy, whether it's because I'm worried about something or we think there could be an issue with the underlying implant.

So, we do image them usually over time. And I know as a breast surgeon, we're trained to look for what would be complications with an implant so that we would be able to pick that up and send them back.

Host: So theoretically though, after a patient has had a mastectomy, we don't need to worry about tumors in that breast anymore, right?

Dr. Ashley Newman: Well, cancer can still recur. This is another, I think, piece of misunderstanding. When we do a mastectomy, it is impossible to remove every single cell of breast tissue. Impossible. It goes to the level of the skin. There's no way. We estimate we probably leave somewhere around 5-10% of breast tissue, depending on the approach and the patient.

So, knowing that there is always the risk of a cancer popping up. The risk is significantly reduced after a mastectomy. If you look back at studies, for risk reduction in the BRCA mutation carrier population, the risk estimate is somewhere around 95% reduction. So, it's powerful risk reduction, but it's never zero. Patients still need a clinical breast exam even after a bilateral mastectomy. I usually recommend for the first two to five years after their surgeries that they see me at least twice a year.

And then, from there, we can go to annual visits if they're also comfortable with other providers that they're seeing. But these need to be done and it needs to be done with people who know how to examine a reconstructed breast because it will feel different. There's scar tissue that forms. A very common procedure that's done at the time of the implant exchange is something called fat grafting, which is also done by plastic surgeons where they use liposuction to harvest fat from a different portion of the patient's body. It's usually their flank or their thighs. And then, they inject it into the reconstructed breast to smooth out the superior contour where the implant would meet the muscle. The problem with that is that fat dies when this happens and it causes fat necrosis, which feels firm like a cancer recurrence would, and often leads to additional workup with imaging, even sometimes biopsy. So, you're never totally out of the woods if you've had a breast cancer diagnosis. But risk does go down with time. And with appropriate followup and screening, it's still a very manageable, very low risk.

Host: Well, I want to make sure we have time to talk about the systemic approaches, I suppose. So, Rami, we talked about hormone therapy. You talked about sort of mini tamoxifen, baby tamoxifen, Baby TAM as an approach. And I want to talk about the chemotherapy and the immunotherapy piece in addition. But before we leave hormonal therapy, is there anything that should be said about that?

So, here's what I know. I'll tell you what I know and you can correct me just for time's sake. Patients get at least five years of tamoxifen. They can get an aromatase inhibitor if they're postmenopausal. You did mention ovarian suppression, and I wanted to at least highlight what that is for everyone, to speak to that a little bit. Now, that would be only in premenopausal women who still have active ovaries, right?

Dr. Ramy Sedhom: Yeah, correct. So in the endocrine space, ovarian suppression is often used in premenopausal patients to essentially make them menopausal. This is based off many randomized studies that have shown, you know, up to 15-year benefits, about 8-10% risk reduction by including ovarian suppression.

But I would share that this is mostly in "high-risk patients" who otherwise would have needed chemotherapy. So, that might be just a good tip that if they needed chemotherapy, there may be a benefit from ovarian suppression. There's a lot of nuance, which we can get into in a minute, but that's maybe one thing to just quickly consider a tip.

Host: Now if a patient does not have hormone receptors, and they don't have ERBB2, which used to be HER2, they're considered triple-negative. And so, their only option is chemo. But in patients who do have hormone receptors, they're also potentially going through chemotherapy, right, in addition to the hormones. I do know that patients who have hormone receptors generally do better though patients also who have Herceptin itself, which is for HER2, is highly effective. And the triple-negative folks have the most difficult situation, because you don't have the benefit of the hormone suppression that you can gain, right?

Dr. Ramy Sedhom: Yeah, that's right. So, I might suggest, for example, quickly walking through how we would approach different segments of disease based on stage. And I'll try to highlight what the goal of each therapy is.

So when I'm first meeting someone, and let's say the ideal scenario is I'm seeing them right after Dr. Newman at their initial visit, I'll often draw for them a 2x2 table. And I'll write at the top ER/PR. And I'll write on the left HER2. And I think for simplicity's sake, just imagine that ER and PR always run together. So if you think about it, each test can be positive or negative. So, you can kind of have one of four quadrants. So, one situation might be ER/PR positive, HER2 negative. One might be triple positive, HER2-positive, but ER/PR negative or triple-negative.

And what I'll often tell people is we really approach, just at least philosophically, HER2-positive disease and triple-negative disease in the same way. And basically, if it's stage I, two, or three, the goal is to cure the patient. And we have different criteria for who benefits from chemotherapy before surgery. And again, just pretty simple way of thinking about it is if you're stage II and beyond, you'll likely benefit from neoadjuvant, so treatment before surgery.

And I think the biggest thing for that, aside from downstaging the patient and making the surgery easier or more feasible, is it teaches us a lot of biology. Because if you imagine you have a visible tumor that you can track and follow. And if all of it's gone at the time of surgery, we have what we call a pathologic complete response. These are patients who tend to have a much better long-term prognosis than those who had some residual cancer cells.

And what's happened in the drug development space, and again HER2-positive and triple-negative disease has the ability to escalate therapy when they have more resistant biology. So, that's been, I think, the big approach these days for how to approach from a chemotherapy perspective.

Just as there's been deescalation trials in radiation-oncology, there's also been deescalation trials in medical oncology. So, we now have approaches where we give less chemotherapy. For example, a classic scenario is an early stage HER2-positive cancer where we'll only give 12 weeks of a weekly taxane, paclitaxel with a single HER2 drug. And I think this has been a game-changer for patients too, because oftentimes less is more.

To simplify hormone-positive disease, so again, think about the bottom left of that quadrant where you're ER/PR positive and HER2 negative. We really only want to give chemotherapy if it's a bad biological tumor. And we have these genomic assays and there's many different ones. I'd say the most common one that we use is something called an oncotype. So, this is a genomic assay that basically separates patients into high risk, low risk, or intermediate risk. And I'll say chemotherapy has the largest benefit in high-risk patients.

I was alluding earlier that there's a national trial that's randomizing patients to ovarian suppression versus chemotherapy, and that's specifically in the premenopausal intermediate risk. So in the big TAILORx study and in other studies that looked at the same question, they found that in premenopausal patients, there was a signal of benefit from chemotherapy regardless of this oncotype score.

But what we all believe, and there's now a study looking to answer that question, is it likely was the impact of what chemo does on a young woman's ovarian function rather than the chemotherapy itself. And I think that just calls into question, just a new overarching theme in breast cancer, which is, I think, the days of anatomical risk and anatomical staging is changing to be more biological risk. So, we now see scenarios where people have stage II or even stage III breast cancers where we may not be recommending chemotherapy and instead leaning more on, you know, maximum hormone suppression or use of endocrine therapy. And we do see sometimes stage I cancers where the biological risk is so high that we are recommending chemo. So, I would say that's new adoption, and something that we often work very closely with our surgeons in terms of sending the right tests at the right time.

Host: So, you guys talked about this biological risk, and I'm not going to ask you questions to define it a little bit more. Is it defined based on oncotypes that you get back, kind of prognostic factors on the tumor itself? I assume you're measuring proteins and various other factors on the tumor itself. And then, you also mentioned biology in the setting of neoadjuvant chemotherapy where you're treating a patient, you're seeing how they actually respond to the therapy. And I don't know if you would do neoadjuvant hormonal therapy. And you do. Yes, you do. Okay. Ashley, you're shaking your head. So then, before you do anything surgically, you're seeing how this tumor's responding. And so, those are the two contexts in which you you both refer to biology. Is there more to it than that?

Dr. Ramy Sedhom: So, I would say the easier part to identify is the biology from response to chemo. I think that's been a validated surrogate endpoint. And again, we separate them into pathologic complete responses, partial responses or no responses. We do have patients who, unfortunately, their disease grows despite the best chemotherapy.

The neoadjuvant hormone therapy, I would say, is a bit more nuanced. I would say, oftentimes, it's maybe more for patient context or patient preferences. Oftentimes, for example, Dr. Newman and I will have a teacher who it's near the end of the school year, and she doesn't want to have surgery until the summer. So, we'll discuss maybe going on hormone therapy for a few months just to keep the cancer from growing. And we do learn a bit about its biology.

But then, you also have—and I think, Kendal, maybe this is something that goes close to home too—is it's hard to know the biology of the patient. So, unfortunately, something we haven't discussed yet is that the number one risk factor for breast cancer is age. And unfortunately, as people get older, the risk for breast cancer, you know, exponentially increases. I'll often quote, you know, for a 20-year-old woman, it's about one in 200,000 chance sometimes to develop breast cancer, depending on, of course, family history. And by the time you become 80, it's almost one in eight or one in nine. And the hard part is as you become 80 or 90 years old, you also have other comorbidities.

Other things that make the benefit of surgery may be difficult to quantify, a lot of our patients have caregiving responsibilities. They have a different tolerance for side effect. So, sometimes, for example, we will test the biology of the host, which is the patient and also of the disease. Because if someone has, for example, rapidly growing disease, we are not doing them any benefit from surgery. And these are situations where we'll often say, let's start with the systemic therapy first, just to make sure that before they go through anesthesia and before they go through all these other curative intent options, that we are not just seeing the tip of the iceberg.

Host: So, I'm getting from this that it's evolving into some degree. It's complicated. I mean, I'm hearing my desire to keep this in different categories, and I'll say, "Oh, stage I, you do this. Stage II, you do that. Stage III..." that you guys are creating a much more dynamic picture here of how this is done.

Dr. Ramy Sedhom: And I think maybe it's always good to use analogies that might make sense to people. So, I also imagine you guys are seeing a lot of lung cancer in your practices. And I think just as the world of lung cancer has really separated it into almost 20 or 30 different subtypes of non-small cell lung cancer, have this mutation or that mutation, we are still really at our infancy of understanding the biology of breast cancer. And I might give one example.

Recently, two of the biggest findings in HER2-positive disease is that if you have a hormone positivity, meaning if you're triple positive, you might benefit from all the same intensifications of hormone therapy as someone who's HER2-negative. So, you've probably heard of CDK4/6 inhibitors, which, again, were a game-changer in hormone-positive breast cancer. We now see that they can work even in really advanced HER2-positive disease.

I actually have a patient right now who's on her ninth line of HER2 therapy, and it's actually been her best therapy to add a  CDK4/6 inhibitor to her chemo. We are also finding that ovarian suppression also works in HER2-positive disease. So, I think, my prediction is in 10 to 15 years, we're going to have a lot of different ways to segment the breast cancer population.

Host: There's two remaining topics I want to hit on, and we're running up against time, but I really want to hit on two things. And these are related to some degree. So, we didn't talk about the metastatic population. I have a dear patient in my practice who had years ago, maybe 10 years ago, DCIS was treated aggressively, and then came in with back pain and had metastatic lesions in her spine. She has been under treatment and has done very well. I mean, it's been three, maybe four years now, and she's been doing well. She's fine.

I have another patient in my practice diagnosed 13 years ago with metastatic breast cancer. She walked in with back pain and was found to have metastatic lesions to the spine. She's 13 years out. She's still working, and still smoking, which is not as good a thing.

But my point is I feel like dynamically we're seeing progress in real time. We used to quote people that had metastatic boney lesions particularly—and I know there's a difference between bone disease and organ disease—but five years or so, but it seems like progress is happening in real time.

And so, I want to ask where is that progress? We haven't talked about immunotherapy and I'm curious if some of it may be there. So, I basically took the two questions I had, which was role of immunotherapy and dealing with me metastatic and rolled it into one big question.

Dr. Ramy Sedhom: So generally speaking, when we have metastatic disease, we would often share with patients that the goal is disease control and not cure. I would say we're always happily surprised that sometimes there are exceptions to that rule. But I think that's the way we often like to frame it.

So if I'm looking at the triple-negative space, as you had mentioned earlier, Kendal, it's really chemotherapy that's driving most treatments. There's been a lot of trials showing that immunotherapy does have a role for this patient population. Typically, there are ways to predict who benefits most from chemotherapy, but it's not a perfect risk prediction model.

And a lot of modern-day trials are looking at what are the best combination therapies to enhance the role of immunotherapy. And there's a whole field of science looking at how do you make everyone's tumor hot so they're most likely to respond to immunotherapy? But generally speaking, the experience for triple-negative breast cancer is likely that you're going to be on several sequential therapies.

The paradigm for the most part is to give one single therapy at a time. There's no benefit from combination, as opposed to one single drug at a time. So, a lot of how we sequence is based on patient preferences, whether or not they have neuropathy, whether or not they have pneumonitis, risk for X, Y, or Z. And unfortunately, our prognosis for triple-negative breast cancer is still measured in a few short years, two to three years for the average patient. But again, that's the average scenario.

For HER2-positive disease, very different prognosis. These are patients that can, as you said, sometimes live a over a decade. We have many HER2-positive patients where sometimes we're discussing them in tumor board to say, "Hey, this woman is on her ninth year of no evidence of disease." And the question we're often asking is, "Is anyone comfortable stopping therapy?" Unfortunately, there's not a lot of data on which patients are safe to stop therapy on. But thankfully, there's been so many advances in HER2-positive breast cancer, that we have women living for sometimes over a decade.

So, we would often frame these conversations a little bit differently. We would say that in the best case scenario, you might be living for another 10 years, if not more. In the worst case scenario—and this is where biology comes to play—it can be less, but the only way to know is to actually look at milestones, which is how long does each sequential therapy work?

I would say most of our HER2 therapies—our best HER2 therapies—are given early and earlier. So for example, the big drug this past year has been in HER2, which was often used as a last line effort, and then it was second line. And now, it's really almost moving into first line in every different indication, even in the curative setting.

And then for a hormone-positive disease, we sometimes use chemotherapy, but we often try to maximize the use of hormone therapy first. So for metastatic hormone-positive breast cancer, some patients may be on five or six different lines of hormone therapy before they even have to use chemo, and that's been both a blessing and a curse. The blessing is people, for the most part, can live normal lives for many, many years before they're subjected to chemo. But I often find that when they're in that scenario that they're using their first IV therapy, it's a huge psychosocial burden because they now sometimes feel like patients.

And I'll just maybe want to share and highlight one trial that I think challenged a lot of conventional wisdom, which was how to treat "visceral crisis." So just to define visceral crisis, it was impending organ failure. You know, think about new breast cancer with multiple lung mets or high bilirubin and transaminitis. So, it was a really cool trial that actually randomized patients with hormone-positive breast cancers and visceral crisis to hormone therapy versus chemotherapy. And they actually found that hormone therapy not only worked faster, but it actually improved survival to a greater extent than chemotherapy. So, it's actually really showing the power of modern-day hormone therapy.

Host: So, it seems like, Rami, you're laying out so far that a lot of the success we're seeing in metastatic disease relates to hormones and HER2. It's these receptors that are driving a lot of it as opposed to chemo itself. Because if I know of a chemotherapy agent and I knew about it in medical school, I'm getting to the age where that's been around a while. And a lot of these chemotherapy agents, it seems like there hasn't been a ton of advances, but there have been advances in the hormone area and then to some degree in human immunotherapy.

Dr. Ramy Sedhom: Yeah, absolutely. And I think maybe the one cutting-edge therapeutic in the chemo space is these concepts of antibody drug conjugates, which are looking at different linkers and how they can be partnered to deliver chemotherapy or even sometimes HER2 therapy in a more meaningful way. It's now made it to first-line in the triple-negative space with immunotherapy in combination. So, a great example of combining two separate modalities to improve patient outcomes. I think that's the wave of the future.

And maybe from a diagnostics perspective, there's a lot of work in the area of looking at circulating tumor DNA and trying to understand biology at the basic cellular level. And I think that's a potential opportunity. It hasn't quite made it there yet to be primetime, but it is a conversation almost every one of our patients has, and I'm sure tests you're probably seeing in the media tab of your patients, which a lot of companies are looking in this space.

Host: So, I mean, I think we could have done two podcasts on this by the amount of time it took us to get to this point, we definitely could have. Because there's just a lot to talk about. There's all kinds of interesting things. And this is a disease, I think, that impacts many of us. My mother died of breast cancer when I was five years old. So, I know what it's like to see the impact of this disease, which can hit families when kids are young.

And so, I think breast cancer is just a disease that we all want to know about, and we really want to see advances being made. And it sounds like year over year, we're seeing the slow advancing, so that the case fatality rates have really dramatically reduced in the last 20 years or so.

Dr. Ramy Sedhom: Yeah, absolutely. Thanks for sharing that story. And thanks for all you're doing to improve education. And then, I would say the best thing we could do for patients and families is try to prevent breast cancer or catch it early. So, I think it's a lot of the work you and your colleagues are doing around education. And I think for all that's been out there, risk reduction from a weight management perspective is something we underappreciate. I think we're really excited to talk about not just cancer prevention, but cancer interception, which maybe is a future podcast you can host with Dr. DeMichele, who's leading that work around the country.

Host: I want to refer everyone to a previous podcast we did with Lynn Shechter and David Porter on just how do you treat cancer nowadays. And we talked about antibody drug conjugates. It was very interesting discussion to kind of give some background to all the things that you're mentioning, Rami. Ashley, any closing thoughts?

Dr. Ashley Newman: I think the takeaway from this conversation is it's complicated, I totally agree with you. And it's a very patient-driven process. Everything is personalized medicine at this point, whether that's from the patient perspective and choices that they have, and choices they don't have, and even from the provider perspective of saying, "Well, you have this specific type of cancer and this is how we treat this specific type at this specific stage." And I think that's really cool. I think that shows how much progress is being made because we can actually look at this as different disease processes instead of just lumping it all together as one thing.

Host: Yeah, I think the takeaway from me, sort of as an audience member listening to the two of you, is that, first, I'm thankful that there's such empathetic and compassionate physicians that are involved in this space and are also contextualizing care within the patient's life. You're thinking like primary care doctors, Ashley, as a surgeon. And that it's complicated and it needs to be tailored to each individual patient. So, thank you both very much for coming on the Penn Primary Care podcast. And I want to thank the audience for coming. Please join us again next time.