The Breast Cancer Breakdown

How much of a factor is genetics when it comes to breast cancer, and how does that inform the best treatment approach? As Dr. Daniel Morgenstern, who specializes in breast cancer and genetics at UConn Health, explains, there's quite a spectrum when it comes to types of breast cancer, and immunotherapy, while promising, is not effective with a majority of them. Dr. Morgenstern also discusses the evolution of breast cancer awareness, today's recommendations on mammograms, and how personalized medicine figures into the future of breast cancer treatment.

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Dr. Daniel Morganstern:
https://www.uconnhealth.org/providers/profiles/morganstern-daniel

Breast cancer diagnosis and treatment at UConn Health:
https://www.uconnhealth.org/cancer-blood-disorders/services-specialties/breast-cancer

Breast cancer screening at UConn Health:
https://www.uconnhealth.org/cancer-blood-disorders/prevention-screening/breast-cancer-screening

UConn Health Orthopedics and Sports Medicine:
https://www.uconnhealth.org/orthopedics-sports-medicine

Dr. Alessi: Welcome to the Healthy Rounds Podcast, where we provide you with up-to-date, timely medical information from national and international leaders in their fields. This podcast is brought to you by UConn Health with support from the Department of Orthopedic Surgery and a grant from Coverys. This podcast is not designed to direct your personal healthcare, and that should only be done with your physician. 

I’m your host, Dr. Anthony Alessi, and it’s great to have as my guest today Dr. Daniel Morgenstern. Dr. Morgenstern is an associate professor of medicine here at the University of Connecticut, and working at UConn Health in the Carole and Ray Neag Comprehensive Cancer Center. His specialty is breast cancer and genetics. 

Dan, welcome to the show.  

Dr. Morganstern: It’s great to be here.  

Dr. Alessi: Let’s chat a little bit. As we all know, this is Breast Cancer Awareness Month. Nowhere in our history have we seen a more successful campaign than Breast Cancer Awareness Month, right? National Football League players are wearing pink. Baseball players are wearing pink. 

Everything merges at one time. And yet, I guess my real question is, in this period of time where we’ve raised awareness of breast cancer, what has been the result? Are we making headway?  

Dr. Morganstern: Absolutely. I mean, I think if you go back to the 1970s and think about Betty Ford, when we all remember her diagnosed, you know, one of the original problems was that this was a disease in the shadows, and there was all kinds of embarrassment and shame associated with that. 

And as you mentioned, this has sort of been flipped, the script’s been flipped, and, really no one has shame anymore. People are comfortable talking about the experiences they’ve had, peer support among survivors, and again, it’s sort of out of the cloaks of embarrassment and so forth, and really something that everyone feels comfortable addressing with their primary care provider, screening, and so forth. 

So it really has become something that I think has worked to improve screening and outcomes.  

Dr. Alessi: You know, one of the things that’s impressed me most about breast cancer care is the development of a multidisciplinary team that approaches breast cancer. Can you tell our listeners what they should be looking for in a team? 

Because it’s not just a surgical approach, as it has been in the past. Can you talk a little bit about the team here at UConn Health and the approach to breast cancer?  

Dr. Morganstern: So yes, it is a multidisciplinary disease, and our patients will be the first one to tell you that, both in a positive and negative ways. 

In a positive way, they have a group of physicians. You might say the triad is between a medical oncologist, a radiation oncologist, and a surgeon. So they have three people who independently but collaboratively are thinking about their case, and all cases are reviewed at our multidisciplinary tumor board, and this results in sort of a optimized outcome and a tailored outcome for each patient. 

I say there’s a flip side of it, which is I always say that the most multidisciplinary person of all is the patient because they’re subject to both the benefits and also the toxicities of all therapies. So sometimes those are sort of mitigated. For example, we have data that shows that in some patients, if they take an endocrine therapy, they can safely defer radiation therapy. 

So not only do we work together, sometimes we decide who can step aside and patients who can defer various modalities.  

Dr. Alessi: I just want to talk a little bit about probably a somewhat controversial topic that shouldn’t be controversial, and that is mammography, right? When a woman should get mammograms, right? 

We’ve had the Professional Services Task Force, the Federal Task Force come out with their recommendations. And in many cases, that’s been in conflict with the professional societies. Can we clear up for our listeners, when should women begin to go and get a mammogram?  

Dr. Morganstern: Okay. Correct. 

There are different recommendations. The American College of Radiology recommends annual screening for average-risk women beginning at age forty, with the U.S. Preventative Task Force prior to this administration, recommending a more liberal onset that considering once every other year mammography within the forties and not going annually until the fifties. 

I would break down two aspects of how you address this question. One is a public health question. Where is our money best spent in screening and so forth? And the other relates to how screening could harm if misapplied to the wrong population. And what I would say is that unquestionably there is some element of what we call over-diagnosis. 

We know that with the onset of mammography from the nineteen eighties to the two thousands, there was a skyrocketing incidence of early-stage breast cancer, but not a requisite decrease in later stages of breast cancer, and much of that was the DCIS or so-called pre-cancer, stage zero. But I think we’ve pretty much landed at an annual mammography for the average risk patient beginning at age forty. 

Now, very interestingly, Laura Esserman spearheaded a trial that was reported last year called the Wisdom Trial, which was an online phone app-based research which risk-stratified patients for either more intensive screening than annually or less intensive screening than annually based on risk factors like genetic testing, breast density, and so forth. They actually showed with that study that even when they had risk-adapted screening with many women having screening at lesser intervals, the outcomes were essentially the same in terms of the ability to identify early-stage disease and cure rate. 

So this was a very important contribution. There may be more evolution of our guidelines in the future where we can say to someone that based on your polygenic risk score and your risk factor estimates, maybe they can defer to every other year. And that is a growing emerging field that I have a lot of interest in. 

Dr. Alessi: Let’s talk a little bit about taking a step back, you mentioned risk factors, right? I’m assuming those include smoking and other things such as that. But what else? How big a role do genetics and family history play? And do you recommend that if there’s a family history, women begin getting mammograms earlier? 

Dr. Morganstern: So I’ll use our vocabulary a little bit carefully. We can talk about familial breast cancer where there seems to be some overabundance of breast cancer within a family tree, but no gene identified. And then we can talk about those cases where there’s sort of a smoking gun, if you will, BRCA1, BRCA2. 

The latest and most important gene second to those is PALB2. In those cases, we can say that probably about five to seven percent of breast cancers can be explained by a single gene mutation that predisposes the woman to develop breast cancer or man. Alternatively, we know there’s this other familial clustering that occurs in families that is independent of any single gene mutation, and this is the growing field of polygenic risk scores where they look at all throughout your genome, little subtle changes that by themselves don’t do anything very much. 

But if you have a number of these, it does elevate your risk. Again, this is a field that’s a hot field that I hope to be doing some research in terms of risk stratification as well.  

Dr. Alessi: Is it because of the genetics that some women advocate for bilateral mastectomies?  

Dr. Morganstern: So again, we have to talk carefully about which genes and so forth. 

So we call BRCA1, BRCA2, and PALB2 highly penetrant or highly to moderately penetrant genes where the cumulative lifetime risk of developing breast cancer and developing breast cancer at early age is quite high, over 50%. And in those patients, risk-reducing mastectomy and reconstruction has come a long way. 

Obviously, it’s an option for those patients, although there are many patients who choose to do surveillance with enhanced surveillance such as MRI as well, and this has been shown to save lives as well in that patient population. So, there is an alternative to risk-reducing surgery. When we have lesser penetrant genes such as CHEK2, ATM, which might be having a lifetime risk of breast cancer anywhere from like 15 to 30%, in those individuals, most do not opt for risk-reducing surgeries. 

Dr. Alessi: I’m going to shift gears a little bit and get into a field that’s somewhat confusing even for me, and that is receptors, right? Are receptors good? Are receptors bad? Are some good, some bad? Because we hear about these receptor-positive, receptor-negative tumors. Can you give us the Cliff Notes version of it? 

Dr. Morganstern: Absolutely. So the most important thing to take home is that most breast cancer is estrogen receptor or hormone receptor positive, 70% in fact. So when we think about that, we also think about that gains and improvements in care in that 70% majority make the most public health impact. About, depends on where you get your data from, but roughly 10 to 15% respectively of HER2 receptor-positive and triple-negative breast cancer, namely negative for the estrogen receptor and the HER2 receptor represent the remaining population. 

But a full 70% is by far the most common type of breast cancer, and the most curable type of breast cancer as well is estrogen receptor-positive.  

Dr. Alessi: So it’s good to have estrogen receptors?  

Dr. Morganstern: Right. It’s because estrogen-dependent tumors respond to an armamentarium of things that are lesser impact in terms of side effects and tolerability on patients such as estrogen blockers, tamoxifen, aromatase inhibitors, and soon to be approved is a new class of drugs called SERDs, or selective estrogen receptor, down-regulators or degraders. 

And one that appears to be on the cusp of FDA approval as a preventive, after a breast cancer diagnosis is a compound called juridestrant  

Dr. Alessi: So we know we’ve been hearing a lot about immunotherapy for cancer, right? Most notably, we had Dr. Callahan on recently, and we talked about melanoma and a new term for me, neoantigens, and she explained that. 

Where are we with that in breast cancer? Will we someday or are we on the verge of an immunotherapy, um, for breast cancer?  

Dr. Morganstern: Well, sort of circling back to that seventy percent, in that seventy percent of people, no. And there is a good reason which you mentioned, which relates to those neoantigens and, and effectively, estrogen receptor-positive breast cancer so closely resembles normal breast tissue that there are not these neoantigens present by and large. 

Okay. And we don’t see breast cancer developing amongst immunocompromised individuals. So there’s the sense that at least the most common type of breast cancer is not under immunosurveillance to start with, and hence why it’s not been a particular success, but continues to be sub-- explored in estrogen receptor-positive. 

Conversely, in estrogen receptor and HER2 receptor negative, aka triple-negative breast cancer, some of which is represented by carriers of the BRCA1 and BRCA2 mutation, there are these neoantigens. And, we’ve shown that an immunotherapy called pembrolizumab or brand name Keytruda, has shown improvements in survival both in early-stage breast cancer when given prior to surgery in combination with chemotherapy, and we’ve seen also improvements in how long women can live after a relapse of triple-negative breast cancer using that same drug integrated with chemotherapy. 

Dr. Alessi: That’s very interesting. In wrapping things up, what’s next? What are we going to hear about next in the field of breast cancer treatment?  

Dr. Morganstern: Well, I think the story continues to be one of what I would call divide and conquer. So we have our subtypes of breast cancer I just talked to you about, hormone receptor-positive, triple-negative, and HER2-positive. 

And we are gradually subdividing this broad array of estrogen receptor-positive into those that have mutation of the estrogen receptor, mutation of the PI3 kinase receptor. And as we drill down all these molecular differences, that’s where we’re going to see our advances. So there are going to be drugs developed for subpopulations within these larger groups, and they’re already being done with three novel agents approved actually within this year for estrogen receptor mutated and PIK3CA mutated estrogen receptor-positive breast cancer. 

So that process of subdividing and personalizing the treatment is the path forward.  

Dr. Alessi: Dan, thank you for your time today. We really appreciate it, you sharing your knowledge with everyone. Welcome to UConn Health, and we look forward to chatting again in the future.  

Dr. Morganstern: Thank you so much.  

Dr. Alessi: Many thanks to my guest today, Dr. Daniel Morgenstern. If you have any questions or ideas for future programs, you can reach out to me at healthyrounds@uchc.edu. Jennifer Walker is executive producer for the Healthy Rounds Podcast. Chris DeFrancesco is our studio producer, and Tessa Rickart is in charge of social media. Until next time, this is Dr. Anthony Alessi. Please stay healthy.