Advances in Lobular Breast Cancer Research

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic, overseeing our Taussig Phase I and Sarcoma Programs.

Today, I'm happy to welcome Dr. Megan Kruse, medical oncologist in the Taussig Breast Cancer Program and an Associate Program Director for the HemOnc Fellowship at Cleveland Clinics Cancer Center. Welcome, Megan.

Megan Kruse, MD: Good morning. Thanks for having me.

Dale Shepard, MD, PhD: Absolutely. So maybe you could just briefly tell us a little bit about your role here at Cleveland Clinic.

Megan Kruse, MD: Sure. So I am a breast medical oncologist and my particular area of focus, both clinically and in the research space, is about lobular breast cancer, which we often refer to as a very rare cancer because it only represents about 10 to 15% of all breast cancers in the US. But when you think about that, 10 or 15% really equates out to about 40,000 cases of breast cancer a year, which is still a pretty big number.

Dale Shepard, MD, PhD: I guess a question would be, why lobular breast cancer? What made you focus on lobular breast cancer?

Megan Kruse, MD: Yeah, I think it's an area of interest, and often frustration, for a lot of breast medical oncologists because we know that these patients have what should be good prognosis tumors, they're usually really strongly ER-positive and PR-positive, HER2 negative, but unfortunately they tend to have late recurrences. And when they have recurrences, they can be particularly difficult to find because the organs that are involved are not the traditional places that we think of for breast cancer recurrence.

So these patients may have pleural effusions, peritoneal carcinomatosis, leptomeningeal disease, orbital involvement, all of which is somewhat difficult to diagnose and also really symptomatic for the patients. When these events happen, the standard of care is to use endocrine-based options, which worked for a period of time, but ultimately, the cancers will become resistant to them. And after that, these cancers really are not very chemo sensitive, and so I think the patients, as well as the clinicians, are often very frustrated that it seems like there's little we can do once we've exhausted our endocrine-based options.

So because I saw a clinical need there and had heard patient stories that were pretty dramatic about how these recurrences happen, I was interested in improving the way treatment is given for metastatic patients, but also improving our treatments and approach in the curative-intent setting, so we can try to prevent those nasty recurrences later on.

Dale Shepard, MD, PhD: As a rare subtype of breast cancer, 10 to 15%, you mentioned ER positivity, PR positivity, HER2 negativity, how often should we be concerned that these are missed, that somebody may have a lobular breast cancer and it's sort of being treated in a different way?

Megan Kruse, MD: So I think the biggest area of concern, for patients certainly, is the cancer's being missed at the time of their initial screening. Once the cancer is diagnosed, usually our typical histology reviews are quite reliable for differentiating invasive lobular carcinoma from invasive ductal carcinoma, so I think by the time a patient reaches our door with a diagnosis we feel pretty good about knowing for sure that's what they have.

But certainly, these cancers are really hard to detect on mammograms, whether it's our conventional 2D mammogram or even newer 3D mammograms, and often require a breast MRI to be found reliably. Screening breast MRIs are not something that we do routinely in the community, so I think that that's a big area that patients get frustrated about because they may notice subtle changes in their breast and have multiple negative or normal mammograms before they're officially diagnosed with their lobular breast cancer.

Dale Shepard, MD, PhD: So should there be some sort of guidance in terms of patients most likely to benefit from an MRI? Is there some standardization of that or should there be?

Megan Kruse, MD: I think so. So that's one of the research questions that we're attempting to answer here in our lobular research program, along with help from our breast radiologists. Dr. Laura Dean is helping us to try to develop better guidelines for which patients in the general breast cancer screening community would benefit from breast MRIs, and which symptoms may trigger earlier breast MRIs, with the concern for lobular breast cancer at the focus.

The other thing would be to make sure that these patients, once they've already been diagnosed with a lobular cancer, do have screening MRIs as part of their survivorship care, which is often something that I think gets missed in clinical practice for many of us. There are really no existing guidelines about how to incorporate screening breast MRI for these patients. So we're hoping to produce a little bit more evidence that can help clinicians make that decision, with the ultimate goal of making a guideline that would be easier to follow.

Dale Shepard, MD, PhD: So certainly, diagnosis and knowing you're on the right track from the beginning is hugely important. You said that there's some research going on in that area. Can you tell me a little bit more about that?

Megan Kruse, MD: Yeah. So we actually, when we were starting to think about the questions to answer about lobular breast cancer, we really took it all the way back to the basic assumptions we all hold about breast cancer diagnosis, knowing that those largely apply to invasive ductal carcinoma and said, "How can we break this down and really rethink our assumptions and make that foundation for lobular breast cancer?"

So actually, the biggest way that we've addressed this is through a multi-institutional retrospective review of invasive lobular cancers over the last 25 years. So this is an effort from Cleveland Clinic, as well as Ohio State University and the University of Pittsburgh Medical Center. We're calling ourselves the Great Lakes Invasive Lobular Consortium. So hopefully you'll see more research coming out from this group in the future.

But this initial attempt actually created a retrospective registry of over 35,000 invasive lobular cancer patients diagnosed at our institution. So we could really look at what the clinical presentations are, what the treatment patterns have been and what the clinical outcomes are. Because right now the treatment patterns, at least in guidelines, are exactly the same for invasive ductal carcinoma as invasive lobular carcinoma. I think when you talk with clinicians, there is some feeling that that's maybe not entirely appropriate, but we don't know how to change it.

So we were hoping that we could look for areas where maybe the treatment patterns are diverging in a real world setting, or if we found some difference in survival outcomes for lobular patients compared to ductal patients, it would really create some excitement about looking specifically at lobular patients for treatment trials moving forward.

Dale Shepard, MD, PhD: So certainly, your statement at the beginning where you said that this represents 10 to 15% of breast cancers, and that adds up, an impressive 35,000 patients in a database underscores that, right?

Megan Kruse, MD: Right, exactly. So when you look at single institutions, there may not be that many patients that we think that we can look at for their data. And certainly, when you look at national clinical trials, very rarely do we see any breakdown of the patients by their histology. So I think that that would be a huge step forward, is just to say, "Can we get that information? Can we make invasive lobular cancer a preplanned subset of our clinical trials that look at hormone-sensitive breast cancer?" Because if we're not asking the question, I don't think we can reliably change the way we approach treatment for these patients.

Dale Shepard, MD, PhD: So from a treatment standpoint, is there anything in a neoadjuvant setting for instance, that you think needs to be changed from what we know at this point?

Megan Kruse, MD: I think there's a huge opportunity there, and that's probably our best place to study these cancers because we would actually have the tumor there, ready to look at, both pre and post-treatment. So we could actually see what our treatments are doing and assess things like the tumor microenvironment to determine if there's clues there of how we might be able to improve the response to treatment. Right now, our approach to the neoadjuvant treatment of invasive lobular cancers is exactly the same as invasive ductal cancers. So that would be with aggressive chemotherapy, with the intent of down staging the tumor.

And more often than not, that's actually a consideration for these patients because they tend to present with larger tumors and greater lymph node burden, probably related to some of those delays in screening that we talked about already. I think because we have some evidence showing that chemotherapy may not be as helpful for invasive lobular cancers as it is for invasive ductal, giving aggressive neoadjuvant chemotherapy really feels unsatisfying to the clinician, and to our patients who are really savvy and well-read and have picked up on this theme that lobular cancers don't seem to respond as well to chemo.

So I hope in the future that these patients are able to be enrolled in trials that are looking at novel approaches to neoadjuvant therapy. And certainly, there are some trials out there that are incorporating immunotherapy with the chemotherapy or with other targeted therapies. So things like CDK4/6 inhibitors, along with preoperative endocrine therapy, to try to improve the response rates for patients with lobular cancers.

Dale Shepard, MD, PhD: So do we currently have any of those trials ongoing? Are we planning on opening any of those types of trials soon?

Megan Kruse, MD: So right now, the patients that we have with lobular cancer are able to go into the trials that we have open for hormone-sensitive cancers in the neoadjuvant space. So we don't have a lobular specific trial, and actually there are no lobular specific clinical trials in the curative-intent setting that are open right now. So that is something that I'm working with, certainly our group here, as well as some of the national research groups to try to advocate for something like that to occur.

At the very least, I think we should encourage these patients to participate in clinical trials so that the number of ILC patients goes up, and then that specific subset can be looked at from a statistical analysis point of view. But yeah, right now everything would just be limited to hormone-sensitive neoadjuvant trials. The biggest one we have here is actually a trial called FB-12, which is looking at the addition of HER2 targeted agents to standard chemotherapy for patients who are HER2 negative, but found to be abnormal HER2 signalers by a novel assay.

Dale Shepard, MD, PhD: It sounds like there's a huge unmet need there in that space.

Megan Kruse, MD: Yeah. Because many times we will treat these patients with chemotherapy and find that their tumors really don't shrink at all at surgery. We're still left with larger surgeries, axillary nodal dissections, and the morbidity that comes with that, and potentially having exposed them to drugs like anthracyclines with long term co-morbidity impact.

Dale Shepard, MD, PhD: So I guess moving down the treatment pathway, you did mention surgeries, is there any anticipation that there would be changes in surgery or radiation for these patients, or is this probably going to be more of a systemic treatment issue?

Megan Kruse, MD: I think it's largely going to be a systemic treatment issue. We have talked a little bit about whether reconstruction options and radiation options should be different for patients with invasive lobular cancer, knowing that they may have more microscopic involvement of margins and things like that, or multifocal disease that wasn't apparent at the time of their diagnosis.

But I think largely, it's going to be up to us, as the medical oncologists, to really move the needle here, trying to make systemic therapies more effective so that patients can have smaller surgeries and potentially avoid radiation.

Dale Shepard, MD, PhD: Is there currently ... Are there currently trials in an adjuvant setting? You mentioned that there weren't any currently in a neoadjuvant, anything on the adjuvant front that looks particularly promising?

Megan Kruse, MD: So I think that the trials in the adjuvant setting that we're most interested in are these series of trials that look at endocrine therapy with the combination of CDK4/6 inhibitors for patients with high risk hormone-sensitive disease. Those trials are for all comers with hormone-sensitive breast cancer, kind of a theme here, but we have advocated to get the lobular patients reported out in those trials.

I think that's a really good example of where we may see a differential benefit, just speculating, because we know that lobular cancers tend to be more hormone-sensitive and get their largest benefit from endocrine therapy. So if we're enhancing endocrine therapy, I think that's what we're going to see our biggest impact. And if those approaches look good in the adjuvant setting, I think they will move forward to the neoadjuvant setting.

The only trials that I know of that are specific to lobular cancer actually are in the metastatic setting, where we're kind of looking at the right endocrine treatment sequencing approach for these patients.

Dale Shepard, MD, PhD: So are those trials that we have ongoing here at Cleveland Clinic?

Megan Kruse, MD: We do not yet. Right now, we're working on getting those open, but I hope to have them in the future.

Dale Shepard, MD, PhD: So what kind of timeline do you think we're looking at, Megan, in terms of some of these trials coming to fruition and making some significant changes in our guidance?

Megan Kruse, MD: I think that a lot of the retrospective and translational work that we're doing here at Cleveland Clinic, looking at genomic predictors of response and the immune microenvironment in invasive lobular, we should have that kind of information in the next couple of years. And of course, then that would translate to creating larger interventional studies that could happen over the next five, probably, to 10 years.

One of the things that's really challenging about studying invasive lobular cancer is that the recurrences tend to happen late. So if you look at five year survival, the numbers are actually really excellent. When you go out to 10 year survival, that's where you see a decrement. And so in order to study those patients, it's really, really challenging to do with our typical follow-up for breast cancer studies. So that makes either the neoadjuvant space or the metastatic space a little bit more interesting for interventional trials.

But certainly, the work is going to take quite a while, which gives us the opportunity to really engage patients and try to bolster accrual numbers over time.

Dale Shepard, MD, PhD: You briefly mentioned genomics. This is, of course, hormonally driven, being ER/PR positive, but is there a role for doing next generation sequencing for these patients and incorporating some sort of genomics analysis? And if so, when do you think about doing that?

Megan Kruse, MD: I definitely think that there is. We are actually advocating in our patients to do that early in their metastatic disease course, likely from tissue obtained at the time that you confirm that they even have metastatic disease. And from other studies that have been reported in the literature, we do see a higher incidence of HER2 mutations, as well as PIK3CA mutations, for patients with lobular cancer, both of which are potentially targetable. With the PIK3CA mutations, that would be with the FDA approved medication, alpelisib, and with the HER2 mutations, that could be on a number of genomically driven clinical trials.

So I think that that is really important to do early on, and maybe a step that we often miss since we know, okay, we'll put patients on endocrine therapy and we'll think about that later. But probably the earlier we get that data the better. We are actually involved in a collaboration to do dedicated genomic testing on bank samples that we have for patients with lobular cancer. We'll be looking at their genomic results at different time points. So prior to any treatment and then after treatment, if there are biopsies available, to assess what changes we see and maybe shed a little guidance on should these patients have actually repeat biopsies for genomic testing over their treatment course.

Dale Shepard, MD, PhD: Yeah. That's an important question. It seems like maybe getting that message out about sequencing is important since these typically are HER2 negative, but then you said that there's a high frequency of HER2 mutations.

Megan Kruse, MD: Right.

Dale Shepard, MD, PhD: So it's an important thing. So again, back to the fact that this is not the most common form of breast cancer, do you get a sense for how comfortable most physicians are in treating this particular variation?

Megan Kruse, MD: It's funny. These are often the treatment conversations that come up at tumor board because I think we often feel inherently a little bit uncomfortable making the same recommendations for lobular patients as we do for ductal patients. I think that conversation largely centers around recommending chemotherapy in the adjuvant setting. That tends to be where we feel most conflicted because we know that these tumors tend to be locally advanced at presentation, but when you feel that chemotherapy doesn't work very well, making that recommendation can be tough.

So we definitely see referrals for these patients. We talk about them at tumor board a lot. And as we've gotten some interest out there, in differentiating ourselves at Cleveland Clinic with a focus on lobular breast cancer, a lot of patients are actually finding their way to us saying, "I'm happy to help in whatever research you are doing. I want there to be better guidance for patients like me." So even if clinicians are not necessarily saying that they feel uncomfortable managing these patients, I certainly think you do second guess those innate treatment decisions a little bit more when you're dealing with a patient with lobular breast cancer.

Dale Shepard, MD, PhD: It sounds like you have a really a robust program you're trying to develop here, looking at lobular breast cancer. What are you most proud of as you've developed a program to look at this disease?

Megan Kruse, MD: It's been a really interesting road and I've learned a lot in terms of thinking about this and what's important to both clinicians and patients. So two things that I'm most proud of, from a research standpoint, I really think that this retrospective work for the 35,000 patient registry is going to have the potential to make a lot of impact. It'll be the first time that we have such detailed treatment records and outcome records for our patients.

So we can really dig deep into a lot of the questions that we've been trying to ask, but the data sets have been limited. So a lot of time and energy has gone into that, but it's also been great to work through what are the questions we even want to ask? So I've learned a lot in that process. That work has been submitted to the San Antonio Breast Cancer Symposium and should be presented at that virtual meeting in December.

And then from a clinical and patient-facing standpoint, we actually last year had a Lobular Patient Symposium, a one night event where we had a number of patients gathered together and a panel of people who are interested in lobular cancer talking about these kinds of issues. It was a great forum to have patients engaged in asking the questions that matter to them. I think that helped us as clinicians and researchers to know where will our efforts be most helpful.

And actually, that program was broadcast over a Facebook platform and had engagement all over the country. We had hundreds of patients participate, and I've actually seen a number of patients in clinic who were able to participate over the virtual platform. So I think the outreach there is one of the things that I'm most excited about, and I hope that we're able to continue that in our new, virtual education world.

Dale Shepard, MD, PhD: That's great that you're able to have such a broad impact. So well, Megan, I appreciate all of the insights on this topic. Any additional comments?

Megan Kruse, MD: I would just encourage anyone out there who has an interest in this topic, potentially to reach out to us at Cleveland Clinic, and to me specifically. We're always looking for collaborators on these research ideas because the key to getting these trials done is really having multiple sites involved and finding these patients. So please keep an eye out for them, stay engaged.

And for additional information, there is a lovely website run by the Lobular Breast Cancer Alliance that you can check out. Patients are very engaged there, and it actually has a reading list of all the seminal articles surrounding this topic. So very, very helpful if you're interested in more information.

Dale Shepard, MD, PhD: Well, very good. Well, thank you very much for joining today.

Megan Kruse, MD: Thank you.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real time updates from Cleveland Clinics Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.