Assessing Pathology and How It Impacts Early HER2 Breast Cancer Treatment

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In “Beyond Diagnosis: Early HER2-Positive Breast Cancer,” Cleveland Clinic breast oncologist Megan Kruse, MD, and host John Mangels discuss how clinicians can navigate increasingly complex treatment decisions while helping patients understand their diagnosis and care.

Each installment of this series explores key aspects of early HER2-positive breast cancer care, including interpreting pathology, navigating evolving therapies, individualizing treatment, and supporting patients through shared decision-making.

In this first episode, Kruse discusses interpreting HER2 status and hormone receptor status, resolving equivocal pathology results, and communicating the complexities of an aggressive but highly treatable disease without losing sight of hope.

The following is a transcript of their remarks:

Mangels: Welcome to “Beyond Diagnosis,” where we talk with doctors about treatment decisions and communicating with patients. I’m your host, John Mangels. HER2-positive breast cancer is a particularly aggressive disease. Targeted therapies are improving patient treatment options, but those advances have also made care more complex.

Today, we’ll explore how breast oncologists make clinical decisions, adapt treatment as new information emerges, and help patients understand their choices. Our guest is Dr. Megan Kruse. Dr. Kruse is director of breast medical oncology and co-leader of the breast cancer program at Cleveland Clinic. Dr. Kruse, thanks so much for being here.

Kruse: Thanks for having me. I’m excited about this conversation today.

Mangels: A HER2-positive diagnosis involves distinct disease subtypes. What do you look for in immunohistochemistry results, FISH [fluorescence in situ hybridization] results that informs your treatment plan?

Kruse: So when I first meet a patient, I tell them that their pathology report is the roadmap to their care. And so having their estrogen receptor, progesterone receptor, particularly their HER2 results, is incredibly important for me. And those initial HER2 results that we get back are actually their immunohistochemical results.

So that’s graded on a scale from 0 to 3. And our 0 and 1+ results are considered negative. Those are patients that would not receive HER2-targeted therapy. For the patients that have 3+ results on immunohistochemistry, those are definitively HER2-positive. That tells us that some type of chemotherapy and HER2-targeted therapy will definitely be part of their plan.

And then the 2+ results are what are considered equivocal on immunohistochemistry, and that’s where we reach for FISH as a secondary test to help clarify the situation of if a patient actually is HER2-positive or not.

Mangels: So the gray area, I guess is the most difficult part of this. When do you reach out to your colleagues in pathology or perhaps to your colleagues on the tumor board?

Kruse: So occasionally we will get equivocal results by both immunohistochemical testing or FISH. And when that happens, typically we’ll go back and do another wave of testing, either looking at another site on the original biopsy, having another pathologist take a look at it, or even getting another biopsy to repeat the testing altogether. And those cases, when they come up, definitely are presented at our tumor board.

And so there we meet with multiple pathologists, multiple breast medical oncologists, surgeons, radiation oncologists to get a general sense of what to do when the picture is unclear. And for the most part, when it comes down to any sort of HER2 positivity, we really want to give the benefit of the doubt of giving these HER2-targeted agents, largely because they’re so effective and the disease can be so aggressive if you don’t meet it with the right treatment.

Mangels: Is it helpful to know the degree of HER2 gene amplification or protein overexpression?

Kruse: Yes, absolutely. So that’s really what immunohistochemistry is telling us is how much HER2 protein really is there. And we know that the degree of protein really does equal out to the sensitivity of these medications that we use. And so this whole system is really founded on how strongly HER2-positive is the cancer, and then that determines how intense the treatment should be.

Mangels: For a long time, HER2 status was thought of as a binary. You were either positive or negative. Lately, HER2 low, HER2 ultralow have been proposed as new subcategories. How do you distinguish between those two and how do they affect your treatment plan?

Kruse: Yeah, so that has made everything a little bit more complicated for both providers and for patients because our patients are very well informed. They’re reading about this. And the development of the HER2-low state really has been a push forward in allowing patients better treatment options.

So what I tell patients and when I talk with referring providers is that HER2 low, even if it’s reported on all pathology reports, really only matters for metastatic breast cancer.

When we’re talking about early-stage breast cancer, we stick to the original positive and negative. The HER2 low and ultralow open up as more of a treatment consideration or a candidacy indicator in the metastatic setting, but functionally they’re not distinct biologic classifications that would change upfront staging, prognosis, and treatment patterns for stage I through III breast cancer.

Mangels: About half of HER2-positive tumors also express hormone receptors [HR]. How does HR status influence your strategy?

Kruse: When you see a patient that has both hormone-positive and HER2-positive breast cancer, you know that endocrine therapy or anti-estrogen therapy will also be part of the discussion. It also influences what you expect the chemotherapy outcomes to be. So we know we’re more likely to see those complete responses to presurgical chemotherapy in the hormone receptor-negative patients than we are in the hormone receptor-positive patients.

And so it helps us guide patients a little bit in terms of the expectations of what we might find at the time of surgery, but also to give them the hope that even if there is residual disease in the breast or in the lymph nodes after their preoperative chemotherapy and HER2-targeted therapy, that we still have that endocrine therapy yet to go, and there’s a very meaningful part of their treatment yet to be had.

Mangels: We’ve talked about a number of nuances, a number of variables. Those, I’m guessing, can be confusing to patients. How do you explain the kinds of things that we’ve talked about in a way that’s understandable and helpful to your patients?

Kruse: It’s absolutely a challenge. I would say that the biggest factor here is time and repetition. When we first talk to patients about this, it typically is in a longer consultation visit, whether that’s 40 minutes or 60 minutes, depending on your practice, it really takes time to go through each of these variables and say why it matters for the treatment pathway that they are on.

I always try to have written information for my patients as well. I bring a blank sheet of paper and I write out each of these variables and what they mean and how it impacts the treatment decision. I also always ask my patients to have somebody in the room with them, another set of ears, another set of eyes. They can be taking in the information while a patient can be very overwhelmed with just having the cancer diagnosis, just hearing that you may need chemotherapy.

And we always revisit the information. So the first visit really is that, it’s just a first. The repetition matters. And so when we’re planning treatment, especially if we have to go into aggressive treatment pretty quickly, sometimes these patients start treatment within a week, we really say, “OK, that’s enough for today. We’re going to bring back and do another visit with our pharmacist, our nurse, with me to go over this again,” and get into some of the fine details that they may have and questions that they may have about their treatment plan. And when that’s the case, they go home, they think about it, they come back, and we’re able to dive in a little deeper.

So I consider it a layered conversation and I try to get maybe the top three to five points I want to get across in the first visit and then we come back around and repeat it again.

Mangels: Let’s stay with patient communication. We both have used the term “aggressive” to talk about HER2-positive cancer, but we’ve also both acknowledged that there are new treatments, I mean rapidly evolving new treatments that are improving outlook. How do you talk to patients about both parts of that reality while not enhancing fear, but also not encouraging false optimism?

Kruse: Yeah, that’s a great point. And it’s a fine line that we’re always trying to walk in these conversations. I would say for the majority of patients with HER2-positive disease, especially in this early-stage setting, we are talking about curing them of their cancer, right?

So you start there. You say, “What is our ultimate goal? Our goal is to keep you cancer-free for a lifetime.” And normally what I will say there is because the cancer is HER2-positive, it means that the road may be a little bit more complicated and there may be more hurdles for us to tackle, but the long-term outcome is really, really good and optimistic and that prognosis is excellent. And you often get a sense from your patient of how much they’ve already looked into this, how afraid they are, what they know about these different staging elements and treatment elements. You can often feel that out in the first 5 to 10 minutes that you’re with a patient.

And then I adapt my language based on that, but I try to hinge on the optimism and our overall goals here, but say that it can be a difficult path. And the other thing that can happen is a lot of patients will hear, “Well, HER2-positive disease now is very curable. Why do I have to go through all of this to get to that great prognosis?” And there we talk about the fact that prognosis is only this good because we have treatments that are this effective, and without using those treatments, then we’re worried prognosis may not be as good.

So it’s a different conversation with every patient, which is exciting. It’s what keeps it interesting. It’s where we feel like we can help a lot, but I feel like you can’t lose the hope in the massive amount of information that patients get during these first visits.

Mangels: Let’s talk about it from the clinician’s perspective for a moment. So treatments are evolving rapidly. There’s a lot of information coming in, a lot of clinical trial results. How do you stay current? How do you manage that complexity? Are there algorithms that you use? How do you make your decision, keeping in mind how much information is coming in?

Kruse: Yeah, the space can be completely overwhelming. HER2-positive disease is one of those states in breast cancer that a few years ago was pretty straightforward and we knew what to do, and it was actually a very satisfying place because the treatment decisions were clear and patients have done very well.

Now there’s a lot of choice, there’s a lot of opportunity, which is great for individualization, but it’s hard for the clinician’s brain. I find that working through all this data, it’s really helpful to view medicine as a team sport here. I talk with my colleagues a lot.

Again, this is where the tumor board is very helpful. When we have cases where we’re just not sure or we’re pretty sure, but we could use the backup of our colleagues to say, “Yeah, I would do the exact same thing.” I find tumor board to be incredibly helpful.

And I do a lot of peer education, so I listen to programs of experts talking about new data, how they’re contextualizing it, how they’re applying it. And I always find that after new data comes out, after a conference happens, those first few months, we’re all sort of figuring out where we find our feet and how we’re going to apply the data.

Thankfully in breast cancer, both our internal and national guidelines move pretty quickly because we see new data coming out frequently. We have new drug approvals very, very often. And so we’ve gotten used to rapidly putting these new options into the guidelines so they can reach patients sooner. But it does require a lot of independent time, reading, practice, and reflecting on the options that you have at your disposal.

Mangels: I imagine, and having debrief sessions soon after conferences is probably helpful as well.

Kruse: It’s huge. It’s actually the most important part of medical conferences, are really those hallway conversations that you have, the dinner conversations you have with colleagues where you’re really thinking about what does this mean? We all have the numbers, we all have the clinical trial population, we can take that in, but how do we actually apply it? And that is more of the art rather than the science.

Mangels: And I’m guessing that as treatments get more and more individualized, that’s really where it becomes even more complex because you are literally treating one patient somewhat differently than another.

Kruse: Absolutely. Every patient encounter is its own unique situation, and that is not just the data that we learn from these trials and what’s in the national guidelines, but everything that comes along with an individual patient’s story, right? What other medical problems do they have? What is their situation in life? Are they working? Do they have family? Who’s going to support them? Are they on medications that may make giving the optimal treatment more complicated?

And so when I’m teaching our trainees about this, I say, “You need to learn the trial data so you know where to start.” And then all this practice of medicine and all the observership that we do is really figuring out how you layer in the individual patient situation and how you can adjust what the textbooks say, what the papers say, because very rarely is the patient sitting in front of you the exact same profile of the patients that are in the clinical trials.

Mangels: Thanks so much for your insights, Dr. Kruse. And thank you for joining us on “Beyond Diagnosis,” where we explore not just what physicians know, but how to effectively and compassionately share that knowledge with patients. See you next time.

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