How to treat HER2+ Breast Cancer in 2024 with Dr. Harold Burstein

Welcome to the Discussion on HER2+ Breast Cancer Hello everyone I am Rahul Gussain. Speaker 2 And I'm Rohit Gussain. Speaker 1 And we are oncology brothers today. With us we have Doctor Harold Burstein, a world renowned medical oncologist from Dana Farber Cancer Institute. We're hoping that Doctor Burstein will walk us through his approach in treating her two positive breast cancer using an algorithm. Al, thank you so much for joining us. Speaker 3 I'm glad to finally be with the brothers. Speaker 2 Well that's very kind of you. Thanks so much for taking the time hell. So diving into our early stage hell here we often especially when less than 2cm or no negative, we proceed with surgery followed by adjuvant TH that is paclitaxel and trastuzumab for 12 weeks followed by radiation and complete a course of trastuzumab for about a year time. Treating Small, Node-Negative HER2+ Breast Cancers How does your management truly differ if it is less than 1cm or if the disease is between 1 to 2cm? Speaker 3 Sure. So I mean as this audience knows, when trastuzumab was being developed, it was essentially piggybacked onto ACT type chemotherapy regimens. So you got AC and then you got paclitaxel with or without the addition of trastuzumab and that was a tremendous advance, obviously one of those handful in a career kind of drugs that you see come forward and and became the standard of care. Patients who had smaller Stage 1 cancers were not eligible for most of the pivotal trials of adjuvant trastuzumab and it was not known if all of that treatment would be necessary for them. So our group trial led by Sarah Tellaney and our group provide a lot of leadership on this, did the experiment of essentially just lopping off the AC phase of treatment. We prospectively treated around 400 patients who had stage 1, her two positive breast cancers and the goal was to show that if you gave paclitaxel trastuzumab or TH that there would be a very low risk of cancer recurrence. And what we showed in the original publication and has been documented longer follow up is great results for that group of patients with systemic recurrence risks of less than 4 to 5%, a couple of extra percentage points of local recurrence, but you know a very favorable overall long term prognosis. So that really has become our go to regimen for tumors that are 2cm or less. An interesting question is where you draw the lower limit of treatment and there's no actual rules or guidance on that because no one's done a study of you know what's the best treatment for three to 4mm, her two positive cancers As part of our street gallon consensus panel activities, this is a group that meets every two years and issues guidance for treatment of early stage breast cancer. We have surveyed the panelists and asked them what size threshold tumor would make you recommend adjuvant treatment for a her two positive cancer. And what's interesting is the break point is right around 3 to 4mm, which seems kind of like a crazy amount of cancer to be treating, but right there is where most oncologists surveyed would begin to recommend adjuvant TH therapy. Speaker 2 Thanks for going on with that. Role of Neoadjuvant Therapy in Early Stage HER2+ And I know that as you mentioned the importance of adjuvant treatment here. Now, is there any role for neo adjuvant treatment here in less than 2cm and node negative, especially when we rely on pathological response being a prognostic marker here? Speaker 3 Yeah. So you make a great point which is in higher stage her two positive cancers, neoadjuvant is the preferred approach and I'm sure we'll be talking about that momentarily. For stage 1 cancers when the axilla is clinically node negative, I think it's really hard to see that you need to offer neoadjuvant treatment for a couple of reasons. One is almost by definition they are operable at that point. They can have breast conserving surgery. So none of the surgical benefits of downstaging the tumor really come into play except in really unusual circumstances you might imagine. The 2nd is that you know if unfortunately you are undergo surgery and the patient is found to have more extensive disease, we still have excellent therapies for that in the way of regimens that we'll talk about built around trastuzumab and bertuzumab and chemotherapy. So it's not like you forfeit a major opportunity to do that. So in our practice stage one, you know tumors right around 2cm or smaller, we're usually using just surgery first, if it's 2cm or bigger or and or if there's nodal involvement, I think neoadjuvant is the preferred approach. Speaker 1 I'll thank you for going over that. And you've mentioned post surgery, if the patient is upstaged with their disease now let's say you have no positive disease, then adding protuzumab is a fair option and that's based off affinity trial. Dual Anti-HER2 Therapy for Locally Advanced Disease Talking about upstage, this is a good segue to locally advance where dual anti her two can potentially play a bigger role how your treatment approach for a larger tumor or mode positive disease. Speaker 3 So exactly as you just said, we know that adding another anti her two targeted drug here pertuzumab does a couple things. So one is in the AFFINITY trial, it improved the rate of longer term tumor control and in several preoperative studies, it was shown that it improved the rate of complete pathologic response. So based on that, our preferred approach for tumors that are 2cm or bigger or thereabouts or that affect regional lymph nodes would be a preoperative treatment plan. We usually use TCHP. There's controversy over whether some patients should still get anthracyclines or not, but we usually use TCHP 6 cycles of that and then they would proceed to surgery. And here's an opportunity in your algorithm captures this, which is to tailor the adjuvant phase of treatment based on the extent of response to the TCHP. So approximately 60 or 65% of the patients will have a complete pathologic response with TCHP. About a third 30 to 40% will have residual tumor. For those with residual tumor, we know that switching them from an HP based maintenance regimen over to TDM one or Trastus M tansing can further reduce the risk of recurrence. And at the San Antonio meeting just this past December, there was long term follow up from the Catherine trial which very nicely showed that as had been earlier reported it reduces the risk of recurrence now with longer follow up a clear survival benefit and a meaningful improvement in disease free survival as well. So this is a nice example where the preoperative model is clearly preferred. It achieves surgical downstaging for the breast and the axilla. It provides highly effective adjuvant treatment and it allows us to tailor or individualize the treatment on the backside based on the extent of response. Speaker 2 Right. Just to reiterate that that was magnificent results that we saw about 8 year follow up with Idfs and oral survival benefit from Catherine trial utilizing TDM one and residual disease. Assessing Pertuzumab's Role in Adjuvant Treatment Now talking about the adjuvant setting, how much truly is pertuzumab adding here if one was to undergo surgery? Speaker 3 It's a great question. And in the AFFINITY trial, there was modest benefit in terms of overall survival particularly in the node positive group tend to recommend pertuzumab only in the setting of node positive disease or in the preoperative setting. In the preoperative setting, we really use it because it's more likely to achieve a pathologic complete response and therefore spare someone perhaps the need for the TDM one on the backside. So it's ended up, you know, being an important part of the regimen though, you know, I think in smaller tumors and in the maintenance phase, you know, one could ask whether it's proven to be essential and I'm not sure that it's truly proven to be essential in those contexts, but we still use it. Debate on Anthracyclines in HER2+ Breast Cancer How you mentioned controversy around Anthracycline at SABCS 2023 you presented any discussion around that in your clinic. Is there any patient that perhaps would get anthracycline in her two positive disease? And then, talking about controversy, I would also like to know who is getting neuratinib. Speaker 3 Sure. So at San Antonio, I had the pleasure of being the moderator for a great debate between Martine Picard and Ginger Borges on the role of anthracyclines. And as we said a moment ago, anthracyclines followed by taxanes were sort of the core regimen prior to the development of trastuzumab. And actually in some beautiful retrospective work from Dan Hayes and others, the group of tumors that most benefited from anthracycline based chemotherapy were in fact her two positive breast cancers. So there was a clear biomarker rationale for continuing anthracycline. Having said that, if you look at trials like the BCIRG trial and several of the other studies that have come forward since then, it's hard to see that anthracycline still have a major role, particularly when you're giving dual anti her two therapy. So if you look at a neoadjuvant study like the Trifiena study when you gave TCHP, you saw path CR rates that were exactly the same as anthracycline based regimen with trastuzumab and pertuzumab. So given that and given the side effects of the anthracyclines and I think most Americans have actually moved away from anthracycline based chemotherapy. Though what was interesting at our debate is that around the world anthracyclines remain widely available, widely used and are still a major component. I would say that TCHP is our standard go to for these stage two and three, her two positive cancers. Speaker 1 Absolutely. When to Consider Neratinib in Adjuvant Treatment And you and Roy touched base on residual disease with the Catherine trial coming back to neuratinib. Speaker 3 Who is getting Yeah, so neuradin. Speaker 1 Your clinic. Speaker 3 Sure. So neuradinib was studied in the adjuvant setting in the EXTINET trial. So as the audience knows, neuradinib is a small molecule Tarzan kinase inhibitor which is orally available. So neuradinib was studied in the EXTINET study for patients who'd had one year of trastuzumab and then we're randomized to ongoing therapy with Neuratnib or no further treatment. The study was done at a time before the availability of Bertuzumab and before the availability of TDM one in the refractory neoadjuvant setting. And in that study there was a benefit for continuing therapy with Neuratnib particularly in women who had ER positive, her two positive cancers. So that is an option. Having said that, we don't actually use all that much of it for a couple reasons. One is that nowadays with the use of both trastuzumab and pertuzumab, it's unclear that there would be a further role for ongoing extra year of Neuratina based therapy. Secondly, you know as we've just been discussing the Catherine data, give us a salvage opportunity if you will in the residual disease setting. 3rd is the drug had you know fairly substantial side effects particularly diarrhea and lower GI toxicity which made it hard to complete the course of treatment. So it is an option for very high risk tumors that are ER positive and her two positive, but I would not say it's a a standard component for the vast majority of women with her two positive breast cancer. Speaker 1 Thank you for covering that. And again in my practice, same thing. I've rarely used the retinib. Algorithm for First-Line Metastatic HER2+ Disease Now let's dive into metastatic disease. How your take care? There's a lot happening. Speaker 3 So current practice, our algorithm would be THP and then sort of as you've indicated shifting to the maintenance phase of HP. If the tumor is also ER positive, I often introduce endocrine therapy at that point as well and then they're followed. If they should progress in the future, then they have options of reintroducing the taxane or switching to TDXD or switching to TDM one which is a little bit less toxic or using the tecatinib based regimens of trastuzumab keep citabine and tecatinib. We don't exactly know which of those is the best for long term results because most patients are going to get most of these regimens. And so it's not a question of now or never, it's just a question of what regimen do you pick next. So once you get beyond those four regimens, then there's a whole raft of other choices that you might choose such as chemotherapy with trestuzumab and here we use a lot of iribulin or platonating chemotherapy or venerelbine based chemotherapy. There are small molecule tyrosine kinase inhibitors though you don't actually know a lot about the value of those drugs like neurat, nibirilopatinib after two catnib based regimens you've listed here marchtuximab which is another alternative to ongoing trastuzumab based therapy. And we know that most patients will get somewhere between 8:00 and 10:00 lines of of treatment for her two positive metastatic disease. So I think it's hard to be too dogmatic here, but that's kind of our algorithm and how we think about it. Speaker 2 Thanks so much. Hell, And these are just certainly very exciting times. When did we ever think about an advanced disease? We'll be having maintenance talk for years and years time and then you're talking about even second and third line and eight to 10 lines rather. Treating HER2+ Breast Cancer with CNS Involvement Now we know that we have well established that first line regimen THP followed by HP. In second line. We have very promising data from her to climb with the triplet regimen and San Antonio Breast Cancer Symposium. We saw TDM one combined with Tukatnib in her two climb O2 regimen with CNS metastatic disease too. And TDXD also has CNS activity. When a patient with CNS meds does come to your office, how does how do you maneuver through this treatment algorithm I've. Speaker 3 I called the Lynn rule after Nancy Lynn, my colleague here at Dana Farber, which is that, you know, the best drugs for the CNS are found by finding the best drugs that work outside the CNS. There's no magical drug that works like in the brain that doesn't work everywhere else in the body. So the way to screen for drugs that are active in the CNS is to screen for drugs that work really well outside the CNS. And that's how TECAT, NIB, TDM, one, TDXD have all been developed. You know I think most of this is driven by you know what you think of as your best agent. So in patients who have not had TDXDI think many of us would reach for that as the first choice to catnip trastuzumab Cape side, I mean clearly has activity there as well. And as you mentioned there was a cohort of patients in those trials who had prior CNS disease and and were included in the study and and clearly benefited as well. So the biggest issue there has been that it's changed the way we think about managing CNS Mets. So in a patient who has minimal disease in the CNS but but multiple lesions, we might actually try a drug based regimen 1st instead of doing whole brainer radiation for isolated lesions. We still think a lot about surgery or more commonly stereotactic radio surgery and then coming in with some of these drugs that are known to have CNS activity. But that's been you know a real transformation as well given the potency of these drugs in the CNS. And it's a similar story to when you start talking about, you know, your Alka associated lung cancers and electinib and other situations where you have highly potent drugs that work within the CNS. Speaker 1 Absolutely, exactly. We've seen a lot of this, especially in lung cancer where we're relying on oral actionable mutations that you can target and you have phenomenal responses even with CNS disease. Navigating Third and Fourth Line Metastatic Treatments How so in this situation once the disease has progressed? Second line, you've mentioned marzutoximab, we have it up here. Sophia trial was the one in the final update. It did not show overall survival benefit. Also TDM one we don't have much data on how to use another ADC. Once you've used TDXT, how do you go about in 3rd or 4th line settings? Speaker 3 Yeah. So you know I think the first thing to emphasize is that again there is a there there are major marketing issues here and you know it does obviously affect the duration of the course of therapy. But what we don't know is, is there really a clinically and biologically definable strategy that's best. So you know I think This is why here in the setting of metastatic disease where we historically have not focused on longer term overall survival, the fact that drugs like TDXD and combinations like to cat NIB with trastuzumab, Cape cytamine are showing overall survival benefit is, is really important. But now that they're in the market, what you want to say is are they showing survival benefit because you use them in second versus third line or first versus second line because unless you plan crossover, all you're doing is just saying well the drug is still active. And I I I'd like to see more trials where there was planned crossover with some of these more potent regimens. Having said that, I think for most of us if the patient's, you know, tumor is resistant to a THP type regimen right now, then TDXD you know which outperformed TDM one quite readily would be the next choice. Beyond that, I think it's a dealer's choice of the tacatinib, trastuzumab, capacitabine versus the TDM one based regimen. We don't really have much data for either of those. After TDXD, 4th line is whatever you didn't use in the third line at that point. And then once you get to 5th line and beyond, you have the choices that you've listed here. And we all use these kinds of regimens, but there really are no data whatsoever on how these stack up against either these contemporary ADC based programs, Pertussumab based programs or after prior CDK, not CDK prior TKI based therapy. So we use all these things, but there really isn't a lot of data to say which is the preferred one and and which way to go. Clinical Pearls for TDXD-Induced Pneumonitis Management Thanks for covering that Hal. Before we close, just a quick thing on side effects the as it matters from quality of life standpoint for these patients, I know that we TD with TDXD, the common ones that we see are fatigue and nausea which in community we are very well able to manage that. But the dire complication is pneumonitis, which is associated with mortality here. Hal, what is your clinical practice here and some of the important clinical pearls that you'd want us to learn from that? Speaker 3 Sure. It's a, it's a really important point. You know we're seeing a lot of pneumonitis as a side effect of our breast cancer drugs. It's a black box warning for the CDK 46 inhibitors and obviously part of the TDXD label as well. So the first thing to say is it's important to alert your clinical team, your nursing staff and your patients that this is a potential side effect. So if they have shortness of breath dyspnea, you want to hear about it sooner rather than later. It's almost always treatable with early intervention, high dosteroids and other supportive care, but it's important to have a low threshold to evaluate patients for this. Now having said that, our radiologists are very aware of this also. And so all the time when patients are on these drugs, they're saying, well, you know, maybe there's a little tiny bit of ground glass opacity or something like that. And you know, there are elaborate algorithms that have been published that you can read to sort of gauge whether or not to, you know, halt treatment or see if things get better. Of course, there's tons of flu and COVID around now as well. So a lot of patients are getting upper respiratory infections with ground glass opacities and that can confuse things as well. So you know you have to use your clinical judgment here to sort all this through in a in a constructive way. I do think it's something you have to pay attention to though. So we tend to get staging scans every 12 weeks or thereabouts and that's usually when we look for ground glass changes or other evidence for pneumonitis. Again, the warning labels might say perhaps more frequent CT imaging. I I when I talk to clinicians around the country, that is. Probably a good, I perhaps a good idea, but not always done so every six weeks or things like that because of, you know, the realities of care. But it's just something that I think people need to be very alert to. And again, educating the patients is probably every bit as important as, as educating the clinical team. Key Takeaways on HER2+ Breast Cancer Treatment Thanks so much Hal. Well, we've covered a lot in past few minutes here. Hell, thank you so much for joining us and going over the current standard of care for her two positive breast cancer for our listeners. Let us go over a quick recap with Doctor Harold Burstein from Dana Farber. We have covered the current standard of care treatment options for her two positive breast cancer in early phase adjuvant trastuzumab and paclitaxel based off of APT trial remains a good option in a large tumor and or no positive disease specifically more than 2cm neoadjuvant chemotherapy and anti her two therapy play an important role. Speaker 1 And then in metastatic disease starting off with dual anti, her two therapy along with dosataxel at this time remains the mainstay. Then TDXT or Tocatinib based regimens are feasible treatment options. Speaker 2 We will eagerly await on full data for Tocatinib and TDM, one combination from her two climb O2 trial especially with intracranial disease with more and more use of TDXC in our clinic. We also have to appreciate how to manage some of these important side effects from all these particular agents. Thank you for joining us today. Also check out our triple negative and hormone receptor positive breast cancer discussions. We are the oncology brothers.