Vision for treating and curing HER2-positive metastatic breast cancer (mBC) in the future

DR LOVE: Welcome to Oncology Today: Management of HER2-positive metastatic breast cancer. This is medical oncologist Dr Neil Love. For this program, I met with Professor Giuseppe Curigliano from the European Institute of Oncology in Milan, Italy. In addition to this interview program, there is also a corresponding presentation with Professor Curigliano’s slide presentation. To begin, I asked him to make some predictions about the management of metastatic HER2-positive breast cancer in the future.

PROF CURIGLIANO: I believe in 2 years from now potentially we will have a new standard of care in the first-line setting. So in my opinion the study comparing trastuzumab deruxtecan to pertuzumab, trastuzumab, and taxane will favor trastuzumab deruxtecan because according to the data that we have in the second-line setting, we have a better median progression-free survival and overall survival. So in the future I will see in the first-line setting trastuzumab deruxtecan.

What I would like to understand is if in the post-neoadjuvant setting, so I mean for patients who received neoadjuvant chemotherapy with pertuzumab/trastuzumab/taxane and anthracycline, with residual disease, if trastuzumab deruxtecan will be better than T-DM1. We know very well that in the metastatic setting the activity of trastuzumab deruxtecan is impressive in terms of complete response and partial response, so if I would like to speculate I believe this drug will have a role also in the early breast cancer setting.

We have to be very careful about the risk of ILD because in the curative setting of course ILD may be a big issue. So we have really to understand how to better recognize patients at risk of ILD.

Another speculation that I can do, it’s very probably speculation, is should we identify some patients that can be cured in the metastatic setting. With the complete response of 20% and partial response of 60% and overall clinical benefit rate of 86% in the second line I believe some patients with metastatic disease can be potentially cured with trastuzumab deruxtecan, maybe de novo disease, maybe patients with oligometastatic disease. So we need dramatically to design also trials in which the primary endpoint is the overall survival in some patients that potentially can be cured in the metastatic setting. Therapeutic index of this drug is so impressive that I believe we can start thinking about curing some patients with HER2-positive metastatic breast cancer.

DR LOVE: In that regard, particularly in solid tumors, one of the things that we hear a lot of people talking about is MRD or circulating DNA. Do you see any role for that in your vision for cure?

PROF CURIGLIANO: Yes. This is a very important question. So let’s assume that we have patients with complete response in the metastatic setting. So what we can do, we can design a clinical trial assessing minimal residual disease with a liquid biopsy, and we may think in those patients with negative ctDNA to discontinue treatment and to observe them. So the idea of the trial should be treat, achieve a complete response, then test with a liquid biopsy, and in those patients with negative ctDNA randomize to maintenance treatment versus no treatment and assess the time to recurrence. I believe that liquid biopsy will really have power to better identify those patients that are cured.

DR LOVE: So kind of getting back to your vision for the near future, we’ll talk in a second about T-DXd moving up. You even bring up the possibility of the adjuvant or neoadjuvant setting. But what about tucatinib? Do you see a continuing role for that, particularly in people with brain mets? I mean at this point it’s kind of hard at least for me to get a feel for relative efficacy in the brain of T-DXd versus tucatinib, whether or not tucatinib is going to add anything to it. Any thoughts about how tucatinib fits into your vision?

PROF CURIGLIANO: Now I believe tucatinib is the more potent tyrosine kinase inhibitor that we have. We have a trial in the post-neoadjuvant setting comparing T-DM1 plus tucatinib versus T-DM1 alone. If in this trial we will demonstrate a benefit in terms of invasive disease-free survival and potentially overall survival I believe the future will be to incorporate tyrosine kinase inhibitors in combination with the ADCs. Because dual blockade is better than single blockade.

So in my vision tyrosine kinase inhibitors will still have a role both in the adjuvant and in the metastatic setting because dual blockade on the extracellular domain and intracellular domain may improve activity of anti-HER2 therapy. And since now we have trastuzumab deruxtecan in the second line we have some old preclinical data and also current preliminary data that demonstrates that the mechanism of resistance to antibody-drug conjugate is the downregulation of the receptor, so giving after an ADC a tyrosine kinase inhibitor may upregulate to gain the receptor.

We have some preclinical data that clearly demonstrates this. So tyrosine kinase inhibitors may be essential to resensitize HER2-positive cells to the activity of a new ADC but can be synergistic combining the ADC to the tyrosine kinase inhibitor. So tucatinib will have and may have a critical role in this treatment strategy.

DR LOVE: That’s interesting. I haven’t heard about this idea of downregulation of the receptor. Does that apply to T-DXd?

PROF CURIGLIANO: Yes. We have some data from the DAISY trial. That is a proof-of-concept trial where patients are treated with trastuzumab deruxtecan with serial biopsies. And once the patient has progression to T-DX, if you reassess the biopsy you have a downregulation of HER2 receptor. Similar data have been observed in DESTINY-Breast03 and presented during the San Antonio Breast Cancer Symposium demonstrating that patients who develop resistance to trastuzumab deruxtecan may have a downregulation. So it’s obvious that once you bind the ADC to the receptor, and you activate the mechanism of endocytosis, you have a reduction of the expression of the receptor, and this could be a potential mechanism of resistance to new-generation ADCs.

DR LOVE: That’s really interesting.

Optimal treatment of HER2-positive mBC with brain metastases

DR LOVE: The idea — you mentioned the trial combining tucatinib and T-DM1 in the post-neoadjuvant KATHERINE space, and I guess one of the things, and I’m not sure how big of an issue it is, that I didn’t realize at first, was I guess the KATHERINE trial didn’t really show a decrease in brain mets even though I guess T-DM1 does have some activity in the brain. But the trial itself really — so how much do you think right now brain mets are an issue in terms of first relapse?

PROF CURIGLIANO: Oh, they are really an issue. You are correct. In the KATHERINE trial the use of T-DM1 does not reduce the incidence of brain mets. In the first analysis the investigators performed there was a higher incidence of brain mets in the T-DM1 arm with respect to the standard of care.

HER2-positive cells have a specific tropism for brain tissue, so I believe we have to think about new treatments that may prevent brain mets. And I really believe that the trial exploring the combination of trastuzumab deruxtecan plus tucatinib may provide those information.

I don’t know if we can extrapolate the data from other diseases, but you know better than me that in small cell lung cancer prophylactic radiation therapy is really used to prevent brain mets in small cell lung cancer. I don’t believe we can do this in patients with breast cancer because the overall survival rate is completely different from small cell lung cancer. But I really believe the use of the new agents in the post-neoadjuvant setting may really reduce the risk of progressing in brain. So I will say for the future really important positive data in this setting.

DR LOVE: Yeah. It’s funny you bring up lung cancer because I was just flashing actually on non-small cell lung cancer, where in EGFR-mutant patients you have osimertinib, which decreased the incidence of brain mets in the adjuvant therapy by 90%. And even though they don’t have survival benefit, just the decrease in brain mets there is such a great benefit to patients.

That also brings up, again, lung cancer to me, it seemed like maybe really the first beginning of this, of using systemic therapy and holding off on radiation or local therapy to the brain. And of course that’s an issue now particularly with tucatinib. How do you approach that? In what situations are you comfortable using HERCLIMB, or tucatinib? And I guess one of the questions that comes up in lung cancer is if you have somebody who has no neurologic symptoms, that’s fine, but suppose they do have some neurologic symptoms, some cerebral edema, do you automatically do to radiation therapy or will you use systemic therapy also?

PROF CURIGLIANO: I like this question. I thank you very much for raising this question. My clear message is the following: If you have active brain mets that are asymptomatic my advice is to start systemic therapy. Because you have the opportunity to reduce the burden of the brain disease without offering of course radiation therapy. That can be reserved only for patients with symptomatic disease. So in my personal experience once you have brain mets that are asymptomatic my advice is to start with systemic therapy, exactly like in oncogene-addicted lung cancer.

Finally, HER2-positive metastatic breast cancer is an oncogene-addicted disease. So if you give a very effective treatment, specifically like tucatinib/trastuzumab/capecitabine, but also trastuzumab deruxtecan, you can achieve an excellent response, and you can delay the use of radiation therapy. So this is my endorsement, and this is my advice for those patients.

DR LOVE: So another question, kind of a straightforward question, but I’m not sure exactly of the answer, is second-line therapy in metastatic disease in patients who get typical first-line therapy, taxane/pertuzumab/trastuzumab, in patients with brain mets; the debate there. I mean you said that the standard of care second line is T-DXd, but suppose they have very little systemic disease and a lot of brain mets. Are you still going to go with T-DXd?

PROF CURIGLIANO: Oh, this is a very interesting question. It’s a debate, actually. Looking at the data, according to evidence-based medicine, so which is the best of care in the second-line setting, we don’t have data with tucatinib in the second-line setting. So we have only 1 study, that is the DESTINY-Breast03, and we have an improvement in median progression-free survival, 28 months, unprecedented, and an overall survival benefit. So according to evidence-based medicine also patients with brain mets should receive trastuzumab deruxtecan. And I should reserve the use of tucatinib and trastuzumab and capecitabine following an ADC, so following trastuzumab deruxtecan.

So if you have also patients with limited visceral disease and only brain mets you should give the best of care that we have now, so it’s T-DX.

I must confess in some patients I gave tucatinib, trastuzumab, and capecitabine, but I did this before looking at the data of the DESTINY-Breast03. T-DX is also effective in brain mets, and you will not deny to the patient the opportunity to receive also tucatinib in the third line.

Attrition rate in HER2-positive disease is very low. I have patients with brain mets living for more than 10 years. So you have very effective treatment, and you may prolong survival with an excellent quality of life.

DR LOVE: So another situation, and this was dealt with a couple times now with ASCO Guidelines, is the patient who’s getting let’s say first-line therapy for metastatic disease and develops new brain mets, but the systemic disease is stable and this paradigm of in that situation treat the brain locally and keep the systemic therapy going. And still in the current guidelines in spite of all this new data with brain mets and tucatinib, et cetera, do you still follow that paradigm?

PROF CURIGLIANO: This is an excellent question. You are right. If you have only brain progression you should treat with radiation therapy and then proceed with the same treatment. I think it’s time to design clinical studies for those patients. We need to understand if changing treatment may improve the overall survival or the median progression-free survival.

So when you have a clear progression with symptomatic disease in my opinion we should change treatment. So if you have a symptomatic brain met, and you know perfectly that radiation therapy will not be enough to control brain disease, in my opinion we should change systemic therapy because you will offer to the patient an overall survival benefit. But in order to answer to your question we need to design new trials in which we compare local treatment, the same treatment, systemic therapy, versus changing the systemic therapy. This is the best way to answer to your question, and it’s time to do this trial.

DR LOVE: Here’s another clinical scenario, I don’t know how often it comes up, but the patient who maybe has had neoadjuvant therapy, adjuvant therapy, NED, and then presents with a brain met that gets resected. No other disease, and the disease in the brain’s been resected. Do you treat in that situation? And if so, with what?

PROF CURIGLIANO: This is an excellent scenario. Usually it depends on the time to brain mets. So let’s assume that you have a patient that completed adjuvant treatment and will relapse with a single brain met after 2 years. Usually I perform the resection, surgical resection, and radiation therapy in the tumor bed, and in the majority of the cases I propose no treatment, just watchful waiting. Let’s see what will happen.

And in many cases, because I have several patients with this scenario, in many cases I don’t have an early relapse of the disease. So you can stay without active treatment also for 1 year. Because the oligometastatic disease with a single brain mets is a very rare scenario that is related in the majority of the cases of single-cell niche in the brain growing after 1 year, so you can also consider to do also only local treatment without starting systemic therapy.

Screening for and management of T-DXd-related interstitial lung disease   

DR LOVE: So my mind is really focused on this topic because last night we did a webinar with Peter Schmid and Joyce O’Shaughnessy, and of course we were talking about all this, among other things, and I’m just kind of curious — I’m going to kind of compare notes on what I heard last night from those 2 to you, because of course they have the same vision that you do, T-DXd is going to move up, first line, going to look at post neoadjuvant, et cetera. But then of course you have the issue, as you mentioned, of ILD.

So one of the questions that we got into, which I feel like I think I’m hearing different answers to, is what is the appropriate screening for ILD, particularly in terms of imaging. I’m hearing more and more — last night they were talking about trying to get CT scans like as often as you can for as long as you can, like every — maybe every 9 weeks or so. And then in terms of how that’s going to work in the adjuvant setting. Are we going to be imaging these people?

And then the other question that we were getting into is what’s the goal and the strategy in terms of ILD. And what they were talking about last night was A) Picking it up on imaging before there’re symptoms, B) Lowering the dose and then retrying it in the patient who doesn’t have symptoms. So does that paradigm and that thinking line up with the way you’re thinking through it also?

PROF CURIGLIANO: We have to distinguish between assessing the risk of ILD in a clinical trial and in the real-world setting. Looking at the data in clinical trial, incidence of ILD was close to 15% in the DESTINY-Breast01, heavily pretreated patients, can be reduced to 10% in the DESTINY-Breast02.

So it means less chemotherapy you received before and less risk of ILD you have. So this is the first point.

The second point is in less pretreated patients the real risk of ILD, of fatal ILD, Grade 4 and 5, is zero. In the DESTINY-Breast03 no patient died for ILD.

So you may have then different clinical scenarios. You have an ILD Grade 1 and 2. In this case you can identify ILD very precautious because if you ask a patient, please, if you have cough, or breathness, contact me as soon as possible. And so usually I try to perform the CT scan in the real world once the patient will refer to me symptoms. And in my clinical practice I identify the ILD Grade 1 and 2. And usually I can treat them with steroids, and they can rechallenge again with the same treatment with very low risk.

ILD is a common toxicity. It’s described with docetaxel, with paclitaxel, with immune checkpoint inhibitors, with T-DM1, with abemaciclib also. So it’s not new clinical complication of drugs. We know very well that other drugs may have this risk.

In Italy we have an expanded access program including more than 1,000 patients, heavily pretreated, who received trastuzumab deruxtecan. The incidence of ILD in the real world, so not in a clinical trial, was very similar to what we observed in DESTINY-Breast01.

So my message is that we don’t need to screen patients with CT scan every 9 weeks. We should screen patients according to patients’ symptoms. We have to be careful to those patients who may have a potential high risk of ILD, heavily pretreated with other drugs that may increase the risk of ILD. And what we have to do is to take care of our patients, of course, increasing awareness of patients, increasing awareness of nurses, because nurses are very important to prevent and to do a very good monitoring of potential risk, and then treating as soon as possible in order to avoid a fatal evolution.

In my practice I saw no patients dying for ILD, and I see a lot of patients in my practice.

DR LOVE: So it’s always hard to pull out for the docs in practice kind of what they’re supposed to do so to speak. But one general concept that I’ve been hearing, and it sounds like maybe you don’t have the exact same approach, I’ve heard a lot of people say if you have symptomatic ILD, Grade 2, stop the drug and don’t restart it. It sounds like maybe you’re not exactly in that boat or are you?

PROF CURIGLIANO: You cannot restart treatment. If you have a Grade 2, you have to stop treatment. But you should know we are going to start with a clinical trial supported, of course, by some company, in which we will explore the opportunity to rechallenge in Grade 2. Because if you have a Grade 2, and you have complete resolution of the CT scan and of the symptoms, which is the reason why you don’t have to restart, if you gave a clinical benefit to patients.

The clinical trial we are going to design is for patients who had a toxicity from trastuzumab deruxtecan and for any reason they stopped treatment with responsive disease. So the idea is to do trastuzumab as a maintenance therapy, and once you have new progressive disease to rechallenge again with trastuzumab deruxtecan. So discontinuation trials are very common, but we have to answer this question. We have to understand if with ILD Grade 2 you can rechallenge or not.

Gastric toxicities associated with the tucatinib/trastuzumab/capecitabine regimen and with T-DXd; differences in the toxicity profiles of these therapies between patients with HER2-positive and HER2-low breast cancer

DR LOVE: You were mentioning toxicity. A couple of toxicity questions that I’ve heard people bring up, one getting back to HERCLIMB. I’m curious what the typical tolerability issues are and particularly how you deal with diarrhea.

PROF CURIGLIANO: Yes. This is a very good question. Diarrhea with tucatinib, trastuzumab, and capecitabine is very common. So you may have a rate of Grade 3 and 4 that is close to 15%. What usually I do, I start treatment with full dose. If the patient is going to experience diarrhea after 1 week I start as soon as possible antidiarrhetic treatment in order to understand if you can reduce the grade of toxicity. So if you have a Grade 1 and you start as soon as possible you may prevent a Grade 2 and 3 because Grade 2 and 3 is an issue for a patient. Diarrhea Grade 2, it’s really a clinical issue. So I mean you can prevent diarrhea using antidiarrhetic treatment.

Even if you use an antidiarrhetic treatment and you have still diarrhea usually what I do, I reduce the dose of capecitabine, and I leave a full dose of tucatinib. So in that case I prefer to have the full dose of the anti-HER2 treatment and to reduce the dose of chemotherapy.

DR LOVE: So same question in terms of toxicity with T-DXd. We hear about chemotherapy-like toxicity, GI issues, maybe even a little bit of alopecia. What have you seen in that regard? Do you use pre-emptive GI meds for example?

PROF CURIGLIANO: Yes. What I do usually is when I use trastuzumab deruxtecan a moderate antiemetic treatment strategy, so the same thing that you usually do with chemotherapy that may induce nausea and vomiting Grade 2. So I use a premedication with steroids and eventually with ondansetron or granisetron, something like this. Sometimes you can use also olanzapine. That is very effective to reduce the risk of emesis induced by T-DX.

It’s very strange, nausea and vomiting of trastuzumab deruxtecan is not reported by all patients. There are some patients who may receive the treatment without premedication, but if after the first cycle you had nausea and vomiting it’s better to do a premedication before starting the second cycle because the quality of life will be better, of course.

DR LOVE: I had a community-based physician say that she thought that she saw more T-DX toxicity in patients who were getting treated for HER2-low disease than HER2 positive, and I was like I never heard that. I couldn’t really think about it. And then I was thinking well maybe they had more chemotherapy. Is there any evidence that the toxicity’s different in HER2 low? You wouldn’t think so, but she was bringing that up.

PROF CURIGLIANO: Just to extrapolate, during the San Antonio Breast Cancer Symposium some data had been presented on sacituzumab govitecan and safety of sacituzumab according to the level of TROP2. So here you are asking the same question, why you have a different safety profile in HER2 positive and HER2 low. In the data of sacituzumab there is no difference, so diarrhea is exactly the same in TROP2 low and TROP2 high.

In trastuzumab deruxtecan it’s a different type of patient because patients who are receiving anti-HER2 therapy received radiation therapy in the past, and so they have a different approach to an anticancer treatment. Patients who are receiving trastuzumab deruxtecan in HER2 low the majority of the cases are HR positive, so they received maybe CDK4/6 inhibitors in the first-line setting, plus endocrine therapy. So once you start with an antibody-drug conjugate, that is finally a smart chemotherapy, maybe they may have more nausea and vomiting.

Also in my practice I observed something similar because coming from an endocrine therapy plus a biological agent they may have more side effects when you start again with the chemotherapy. This is of course no capecitabine — it’s not capecitabine, it’s really chemotherapy.

Approach to endocrine therapy for triple-positive disease; emerging data with the AKT inhibitor capivasertib

DR LOVE: Very interesting. One more question before we get to your cases. You were mentioning endocrine therapy, and I’m just kind of curious what your approach is to endocrine therapy in triple-positive disease, how you integrate it into first-line therapy, later-line therapy, and what do you think about the efficacy of endocrine therapy in HER2-positive converted to HER2-negative disease?

PROF CURIGLIANO: We have some interesting data in the San Antonio Breast Cancer Symposium and also in ESMO Breast; so you had the opportunity to use trastuzumab, abemaciclib, and endocrine therapy. There is the monarcHER trial. In the monarcHER trial there is a benefit in median progression-free survival and in overall survival in the luminal subtype cancer, it’s very interesting, so in those patient that according to a molecular characterization are luminal cancers. So I believe we need more studies to better explore the activity of endocrine therapy plus anti-HER2 therapy in the triple-positive population because overall I really believe that you may identify a subgroup in which you may have an overall survival benefit.

According to the standard of care actually what I am doing is to use chemotherapy plus anti-HER2 in the first line and then to do a maintenance therapy with anti-HER2 therapy and endocrine therapy. You know that there is a trial ongoing that is exploring the activity of palbociclib in the maintenance setting. So the trial is exploring endocrine therapy plus anti-HER2, like the PERTAIN trial, versus palbo/endocrine therapy/anti-HER2.

If that trial will demonstrate — also the PATINA trial is the name, a median progression-free survival benefit I believe in the triple-positive population we should really think about exploring if chemotherapy-free regimens also in the first-line setting, maybe selecting patients according to molecular characterization and not according to immunohistochemistry.

DR LOVE: I was just thinking about the fact that we know that the path CR rate is lower in people who are ER positive, HER2 positive, do we know anything about response in metastatic disease ER positive — triple positive versus ER negative, HER2 positive?

PROF CURIGLIANO: It’s exactly the same. Response rate in the CLEOPATRA trial is better in HR negative, HER2 positive versus HR positive, HER2 positive. So there are some studies exploring also predictive factors like PI3-kinase mutational status. If you are PI3-kinase mutant you have less response to chemotherapy plus dual blockade in the metastatic setting and in the early cancer setting. And we have some studies in the metastatic setting exploring dual blockade plus alpelisib in triple-positive disease that is PI3-kinase mutant.

So you are right. If you are HR positive, HER2 positive you have less response, in some cases because you are also PI3-kinase mutant.

There are registrational trials with alpelisib, pertuzumab, and trastuzumab. One of these trials is the ALPHABET trial that is a trial ongoing in Europe within International Breast Cancer Study Group and BIG network. Patients with triple-positive disease receive chemotherapy plus anti-HER2 therapy, then are tested for PI3-kinase mutational status, then as maintenance therapy receive endocrine therapy plus anti-HER2 versus endocrine therapy, anti-HER2, and alpelisib if PI3-kinase mutant.

DR LOVE: That’s interesting.

We were talking too about these new agents that are coming along. I guess capi — I forget how to say it.

PROF CURIGLIANO: Capivasertib. Capivasertib.

DR LOVE: Yeah. Yeah. Capivasertib.

PROF CURIGLIANO: Yes.

DR LOVE: I’m kind of wondering whether or not that’s going to push away alpelisib. I don’t know. What do you think?

PROF CURIGLIANO: If we look at the data presented in San Antonio, the CAPItello trial demonstrated that capivasertib may improve median progression-free survival independently of the PI3-kinase mutational status or AKT mutational status. But if you compare SOLAR-1 to CAPItello, in PI3-kinase mutant alpelisib, that is an alpha-selective PI3-kinase inhibitor, improved median progression-free survival from 3 months to 11 months. Capivasertib improved median progression-free survival from 3.9 months to 7 months. So it’s a good AKT inhibitor but it no so selective for patients with PI3-kinase mutation.

So my idea is to give alpelisib to all patients with a PI3-kinase mutation and to consider capivasertib for those patients without the mutation because it’s an opportunity to have a second-line endocrine therapy following progression to CDK4/6 inhibitors.

DR LOVE: Yeah, I was fascinated that with capi they have this I think 4 days on, 3 day off thing.

PROF CURIGLIANO: Yes.

DR LOVE: And I wonder, because with alpelisib of course everybody has so much difficulty with toxicity, have they ever tried that kind of approach with alpelisib?

PROF CURIGLIANO: No. They did not because half-life of alpelisib is very short.

DR LOVE: Right.

PROF CURIGLIANO: So if you stop treatment you may have of course increase in proliferation rate. But you are right, this type of schedule, let’s call it bortezomib like. In proteasome inhibitors you do exactly the same thing. You may reduce the incidence of hyperglycemia and also diarrhea and mucositis. But you should consider that with capivasertib of course you don’t have exactly the same high selectivity of alpelisib on the PI3-kinase pathway.

Another point is that we have new PI3-kinase inhibitors that will not induce hyperglycemia. So the future will be bright in this setting because the new generation of PI3-kinase inhibitors may reduce the risk of diarrhea and may reduce the risk of hyperglycemia. So it’s very important also to know this.

DR LOVE: That is really interesting.

Case: A woman in her mid 40s with a family history of breast cancer and upper limb soft tissue sarcoma who presents with a right breast lump and axillary adenopathy on self-examination

DR LOVE: Let’s talk about your cases.

PROF CURIGLIANO: So this is a patient of 45 years old, premenopausal, no comorbidities, with a family history of a mother with breast cancer and upper limb soft tissue sarcoma. So the patient detected a lump in the right breast and right axillary adenopathy at self-examination.

So we saw the patient finally. We confirmed the presence of, in the mammogram, of a tumor that was 75 mm with multiple right axillary adenopathy.

We performed a CT scan as baseline staging, and we discovered also multiple liver metastases. Of course we did a biopsy in the primary breast tumor, and we performed the diagnosis of invasive ductal carcinoma, ER 90%, PR 35%, HER2 negative, with a Ki-67 of 25%. And since she was a young woman with a family history we also performed germinal BRCA testing, and we discovered that there was a pathogenic mutation of BRCA2, a variant that was c.6405_6409. So there was a germinal BRCA mutation.

So this is a de novo metastatic breast cancer, ER positive, HER2 negative, with a germinal BRCA mutation. So which is the standard of care in this case? What should we do in the first-line setting?

So since it was ER positive, and we have evidence of overall survival benefit with CDK4/6 inhibitors, we started the first-line therapy with LHRH analog triptorelin, letrozole, and ribociclib. So we started finally in August of ’21 this type of treatment. We decided for the CDK4/6 inhibitor of course because we have an overall survival benefit. So in the MONALEESA-2 you have an improvement in overall survival that is also observed in de novo metastatic disease.

So after 4 months we performed a new CT scan, and there was a partial response. Then we performed a new CT scan in February 2022, and there was progressive disease. So what we have to do now? So what we decided to do is to do a liver biopsy to better understand which is the biology of the disease. And we discovered that that was a metastasis from breast cancer, ER positive, PR negative, HER2 1+, with a PI3-kinase that was wild type.

So now we have different options. The first one was to consider fulvestrant plus everolimus. The second one was to offer to the patient a PARP inhibitor because there was a germinal BRCA mutation. And the final option was to propose trastuzumab deruxtecan, because this was HER2 low, in the setting of a clinical trial that was the DESTINY-Breast06 evaluating trastuzumab deruxtecan in HER2-low disease including HER2 0.

So we gave to the patient the DESTINY-Breast06. So she started the trastuzumab deruxtecan; so she was randomized in the arm of trastuzumab deruxtecan. As a toxicity she had nausea and vomiting, so we did an antiemetic premedication with 5-HT3 receptor antagonist plus NK1 receptor antagonist and dexamethasone.

And the CT scan after 2 cycles observed responsive disease but ILD Grade 1, so the appearance of a small nodule in the lung. Of course according to the use of the clinical trial we stopped treatment, we performed adequate dexamethasone treatment, then the micronodules resolved, and since it was a Grade 1 we started again with trastuzumab deruxtecan. And the patient is still on treatment with trastuzumab deruxtecan with responsive disease.

So this is a clean-cut case in which you have several targets. You have the HER2 low, you have the germinal BRCA mutation, and unfortunately was not PI3-kinase mutant.

Every time you have HR-positive disease, even if HER2 0, it’s really important to perform a new biopsy in order to reassess the HER2 status because HER2 status is an effect of endocrine therapy. If you receive an endocrine therapy you may upregulate the epidermal growth factor receptor pathway and you may have a switch from HER2 0 for HER2 1+.

Another important point of discussion is when you have HER2 as a target and the germinal BRCA mutation which type of treatment you should use, trastuzumab deruxtecan if HER2 low or PARP inhibitor. In this case we decided to use trastuzumab deruxtecan because according to the data of the DESTINY-Breast04 you may have an improvement in both median progression-free survival and overall survival. And in a germinal BRCA-mutant patient you don’t have a benefit of overall survival neither with olaparib and neither with talazoparib. So you have progression-free survival benefit but no overall survival benefit. That’s why we decided to propose first trastuzumab deruxtecan.

Another question, of course, is how to sequence treatment in such evolving drug landscape. You have CDK4/6 inhibitors, then you have PARP inhibitors, you have trastuzumab deruxtecan. Can you use such sacituzumab govitecan in later lines? Because sacituzumab govitecan in the TROPiCS 02 demonstrated a progression-free survival and overall survival benefit in the third-line setting.

So it means that in the future in HR-positive disease we have really many, many treatment options, and what will be real important is to identify the optimal sequence. My idea that is Bonadonna, let’s say dogma, in the sequence of treatment you have to select every time the best treatment, and the best treatment is the one that will provide to you an overall survival benefit. So sequence should be based on the data, the TAR referring reporting, not only median PFS benefit, but also overall survival benefit. And that’s why we selected T-DX before the PARP inhibitor in this patient.

DR LOVE: So another thing I was thinking about as you were just beginning to present the cases, how do you manage localized disease, she didn’t have mets, in a patient who’s HER2 positive, then I realized she was HER2 low. But as long as we’re talking about HER2 positive I’m curious how you approach patients who have localized disease, HER2 positive, but also BRCA positive. I think it’s not that common to see that, and of course we have the OlympiA data, but they didn’t include HER2 positive, so what do you do about that?

PROF CURIGLIANO: This is an excellent question. You should know that also HER2-positive disease can be germinal BRCA mutant. I have several patients that are HER2 positive and are germinal BRCA mutant.

So in the adjuvant setting of course you should make your decision based on the data that you have from clinical trials. So if you have HER2-positive disease the adjuvant treatment should be anti-HER2 therapy because according to the data that we have you have an overall survival benefit in that setting with a curative rate that is very high.

If you are not HER2 positive, and you are HER2 low, HR positive, you have the data of the OlympiA trial, including a small subgroup of patients with HR-positive disease. So let’s say high-risk HR-positive, germinal BRCA mutant. In my opinion you should give a PARP inhibitor and not abemaciclib. Why? Because olaparib has an overall survival benefit. And you have a selection of patients according to gene addiction, and the germinal BRCA mutation is a clear gene addiction. So in my opinion the PARP inhibitor is better than abemaciclib in this population.

DR LOVE: In the patient with HER2-positive disease, and you brought up the issue of following the usual HER2 algorithm, but again, if you have a patient who’s got a BRCA germline mutation when or if at all to use a PARP inhibitor in metastatic disease.

PROF CURIGLIANO: You cannot combine, unfortunately, T-DM1 with a PARP inhibitor in the high-risk population because you have an increased risk of hematological toxicity. So if you have a high-risk HER2 positive, I mean neoadjuvant treatment with residual disease, the standard of care should be T-DM1. So I don’t see any data to support the use of olaparib in this patient population.

It's an interesting question, but we don’t have data.

DR LOVE: What about in the metastatic setting? At what point, if any, would you use a PARP inhibitor in a patient with HER2 positive?

PROF CURIGLIANO: After a failure of at least 3 lines of anti-HER2 therapy. If you failed the dual blockade, trastuzumab deruxtecan, and tucatinib, I can consider in the fourth-line setting to change treatment strategy and to offer a PARP inhibitor because in third line you have no single trial demonstrating an overall survival benefit. The margetuximab trial is not positive. The NALA trial is not positive. And so you can offer a PARP inhibitor that is also potentially better tolerated with respect to chemotherapy plus an anti-HER2 therapy.

DR LOVE: This concludes our program. Special thanks to Prof Curigliano, and thank you for listening. This is Dr Neil Love for Oncology Today.