Counseling patients with newly diagnosed metastatic breast cancer (mBC); role of patient-reported outcomes and advocacy

DR LOVE: Welcome to Oncology Today, Management of Metastatic Breast Cancer. This is medical oncologist Dr Neil Love. This program is a follow-up to a live CME activity we conducted in Chicago during the ASCO meeting in early June. I met with Professor Giuseppe Curigliano from the European Institute of Oncology in Milano, Italy, to further discuss many of the issues that came up during the meeting.

To begin, he commented on some of the thoughts he has as he thinks about encountering a patient for the first time with metastatic breast cancer.

PROF CURIGLIANO: Well, the first thing I do usually, since sometimes you see these patients for the first time in your life. And so you have in front of you a woman, in the majority of the cases with a husband, sometimes with a son or daughter, and she’s very worried about this because she arrived after consulting “Dr Google” and she realizes already that she has metastatic disease that is uncurable. And maybe you have been selected because she downloaded a video from the website, seeing you discussing with Dr Neil Love, and maybe you presented an important study that can improve overall survival.

So what I do with this type of patient, usually I say I am sorry because you have metastatic disease. It’s really important to be empathic with them. The second thing that I do is try to recognize that there is a solution for this problem, so we have a treatment. You can be better. You can improve your clinical situation. And the third thing I do usually is to be honest with them. So I say to them that we can take care of her, but we cannot cure the disease.

But finally what I do every time is to give hope, because now we have some really important treatments. In some diseases, like the HER2-positive disease, even if you are metastatic, if you have 1 single bone lesion or 1 single liver lesion, the quality of care and the efficacy of the treatment you propose is so outstanding that I have many patients that despite metastatic disease they can live 10 years or longer than 10 years, specifically in the HER2-positive disease.

So compassion, being honest with them, being empathic, and then explaining to them that this is metastatic disease but giving hope. This is my approach.

DR LOVE: So as we go through some of these topics I’m going to bring up some of your papers. And one that I think maybe we can emphasize as we go through various parts of metastatic disease, of course that was the topic that we were covering, I noticed you did a number of papers related to the issue of quality.

PROF CURIGLIANO: Yes.

DR LOVE: And some of them looked like pretty deep exploration of the issue. And thinking about that woman that you just described, how does — and the whole issue of patient-reported outcomes and advocacy, et cetera, where does that come in, again, in your initial discussion with the patient, initial thoughts about the patient?

PROF CURIGLIANO: Well, I believe when you have metastatic disease you need to not only improve overall survival, median progression-free survival, but you need to realize that the quality of life is most important. And today we have specific tools that were not available 20 years ago. You have digital tools, and the patient can really report toxicity and quality of life by their self.

I remember a trial that has been done 10 years ago comparing self-reported outcome, or patient-reported outcome, with respect to assessment of quality of life and toxicity by the medical oncologist. That was completely different because the time you collect toxicity in front of a patient can be 7 to 8 minutes. So say how are you? Did you have any side effects? Oh, I had a little bit of diarrhea, so you report 1, 1 and 1 as the grade of toxicity, and so the quality of life is excellent according to doctor assessment. But if you have diarrhea, Grade 1, for 10 to 15 days or for all the intercourse of the cycle, of course this means that your quality of life is very poor.

So I remember we did the patient-reported outcome analysis in the DESTINY-Breast03, that was the perspective randomized trial evaluating trastuzumab deruxtecan versus T-DM1, and of course the PRO were really excellent when reported by the patients, because trastuzumab deruxtecan can really give a rapid response with symptomatic improvement, and if you check that paper the time to first hospitalization was almost 1 year with trastuzumab deruxtecan versus a few weeks for T-DM1.

DR LOVE: Wow.

PROF CURIGLIANO: So this means, of course, that we need really to collect the data of quality of life but completely reported by patients not by the investigators, because as an investigator I have many bias. First you have a drug that works, so you are convinced that you will change the standard of care. And when you have positive data of a drug you have a lot of bias, and you can under-evaluate the quality of life of patients.

DR LOVE: Yeah, that’s really a great point.

Individualized selection of up-front therapy for patients with HR-positive, HER2-negative mBC

DR LOVE: It kind of leads into some of the things I was going to get into, and one that came out at the meeting, which has been out there for a while, but I thought we had a little bit of an interesting twist on it, was very simple, choice of CDK inhibitor in the first-line setting.

And you may remember that we had 1 case presented of a patient who was on ribo. The patient had hepatotoxicity, they tried to adjust the dose, going back and forth trying to keep them on ribo. And then we had another doc saying well I don’t even use ribo in older patients. I just use it in younger people because the older people, they don’t like it, and they’re still getting 5 years of palbo. And it made me wonder about this issue of chasing the data. We’re so fixed on overall survival that we don’t really look at the patient. Any thoughts?

PROF CURIGLIANO: Before the publication of the final data with CDK4/6 inhibitors I published a paper are all CDK4/6 inhibitors created equal. When you have a patient in front of you, you have to consider that all trials with CDK4/6 inhibitors had as a primary endpoint progression-free survival, and all CDK4/6 inhibitors improved median progression-free survival in all the clinical trials. So selection of a CDK4/6 inhibitor should be based also on patient expectations, patient comorbidities and sometimes patient preferences.

For me, palbociclib is still an excellent agent. It's my first choice for patients with comorbidities or for patients that are elderly because the quality of life is very good. And I have personally patients for more than 4 years with palbociclib. Of course, if you have a younger patient that is premenopausal with known metastatic disease, you should be honest, you should discuss with her the secondary outcome of the clinical trials, explaining that some CDK4/6 inhibitors improved overall survival.

And that’s why in younger patients of course my first option is ribociclib, but I must confess that I had some younger patients developing liver toxicity. That is very common with ribociclib, and despite I reduced the dose to 400 mg, 200 mg, there was still liver toxicity. And then what I did is to switch to another CDK4/6 inhibitor, and I gave palbociclib, and there was absolutely no liver toxicity. So case by case discussion, being honest with the patient, presenting the data and explaining the magnitude of clinical benefit for any CDK4/6 inhibitor, but don’t forget that we cure patients and not breast cancers.

DR LOVE: Where does abemaciclib fit in in the metastatic setting? Is there any particular patient profile? Do you feel like there’s positive survival data there as well?

PROF CURIGLIANO: Yes. I believe in primary resistant disease we have clear overall survival benefit. My preferred treatment with abema is for patients with poorly — rapidly progressive disease and main liver disease. Usually it’s an excellent agent. You can achieve an impressive response rate, and you can improve also the outcome. It’s a different CDK4/6 inhibitor. It’s more on target than CDK4, and that’s why maybe in the adjuvant setting there is a clear benefit for abemaciclib in the monarchE trial.

Selection and sequencing of treatment for patients with HR-positive, HER2-negative disease who experience progression on CDK4/6 inhibition

DR LOVE: So let’s talk about patients who have progressive disease on CDK4 inhibitors. I think this is one of the more complicated areas in oncology nowadays, which of course now also has a very strong biomarker component, and of course we talked about that at the meeting. So I guess a number of questions came up at the meeting, and I’m just kind of curious what your take is. One is we talked about the patient who’s both PIK3-positive and ESR1-positive. I’m curious about how you think through that scenario.

PROF CURIGLIANO: The median progression-free survival of CDK4/6 inhibitor with alpelisib, according to the BYLieve trial is 7 months. The median PFS of elacestrant in those patients who received more than 1 year or close to 18 months of first-line CDK4/6 inhibitors is 8.5 months. So if you have both an ESR1 mutation and a PIK3 mutation of course my preferred choice is elacestrant in endocrine-sensitive disease, because you may have a longer benefit in this patient population with monotherapy, so why should I consider a PI3 kinase inhibitor like alpelisib? In using, hyperglycemia, cutaneous rash and sometimes also diarrhea.

A different scenario is with capivasertib. Of course now you have patients with PI3 kinase mutation, AKT mutation or PTEN deletion, that may derive a benefit from the combination of fulvestrant and capivasertib. It’s a good treatment option. There is less toxicity with respect to alpelisib, but don’t forget that in the post-CDK4/6 inhibitor setting median PFS with capivasertib plus fulvestrant is 5 months.

DR LOVE: How do you find using capivasertib, and particularly the schedule, the 4 days on and 3 off? How does that work with patients, and what do you see toxicity wise, particularly compared to alpelisib?

PROF CURIGLIANO: Capivasertib is much more better tolerated than alpelisib in the metastatic setting. If you have a fit patient, of course you don’t have hyperglycemia, in terms of diet. Cutaneous rash is less common. Diarrhea can be an issue, but you can manage eventually with loperamide or any other treatment.

I prefer to use capivasertib, but for those patients that eventually progress on CDK4/6 inhibitors and have let’s say AKT alteration, that is very common, quite common, like PI3 kinase, and of course in this patient population that is clearly resistant, a combination drug can give better control of the disease. In the endocrine sensitive, as I said before, if you have ESR1 mutation I prefer to give monotherapy.

DR LOVE: That was another issue that I’m not sure has really gotten out there successfully, about how important it is to look at the time the patient was on a CDK inhibitor, and as you’re referring, endocrine sensitivity or resistance. Generally, are you looking at a year or less as being endocrine resistant? Or what numbers do you use?

PROF CURIGLIANO: Yes. We use usually the ABCs1 definition, so progressing within 1 year of first-line CDK4/6 inhibitor is considered usually endocrine-resistant disease. But you know perfectly that the majority of the patients, almost 70% of them, can receive a CDK4/6 inhibitor when relapsing or first line for more than 1 year. So it’s quite common to derive a longer benefit by first-line CDK4/6 inhibitors. A different patient population is the patient population that relapses during adjuvant endocrine therapy. This is a clearly resistant population in which first line usually is fulvestrant plus a CDK4/6 inhibitor, and usually within 1 year they will relapse. And that’s why here you need to consider something different, like chemotherapy, or now that we have trastuzumab deruxtecan in HER2-low, trastuzumab deruxtecan.

DR LOVE: Right. And of course another issue that we got into there was you were talking about elacestrant, but there are a couple other SERDs in development that are not currently available, camizestrant and imlunestrant, and I think Sara Hurvitz was talking about her perception that — I think what she said was they seem equal efficacy wise, they have slightly different tolerability. It sounds like CDK in a lot of other situations in oncology, where you have multiple — PARP inhibitors, multiple agents within the same class, where you can’t really differentiate efficacy, but they have a little bit different tolerability. Do you buy into that?

And another thing she mentioned was bradycardia I think was seen maybe with elacestrant mainly. I saw a bunch of papers. I guess you have an interest in cardiac issues in oncology also. I was curious, and I guess elacestrant’s on the list now. So again, any thoughts about these 3 agents and where things are heading? Do you think eventually they’ll be combined with other things and whatever trial successfully combines them, that’s how they’re going to be used? And what about cardiac issues?

PROF CURIGLIANO: Elacestrant specifically is not giving bradycardia. It’s more the PROTAC inhibitors that can give to you bradycardia. Because the mechanism of action of PROTAC is a little bit different. They degrade the estrogen receptor at the level of the proteasome, and so it means you can also induce a QTc prolongation and bradycardia. But as you correctly stated, we have different oral SERDs; camizestrant that is going to be approved soon, imlunestrant and elacestrant.

Camizestrant is a different mechanism of action than elacestrant. It’s more on target and so can induce also some problems on the cardiac level. I mean QTc prolongation is more common with camizestrant than with elacestrant. And another point, camizestrant can induce also fatigue much more than elacestrant. It can induce also diarrhea, because as you know perfectly estrogen receptors can be also expressed in the gastrointestinal tract, and you may have with these agents sometimes diarrhea.

So the magnitude of clinical benefit of all these agents usually is between 7 and 9 months according to the endocrine-sensitive or the endocrine-resistant population.

So the first question is whether you can combine with other agents, and we have data with imlunestrant. Imlunestrant has been combined with abemaciclib with very good activity, very similar to the combination with AI, but has been combined also with everolimus with an impressive median progression-free survival improvement in a small cohort of patients progressing to first-line CDK4/6 inhibitors.

I don’t know how much these agents will be incorporated in clinical practice. I see for the majority of them a role in the second-line setting. It would be very difficult to position them in the adjuvant setting because of the safety profile of an oral SERD is completely different in respect to tamoxifen or an AI.

But you know that there are some trials that are based on interception of ESR1 mutation, specifically the SERENA-6 is testing patients for ESR1 mutation without radiological progression, and once you intercept the ESR1 mutation you anticipate the use of the oral SERD like in the PADA-1 trial. So if this trial will be positive we will have a new patient population that are patients without radiological progression but with an ESR1 mutation that has been intercepted with the liquid biopsy.

DR LOVE: No. I love that concept, and I see that being done in other tumors, at least conceptually the same. But the other thing, though is — so the way things work in oncology it seems like when you — if you have multiple agents in the same class, and then you take 1 of them, and you add it to something else, and it’s helpful, then usually people stick with the drug that was used. But now you brought up a whole bunch of issues with cami. Do you see that as a major obstacle, or do you think people will get used to it and be able to use it?

PROF CURIGLIANO: This is an excellent question because you should consider that if camizestrant will be approved based on this trial you need to test the patients every 3 months with a liquid biopsy. So maybe in the United States there will be Medicare that will cover this, but in countries like Europe it’s important to recognize that maybe if you want me to use camizestrant you will need also to pay for my liquid biopsy. So I deeply believe that intercepting the progression before radiological progression may improve the outcome, at least median progression-free survival.

But we have also to discuss about sustainability and of course also about patient compliance, because in order to do something like this you need to assess every 3 months as a standard of care to do this liquid biopsy.

Current and future role of HER2-targeted therapy for HER2-low and HER2-ultralow mBC

DR LOVE: So let’s move on and talk about HER2-low and -ultralow disease and HER2 assays. It’s really incredible for us, now we’re trying to deal with everybody else in oncology. We’ve been dealing with T-DXd in breast cancer, of course, then the lung cancer and GI people came along, and now everybody is trying to figure out what to do, and they have no experience in this area, particularly HER2 testing seems — it’s almost scary when I hear about what’s going on.

So can you kind of review? I mean, we’ve got — now we’ve got the pan-tumor approval for IHC 3+, we’ve got — obviously that’s a huge thing. And we’ve got all this data with HER2-low, -ultralow. We had a case the other day, and people were like can we just give it to somebody who’s HER2 0. So you’ve obviously been in the middle of all this.

Let’s just start out with HER2 testing and even the issue of is HER2 even — I mean, I guess it’s the target, but you kind of wonder what’s going on in general with ADCs. You have TROP ADCs where you’re not even measuring it. So you can imagine the people out there in the grandstand are a little confused, so can you help us?

PROF CURIGLIANO: First of all, HER2 is not only a predictive biomarker, but is also a prognostic biomarker. Just to remind you, when Dennis Slamon for the first time described HER2 it was on brain mets, and the name is HER2/neu, neurological.

DR LOVE: Right.

PROF CURIGLIANO: That’s why it was called HER2.

DR LOVE: Really?

PROF CURIGLIANO: Yes, absolutely.

DR LOVE: Oh. That was neurologic. Wow. That’s cool.

PROF CURIGLIANO: And so finally he first published this beautiful trial in the metastatic setting demonstrating that the combination of trastuzumab and taxanes may improve overall survival, and then we moved it into the adjuvant setting.

The first-generation ADC was T-DM1, but a study has been done with T-DM1 in HER2-low. Adam Brufsky published this trial, and response rate was very low. I remember it was 4.6%, T-DM1 in HER2-low. And then there was another trial in the adjuvant setting, the NSABP B-47, a large prospective randomized trial with trastuzumab versus chemotherapy alone in the adjuvant setting for HER2-low; completely negative.

Trastuzumab deruxtecan is another agent. It’s an ADC that can target also lower-level of HER2. But let’s look in detail in the data. The hazard ratio in HER2-low disease in the intent to treat population, including HER2-low and HER2-ultralow, is 0.63. But if you check the hazard ratio in HER2-ultralow, I mean any staining between 0 and 1, the hazard ratio is 0.78. And if you check the activity of trastuzumab deruxtecan in HER2 3+, the DESTINY-Breast03, the hazard ratio is 0.3. So it means that increasing level of expression of HER2 predicts an improved outcome, so it's a spectrum of HER2 expression.

So the most important message is that TDX may work also at lower levels of HER2, but the more expression you have the more benefit you will derive. And what will be essential now for our pathologists, since it’s very easy to test 1+ and 2+, we have the ASCO-CAP, but ASCO-CAP is not explaining to you how to test HER2 0, if there’s any staining between 0 and 1+. So I believe we need a new revised version of ASCO-CAP addressing also the issue of HER2-ultralow because up to now the pathologists are really in difficulty according to the ASCO-CAP definition to define what is HER2-low. So my advice is report HER2-low as HER2-ultralow as 0 but describe in the report how many cells are positive under 10%.

DR LOVE: So let me go through with you a few questions related to T-DXd in general and HER2-low particularly. One is the issue of sequencing. We actually did a meeting, I think a couple hours after the HER2-low data was presented a couple years ago, and immediately people were saying, “Well, ER-positive, HER2-low, okay T-DXd first. But triple-negative, there’s better data with sacituzumab, so sacituzumab first.” So I’m curious particularly how you sequence those 2 ADCs in this setting.

But one thing that I don’t think we’ve talked enough about is the clinical status of the patient and how that affects the decision. Because to me if you have a patient without visceral disease, who’s relatively asymptomatic, that’s very different than a patient with a lot of disease and a lot of symptoms, in terms of this decision, and that maybe this algorithm of one versus the other has to be maybe consider the patient’s clinical status also. Any thoughts?

PROF CURIGLIANO: This is an important question because we know that if you compare the median PFS with the first ADC to the median PFS of the secondary ADC in sequence the median PFS will be shorter. So we need to understand those so that once a patient progresses on trastuzumab deruxtecan, and is HER2-low, of course you will have a visual progression in the majority of the cases, and the use of a secondary ADCs will have an underperformance with respect to the first ADC.

First, you have to consider the general condition of the patient and the performance status. Second, you have to evaluate the toxicity of the previous ADC, because if you add only hematological toxicity you can rechallenge with another ADC with the help to have again a response rate and potentially an improvement in median PFS. But what to do if you have an ILD? A Grade 2 ILD in the progressive disease. What to do if you have a massive gastrointestinal toxicity? What to do if you add a hematological toxicity?

So I believe we need more studies on sequencing of ADCs, but the ideal study should consider a model like the SONIA trial. So let’s say you start with an ADC, you use it for a longer time, and then at progression you use chemotherapy as an interval and then another ADC, or eventually you consider the sequence of 2 ADCs directly, and then you evaluate median progression-free survival 2 as a primary endpoint. This is what is going to be done when testing trastuzumab deruxtecan and datopotamab deruxtecan, an anti-HER2 and anti-TROP2, but we need of course to generate more real-world data.

DR LOVE: Yeah. I’m just looking at one of your — one of your many papers on this topic. I like that your titles are always cool. I like them. So “Think ‘HER2’ different: integrative diagnostic approaches to HER2-low breast cancer.” Pathologica. We don’t usually read that. So I guess you’ve got to interact with the pathologist. I mean, I guess everybody has to deal with their local pathologist, as well, in terms of IHC even, at this point, in these other tumors.

You mentioned ILD. And again, we’re dealing with the lung — everybody’s asking what do we do type thing. In general, do you think that — the algorithm we’ve heard from the breast people is very frequent imaging, as frequent as you can get it, maybe every 9 weeks. Obviously, if they have any symptoms you need to work up. But the main thing has been Grade 1, stop, use steroids, retreat. Grade 2, don’t use it again. Now that’s the message. So my question to you, is that the message we should be giving to the lung and GI and all these other people about prevention and management of ILD?

PROF CURIGLIANO: Okay. The first thing is to screen, as you said perfectly. So it’s important to increase awareness of the patient but also to screen with CT in order to understand when eventually the ILD is going to appear. According to the recommendation, the screening should be done every 6 to 8 weeks.

What I do in my clinical practice is if patients are symptomatic I can also delay more than 8 weeks. The second point is to scan, because the best way to detect an ILD is not a chest x-ray but is a CT scan, because you can identify also a Grade 1 ILD. The third point is to synergize, of course, with the pulmonologist because once an ILD is detected of course you can start steroid treatment, but it’s really important to interact with the pulmonologist in order to understand which is the level of ILD and the Grade of ILD and the appropriate treatment. Four, stop trastuzumab deruxtecan. Every time you have an ILD you have to stop; Grade 1, 2 or 3 you have to stop. And finally, you have to start steroids at appropriate dose, 1 mg/kg if you want to have a rapid resolution. So this is the summary of what you have to do to better recognize and to avoid a fatal evolution.

Selection and sequencing of therapy for patients with metastatic triple-negative breast cancer

DR LOVE: So one of the other topics we talked about was the use of checkpoint inhibitors, particularly in triple-negative disease. And before I ask you about breast, I’ve got to ask you about something I saw that’s coming up, and I wondered — I know you’ve done a lot of work combining IO with other things, like pembro. I was curious. I saw this paper. It was actually in a Gyn, but I’m curious if you’ve heard of it. Vibostolimab coformulated with pembro. KEYVIBE-005. Anti-TIGIT/anti-PD-1 coformulation.

PROF CURIGLIANO: Yes. I know this.

DR LOVE: What do you think about that?

PROF CURIGLIANO: Yes.

DR LOVE: What is it? It sounds pretty cool, but what is it?

PROF CURIGLIANO: It’s a bifunctional antibody.

DR LOVE: Wow. That’s what it sounds like. That’s what it sounds like. I thought so. Oh, my God.

PROF CURIGLIANO: Actually, you have many bifunctional antibodies under development. Some of them can target 2 immune checkpoints, anti-TIGIT and anti-PD-L1. Some others can target entire 2 anti-PD-L1. Some others can target also vascular endothelial growth factor receptor and anti-PD-L1. There are many of them under development.

It’s a new generation of ADC that can target with the bifunctional antibody 2 different targets, then you can also conjugate with the chemotherapy, so it’s really complex what is going on in drug development. Please.

DR LOVE: That’s for sure. But now this is a bispecific, right?

PROF CURIGLIANO: Bispecific, yes.

DR LOVE: Not an ADC.

PROF CURIGLIANO: Not an ADC.

DR LOVE: I mean, I’ve heard about this.

PROF CURIGLIANO: This is a bispecific, yes.

DR LOVE: So do we know that even some kind of bispecific can cause a response like an IO?

PROF CURIGLIANO: Yes, it can induce a response that sometimes is better than an IO. I am using now some bispecifics in clinical practice. You should be aware that any bispecific can also induce more frequently or infusion reaction or inflammatory response syndrome because they are very similar to drugs that can enhance the immune response at the limits, so you have to be very careful because you have also to know how to manage an inflammatory response syndrome.

DR LOVE: Well, I mean, you have CD3 bispecifics, and now there’s one in small cell cancer of the lung that causes cytokine release syndrome.

PROF CURIGLIANO: Correct.

DR LOVE: So, I mean, I guess that’s kind of I guess what you’re talking about.

PROF CURIGLIANO: Yeah.

DR LOVE: But these things sound really cool.

Okay, but getting back to today in triple-negative breast cancer, I guess some of the practical issues that we talked about are the patients who present with metastatic disease, and whether getting first-line therapy with an IO plus chemo, and particularly looking at second-line therapy. Anything you want to say about that whole clinical scenario and how you approach these patients? And any advice you would give to docs in practice about this scenario?

PROF CURIGLIANO: In the first-line setting it’s first essential to test for PD-L1. In the metastatic setting pembrolizumab is approved only for CPS score more than 10. So if you don’t test in the metastatic setting, and then in the primary, because sometimes in the liver biopsy you will not find PD-L1, but you can find it in the primary tumor. So if you are PD-L1-positive the standard of care is an immune checkpoint inhibitor plus chemotherapy. That can be any chemotherapy plus pembrolizumab or atezolizumab plus nab-paclitaxel that is only approved in Europe.

The critical issue is what to do in second line, because we don’t have so many options in the second-line setting. Up to now the best treatment you can offer, if you don’t have — if you don’t have a germinal BRCA mutation, is sacituzumab govitecan. You have the data of the ASCENT trial, prospective randomized trial evaluating the activity of the anti-TROP2 sacituzumab govitecan versus standard of care in patients with triple-negative breast cancer. And sacituzumab govitecan improved both median progression-free survival and overall survival.

We are waiting, of course, for other data, datopotamab deruxtecan. And finally, don’t forget that also trastuzumab deruxtecan can be used in this setting, because if you have a triple-negative, ER-positive/PR-negative, ER-negative/PR-negative with the low-level expression of HER2, trastuzumab deruxtecan can be also an excellent option. 

DR LOVE: So I want to talk a little bit about PARP inhibitors. You’ve written a bunch of papers there. And I guess the first question I have is where do we stand in the use of PARP inhibitors in the adjuvant setting? And also I see you have a bunch of papers about working patients up in the adjuvant setting, germline testing and somatic testing. Again, outside a clinical trial setting, in a community-based setting, what do you consider standard in terms of looking for BRCA and other alterations? What kind of testing do you recommend? And how does that affect the way you prescribe therapy?

PROF CURIGLIANO: According to ASCO/SSO Guidelines we need to test for germline BRCA mutation in any patient. I don’t believe we should limit only to triple-negative breast cancer patients, but also to HR-positive breast cancer patients. You know that the OlympiA trial was a prospective randomized trial evaluating the activity of olaparib for 1 year in both triple-negative and HR-positive disease, and the trial demonstrated an improvement in invasive disease-free survival but also in overall survival.

Unfortunately, the trial was only for germline BRCA mutant, but during ASCO we had some very interesting data presented on the activity of olaparib in somatic germline — somatic BRCA mutation and also in PALB2 germline mutation. This was a trial in the metastatic setting, very few patients, but there was a huge activity of olaparib in PALB2 germinal mutant but also in somatic BRCA mutation.

So my advice is test everybody for the adjuvant setting because if you have a high-risk patient, HR-positive or triple-negative, and you are germinal BRCA mutant you can offer olaparib. That can improve overall survival.

DR LOVE: Of course, one of the questions that comes up is what about in the neoadjuvant setting in the patient with residual disease. Do you give a PARP inhibitor, IO or both?

PROF CURIGLIANO: Oh. This is an excellent question. What I do in my practice, if you are a high-risk patient with residual disease and triple-negative breast cancer, I give both pembrolizumab and olaparib because we know that essentially there is no safety issue. You can combine them. There is no evidence because there is no prospective randomized trial. It’s only an extrapolation, but I assume that if you combine both, I don’t believe you will give any problem to the patient. You can do this.

Emerging innovative interventions for the treatment of mBC

DR LOVE: So I want to talk about a few other topics. Again, I saw some papers that I was really curious about. One was in Cancer Treatment Research, “Fast Mimicking Diets and Other Innovative Nutritional Interventions to Treat Patients with Breast Cancer.”

PROF CURIGLIANO: I was a coauthor of this paper, of course. You know now we have the fast mimic diet, finally. It means being for a long time without any food. Usually in people more than 50, like me, you should fast from 8 PM to 6 AM in the morning, so you should not have dinner.

Some of these trials in other settings seem to demonstrate a better outcome in terms of control of diabetes or any other disease. And now there is a line of research, not only in breast cancer, but also in other diseases, evaluating the effect of this type of diet in patients receiving neoadjuvant or adjuvant chemotherapy.

These trials are of course ongoing. We don’t have until now any evidence that can be useful for the patients, but I believe the study of metabolism is in the future can be really important also in cancer patients because I am sure that the activity of some drugs can be also correlated to the metabolism and to the diet. So we need to do more studies on this. This is, of course, not evidence based until now.

DR LOVE: So the reason I brought that up, and I’ve been asking people about it, because I’ve always been interested in this, although like you I’m not sure exactly where it’s heading. But we did a program recently on myelofibrosis with Ruben Mesa, he’s a myelofibrosis guru, and we had just reviewed 2 papers on new agents in myelofibrosis that did not improve symptoms in people already treated with ruxolitinib, and they did a randomized study on the Mediterranean diet, which is really a low-fat diet.

PROF CURIGLIANO: Yes.

DR LOVE: A lot of plants and vegetables, just simple. And they saw a difference in the inflammatory symptoms.

PROF CURIGLIANO: Yes.

DR LOVE: And that made me think, I wonder, we’ve always looked at diet for other reasons, but now that we have immunotherapy I wonder specifically if there could be a connection between diet and immunotherapy. Any thoughts?

PROF CURIGLIANO: There are 2 different evidence from immune checkpoint inhibitors. The first one is that potentially obese patients may derive less benefit from immune checkpoint inhibitors, and this means that if you have an environment with a high level of inflammation potentially you can reduce the activity of immunotherapy. Of course, these are only based on retrospective analyses. And so it means that if you have a low caloric intake, and you reduce potentially all the inflammasome biomarkers, you may potentially derive more benefit from immunotherapy. And that’s why some studies that have been done and are ongoing with this type of approach are mainly in triple-negative breast cancer using neoadjuvant immune checkpoint inhibitors.

DR LOVE: I’ve heard that there’s a big US cooperative group study, I think it’s looking at diet intervention in the adjuvant setting. I’m not sure exactly what they’re doing. I heard it’s —

PROF CURIGLIANO: So you remember there was a large prospective randomized trial using metformin.

DR LOVE: Right, yeah.

PROF CURIGLIANO: Exactly.

DR LOVE: But this is something else.

PROF CURIGLIANO: And the trial was completed and unfortunately was negative.

DR LOVE: Right, right. Go ahead.

PROF CURIGLIANO: Dr Love, the most important thing, when you do a trial with diet you cannot assess the compliance because you don’t know if the patient will follow exactly the low-caloric intake that you are prescribing. You need just a glass of wine to break the compliance, so it’s very difficult to do trials like this.

DR LOVE: So here’s another topic I’ve been interested in, and I saw you had several papers on it. I actually was approached by a patient advocacy group, and I immediately understood the issue. It was an advocacy group for lobular cancer of the breast.

PROF CURIGLIANO: Yes.

DR LOVE: And they were like where’s our stuff? Which I understand, because lobular gets lumped in with ER-positive, HER2-negative. But then they read, and they see that it’s not the same, obviously, clinically. And I see that you’ve had some papers looking at lobular. At this point, any sense of whether we’ll ever be able to find a target there that maybe we can’t find, cadherin or anything?

PROF CURIGLIANO: Well, personally I believe lobular cancer is a different biology with respect to ductal cancer. We have a lot of evidence that the presentation of lobular cancer is usually with nodal involvement, even if a small tumor, is multifocal disease in the majority of the cases, can be bilateral. Lobular cancer may derive more benefit from aromatase inhibitors with respect to tamoxifen, and we have also evidence from the BIG 1-98.

In lobular cancer it’s more common the upregulation of PI3 kinase mutation, so then definitely I believe we need to design clinical trials for lobular only. And the other point is we need prospective randomized trials to evaluate the activity of chemotherapy in the adjuvant setting in this disease, because as you know perfectly the first option for a lobular cancer, even if node positive, is endocrine therapy. So for sure we need to better understand the biology, and we need to design clinical trials specifically for lobular cancer patients.

DR LOVE: I wonder if that’s going to happen, but it sounds like a great idea.

Here’s another topic that I saw a bunch of papers on that I was very interested in, inflammatory breast cancer and immunotherapy. And I was thinking, I don’t think I’ve seen much on that.

PROF CURIGLIANO: We have a clinical trial ongoing, actually, using pembrolizumab plus low-dose metronomic chemotherapy in inflammatory breast cancer. Inflammatory breast cancer is a completely different disease. Some patients may present to you with an inflammatory disease, and these are difficult to treat cancers with less response. Even if HER2-positive or triple-negative they are less responsive to the standard of care. And we really don’t know very well, which is the biology behind an inflammatory breast cancer.

So it’s essential to design clinical trials for them. There is a patient advocacy group working on this and very few investigators all over the world. I just remember one trial of Hope Rugo, some trials of Massimo Cristofanilli and my trial that is ongoing. It’s a rare disease, but even if there — even if rare, it’s there, and you need to tailor clinical trials for that.

DR LOVE: So I guess the last question I was going to ask you is maybe to speculate a little bit of where you think breast cancer’s going to be in the next 5 years.

PROF CURIGLIANO: Oh. This is an excellent question. What I see in the future is more interception. So I believe we will have more trials of screening for the high-risk population in which beyond MRI, mammogram and ultrasound we use also liquid biopsy to intercept the disease before the appearance. This is for the primary prevention.

And then in the adjuvant setting what I see a lot is a lot of trials with liquid biopsy in which patients in their adjuvant treatment will use circulating tumor DNA to better stratify the risk, and in those patients with no clearance under the standard of care I see new clinical trials in which the primary endpoint will be ctDNA clearance. So I see incorporation of many assays that may intercept in the adjuvant setting the progression of disease.