Ask the expert: Hormone receptor-positive breast cancer with Dr. Gupta

In this presentation, oncologist Sameer Gupta, MD, MPH, shares information about the importance of hormone receptor status in getting the right treatment, explains the complexities of HR-targeting therapies, shares the newest treatment options and research breakthroughs, including breaking news from ASCO 2022. Dr. Gupta then answers questions regarding both early-stage and metastatic hormone receptor-positive breast cancer.

Webinar transcript

Sameer Gupta, MD, MPH:

The structure of the program, as Janine said, is going to be a brief presentation. I will primarily focus on some of the updates from the American Society of Clinical Oncology meeting pertaining to ER-positive, or estrogen receptor-positive, disease. And then we'll open the forum up to questions that you can submit in your chat box.

So let me just start sharing. As I mentioned, we will talk about some of the studies. I will briefly review some of the options available for estrogen receptor-positive breast cancer also, and I'm happy to answer any questions at the end of this topic. Just as a disclosure, I'm a speaker and consultant for Daiichi Sankyo and AstraZeneca, and we will be discussing some of those products today. So, we will start off by discussing some of the advances in the early-stage setting.

As many of you know, the goal of adjuvant systemic therapy, why you see a medical oncologist, is to eliminate or delay the appearance of micrometastatic disease. The strategies that we use in the clinic are anti-estrogen therapy for patients who have ER-positive disease, chemotherapy for patients who have ER-negative disease, HER2-amplified disease, and some patients with ER-positive disease, and HER2-directive therapy for patients who have HER2-amplified disease. And now with KEYNOTE-522, immunotherapy with Keytruda for patients who have triple-negative disease, current strategies include individualizing treatment to the patient, and various factors come into play when we decide the right treatment for the right patient. So we have to factor in, what are the risks? What are the benefits? What are the organ functions? Age comorbidities? And as you're aware, various prognostic and predictive factors: tests like Oncotype or MamaPrint that you may have had, or your providers may have discussed with you. That really decides and tells us in the ER-positive setting how high risk that ER-positive disease is and whether chemotherapy would be a benefit or not.

There have been significant changes in the recommendation for adjuvant anti-estrogen therapy in the last few years, including addition of ovarian suppression in younger patients and the incorporation of drugs like abemacilib, or Verzenio, in the earlier-stage setting, primarily high-risk test setting with lymph node-positive disease, higher tumor turnover with high Ki-67, as well as now, the use of targeted therapy with olaparib, which is a PARP inhibitor, in patients who are BRCA1 and 2 positive who still have some residual disease.

So, this is just an update from the ASTRA study, which basically looked at women who were premenopausal and were taking tamoxifen. What is the benefit of adding ovarian function suppression? This is an 8-year follow up. The 5-year follow was presented before.

The SOFT trial was another trial that has been reported out, and it did show a benefit even at 8 to 12 years of adding ovarian suppression to tamoxifen. This study had already shown some benefit, around a 3 percent disease-free survival benefit at 5 years, and at the American Society of Clinical Oncology meeting recently, what they did is they showed what was happening at 8 years when the patients were followed for a longer period of time. The study designed just as you know, were premenopausal women age less than 45, all women had estrogen receptor-positive disease, stage I to stage III had been treated with definitive surgery, and patients had received chemotherapy. So this is a little higher risk population. Ovarian function was evaluated and patients were randomized one-to-one to receive tamoxifen or tamoxifen plus goserelin, which suppresses ovarian function, and the primary endpoint was disease-free survival. So, you can see the top curve is basically the disease-free survival. The patients who got ovarian suppression, and there was a 6 percent benefit in preventing the disease from coming back as time passes on.

So, at 8 years or 9 years, you can see that difference starts to increase. This adds to the evidence that in the right patient, optimizing anti-estrogen therapy adds a lot when it comes to long-term survival. This adds to some of the studies we've seen from 5 years versus 10 years of tamoxifen and this adds to the SOFT and the TEXT trials. In the right setting, your providers will talk to you about anti-estrogen therapy, not only for 5 years, but also for 10 years.

The other strategy that is also done is not only using tamoxifen with ovarian suppression, but actually switching tamoxifen out for aromatase inhibitors. That has also shown to be of benefit in the right patient population. Just overall survival hasn't shown a big difference right now, but that may change as time goes on.

Moving to new data in the metastatic setting, as Janine mentioned, trastuzumab deruxtican has now been approved in the HER2-low metastatic setting or unresectable setting. I think one of the big things in the ER-positive setting is now we see data not only from this drug, but another drug I will talk about shortly, which are antibody drug conjugates, and this is a new paradigm in estrogen receptor-positive disease, where you have an antibody that is directed to a receptor, and it has a chemotherapy payload. The drug is stable in the blood, and it is internalized into the cancer cells and then broken up. So the chemotherapy is delivered in a much more targeted fashion. The way I describe this to my patient, it is more of a tomahawk with using the receptor and delivering chemotherapy into the cancer cells.

Trastuzumab deruxtican, we’ll start with this, is already approved in the HER2-amplified setting and the DESTINY Breast-04 was the first trial that compared it in the HER2-low setting. What is HER2-low? HER2-low is an unmet clinical need. When we test for HER2, we use immunochemistry or IHC. You may have seen the reports that said the HER2 is 0, 1+, 2+, or 3+.  3+ is typically considered to be amplified. And HER2, 2+ is reflects to FISH to test for it. So your HER2-negative patients currently do not receive anti-HER2-directed therapy in the metastatic setting. HER2-low, for this study, was defined by IHC score of 1+ or 2+, and FISH was negative. So technically they could not have received HER2-directed therapy in the metastatic setting unless this drug was available.

As I was mentioning about trastuzumab, this is an antibody drug conjugate. It has trastuzumab, which is basically Herceptin bound to chemotherapy, and the drug is made available inside the tumor. It is internalized by the cancer cell and then broken down in the cancer cells and the payload is delivered, or the chemotherapy is delivered, in heavily pretreated patients. You can have, with HER2-low positive disease, median progression free survival was 11.1 months, and overall response rates for 37 percent. DESTINY Breast-04 was the first randomized phase III study of trastuzumab deruxtican for HER2-low patients. Again, these patients were estrogen receptor-positive also. So, this study is applicable to patients who have endocrine refractory, hormone receptor-positive disease. The primary endpoint was progression-free survival. The secondary endpoint was PSF.

Just to clarify, the hormone receptor-positive was around 480 patients. A lot of these patients were hormone receptor-positive. This was compared to standard of care therapy, which could be capecitabine, gemcitabine, paclitaxel, Halaven, nab-paclitaxel, or Abraxane. And if you look at the progression-free survival, compared to whatever our current standard of care is, the median progression-free survival was 5.4 months. So 50 percent of patients would have disease response for greater than 5.4 months. Unfortunately, 50 percent will have disease response for less than 5.4 months. However, the same curves now change for trastuzumab deruxtican, for the median PFS of 10.1 months. This is in the hormone receptor-positive setting in all patients. If you add the patients who are hormone receptor-negative and HER2-low, PFS was 9.9 months and 5.1 months. So, kind of similar efficacy that you can see across the whole patient population. This definitely adds to a significant improvement in the PFS, and it adds to the drugs we can use in improving survival. It really changes how we are now approaching patients with recurrent disease or metastatic disease. We are not saving this drug only for HER2-amplified patients, we are actually seeking out patients who are HER2-low, where we can actually offer them these drugs.

The other antibody-drug conjugate that was able to show some benefit in the estrogen receptor-positive setting is sacituzumab. This drug is also called Trodelvy. It is already approved in the triple-negative setting, and it targets a receptor called Trop-2 and delivers chemotherapy into the cancer cells which are expressing Trop-2. So this study, the TROPiCS-02 study, basically looked at using this drug in the estrogen receptor-positive setting. Patients were randomized one-to-one to receive Trodelvy versus physician choice, capecitabine, eribulin, vinorelbine, or gemcitabine. These are all four drugs that are standard of care, and there was progression-free survival benefit of a few months, 34 percent reduction in the risk of disease progression. Overall survival benefit was not mature, but the follow up is anticipated. Both these antibody-drug conjugates now make available more targeted therapy for patients who have ER-positive disease along with all the ER-directed therapy that was available before already.

This is the last study we'll talk about. This is the MAINTAIN trial in the metastatic hormone receptor-positive setting, [after progression with a CDK inhibitor]. Use of CDK4/6 inhibitors, such as Ibrance, Kisqali, or Verzenio, along with anti-estrogen therapy, is now first-line FDA approved. The big question is what to do if someone has progressive disease. Can you continue the CDK4/6 inhibitor, or do you have to change that backbone? This study really tried to see, can we add and get more benefit by switching the CDK 4/6 inhibitor? What they did is they randomized 120 patients who had already progressed on endocrine therapy and any CDK4/6 inhibitor to receive ribociclib, or Kisqali, plus switch endocrine therapy, or placebo plus switch endocrine therapy. What they saw was there's definitely benefit of adding ribociclib when patients have not got it first line, in the second line setting, and you can get another option for patients in controlling the disease for a longer period of time. You got a hazard ratio of 0.57 in the progression-free survival.

MAINTAIN was the first randomized trial to show benefit of ribociclib and switch endocrine therapy after CDK4/6 inhibitor progression. One key part is palbociclib, or Ibrance, was the prior CDK4/6 inhibitor in 87 percent of patients. So one can say that patients who get Ibrance, they can get Kisqali in the second line, and that may be a viable choice. There was a 43 percent risk reduction of progression or death with ribociclib versus placebo, and higher PFS rate at 6 and 12 months.

With this, I would like to finish my part of the presentation and open the forum for any questions.

Janine E. Guglielmino, LBBC:

Thank you so much, Dr. Gupta. You really ran through a lot of recent research to help people understand some of these studies that were presented at ASCO just a couple months ago. We already have quite a few questions, so I'm going to go ahead and get us started. I'm going to kick us off with a question from someone who couldn't be with us tonight and emailed us in advance in the hopes we would address her question. Her question was, is 5 years still the recommended duration for hormonal therapy, or are researchers seeing better outcomes for longer periods, such as 7 years or 10 years?

Sameer Gupta, MD, MPH:

Right. So this goes down to the ASTRA study I presented at the beginning of the talk, and that is actually yet another trial that says that extended duration anti-estrogen therapy in the right patient population would be of benefit. In my practice, I tell patients already, if you have higher-risk disease and you are someone who's only in their thirties or forties, we really need to have a talk at the 5-year to see how you tolerate it, your anti-estrogen therapy first and foremost, and then talk about 10 years. But, tamoxifen 10 years is better than 5 years. There was ATLAS study and the AToM study, and then you have your MA.17, which also showed that extending the aromatases inhibitors would be of benefit. Some clinicians also use Breast Cancer Index to decide that, but as a rule, younger patients, patients have lymph node-positive disease, patients where you worry about what is the risk of late relapse, and patients who can handle their anti-estrogen therapy well, and they don't have problems like bone density. I won't say it's a blanket recommendation, but I think it is absolutely a discussion to have with your providers at the 5 years that, okay, am I a candidate for 10 years or not?

Janine E. Guglielmino, LBBC:

Thanks Dr. Gupta, and just a couple of follow ups to that. We have a couple of folks who are triple-positive, so they also have HER2-positive disease, and are curious whether the amounts of time that you would take hormonal therapies would be different because of the HER2 status.

Sameer Gupta, MD, MPH:

I think that's a very good question in general, Janine. What I would say is if anyone needed chemotherapy at the time of their diagnosis, they automatically, to me, are at a higher risk for later relapses also. So yes, that is a triple-positive patient because they got Herceptin. But again, the other part is, I don't know if they had a pathological response or not, if they got new adjuvant therapy, so there are various factors, but yes, a triple-positive patient should definitely talk to their provider about whether they are the right candidate or not.

Janine E. Guglielmino, LBBC:

Okay. Thank you. Then another question sort of in follow up to something that you mentioned, is someone asking whether if you had an early-stage, hormone receptor-positive breast cancer, would you expect if they had a recurrence that it would also be hormone receptor-positive, or could it change some?

Sameer Gupta, MD, MPH:

Yes, that's a very good question. I like these questions because these are things that I probably talked about already this morning with my patients. These are real-world scenarios that happen. So yes, if someone had a recurrence, not a new cancer, a new cancer can have any receptors, but if someone had a recurrence, you always want to biopsy it because you can have change in the estrogen receptor. You can have change in the, HER2 receptor, you know, the HER2 can change maybe at least 10, 15 percent of time. So there can be tumor heterogeneity. Also, what we've realized is even in the metastatic setting, if someone has ER-positive disease and it's been 6, 7 years they've been on treatment, they can actually lose their estrogen receptor. So, I tell patients, cancers are trying to evolve and trying to outsmart what we are trying to do to control them. They will come out with resistant pathways or resistant mechanisms. You always want to test if the biopsy is easy to do.

Janine E. Guglielmino, LBBC:

Thanks for answering that question. We have a number of questions about the Breast Cancer Index test and what you think about that test, whether it's useful, whether your risk of distant recurrence could change after 5 years.

Sameer Gupta, MD, MPH:

I think Breast Cancer Index is a useful addition. It is in the NCCN guidelines now, I think. My only question about the Breast Cancer Index is the long-term follow up. And when I talk about long-term follow up, I'm looking at 15 years and 20 years because hormone receptor-positive disease, even if I tell a patient, your risk of recurrence is 0.2, 5 percent, a quarter of percent a year after 10 years, and someone is only 40, it adds up. The late recurrences can happen. All of us know patients where they were diagnosed with breast cancer 20 years ago, and now they have a recurrence. That is one of the things I tend not to use it too much.

In all honesty, I tend to look at how their initial presentation was to make that decision. But a lot of clinicians, I have my partners who love the test. Every clinician is kind of trying to decide whether that's the right test that they would want to present to patients. I think the key part, the other part of Breast Cancer Index is it does not factor in the tolerability. So, to me, continuing anti-estrogen therapy is really useful, but it needs to not impact quality of life. It should be something that the patient can tolerate and not feel like that it's a burden to them every day. If they feel like this is a defense shield, and this is something that they want to continue and it is useful, it really can be a very good strategy.

Janine E. Guglielmino, LBBC:

Our next question is from someone who's asking if the percentage of estrogen or progesterone matters, if it's a lower percentage. Is it related to less chance of a recurrence, or to the type of treatment you would get?

Sameer Gupta, MD, MPH:

When we look at the estrogen receptor staining, it can vary from 1 percent to 100 percent. There can be tumor heterogeneity. Some areas may be slightly high and some areas may be slightly low. So this can create a little bit of discussion when it comes to deciding therapy, do you want chemotherapy, do you not want chemotherapy, as a general rule? Patients who have lower estrogen receptor or lower progesterone receptor tend to have higher molecular risk tests results. So, if someone is progesterone receptor-negative, an estrogen receptor is 60 percent compared to 100 percent, their Oncotype may be higher. You don't really use the receptors just by themselves to decide chemotherapy or not. In this day and age, you will use tests like Oncotype. You will use tests like MammaPrint to make that decision.

I recently had someone whose estrogen receptor was 15 percent and progesterone receptor was 15 percent and I was debating, should I treat her like a triple-negative? Because sometimes these will behave like triple-negative, or should I treat them like estrogen receptor-positive disease? So, we got a MammaPrint, which actually showed that the molecular subtype was actually luminal. It wasn't basal type. That told me that, okay, I can treat her like an ER-positive disease.

The other part of your question was if it is less estrogen receptor, you need less anti-estrogen therapy. The by-the-book answer is if your estrogen receptor is positive, it is always worthwhile trying anti-estrogen therapy and see if you can tolerate it, even if it is 10 percent, because there can be some heterogeneity when it comes to staining.

Sometimes I've had patients where one institution reported it as 40 percent, the other institution reported it as 5 percent. So, the receptor expression can be low, the staining can be different. As a general rule, if you have estrogen receptor-positive disease, even if it is 10 percent, you really want to have someone on anti-estrogen therapy. The percentage doesn't really decide the duration, the percentage tells us, okay, what kind of molecular test we would order? You know, it decides whether you should even get anti-estrogen therapy or not. I hope that was helpful in answering those questions.

Janine E. Guglielmino, LBBC:

Thank you. I think one of the themes I'm getting from a lot of your answers is there's so many conversations to be had with your doctor and to explore what your doctor thinks about the tests and how it works with your quality of life over time.

Sameer Gupta, MD, MPH:

I think one of the big things I would say is in 2022, we are very fortunate enough that we just do not have to look at the estrogen receptor and the progesterone receptor in the early-stage setting to make treatment decisions. So please make sure if you have a cancer that is more than five millimeters in size that you are getting that molecular test done. I think that is one thing to take away from my talk. If someone has early-stage disease, which is estrogen receptor-positive, getting an Oncotype, a MammaPrint, or any molecular testing is something that is standard of care. I think that is like very, very important. I have a patient who went to a really big institution down south and the Oncotype was not done for a one centimeter cancer because she was 70, but she's a really good 70, and we did the Oncotype and it turned out high risk. I think the molecular testing, or the next level of testing to get an insight of the DNA biology of the disease, more than just the estrogen progesterone receptor, is super important when deciding the chemotherapy discussion.

Janine E. Guglielmino, LBBC:

Thank you very much. I really appreciate that answer. I'm going to pivot and ask a few questions from our attendees who are living with metastatic breast cancer. And I want to start with this first one: I have metastatic breast cancer and I'm on Ibrance. What can I do once it stops working? I've been on Ibrance for 6 years and my doctor says there's nothing else available.

Sameer Gupta, MD, MPH:

Did they say which anti-estrogen therapy they’re on, off with Ibrance? Typically Ibrance, or palbociclib, is used in combination with an anti-estrogen therapy, either the injection called Faslodex or one of the aromatase inhibitors. I'm so glad that this person is doing well for 6 years on Ibrance. It's really good to know that she's doing so well on it, but, you know, she's basically scratched the tip of the iceberg. That's kind of the term I would use with all the treatments that are available to us. You know, we looked at the MAINTAIN study, now there's data for using Kisqali after palbociclib, but testing for things like PIK3C mutation testing, things like Afinitor, there are so many anti-estrogen therapies available and then you kind of start with chemotherapy.

You definitely can avoid the use of chemotherapy in this setting for many, many, many years. And I think one of the chemotherapies that is used quite a lot in the metastatic estrogen receptor-positive disease is Xeloda, or capecitabine, because it maintains quality of life and patients don't have to come to the office for an IV treatment. I've had patients almost 9 years on just Xeloda in the metastatic setting. So, you know, in HER2, that may be another great option. The only thing I'll tell this person is she has a lot of options. There's a lot, you know, she has a lot of life in front of her.

Janine E. Guglielmino, LBBC:

Thank you. The next question is from someone who is asking about what to do after you have progression on Xeloda and you have had a CDK4/6 inhibitor, can you take a different CDK4/6 inhibitor, do you need to move to a different chemotherapy treatment? What is typically recommended?

Sameer Gupta, MD, MPH:

Right. So, capecitabine or Xeloda is a very good drug. It's been around for a few decades now. It's used in colon cancer and breast cancer. I don't know the details of this person, but what I would say is, even based on what we talked about today with DESTINY Breast-04, I would look at her, HER2 status and see if she's HER2-low, or like 1+ or 2+, FISH negative, or even repeat the HER2 testing. Maybe the HER2 is amplified now. And HER2 may be a very good option for this particular person. So that's one part of it, just looking at the data from the DESTINY Breast-04 study.  I think the other drug that is also a good option, Trodelvy is a good option, but going back to the CDK 4/6 question, I think the MAINTAIN study does give us some insight for patients who have got palbociclib. I think ribociclib may be a viable option. The only comment I would say is the study was only 120 patients, so it's not a 600 patient study. The other thing to also check for is PIK3 mutation testing, Piqray is a very good drug. And if that mutation is not there then Afinitor is a very good drug. The last thing, IV chemotherapy – I'm not going into a deep dive with this question – but in the right patient setting, there is an oral combination of cyclophosphamide and methotrexate, the metronomic low dose, which actually is very well tolerated and can have effectiveness in a lot of patients.

Janine E. Guglielmino, LBBC:

Thanks for answering that. Another attendee is asking about Verzenio. They're curious about why the commercial says that you take it every day and what is the difference there between that and other CDK 4/6 inhibitors?

Sameer Gupta, MD, MPH:

Right, right. If you look at Ibrance, which is the other, more marketed thing, the toxicities of neutropenia do not let you take it every day. You have to give a break. I think that's the thing. The pharmacogenomics of both these drugs are very different. Verzenio is actually twice a day, palbociclib is once a day. It depends on the half-life. It depends on how they bind to the receptor. This is like biology 101. I would have to show them the phase zero trials to have this discussion. But the one thing I can tell them is, this is the way the drug is FDA approved. Verzenio twice a day, 50 milligrams, 100 milligrams, 150 milligrams, and in some patients, 200 milligrams. Palbociclib is 75, 100, 125 [milligrams] daily, three weeks on one week off with careful monitoring for toxicities.

Janine E. Guglielmino, LBBC:

So, there's quite a few questions in our feed wanting to get a little bit more understanding about Enhertu and HER2-low in hormone receptor-positive, metastatic breast cancer. Could you talk a little bit more about how HER2-low is defined?

Sameer Gupta, MD, MPH:

I would encourage people to actually go to the Enhertu website. They have a very good explanation of what HER2-low is, but just to summarize, HER2 is tested by immunochemistry. And the second method to test for HER2 status is by FISH or fluorescent in situ hybridization. When you look at IHC, it is reported out as zero, 1+, 2+, or 3+. So, 3+ is already amplified. The 2+ is then sent off for FISH and it can be reported as amplified or non-amplified. Now there are a lot of patients who are hormone receptor-positive who may also be HER2 1+, or they may be 2+ and FISH-negative.

HER2-low is basically HER2 1+ by immunochemistry or 2+ by immunochemistry and negative by FISH. I was explaining it to my nurse practitioner, basically Enhertu is an option for pretty much everyone now, unless they're HER2 zero. That's the simplest way to clarify that. That instead of being safe for the 15 to 20 percent of patients who are HER2-amplified, meaning 3+ by IHC or FISH-amplified when they're 2+, now it opens up to almost 60 percent of patients who are metastatic disease. This definitely is a big game changer.

Janine E. Guglielmino, LBBC:

Thank you for explaining that. Another question that's coming through, just to be clear, it was approved in the metastatic setting only, it's not currently approved in the early-stage setting?

Sameer Gupta, MD, MPH:

All of this discussion is in the metastatic setting. So that is absolutely correct. They have ongoing studies in the earlier stage setting, post chemotherapy, residual disease, but this is all pertinent to the metastatic setting. Trastuzumab by itself was studied in the HER2-low setting, NSAPB-47 was a study we participated in where we actually treated patients with Herceptin for a year when they were HER2-low, did not show benefit. Some of it is also drug-related and HER2 is not just a monoclonal antibody is an antibody-drug conjugate. I think the big change this year for ER-positive disease is that you have two new antibody-drug conjugates that are now potentially an option, which were not an option 3 months ago.

Janine E. Guglielmino, LBBC:

Thank you. And then one person is asking whether Enhertu can be taken with other ER-targeting agents like Ibrance or anastrozole.

Sameer Gupta, MD, MPH:

Right. Right. Patients in the study were endocrine refractory. There's no reason to take Enhertu if you have anti-estrogen therapy options, or if you have CDK4/6 inhibitor options. I would not jump to Enhertu unless you've already been treated with Verzenio and Faslodex and aromatase inhibiors. I would work on the pills first because Enhertu is IV and it's every 3 weeks. I think the study included patients who had already progressed on the endocrine therapy.

Janine E. Guglielmino, LBBC:

Thank you.

Sameer Gupta, MD, MPH:

It is a single agent drug. You do not combine it with Herceptin. You do not combine it with Perjeta. You do not combine it with chemotherapy. It is a single agent drug because it already has an antibody and it already has chemotherapy.

Janine E. Guglielmino, LBBC:

Thank you. Someone is asking, would you do a tumor biomarker test, a molecular test, if someone has metastatic breast cancer?

Sameer Gupta, MD, MPH:

That's a good question. You know, doing a next generation sequencing panel test like Foundation Medicine, tests like ctDNA (circulating tumor DNA) like Guardant, is standard of care in all diseases now where you have metastatic disease, just to find any kind of other abnormalities. The good thing about breast cancer is that we already have so many targeted agents including these two, one is already FDA approved and the other may get approved in the ER-positive setting. The big important part when it comes to looking for genomic abnormalities in the metastatic setting is really the PIK3 mutation as things stand right now, because it decides if someone is a candidate for Piqray or not, which is a PIK3 inhibitor. So that's the important utility.

The simple answer to that question is, yes, it should be done. If it hasn't been done, it absolutely should be done. It doesn't need to be done on the tumor. You one can do a liquid biopsy also, which is basically a blood test. And the results come back in 7 to 10 days, and can tell you whether you're a candidate for Piqray or not in the metastatic setting.

Janine E. Guglielmino, LBBC:

Great. Thank you. I’m going to move now to some questions about side effects and I am hoping to get to more of these other questions toward the end of our program. There's a number of questions from people about how to maintain their bone health while they're taking aromatase inhibitors. Could you speak to that?

Sameer Gupta, MD, MPH:

Things I speak to patients about is No. 1, you always want to know what your baseline bone density is. I cannot tell you how many times I'll see patients who are postmenopausal, they're 60, they've been diagnosed with breast cancer. And my first question to them is, have you ever had a bone density? And the answer is “what is a bone density?” and mind you, my practice is in Mainline Philadelphia. So this is not like I'm in the middle of nowhere. All postmenopausal women should have a baseline bone density because what we don't know is how much is the bone density loss to begin with? Family history does play in, what kind of physically active person you are does play in maintaining bone health during anti-estrogen therapy is very important. Getting a baseline of the bone density is important.

We in our practice do recommend taking some calcium, we monitor vitamin D levels. There are multiple weight bearing exercises, that's another important part about maintaining bone density. And then we get into pharmacological therapy. Sometimes we'll send our patients to rheumatologists. Sometimes I will manage those patients myself. There are drugs, things like Prolia, things like Reclast, so there are agents that are FDA approved in this setting to maintain bone density. I think monitoring the bone density on these drugs – the standard of care is to monitor it every 2 years. So you want to monitor it.

You know, I've had patients who have mild osteopenia and they really did not want to go any pharmacological treatment. And that's fine. We talked about weight bearing exercises, maintaining vitamin D, trying to get that level up to like 50 or 60, and then they were able to preserve their bone density. So it's very doable. It's very, very manageable. It just requires attention to detail. That is what I would say.

Janine E. Guglielmino, LBBC:

And there's a couple of people who are concerned about taking these medications and the risk for osteonecrosis of the jaw. Can you explain what that is and who might be at most risk for it?

Sameer Gupta, MD, MPH:

I think one of the things to educate patients is it's a side effect where you have non-healing ulcers or non-healing bone areas in the jaw. Typically it is seen more in patients who already have some dental issues. They have implants, or they need them. I can just talk to my experience when it comes to osteonecrosis. It is a condition that is very well recognized it is actually imperative in my practice that before we start any bone-modifying agents, patients are evaluated by their dentist. We want to make sure they do not need any major dental work done.

The other thing to also remember is, I hear a lot of concerns about Prolia and ONJ. One of the important things to remember is when you talk about the package insert, it actually talks about denosumab, which is Prolia and Xgeva. Xgeva is the same molecule. The dose is double Prolia and it's given every month. So, in a given year, the exposure is 12 times of Prolia. So yes, I have seen more, I have seen ONJ on Xgeva. I personally haven't had a single patient on Prolia having ONJ because the dose is so low relative to how we use Xgeva. Same thing with Reclast. We use it once a year, but in patients who have disease in the bone, the drug is used more frequently. If you talk to a medical oncologist, we see ONJ really in more in patients who are getting these drugs much more frequently than someone who's getting it for bone health prophylactically. That's kind of the clinical experience I can share with the audience.

Janine E. Guglielmino, LBBC:

The next question is about how hormone suppressors affect dryness and pain during sexual intercourse and sexual intimacy, what can be done about it, especially in this setting where people have had hormone receptor-positive breast cancer.

Sameer Gupta, MD, MPH:

Right. When I was in fellowship, and I'm dating myself now, like 13, 14 years ago, we had a lot of concern about using intravaginal estrogen, but I think that has really dissipated because the systemic absorption of intravaginal estrogen is really minimal. Meeting with a gynecologist who takes care of patients who have breast cancer is a first step, if that’s possible in your community – because that's one of the biggest challenges I've seen. I've had gynecologists who are very comfortable in managing, co-managing my patients with me and being very comfortable in looking at other alternatives, not only intervaginal estrogen, but sunflower oil or other things. This is one of the big quality-of-life issues that absolutely comes up.

We talk about it before we start. But I think having a good gynecologist, who can co-manage the patient with you, is very important. Mainline Health actually has a specialist who specializes in sexual disorders for patients who are undergoing cancer therapy. That is a very helpful resource to me, to help me help my patients. If you hear any providers saying that they will not give intravaginal estrogen, which can be very helpful to patients, that's little like dated, I would say at this point.

Janine E. Guglielmino, LBBC:

Definitely a point of controversy for a lot of people and an area of confusion.

Sameer Gupta, MD, MPH:

Exactly. That’s one thing I tell my patients is, know you want. Obviously, you don't want to use it excessively, but as little as possible to maintain a good quality-of-life. It is not like a big no-no, it goes down to, oh, I had my lymph nodes taken out and I can't have my blood pressure taken anymore. It falls in that category.

Janine E. Guglielmino, LBBC:

Thank you. Thanks for explaining that. Someone is asking a clarifying question. Can you explain what type of drugs aromatase inhibitors are? Some of my doctors call it chemotherapy, is it chemotherapy? Why is that term used in regard to these drugs?

Sameer Gupta, MD, MPH:

No, they are not technically chemotherapy. They are aromatase inhibitors. Aromatase is an enzyme that is involved in the production of estrogen in the postmenopausal setting from the adrenals and the fat cells of the body. These drugs basically inhibit that production of the minimum amount of estrogen that can still cause breast cancer growth. I think it depends on the physicians. I think the other area of confusion is some practices have participated in the Oncology Care Model, and Medicare actually classified them as chemotherapy for 5 years. So, I've had patients who have brought up the same question to me that “I got a letter from Medicare saying that I'm on chemotherapy, but you told me it's not chemotherapy.” I've heard that question a few times before. But no, they're not chemotherapy. Technically, I like to not call them hormonal therapies because they're not hormone replacement. I like to use the term anti-estrogen therapy because that's what they're doing.

Janine E. Guglielmino, LBBC:

Thank you. The next question is about ways to minimize side effects in general, and improve quality of life, while taking aromatase inhibitors. Is there any effort to decrease the dosages or the strength of these medications from the highest tolerable dose to the lowest effective dose?

Sameer Gupta, MD, MPH:

You know, this has come up multiple times. Unfortunately, the way these drugs were studied in the trials, when they were studied they were dosed in a standard fashion. So Anastrozole, for example, was dozed at, you know, one milligram per day, exemestane, or Aromasin, was 25 milligrams per day, Femara, or letrozole, was 2.5 milligrams a day, and tamoxifen is 20 milligrams a day. But there has been effort. I would say this is one of those unmet needs, but I have seen some improvements. I'll give you an example. When it comes to aromatase inhibitors, there was some recent data where they actually tested for estrogen level and suppression based on exemestane once a week, three times a week, and daily.

And what they saw was that the suppression was equal if you do it three times a week versus daily. I would not recommend this to the general audience today, to please start taking your AI three times a week. That's not what I'm trying to say. But if these drugs are causing quality-of-life issues, which then impacts compliance, at least we have some biological basis that doing it three times a week or four times a week is better than not doing it whatsoever. There is emphasis on trying to figure out if we can get with lesser dose. And I think we are seeing some effort coming out of that.

Janine E. Guglielmino, LBBC:

Great, thank you. Are there any supplements that people should avoid while they're taking aromatase inhibitors?

Sameer Gupta, MD, MPH:

This is a loaded question, so my disclaimer is I'm not a naturopath. When I have a supplement question, I work with very good naturopathic doctors, NDs, and they really are my complementary medicine support person to answer that question. The good part about aromatase inhibitors is there are not a lot of drug interactions, but the problem with supplements is there are so many of them. There are 15,000 – there are more supplements than FDA approved drugs. And every supplement says the efficacy has not been approved by or evaluated by the FDA. So, I really can't speak to what a supplement contains to give that blanket recommendation. I would get input from a naturopathic physician, if you can get access to one.

Janine E. Guglielmino, LBBC:

And, Dr. Gupta, would you want your patient to tell you about supplements that they were taking?

Sameer Gupta, MD, MPH:

Yes, yes, yes, yes. When people are like, “oh, I want to take a multivitamin,” that's fine. But when they get into supplements that I have not seen, I have not heard about, I always get the input from the naturopathic physician.

Janine E. Guglielmino, LBBC:

Great. Thank you. One more question on side effects. One of our attendees hasn't started their anti-estrogen therapy yet because they're at the beginning of early-stage treatment and very worried about feeling like they’re going through menopause again, because she's already been through natural menopause. Is that something she could experience? Are there ways to avoid the common side effects that one gets during menopause?

Sameer Gupta, MD, MPH:

I think that's a very important concern. If this was someone I was seeing in the office, I would go down to what problems they had when they went through menopause. Sometimes I have started my patients on three times a week for a month, to assess their tolerability and make sure that they tolerate their treatment well, before we then increase it to a daily dosing. I think some of it is the art of medicine and the science of medicine. The science says start it at full dose, but sometimes I will start slow and then slowly build up based on their tolerability.

Janine E. Guglielmino, LBBC:

I'm going to move to a mix of different questions from our attendees with early-stage and metastatic breast cancer. One of the questions that I'm seeing repeatedly here is for you to talk a little bit about the Ki-67 test, how it's used in this setting. Is it critical? What does it mean?

Sameer Gupta, MD, MPH:

Ki-67 is basically a proliferation marker. If you look at 100 cells, it looks at how many cells are actively dividing. It can be a very useful test in figuring out the underlying biology of the disease. It is one of the [markers] looked at when the Oncotype test is done. It is one of those 16 cancer-related markers that are tested and built into the algorithm of Oncotype. As a general rule, the higher the Ki-67, the more faster growing cancer it would be. I saw someone who had triple-negative disease. Their Ki-67 is 90 percent. Higher Oncotypes typically will have a higher Ki-67. So, I think getting that information is important. In Mainline Health, in our health system, around two years ago, we incorporated Ki-67 along with our ER, PR, and HER2.

So, if you have all of those four markers, and if you are in a setting where you don't have easy access to Oncotype or genomic testing, like some of the countries outside the US, they actually use IHC 4-panel in making that decision. So, a Ki-67, when you're getting to more than 20 percent, you get into a range where typically your Oncotypes and your MammaPrints would be high. But what I would say is I, we use Ki-67 to tell the patients, okay, your Oncotypes are probably going to be low or probably going to be high, but we still get our Oncotypes and we still get our MammaPrints because we have access to that. Once in a blue moon, I will have patients where the Oncotype or the MammaPrints do not work because of quality control issues, and I have been able to decide chemotherapy decisions based on Ki-67. So, think about it as an adjunct of getting information about your disease. If you can get a genomic test, that's even better than a Ki-67, that would probably be better, but getting a Ki-67 does give you input about the disease biology.

Janine E. Guglielmino, LBBC:

And, Dr. Gupta, can you explain why is it better to get the genomic test?

Sameer Gupta, MD, MPH:

Because the genomic test is not just looking at one factor. MammaPrint is looking at 70 genes. Oncotype is looking at 16 genes and five control genes. You are getting a much broader input with respect to different genes, different survival genes, different proliferation genes that the cancer may be using to grow. You get a better insight than just getting insight from one, just from Ki-67. It's better than nothing, but getting your molecular test. One of the important themes of today's talk in the early-stage setting is if your tumor is more than 5 millimeters, you need a molecular test. That is super important.

Janine E. Guglielmino, LBBC:

Thank you. There is someone asking, how do you compare Oncotype and MammaPrint, and should you be choosing among these tests? How do you know which is the right test to get?

Sameer Gupta, MD, MPH:

I think that's a really good question. Some of it, I would tell you, is practice patterns of what the person has used forever. Oncotype has been around for a longer period of time. For our Canadian audience, it has been around more. It has been around a lot more in the US, and has been used more in the US. MammaPrint used to be done only on fresh frozen tissues, and now it can be done in paraffin embedded blocks. I use both the tests. I tend to use more Oncotype just because our surgeons are much more comfortable ordering it. This is something that we've used for 10 years. MammaPrint is a really good test in figuring out the disease biology, especially as in the example I gave earlier in this talk about whether someone is basal type or luminal type. Sometimes you can find different phenotypes in MammaPrint.

I don't think these tests have been compared head-to-head, It could be a two hour discussion about who should get what tests. I don't think I can get into too many details because there are a lot of nuances, you know, lymph node-positive disease, premenopausal, postmenopausal. There are multiple variables and multiple studies that are out there. The discussion with your provider should be, am I getting a test, and please explain the results to me. That's all, those are really the two questions to ask.

Janine E. Guglielmino, LBBC:

Someone is asking whether liquid biopsies are useful in locally advanced, non-metastatic cancers.

Sameer Gupta, MD, MPH:

So, typically not. In the breast cancer setting, and even in other diseases, when you have locally advanced disease, you basically have disease that is in the lymph node. I hope they're talking about resectable locally advanced disease, not unresectable, just to clarify?

Janine E. Guglielmino, LBBC:

They didn't say, but I would think just from the way the question was asked that it could be removed with surgery.

Sameer Gupta, MD, MPH:

If it can be removed with surgery, there's no use, no data for using liquid biopsy. You know, the yield is much less and it doesn't really change your management. The important thing about breast cancer is there are a lot of markers we can get on tissue. We don't really need to jump to liquid biopsy in this setting.

Janine E. Guglielmino, LBBC:

Thank you. So our next question is about the CDK inhibitors. This is about Ibrance and the low white blood cell count and the different dosages available. Is a lower dose less effective? Is the higher dose better? Do they all work the same? Why are there three?

Sameer Gupta, MD, MPH:

So, there have been retrospective analyses which have shown that those reductions do not change survival. The standard dose is 125 [milligrams], but based on the prior history – if you got chemotherapy before, if you did not get chemotherapy before, how sensitive your white cells are – I think it's a drug that you can use at 75 also. I would not get concerned that if you needed a dose reduction, you lose efficacy. That used to be my concern until I saw the data a few years ago that when you look at patients with dose reduction, the survival did not matter with respect to changing.

Janine E. Guglielmino, LBBC:

Thank you. We have a question from someone who's watching us on Facebook. What is available for people who have an ESR1 mutation and who have had progression after a CDK inhibitor?

Sameer Gupta, MD, MPH:

Okay. That’s a good question. We talk about Faslodex in patients who have ESR1 mutations. There are a lot of companies that are trying to target the ESR1 mutation with orals, selective estrogen receptor degraders. That is an area of active investigation. But my second question to them is, do they have a PIK3 mutation? Because if they don't, then Afinitor, or everolimus, is a good option. If they do, then Piqray would be a good option. There are options definitely out there. Faslodex would be one, a clinical trial, if they can get access to it, for an agent that is targeting the ESR1 mutation would be another good option.

Janine E. Guglielmino, LBBC:

I’m going to ask another Facebook question. I think it's an important one. How do I find out what my estrogen receptor and progesterone receptor percentage positivity are? Where do I look?

Sameer Gupta, MD, MPH:

Right. It's in the pathology report. It should be in the pathology report. If you have access to your health portal, or if you don't, ask your healthcare provider about your pathology report. It is always in the official pathology report. In our health system, our patients have instant access to everything we can look at. If a scan is done, as soon as I see it, my patients see it. It is instant access and the same thing about pathology labs. It is there in the pathology report. That is exactly where I go to look at it also.

If someone has a biopsy, the report may be out saying, if this is a cancer diagnosis, it will say cancer. And then the receptors follow a day later. It depends on the institution. There are institutions where they have a 24-hour policy for pathology reports and a 48-hour policy for receptor. That's kind of the standard that our institution follows. There are some other private labs which could lag behind by three or four days.

Janine E. Guglielmino, LBBC:

And if someone is really not sure how to figure this out, who should they ask? How can they get that information?

Sameer Gupta, MD, MPH:

Talking to your physician is one, talking to your nurse navigator, they are very helpful. They have access to the same information your physicians have access to. If you're going for chemotherapy, your chemotherapy nurse, all your providers, everyone has access to those records. These are not esoteric records. When it comes to someone who's taking care of patients of cancer, this is one of those things you have to cross your Ts and you have to dot your Is. Putting your receptor status is super important to me. I cannot make any decisions till I get the results.

Janine E. Guglielmino, LBBC:

Great. Thank you. My next question is from an attendee who is young and premenopausal and wants to know, if they decide to pause their anti-estrogen treatments for a period of time to try to conceive, is it dangerous? Is it dangerous to do IVF? Does it increase risk for recurrence?

Sameer Gupta, MD, MPH:

It depends. There have been studies that have looked at this question. I think a few years ago at the American Society of Clinical Oncology meeting, some data was presented. You want to at least do anti-estrogen therapy for at least the bare minimum 2 years, and then you can take a break. If this person is premenopausal, I think they are on tamoxifen. I'm assuming they're on tamoxifen if they're thinking about getting pregnant. I've told patients, I've counseled my patients, try to do at least the bare minimum 2 years of anti-estrogen therapy, and then you take a break and then get back on the anti-estrogen therapy. I think one of the big things is there are so many nuances when it comes to this question that checking you over with your provider is going to be super important. There are so many different protocols that the IVF people use that it's very difficult to give a blanket recommendation when it comes to what they are using. Are they using an aromatase inhibitor to induce? I think it also actually goes down to, if possible, having IVF before getting chemotherapy. Fertility preservation is very important prior to getting treatment. That is something to think about.

Janine E. Guglielmino, LBBC:

Thank you. An attendee is asking, she is also premenopausal and if you start tamoxifen and then go through menopause after a year or two of taking that medication, should you switch to an aromatase inhibitor or continue with tamoxifen?

Sameer Gupta, MD, MPH:

Again, a very good question. There have been studies that have shown, [like] the BIG 1-98 study did show a benefit of an aromatase inhibitor. So, there are two studies that have shown benefit for aromatase inhibitors over tamoxifen in patients who can tolerate it. What I tell my patients is, absolutely, you've gone through menopause, you did OK on tamoxifen, this is your good backup drug. Let's try the aromatase inhibitors. You don't like one, you switch to another one, you don't like the second one, you try the third one. And if you don't tolerate them, then you go back to tamoxifen because you knew how you felt on tamoxifen. It is very important to try all four drugs eventually.

Janine E. Guglielmino, LBBC:

Thank you. We have a number of folks here who have lobular, ER-positive, PR-positive disease. Is there any research that shows differences in outcomes with lobular, or differences in treatment? What do you see on the horizon for people coping with lobular breast cancer?

Sameer Gupta, MD, MPH:

The key differentiating part of lobular cells is they tend not to form cohesive masses. They tend to be a little bit more infiltrated. They don't stick to each other. Unfortunately, this does not change our treatment decisions because the treatment decisions are really guided by the receptors more than anything else. There are a lot of people from an academic perspective who are trying to exploit the characteristics of these cells to come up with new drugs, but nothing that is FDA approved right now. So, as things stand right now, your hormone receptor status really decides the treatment paradigm in the early-stage setting.

Janine E. Guglielmino, LBBC:

Thank you for speaking to that. A couple of people are asking about what kind of follow-up they should do after their initial active treatment, especially with the late recurrence risk. How does it change over time, in terms of monitoring?

Sameer Gupta, MD, MPH:

That's a good question. What I tell my patients is that I will see them for the rest of their life. So I do, I see my patients at least once a year. I think education is important. I think educating primary care doctors is important. A lot of centers have survivorship clinics that people, women are transitioned to. I think being cognizant about things like new back pain, anything that is persistent, progressive, is problematic. So those are the acronyms I use in clinic when I'm teaching fellows: the three P’s. If you have a problem, which is persistent, and it is progressive, there is something that needs to be done.

In this kind of breast cancer setting, there's no rule for routine scans. Multiple studies have shown that that does not change survival. So, to a great extent is following up with your provider at least once a year, or twice a year, even if you're 5 years out. Sometimes some providers will do blood work to monitor, a liver function test or bone enzyme test. Some people like to check tumor markers, some people don't like to check tumor markers. That's another Pandora's box we can get into. I think being cognizant of what your normal body is, is very important, and regular medical follow-up is very important. The other thing I would like to say is, some of the drugs, especially aromatase inhibitors, can have some cardiovascular toxicities long-term when we talk about doing them 10 years. We talked about bone health. We did not talk about cholesterol monitoring and cardiovascular risk screening. So that's one thing, we have a cardio-oncology risk program. Once I've passed 5 years, family history, those things build, I will try to get my patient in to see a cardiologist at some point, just from a calcium screening perspective or maintaining the health from an other-body system perspective.

Janine E. Guglielmino, LBBC:

Our next question is from someone who's saying bone mets are the most common place for ER-positive disease to progress. Is it possible for progression to skip to other organs such as the liver, lungs, or brain? Is it specific to the patient, or is it specific to hormone receptor-positive status?

Sameer Gupta, MD, MPH:

So, I think this is where statistics come into play. Statistically speaking, bone mets are one of the most common presentation for recurrence in the ER- positive disease. And yes, they can be the only site of recurrence. However, it also depends on, what is the time lag of diagnosis? If someone had back pain and they were going to a chiropractor, but no one did a scan, and then by this time they also had some disease in the liver or the lung – that's the impossible part to predict. We try not to make an assumption. If someone has recurrence being seen on an imaging study, I will always get a biopsy to check those receptors. I've had patients where they've had recurrence only in their distant lymph nodes without going to the bone, only in the lung without going to the bone. This is where statistically speaking, yes, bones should be the most common, but a person is not a statistic. A person is a person.

Janine E. Guglielmino, LBBC:

Thank you. For our last question someone is asking, when you look over the next 10 to 20 years, what are the approaches that you think are most exciting in hormone receptor-positive breast cancer?

Sameer Gupta, MD, MPH:

So, I briefly mentioned it in my talk, the use of abemaciclib, or Verzenio, in the earlier-stage setting. I think that the monarchE trial has really – that is the first FDA approved agent in the last 20 years in the earlier-stage setting. You can see as time is going on, you're seeing pretty significant changes in the survival curves. I think ER-positive disease is not a single entity. It is a very heterogeneous disease. You have patients who are very low risk and you have patients who are high risk. Identifying it, customizing the anti-estrogen therapy. Is it going to be tamoxifen? Is it going to be aromatase inhibitors? Does someone need ovarian suppression? Does someone not need ovarian suppression? What is the treatment duration, is it 5 years? Is it 10 years? How do we maintain compliance by managing side effects?

I think if you look at the horizon, I see better outcomes, less relapses, because our drugs are getting better. We have better understanding. We try to avoid overtreating patients and we try to judiciously treat the higher risk patients. I think overall, our survival is going to be better. Our disease control is going to be better. Our relapse rates are going to be lower, and understanding how to manage side effects and improving quality of life, how to integrate complimentary therapies. Those are all important things that I can see, even in the last 10 years since I've been doing this, there's a big change in how we are seeing our patients do well and live better.