Listen to Manali Bhave, MD, and Erin F. Cobain, MD, discuss their management of patients with HR-positive/HER2-negative metastatic breast cancer including the current treatment algorithm, implementing genomic testing for assessing molecular resistance and guiding treatment decisions, and answering healthcare professional questions on how to personalize therapy for these patients.
In this podcast episode, breast cancer experts Manali Bhave, MD, and Erin F. Cobain, MD, discuss their management of patients with HR-positive/HER2-negative metastatic breast cancer including the current treatment algorithm, implementing genomic testing for assessing molecular resistance and guiding treatment decisions, and answering healthcare professional questions on how to personalize therapy for these patients. Supported by an educational grant from Lilly.
Faculty:
Manali Bhave, MD
Medical Director, Phase I Clinical Trials Unit
Assistant Professor
Department of Hematology and Oncology
Winship Cancer Institute
Emory University
Atlanta, Georgia
Erin F. Cobain, MD
Associate Professor of Internal Medicine
Division of Hematology/Oncology
Breast Oncology Program
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan
Link to obtain CME/CE credit:
https://bit.ly/4nUJO1O
Link to Oncology Breast Cancers with additional educational activities:
https://bit.ly/4nNGlBY
Dr. Bhave: Thank you for joining us today. Today we are going to actually talk through the management of patients with advanced HR+/HER2‑ breast cancer. I would like to briefly go through and have highlighted some key topics for the treatment of these patients, including a treatment algorithm, as well as how we now incorporate genomic sequencing to better identify molecular resistance in these patients and to be able to target those with the use of now oral SERDs, as well as PIK3/AKT inhibitors. Then I will end with actually the SERENA‑6 data, which is a potentially paradigm shifting way of managing patients that have HR+/HER2‑ metastatic breast cancer in the use of genomic sequencing to identify molecular resistance prior to radiographic progression and switch therapy based off of that ctDNA.
Patients that have HR+/HER2‑ metastatic breast cancer
Let us start with a brief overview of patients that have HR+/HER2‑ metastatic breast cancer on our treatment algorithm. As we are all well aware, CDK4/6 inhibitors alongside aromatase inhibitors are a preferred first‑line treatment for patients that have this disease. That has been well established across a number of pivotal studies that have evaluated three CDK4/6 inhibitors that we have available in this setting. Those are palbociclib in the PALOMA trials, ribociclib in the MONALEESA studies, and then abemaciclib in the monarchE studies. Across the board in all of these studies, we saw a statistically significant improvement in progression free survival with the combination of CDK4/6 inhibitor and aromatase inhibitors.
However, when we look at overall survival, we only saw statistically significant improvement in overall survival with the use of ribociclib alongside endocrine therapy. This was across all of the MONALEESA studies. While we saw a numerical improvement in overall survival with abemaciclib in combination with endocrine therapy, that overall survival did not meet statistical significance. Then unfortunately, with the palbociclib studies, we saw that there was no numerical or statistically significant improvement in overall survival, although on subsequent real world studies, we have seen numerical improvements in both PFS and overall survival with palbociclib. That is important to note.
I do think that all three have a place in the treatment of patients with HR+/HER2‑ metastatic breast cancer based off of the patient's functional status, comorbidities, tolerance, et cetera, and we will be talking through what the preferred first line CDK4/6 inhibitor is a little bit later on when we get to some frequently asked questions.
The other thing to note in the first line setting is that we now have the approval of a triplet therapy for patients that are very high risk. Those are the patients that have endocrine resistance, defined as patients that developed a recurrence on adjuvant endocrine therapy or within 12 months of completion of endocrine therapy. In those patients, we are recommending the use of next generation sequencing to identify potentially a PIK3 mutation that would make that patient eligible for the triplet therapy with inavolisib, which is our PIK3 inhibitor, palbociclib our CDK4/6 inhibitor, alongside fulvestrant, which is the preferred endocrine agent in patients who have progressed on AI. That approval is based off of the INAVO120 study that showed an improvement in PFS and now OS with the use of a triplet agent first line in patients that have high risk PIK3 mutated endocrine resistant disease.
I think it is also important to note that while we have the three CDK4/6 inhibitors approved, they all have differences in toxicities. That really plays into, at least in part, which CDK4/6 inhibitor we utilize.
We know that with abemaciclib, there is a higher risk of diarrhea, so we are commonly educating our patients on what to look out for in the antidiarrheals to utilize to best manage that side effect.
With ribociclib, we see the potential for LFT abnormalities, and we are recommending a routine check of the liver enzymes particularly in the first two cycles of treatment and then monthly for the next couple cycles to ensure that we are not seeing LFT toxicities with ribociclib.
We see myelosuppression across the CDK4/6 inhibitors, but mostly with abemaciclib and palbociclib. Particularly with palbociclib, we see neutropenia. That could be a dose‑limiting toxicity for palbociclib.
We also see some rarer side effects as well. We see that there is an increased risk of VTE with abemaciclib, and then a small percentage of patients that develop an ILD or pneumonitis. Mostly we have seen it with abemaciclib, but I have also seen it with palbociclib and ribociclib but with low incidence.
At time of progression on first line CDK4/6 inhibitor and aromatase inhibitors, we are recommending the use of next generation sequencing to decide on whether a patient is eligible to receive a biomarker driven treatment strategy versus non‑biomarker. If the patient has a biomarker that has been detected, an ESR1 mutation, a PIK3 mutation, or an alteration in the AKT or PTEN pathway, then that patient would be eligible for a targeted therapy. With ESR1, we have the approval of oral SERD therapy as a monotherapy that showed improvement in progression free survival.
In patients that have a PIK3/AKT/PTEN alteration, we have the approval of capivasertib plus fulvestrant, per the CAPItello study, as well as for patients with PIK3 mutations, they also have the option of alpelisib, which is a PIK3 inhibitor in combination with fulvestrant, although, as we are all aware, alpelisib does tend to have toxicities that make it challenging to prescribe that medication.
For patients that have no actionable mutations, we are considering the use of a second CDK4/6 inhibitor per the postMONARCH and MAINTAIN clinical trials that looked at, respectively, the use of abemaciclib and ribociclib as a second CDK4/6 with a switch in endocrine partner, or considering the use of an mTOR inhibitor, everolimus, regardless of biomarker status, in combination with exemestane or single agent endocrine therapy like tamoxifen.
Then, of course, for patients who develop an endocrine resistant disease or have aggressive pace of disease, we are considering the use of ADCs in those patients versus chemotherapy.
SERENA-6 study
Lastly, I will get into the SERENA‑6 study. This was a study in the first line setting for patients with HR+/HER2‑ breast cancer who had received at least six months of therapy with first line CDK4/6 inhibitor and aromatase inhibitor. Those patients underwent serial ctDNA testing. At the time of a detection of an ESR1 mutation, they were then randomized to receive a switch in therapy to camizestrant plus a continuation of their CDK4/6 inhibitor versus continuation of their current therapy, which is an aromatase inhibitor and CDK4/6 inhibitor.
What we saw is this was a positive study that showed an improvement in progression free survival in patients who received a switch in therapy at time of molecular resistance without radiographic progression to camizestrant, which is an oral SERD.
I think from this study, it really was a thought‑provoking study about how we can shift and better utilize molecular testing to intensify treatments where needed and improve patient outcomes. Although we run the risk of potentially utilizing those therapies early on and not having them available later on, we run the risk of overtesting patients, for patients who develop test anxiety related to that, in addition to financial costs. I still think that we are waiting on some additional data on long‑term benefit with a switch in camizestrant at time of molecular resistance before we utilize that strategy.
Frequently asked questions
With that, I will actually get into some frequently asked questions. Let us first start with first line treatment in the metastatic setting. Dr. Cobain, when you think about first line CDK4/6 inhibitors, what are some of the clinical and/or treatment related outcomes that you are looking at that guide that decision for which one you use?
Dr. Cobain: Great question. I think that we all have to acknowledge there hasn't been and probably never will be a head‑to‑head comparison of all three of these CDK4/6 inhibitors in the front line metastatic setting. I think the decision that I make with my patients really takes into account several factors.
One of them is the fact that definitively, ribociclib has demonstrated an overall survival benefit. Albeit I think we have to acknowledge that the overall survival data with the other CDK4/6 inhibitors may have had other contributing factors, for instance lack of data in follow up of these patients that may have contributed to the decreased ability to detect an overall survival benefit that may have actually been there, but just very difficult to prove from a statistical standpoint. However, we have to acknowledge there is a demonstrated overall survival benefit of ribociclib.
I also take into account the side effect profile of these drugs. I will say that I use all three of them in my practice. For instance, when I see patients that are very, very interested, they clearly are able to articulate that one of their major goals is quality of life, minimizing side effects from therapy. In general, palbociclib is an incredibly well‑tolerated CDK4/6 inhibitor, so sometimes that might be a great choice for a patient who is very, very eager to minimize the side effects from CDK4/6 inhibitor therapy.
There might be other patients who really are concerned about immune suppression and the concern that ribociclib and palbociclib may have substantial cytopenias, and abemaciclib is less likely to have cytopenias. Maybe we tried one of those CDK4/6 inhibitors, and the cytopenias were really substantial. That may be a very, very appropriate reason to consider use of abemaciclib.
I think there are all sorts of things I take into consideration, but I think my bottom line is it is appropriate to utilize all three CDK4/6 inhibitors. It is really about finding what is most comfortable and most appropriate medically for the patient that is in front you.
Dr. Bhave: Yeah, I completely agree with you. I think you brought up some really great points. I think when ribociclib first came out and we were asked to order ECGs, that, oddly enough, ended up being a bigger barrier than I thought for patients, because it was challenging to get same day EKGs, it required them to go to a different building of our hospital. Some patients were leaving and then not getting those EKGs done. Now we actually have the ability to do home EKGs through advanced technology. I think that has helped some of my patients when I discuss the necessity for serial EKGs on ribociclib for the first month.
I agree with you that there are other comorbidities and/or when you are talking about the toxicities, there are certain toxicities that are really can be a turnoff for patients when we are going through each of these. I think for patients that are working, diarrhea can be extremely challenging. For patients who are out of the house for most of the day, they have to plan their schedule around the timing in which they take the abemaciclib. For patients that are on QTc prolonging agents, as you mentioned, ribociclib is really challenging. The neutropenia patients who travel frequently or for patients who are going to be in settings where there are a lot of people, the immune suppression that we see with ribociclib and palbociclib is a little bit daunting.
I completely agree with you that I think it involves a discussion on the three available CDK4/6 inhibitors, why we might prefer one or the other based off of the clinical trial data that we have available, but also having the patient involved in that discussion on what is going to help not only improve their clinical outcomes, but also maintain their quality of life.
How about with the three that are approved, if a patient is not tolerating one, are you likely to switch to another or do you prefer coming off that CDK4/6 inhibitor and moving on to next line of treatment?
Dr. Cobain: I think if a patient is not tolerating a therapy but hasn't had any clinical or radiographic evidence of progressive disease, I am inclined to switch to an alternative CDK4/6 inhibitor therapy before I would ever consider moving along to a different line of therapy. The other thing I think that is actually important to note is that we have also been able to manage a lot of these toxicities with dose reduction as well. Sometimes if patients are experiencing significant side effects, for example with abemaciclib and the diarrhea, that being the most common issue, I think, that patients face, sometimes dose reduction actually puts this into a range that is highly manageable.
In the event that we have done our best to dose reduce the medication, and this is a persistent problem, provided that they do not have evidence of clinical or radiographic progressive disease, I am very inclined to try an alternative CDK4/6 inhibitor, and I think we are fortunate that the three agents we have available for use really all do have different profiles, different side effect profiles, and so we often are able to see patients tolerate one drug even if another drug did not go well.
Genomic sequencing
Dr. Bhave: Absolutely. I wanted to shift gears a little bit to genomic sequencing, because we are seeing now use of genomic sequencing more and more in this patient population and more biomarker driven strategies as well. Where in the timeline are you typically getting genomic sequencing done? And if you do not mind telling us how you utilize tissue versus liquid biopsies.
Dr. Cobain: Yes, absolutely. You mentioned earlier some of the data about frontline use of a PI3K inhibitor, inavolisib, for patients that really have developed a metastatic recurrence while either on adjuvant endocrine therapy or very shortly after stopping adjuvant endocrine therapy. For those patients that have a recurrence, especially on adjuvant endocrine therapy, I really think it is essential to get the molecular profiling at time of diagnosis of metastatic disease, because the results of that test could absolutely influence your front line treatment option or management decisions.
I will say that even for patients where I am not considering upfront use of a PI3K inhibitor, I think that given that we often get a tissue diagnosis to establish a diagnosis of metastatic breast cancer, I think it is very appropriate, actually, on that tissue to go ahead and send off the next generation sequencing. One of the reasons is that particularly mutations in the PI3K pathway, often tend to be ones that develop very early on in tumorigenesis. These are alterations that are often present or even detectable when a patient just has a primary tumor. It's very nice to know, well in advance, particularly if a patient does not have an optimal response to initial treatment, what the next option in the algorithm might be. So I am often sending NGS from a tissue biopsy that establishes my diagnosis of metastatic disease.
Then I would say that I am usually repeating NGS testing at the time of progression on initial treatment with aromatase inhibitor and a CDK4/6 inhibitor, most often utilizing a liquid biopsy approach or circulating tumor DNA. One of the reasons I think it is important to repeat NGS at time of progression even if you got NGS testing at time of initial diagnosis is because resistance mutations certainly can emerge after treatment with AI CDK4/6 inhibitor therapy. I think the most well described example of this, as was highlighted in the SERENA‑6 study, is the emergence of ESR1 mutations.
I think when you have NGS results from an initial metastatic biopsy, it is often not clear if at some point that patient would be a candidate for an oral selective estrogen receptor down regulator, but after progression on AI CDK4/6, that is really when you can tell whether or not an ESR1 mutation is present or has emerged, and you can determine a patient's candidacy for those types of treatments.
I will also say that I have seen additional PI3K or even AKT mutations emerge as resistance mechanisms to treatment, and then if a liquid biopsy comes back “quantity not sufficient”, that is generally when after progression on initial therapy, I might have a conversation with my patient about whether or not we wish to obtain another biopsy to have a sense if I do not feel like the ctDNA test has given me adequate information.
Dr. Bhave: Absolutely. I completely agree with that algorithm. As you mentioned in those endocrine resistant patients, that is where we have the approval of the triplet therapy based off of NGS testing, so I would strongly recommend doing it at that as well.
I think the benefit of having tissue frontline, even if you are not going to utilize it in the frontline setting, is to also prepare your patients for what might come ahead in terms of second or third line treatment options, especially if that patient has poorly controlled diabetes and they might be a candidate for a PIK3 inhibitor or AKT inhibitor in the future, to allow time on that first line therapy with a CDK4/6 inhibitor and AI to better manage their diabetes and get them into potentially a position where they could then go on to the PIK3 and AKT inhibitor at time of progression.
Co‑mutations of ESR1 and PIK3
Lastly, I just want to end with a limited population of patients that are in this scenario, but where we see co‑mutations with ESR1 and PIK3. There have actually been several studies that have looked at the occurrence of these commutations. By the time we reach third line therapy, we see a commutation occurrence rate of about 17% to 20%, which is actually a pretty significant number of patients that have these co‑alterations. In those patients, how are you sequencing and what are you thinking about when considering an oral SERD versus a PIK3 or AKT inhibitor?
Dr. Cobain: Great question. I actually just encountered this scenario twice the last week in my own clinic, where both of the patients I was seeing had co‑occurrence of ESR1 activating mutation and a PI3K activating mutation. I think one of the things that I do look at when we get next generation sequencing data back is actually the variant allele frequency of these alterations. For example, if the ESR1 mutation is detectable, but maybe only present at a very low variant allele frequency versus the PI3K alteration, which might be present in say like a 50% variant allele frequency, I am maybe a little bit more confident that the systemic therapy that will address the mutation that is present in the highest frequency is most likely to be effective. That does not mean I will not use the alternative therapy, but I think that is one thing I take into consideration as I am making the decision between the two.
I think the other is really a decision about side effects of these therapies. If patient in front of me is a candidate for both of these agents, and maybe the molecular report is not giving me a clear indication that one or the other is the best strategy, I talk to patients a lot about the side effects of these drugs and what they might prefer, and also understanding just how symptomatic they are from their disease.
For instance, patients that have bone-only metastatic disease that are potentially relatively asymptomatic and we have subtle radiographic progression, they might be most interested in a treatment regimen next that is going to minimize their side effects, which I think when we think about elacestrant for patients with an ESR1 activating mutation, that generally is a very well tolerated regimen in comparison to use of the PIK3 or AKT inhibitors, which often come along with hyperglycemia, rash, diarrhea for some of our patients. If we are fairly confident that even if the oral SERD was not as effective as we might hope, and we would have an opportunity then likely to switch to the alternative pathway of utilizing a targeted inhibitor of PI3K or AKT, some of our patients might be eager to use the therapy first that is least likely to cause substantial side effects.
I think just those are some of the things I take into consideration. However, I think that I am oftentimes really trying to understand which alteration is present, like I said, in the greatest frequency, because I think that, to me, is the probable pathway that would be most likely to be uniformly effective for the tumor as a whole.
Dr. Bhave: Yeah, I completely agree with that. I think sometimes in this patient population and oftentimes I find that their disease rapidly progresses after 2 or 3 lines of endocrine therapy, so we have to be selective about what is most likely to work in that second line setting. It is important to look at the molecular data as well as look at the patient in front of you too and what that patient is going to be able to tolerate.
Conclusion
With that, that wraps up our session on advanced HR+/HER2‑ breast cancer. A lot of wonderful drugs that are available right now CDK4/6 inhibitors and aromatase inhibitors in the frontline setting. Potentially the use of a triplet therapy in patients with endocrine resistant disease who developed a recurrence in the first line setting and have a PIK3 mutation, as well as strategies that are both biomarker driven and non‑biomarker driven at time of progression on first line therapy. I would definitely recommend the use of liquid biopsies for next generation sequencing and default to tissue biopsies at time of progression, if needed, if the liquid biopsy was insufficient. All excellent points. Thank you, Dr. Cobain, for joining us today.
Dr. Cobain: Thank you.