Today we&rsquo;ll be discussing a case of a 65-year-old woman who [is] postmenopausal and was evaluated by her gynecologist with a new lump that she felt in her right breast. She described that as a grape-size lump in her right breast that she just recently noticed. Very rightfully, she was evaluated with an ultrasound that confirmed that there was a mass, indeed, which was about 2.5 cm. And following the workup, she then had a core biopsy, which confirmed a high-grade infiltrating ductal carcinoma. She then underwent a lumpectomy and a dissection, which revealed a 2.3-cm tumor [that] was grade 3, driven by the estrogen and the progesterone hormones, and negative for

This woman went underwent a staging CT scan of the chest, abdomen, and pelvis, which did reveal suspicious lesions in the bone. She therefore underwent a biopsy from the bone that confirmed that this was, in fact, metastatic from her breast cancer and was also driven by estrogen and progesterone hormones and negative for

. So in summary, we&rsquo;re talking about a woman who&rsquo;s newly diagnosed with de novo metastatic breast cancer to the bone, and it&rsquo;s driven by estrogen and negative for

So we&rsquo;ve certainly made a lot of progress for our patients with metastatic disease. And while we [have] not been able to cure this disease, we definitely have made some meaningful improvements for these patients [from] the new systemic therapies that have been introduced for treatment of metastatic disease.

But there are a few factors that obviously play into the prognosis with these patients, and some of these factors are clinical factors: Did this patient have de novo metastatic disease, or was this a relapse that happened within a few months or a very short time after the initial therapy, [even though] the relapse happened years after the initial therapy? Also, important factors to keep in mind are the estrogen and hormone receptor positivity or

positivity, which might drive into the prognosis for these patients. So the prognosis could vary anytime from a few months to many, many years and could also be dependent on the sites that are involved.

Case Review: De Novo Metastatic ER+ Breast Cancer

We have really come a very, very long way for treatment of [estrogen receptor] (ER)-positive breast cancer. And what we have learned is that endocrine therapy is a very effective treatment strategy. Until 2000, we learned that for postmenopausal women specifically, aromatase inhibitors are thought to be a very active class of agents. Because when we compare aromatase inhibitors with tamoxifen, specifically in postmenopausal women, we found that there was an improvement in the time to progression or progression-free survival, and therefore that became a standard of care in the first-line metastatic setting for these women.

Since then we&rsquo;ve now also seen data from trials such as the FIRST trial, which was a phase II trial, and also the FALCON trial, which is a phase III trial, looking at fulvestrant [Faslodex] in the first-line setting when compared [with] anastrozole [Arimidex].

And more recently, since 2012, I think our efforts have all been driven to our understanding the mechanisms of endocrine resistance and trying to overcome that. Because what we&rsquo;ve learned is, it&rsquo;s not that the endocrine therapies are not effective and that they don&rsquo;t work. They do work. But ultimately, after a few years, all these women now are progressing.

So our focus has been to define combination strategies, and we now have combination therapies, including mTOR inhibitor, or everolimus [Zortress], with aromatase inhibitors that are approved based on the BOLERO-2 trial. And we also have a new class of exciting agents called the CDK4/6 inhibitors that are also now approved both in the first- and second-line setting for these women and have changed the treatment landscape for ER

When we think about treating breast cancer, particularly breast cancer that is ER-positive,

-negative, and we think about what we used to do back in the day, say 20 years ago, we only had choices like tamoxifen, which&hellip;was approved in 1998 for metastatic disease. And now we have various choices, and in fact we have choices [that] are specific for premenopausal women and postmenopausal women.

For example, when we think about a premenopausal woman historically, what we have learned based on the meta-analyses from the Dutch group is that when you combine ovarian suppression with tamoxifen, there is a statistically significant improvement in both progression-free survival and overall survival, and that&rsquo;s what we do in clinic with these women.

When we think about postmenopausal women, we have data from so many trials that looked at aromatase inhibitors, and [we] compared them [with] tamoxifen and showed superior efficacy for aromatase inhibitors with respect to time-to-progression and progression-free survival in the first-line setting.

But then we also have trials such as FALCON trial that looked at fulvestrant when compared [with] anastrozole in the first-line setting and showed a significant improvement in [PFS], but these were women who were de novo metastatic patients. So these women were not treated with prior endocrine therapy.

So we were doing all of these various approaches for our women until 2015, when the very first agent, which was palbociclib, a CDK4/6 inhibitor, got approved in combination with an aromatase inhibitor in the first-line setting and showed improvement in [PFS] in the orders of about 28 months based on the longest follow-up data that we have, compared [with] aromatase inhibitors alone.

Since then we&rsquo;ve also had multiple other agents, including ribociclib [Kisqali] [and] abemaciclib [Verzenio], which also in combination with aromatase inhibitors have shown a similar improvement in [PFS]. And so based on the data when we see a class effect with unprecedented improvement in [PFS] in the first-line setting, certainly our first-line choice for patients with ER+ metastatic disease has become a combination of the CDK4/6 inhibitor with aromatase inhibitors.

The Evolution of Treatment Approaches for ER+ MBC

There are a few factors that we take into consideration when we&rsquo;re trying to treat a patient in the first line with metastatic disease. And the most important question that we want to answer for a patient with

[estrogen receptor] (ER)-positive disease is, when would you consider chemotherapy in the first-line setting?

So the rule of thumb, if you will, for an ER-positive metastatic patient would be that you would always want to give them endocrine therapy unless there is a visceral crisis. And with visceral crisis, I&rsquo;m not talking about just presence of metastases. I&rsquo;m referring to a patient with a significant disease burden. Somebody who is presenting with a lot of symptoms, with severe maladies that make you feel [as if] she would benefit with chemotherapy and not endocrine therapy. But otherwise, with every other woman who is not in visceral crisis, the first-line choice is always going to be endocrine therapy. So that&rsquo;s the first factor that we keep in mind.

Outside of that, you want to make sure that they are truly ER-positive from their metastatic site and not

+ or triple negative, because that would perhaps change the way you treat this patient. You want to keep in mind their menopausal status. Because for a premenopausal woman, you&rsquo;re thinking about adding ovarian suppression to endocrine therapy. You want to think about whether they have been treated for their breast cancer or are they presenting with de novo metastasis, as in this case with this woman who presented as such with de novo metastatic disease. Because those factors will drive the choice of therapy for a given woman.

Given that we now have at least four randomized phase III trials, one dedicated to premenopausal women with the MONALEESA-7 trial and three others, such as the PALOMA 2, the MONALEESA-2, and the MONARCH-3 trials, that showed that CDK4/6 inhibitors are effective when combined with endocrine therapy. And all these trials showed roughly a hazard ratio of about 0.5 with a statistically significant improvement in progression-free survival compared [with] endocrine therapy alone. My practice certainly has been to utilize the combination of the CDK4/6 inhibitor with endocrine therapy for first-line treatment, or even second-line if they [have] not received a CDK4/6 inhibitor in patients with ER+ metastatic disease. So I would absolutely consider that treatment for this given woman as well.

[For] the data that we have from these phase III trials, we try to identify if there was a particular subgroup that might benefit more, or might not benefit from this combination. In other words, [for the] biggest combination therapy, they&rsquo;re more effective but come in with their own toxicity. The idea was to try [to] identify a group that might be definitely benefiting from this a lot more than the other group, or a group that may not be benefiting. Well, what we saw [was] that regardless of sensitivity to prior endocrine therapy, [a] disease-free interval from their prior treatment, choice of hormonal therapy, premenopausal status, [the] presence of visceral disease or bone-only disease, there was certainly a benefit across all patient characteristics and all subgroups to justify the use of a CDK4/6 inhibitor with endocrine therapy. So I have definitely been using this combination therapy in the first-line and second-line setting for my patients.

CDK4/6 Plus Endocrine Therapy as First-Line Approach

The MONALEESA-3 trial [was] a randomized phase III trial that actually evaluated the combination of fulvestrant with one of the CDK4/6 inhibitorsin this case&hellip;ribociclib with placebo for postmenopausal women. About 500 patients were then randomized to receiving the fulvestrant plus ribociclib combination, compared [with] ribociclib with placebo, with a primary endpoint of progression-free survival.

What was unique about this trial, compared [with] the PALOMA-3 trial or the MONARCH-2 trial that also evaluated the combination of fulvestrant with another CDK4/6 inhibitorsuch as palbociclib in PALOMA-3 and abemaciclib in MONARCH-2&mdash;was that in the MONALEESA-3 trial, women could get fulvestrant with ribociclib even if they were treatment naive. Meaning, this could be a first-line therapy. And what was seen, in terms of their efficacy, was that the combination of fulvestrant with ribociclib led to a progression-free survival at about 20.5 months compared [with] 12.8 months in the group that had received fulvestrant plus placebo alone, with a hazard ratio of 0.59, which is statistically significant. So certainly, this data suggests that fulvestrant for the CDK4/6 inhibitor could be used as a first- or second-line treatment regimen for patients with [estrogen receptor]-positive metastatic disease.

This combination of fulvestrant with ribociclib could be an appropriate treatment approach. But our patient was 65 [and] postmenopausal, a de novo metastatic patient with disease in the bone, and she could certainly be treated with a fulvestrant with ribociclib-like agent based on the MONALEESA-3 trial, or an aromatase inhibitor with CDK4/6 inhibitor based on the other trials that have justified its use in the first-line setting.

The phase III PALOMA-3 trial evaluated the combination of fulvestrant with palbociclib, and similarly, the MONARCH-2 trial evaluated the combination of fulvestrant with abemaciclib. And these were all patients who had even progressed on their adjuvant therapy, or they had progressed in the metastatic setting after being treated with a nonsteroidal aromatase inhibitor in the first-line setting. So predominantly these were women who were treated with this combination in the second-line setting.

And what the trial showed, [what] both of these trials showed, [was] that the combination of the CDK4/6 inhibitor with fulvestrant led to a statistical improvement in progression-free survival compared [with] placebo with fulvestrant, making it a very valid second-line therapy option. So this is how we utilize fulvestrant in the first- or second-line setting.

Practical Implications of the MONALEESA-3 Trial

New data from the phase III FALCON trial showed that when we utilized fulvestrant in the first-line setting compared [with an] aromatase inhibitorin that case anastrozole for that particular trial&mdash;we saw that the progression-free survival (PFS) favored the treatment with fulvestrant, which was statistically significant in the order of about 16.6 months, compared [with] 30.8 months with anastrozole. Now, what is important to note about that trial was that those were treatment naive. These women had not seen any endocrine therapy in the early-stage setting. And so certainly that kind of dropped fulvestrant in the first-line realm for us.

The FALCON trial was actually designed after we had heard the results from a precedent trial, the phase II first trial, which had shown a statistically significant improvement favoring fulvestrant compared [with] anastrozole, and also showed the overall survival (OS) benefit for that approach. We are yet to hear about the overall survival from the FALCON study, but certainly it is a trial that actually helps us justify the use of fulvestrant in patients with, specifically with de nova metastatic disease or treatment-naive patients.

An interesting subgroup from the FALCON trial was those women with nonvisceral disease. They benefited with fulvestrant a lot more than patients who were treated with nonvisceral disease with anastrozole.

Now, I think that is a little hypothesis generating but an interesting one at that because one can certainly try to use fulvestrant for those with nonvisceral de novo metastatic disease, with the hope that upfront loading approach with a more effective endocrine PARP inhibitor, particularly subgroup, might improve the outcomes for [those] particular women even more.

So based on that and based on [new] data from the MONALEESA-3 trial, which also evaluated the combination of ribociclib with fulvestrant in treatment-naive first-line [estrogen receptor] (ER)-positive metastatic patients. I think we have data that [are] favoring the use of fulvestrant, not only in the second line but also in the first-line setting for our patients.

We really don&rsquo;t have any data thus far that can justify what do we do necessarily for our patients who are now being treated with a CDK4/6 inhibitor, either in the first- or second-line setting. That is something that is evolving, and a lot of research trials are trying to answer this question as we speak. There was one particular trial that perhaps gave us a glimpse of that data. That was the TRINITY trial. It&rsquo;s a phase I-II study that is evaluating ribociclib with exemestane and everolimus. And it did show a small cohort of patients [who] had progressed on a prior CDK4/6 inhibitor and showed that the clinical benefit rate for this triplet therapy in that cohort that had progressed on a CDK4/6 inhibitor was in the order of about 39%. But we have yet to hear the progression-free survival and the phase II data from that trial.

But outside of that we have other ongoing trials but no real data to actually make us understand what we do for a patient in clinic now. So what are we doing in clinic? We are doing what we used to do. We have data from the BOLERO-2 trial that justify the use of exemestane and everolimus in patients [who] have progressed on a nonsteroidal AI, up to 1 line of chemotherapy in the metastatic setting. In fact, in that study, a very small fraction of patients had also received fulvestrant trying to be enrolled for this regimen. And that regimen, when compared [with] exemestane and placebo, showed a statistically significant improvement in progression-free survival of about 7.8 months with a hazard ratio of 0.48. So one can certainly use a BOLERO-2-like regimen with exemestane and everolimus when patients progress on first-line CDK4/6 therapy.

We also have data for combining everolimus with tamoxifen based on the phase II TAMRAD trial, which also again showed that the combination led to a statistically significant improvement in time to progression compared [with] tamoxifen alone. And so certainly we can have different partners, endocrine therapy partners, to combine with everolimus, and use that in the second-line setting without really knowing, or without really having data from trials that are now evaluating, what do we do next after CDK4/6?

Options for Treatment-Naive Metastatic ER+ Breast Cancer

If our patient is asymptomatic, which she was, and had only the de nova metastatic disease to the bone that we talked about, without having significant pain, you might recall that we detected her [suspected] bone lesions with that biopsy just because we did a CT scan and a staging workup. The patient did not present with those symptoms. So I think my therapy would still remain the same with a CDK4/6 inhibitor with endocrine therapy for this woman.

That actually brings us to a very common question that we want answered in clinic when we&rsquo;re seeing a patient with first line, for first-line recommendations of treatment for metastatic disease. When we really think that the patient is in visceral crisis, when we talk about the patient as being symptomatic, are we talking about a mild cough? Are we talking about some shortness of breath? Or are we talking about a woman who [is] significantly short of breath, has significant difficulty with [coughing], we&rsquo;re seeing that her vital signs are being compromised. She&rsquo;s having difficulty breathing or maintaining the saturations at room temperature, and we&rsquo;re thinking about perhaps giving them chemotherapy, thinking that maybe chemotherapy might have a faster impact.

But short of that, if a patient does not advance with visceral crisis, meaning with a significant disease burden or a lot of symptoms or a lack of modalities that go along with the symptoms, I think it&rsquo;s very, very appropriate to treat this woman with a combination [of] a CDK4/6 inhibitor with endocrine therapy.

We treated this woman with fulvestrant with ribociclib in the first-line setting. So if this woman were to progress, at that point I think it would be very appropriate should she not have any significant disease burden with a lot of visceral crises to continue to treat her with endocrine therapy. And you could use and justify the combination of eczema stain with everolimus or tamoxifen with everolimus, based on the results from the BOLERO-2 or the TAMRAD trials, and treat her in the second-line setting with that combination. In fact, when you look at the [National Comprehensive Cancer Network] guidelines, they suggest that a woman with [estrogen receptor] (ER)-positive metastatic disease can be treated with up to 3 lines of endocrine therapy before you have to resort to chemotherapy. Certainly, if there was an appropriate clinical trial option available for her, I would gladly be enrolling her in that clinical trial and reserving exemestane and everolimus or tamoxifen and everolimus in the third-line setting before I had to [resort] to chemotherapy.

We have come a really long way. So we used to treat our postmenopausal women only with aromatase inhibitors. And now we have data for CDK4/6 inhibitors with aromatase inhibitors based on the randomized phase III trials that all unanimously have shown an unprecedented benefit in progression-free survival for these women.

We also now have a glimpse of activity and justification that we can use in clinic to utilize fulvestrant with CDK4/6 inhibitor based on the MONALEESA-3 trial, and fulvestrant alone based on the FALCON trial.

There is an important study, I think, which is actually evaluating head-to-head fulvestrant plus a CDK4/6 inhibitor, in this case palbociclib, with aromatase inhibitors and palbociclib..

We do have an important trial that we&rsquo;re awaiting the results from, which is comparing fulvestrant with a CDK4/6 inhibitor. In this case, palbociclib, compared [with] aromatase inhibitors with palbociclib, based on the PARSIFAL study, and hopefully that will also shed light into whether there is a very appropriate and the best endocrine therapy partner that we should certainly be thinking about in the first-line setting. But until then, I think we definitely have a lot of data to justify CDK4/6 for our patients in the first-line setting, specifically with aromatase inhibitors and now also with fulvestrant.

A Case of Estrogen-Driven Metastatic Breast Cancer

Case Review: De Novo Metastatic ER+ Breast Cancer

The Evolution of Treatment Approaches for ER+ MBC

CDK4/6 Plus Endocrine Therapy as First-Line Approach

Practical Implications of the MONALEESA-3 Trial

Options for Treatment-Naive Metastatic ER+ Breast Cancer

Evolving Treatment Options in ER+ Metastatic Breast Cancer