CDK4/6 inhibitors, such as palbociclib (Ibrance), abemaciclib (Verzenio), and ribociclib (Kisqali), added to fulvestrant (Faslodex) have been welcome additions to the treatment paradigm for patients with 

-mutant, hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, said Sarah Sammons, MD. However, novel therapies are needed to improve upon the limited survival benefit these agents plus endocrine therapy confer. 

“Certainly, if we identify a patient who has an 

 mutation that has progressed on a first-line aromatase inhibitor [AI], the addition of a CDK4/6 inhibitor to fulvestrant is strongly recommended,” said Sammons.

“As an endocrine therapy backbone, fulvestrant is the best we have right now, but we need to do a lot better. A lot of work is ongoing in this population to figure out the optimal treatment for patients. Right now, oral SERDs [selective estrogen receptor degraders] and a few SERMs [selective estrogen receptor modulators] are promising,” Sammons explained.

, Sammons, an assistant professor of medicine in the Department of Medicine and a member of the Duke Cancer Institute at Duke University School of Medicine, discussed the clinical significance of 

 mutations in HR-positive, HER2-negative breast cancer, how to determine the optimal timing to perform genetic sequencing for 

 mutations, and emerging agents, like lasofoxifene, that are poised to transform the paradigm for patients who harbor these mutations.

 mutations confer and how frequently are they identified in patients with breast cancer?

 mutations are most commonly missense mutations that happen in the ligand binding domain of the estrogen receptor. They lead to constitutive activation of the receptor in a ligand-independent fashion.

 mutations occur in up to 40% of patients who have advanced HR-positive, HER2-negative breast cancer after exposure to AIs in the advanced setting.

 mutations are uncommon in primary HR-positive breast cancer; they occur in less than 1% of primary tumors. In patients who have been exposed to adjuvant AIs and still have estrogen-sensitive disease, 

 mutations are fairly rare; about 3% to 5% of the first relapse of metastatic disease will have these mutations. These mutations happen later on in the metastatic course, after exposure to and progression on AIs. 

It is important to note the clinical significance of 

 mutations. In many retrospective and prospective series, 

 mutations have been shown to denote resistance to AIs. A recent study by Nicholas Turner, MD, PhD, [of The Institute of Cancer Research] looked at circulating tumor DNA [ctDNA] in patients from the SoFEA and EFECT trials comparing fulvestrant with exemestane. [The study] clearly showed that patients who had detectable 

 mutations in their ctDNA had inferior progression-free survival [PFS] and overall survival [OS] when they were treated with exemestane. They did much better when they were treated with fulvestrant.

 mutation that appears to be resistant to fulvestrant as well. The Y537S mutation is one of the more common mutations. The PALOMA-3 ctDNA analysis showed that mutations in Y537S were likely to occur in the fulvestrant [plus] CDK4/6 and fulvestrant [plus] placebo arms. [The investigators] concluded that this is potentially a resistance strategy for fulvestrant. Several other very strong preclinical studies have shown that Y537S is resistant to fulvestrant.

We have [some time] to go. Some new treatments, such as oral SERDs and lasofoxifene, look more promising for the specific clone. It will be interesting to see how that pans out.

When is it clinically practical to sequence for 

 mutation affect your treatment decisions?

Some practitioners will sequence all advanced patients at first relapse. However, that is not my practice. At this time, my practice is to sequence patients after they have progression on CDK4/6 inhibition with endocrine therapy in the first-line setting. The reason for that is there can be targetable mutations that can be acquired over the period of receiving CDK4/6 inhibitors. Sequencing patients prior to first-line therapy rarely changes my practice pattern for patients who have endocrine-sensitive disease. For patients who have de novo metastatic disease, or their disease has occurred greater than 1 year after adjuvant therapy, we give standard-of-care treatment with an AI and a CDK4/6 inhibitor.

The PARSIFAL trial was presented this past year and showed that [the combination of] an AI and CDK4/6 inhibitor was not inferior to fulvestrant and a CDK4/6 inhibitor in up front. This confirmed and made us feel better about using [AIs plus CDK4/6 inhibitors] in the first-line setting. 

Interesting, PADA-1 is a clinical trial that has been looking at 

 mutations in the estrogen-sensitive population. These are the de novo patients or patients who relapsed more than 1 year after adjuvant therapy. Thus far, [investigators] found that 

 mutations are rarer in this population, occurring in about 3% of patients. Despite it only being 3%, those who have 

 mutations up front in the ctDNA did have inferior PFS to an AI plus a CDK4/6 inhibitor; the median PFS was around 11 months versus 27 months. 

Interestingly, ctDNA dynamics also seemed to matter. If a patient had a baseline 

 mutation and they were started on an AI and CDK4/6 inhibitor and they were able to eliminate that clone early in their treatment course—which is about two-thirds of patients—patients did just as well as those who didn’t have [an 

We still have further work to do, and PADA-1 is also looking at what to do in those patients who don’t clear their 

 mutation in the ctDNA or those who develop 

 mutations while they are on an AI and CDK4/6 inhibitor. Should we be changing their endocrine backbone to fulvestrant?

At this time, for the majority of patients with estrogen-sensitive HR-positive, HER2-negative breast cancer, an AI and a CDK4/6 inhibitor are still the first-line answer. For patients who progress on adjuvant AIs, we are still recommending fulvestrant and CDK4/6 inhibition based on the landmark clinical trials that looked at that. We know that in that population of patients who progress on first-line AIs that an 

 mutation will be present in about one-third of patients. Do those patients with 

 mutations respond as well to CDK4/6 inhibitors added to fulvestrant as those who are wild type for 

? ctDNA analyses were performed in almost all of the landmark trials looking at fulvestrant and CDK4/6 inhibition, including the MONARCH, MONALEESA, and PALOMA trials. 

Luckily, we have found that patients who have 

 mutations derive substantial benefit from the addition of a CDK4/6 inhibitor. Therefore, the answer is that patients who have baseline 

 mutations still derive great benefit from adding a CDK4/6 inhibitor to abemaciclib, palbociclib, or ribociclib. In the MONARCH-2 clinical trial, ctDNA analysis showed that patients with 

 mutations derived a greater benefit from the addition of a CDK4/6 inhibitor compared with those who had wild-type 

Do you consider switching CDK4/6 inhibitors for patients who progress on one?

The question is, really: Is there efficacy in CDK4/6 inhibitors after progression on CDK4/6 inhibitors? The short answer is that we don’t know from a well-designed, prospective clinical trial yet. There are anecdotal reports and retrospective data showing that abemaciclib may have some activity after progression on palbociclib, but we need more research.

Several clinical trials are ongoing looking at the efficacy of CDK4/6 inhibitors post CDK4/6 inhibitors. Certainly, we would imagine that the endocrine therapy backbone would be changed. If a patient received an AI and palbociclib in the first-line setting, looking at the efficacy of fulvestrant and abemaciclib in the second-line setting would be an intriguing approach. 

What therapies are on the horizon for patients with 

A lot of work is ongoing [trying to] determine the optimal endocrine therapy backbone for these patients. We know that fulvestrant monotherapy in this population has a median PFS of around 4 months, so we would certainly like to do better. Many oral SERDs are being explored in early- and late-phase clinical trials as single agents and in combinations with CDK4/6 inhibitors and other targeted therapies. Oral SERDs may have an advantage over fulvestrant because fulvestrant, given as an injection, has fairly poor bioavailability. The hope is that oral SERDs will have improved bioavailability and therefore improved efficacy. There are a variety of [investigational oral SERDs] out there and we are excited about a few of them. Preclinical work has shown that they seem to be superior to fulvestrant in treating 

-mutant HR-positive breast cancer. We are [far away from showing], in clinical trials, whether [oral SERDs] will truly be superior to fulvestrant. We also don’t know what their adverse effect profiles will be in comparison with fulvestrant. Fulvestrant is very well tolerated from a safety standpoint, so understanding whether oral SERDs will be superior [in terms of efficacy] and will have a good enough safety profile to give as alternatives to fulvestrant is a question that I hope we are able to answer within the next couple of years. 

Another compound that seems to have preclinical activity in 

-mutant breast cancer is the lasofoxifene. Lasofoxifene versus fulvestrant is currently being explored in the phase 2 ELAINE trial in patients with 

-mutant breast cancer who have progressed after a CDK4/6 inhibitor and endocrine therapy. Patients could not have had prior fulvestrant. This trial is ongoing, and we are certainly excited to see the results of it. Then, the ELAINEII trial is looking at lasofoxifene plus abemaciclib in a similar patient population. 

Articles

Sarah Sammons, MD, discusses the clinical significance of ESR1 mutations in HR-positive, HER2-negative breast cancer, how to determine the optimal timing to perform genetic sequencing for ESR1 mutations, and emerging agents, like lasofoxifene, that are poised to transform the paradigm for patients who harbor these mutations. 

Parsing Out Remaining Questions With CDK4/6 Inhibitors in HR+ Breast Cancer 

Tremendous progress has been made to understand the strategies that can be used to overcome 

mutations in estrogen receptor (ER)–positive breast cancer, said Debu Tripathy, MD, who added that potent selective ER modulators (SERMs) may be the key to combat these mutations.

“Selective [ER] modulators can probably, to some extent, be effective [against] 

-mutant cells,” said Tripathy. “The effect to which they can reverse resistance probably depends on many aspects of the agent. These need to be formally studied not just in the lab, but in clinical trials. We are starting to get some hints of that [work], but it’s just the beginning.”

 mutations generally arise following treatment with an aromatase inhibitor (AI), explained Tripathy, so acquiring genomic information after a patient progresses is critical to inform treatment selection.

The novel SERM lasofoxifene is currently being investigated in combination with the CDK4/6 inhibitor abemaciclib (Verzenio) in the phase 2 ELAINEII trial (NCT04432454) in patients with advanced or metastatic ER-positive, HER2-negative breast cancer whose tumors harbor an 

 mutation. Moreover, in May 2019, the FDA granted a fast track designation to lasofoxifene for the treatment of female patients with ER-positive, HER2-negative metastatic, 

, Tripathy, professor of medicine and chair of the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed the role of CDK4/6 inhibitors in ER-positive, HER2-negative breast cancer, the emergence of SERMs, and the growing understanding of 

: Resistance to frontline therapy with a CDK4/6 inhibitor plus endocrine therapy is a huge area of ongoing research. Is there any reason to believe that patients could have non-overlapping sensitivities to CDK4/6 inhibitors?

: When patients progress on a CDK4/6 inhibitor, I will generally discontinue the use of CDK4/6 inhibitors. No clear data [show] that patients who become resistant [to a CDK4/6 inhibitor] may be sensitive to other [CDK4/6] inhibitors; however, some anecdotal data from individual hospital series suggest there could be some non-overlapping sensitivity.

However, we have many other options, which is why I will generally move on to another form of therapy. We need to formally study the impact of 1 CDK4/6 inhibitor after progression on another because we may find that some of these agents perform better in that setting.

Do you order tumor profiling after each progression? When you order the test, do you favor liquid or tissue biopsy?

I tend to get genomics at the very beginning when patients are newly diagnosed, although I may not use that information in the first-line setting. However, it is good to have [the genomic information], especially for truncal mutations. [Truncal mutations] tend to be prevalent in most of the cells, such as 

 mutations tend to be subclonal and may not be present [up front] but may arise later after the patient has been on an [AI].

If I haven’t gotten [genomic information] at the beginning, I will certainly get it at the time of progression on first-line therapy.

mutations differ from other somatic mutations?

 mutations tend to arise in the presence of pretreatment, particularly with estrogen-deprivation therapy, which pharmacologically, would be AIs. The Cancer Genome Atlas published that 

 mutation rates were very low, at perhaps 1% or so at diagnosis and based on the patient’s primary tumor. However, [

mutations] really [arise] after exposure to AIs.

That makes sense because AIs work by depriving estrogen from the environment. To be activated, ERs need to bind to estrogen. So, [AIs] select for any mutations that may occur where a mutation [is present] in the ER that allows it to be activated without the presence of estrogen; that is what most activating 

mutations do. Specifically, upon exposure to AIs, is when we start to see these mutations arise.

Lasofoxifene is an agent that is being evaluated in the setting of an acquired

mutation. How did the findings from the PADA-1 trial help to set the stage for this agent?

 mutations can be acquired and they can be subclonal, meaning that you can see a very low fraction of all the tumor DNA that has that mutation. However, you can’t underestimate that power of a small fraction of activated 

-mutant cells. We do see that pattern of resistance. [Additionally, the trial showed] that patients can have multiple clones.

 mutations? One way is to totally take them out of the equation and to target them for downregulation or proteasomal degradation, which is what selective ER downregulators like fulvestrant [Faslodex] do. However, they don’t do it completely; these drugs don’t completely circumvent resistance. Another way is to use [SERMs] that may not necessarily inactivate the ER, but instead, modulate the ER in the way it behaves, the conformation of it, and how it binds to co-activators, co-receptors, and co-repressors. [Doing this], ultimately, mediates the expression of genes that guide what estrogen does, which is generally a growth signal. 

data provided insight into the differences between lasofoxifene and other SERMs?

Lasofoxifene does have the ability to downregulate the transactivating nature of the ER, including 

mutations. In the lab, we can study how well an ER is able to activate the genes it targets. ERs are known to target numerous genes of interest that lead to cell growth. We can measure to what extent a drug will interact with 

 so that it negatively regulates it. In other words, the genes that are normally transcribed by estrogen are not transcribed. More importantly, growth is arrested. That has been demonstrated 

At the virtual 2020 AACR Annual Meeting, the University of Chicago presented a poster on

data looking at lasofoxifene alone and in combination with palbociclib [Ibrance] vs fulvestrant. What did we learn from these data and how could they potentially translate to the clinic?

Those data are compelling. They show that we can get growth inhibition in 

 mutations and that it can be potentially aided with CDK4/6 inhibitors. Although I don’t have the exact data at hand, I have seen examples of this and other data that show [tumor growth] can be reversed in cell-line models.

What we see in those cell-line models—even in animal models, which are more accurate but may not be the whole story—may not turn out to be the case in the tumor microenvironment and all of the other factors involved. Therefore, although this is very supportive and raises enthusiasm for getting these types of drugs into clinical trials, we need to wait to see what happens when patients are taking these drugs.

The ELAINE trial set the stage for ELAINEII, which is evaluating lasofoxifene plus abemaciclib. What is the anticipated impact of the ELAINEII trial?

The ELAINE trial is comparing fulvestrant with lasofoxifene in patients with 

 mutations. It’s a direct test of the hypothesis that [lasofoxifene] may be more favorable than [fulvestrant], which we now consider a reasonable drug to use when we see 

 mutations or in the second line in general. 

ELAINEII is designed to move [lasofoxifene] further, combining it with a CDK4/6 inhibitor. It will allow patients who have seen prior CDK4/6 inhibitors [to enroll]. There is some anecdotal evidence that responses have been seen with abemaciclib after progression on other CDK4/6 inhibitors.

The approval of abemaciclib was based on a trial that showed responses in refractory hormone receptor–positive disease as a single agent, but those patients had not been previously exposed to CDK4/6 inhibitors. We believe that the combination of these 2 different strategies could bring about more responses and longer time to progression.

The PARSIFAL trial didn’t look at lasofoxifene, but rather an AI plus palbociclib versus fulvestrant. How could those findings potentially affect the landscape?

One of the issues is pairing CDK4/6 inhibitors with different endocrine therapies; we haven’t formally compared that. We do know from the FALCON trial that, when using endocrine therapies alone, fulvestrant is slightly better than AI therapy, particularly in patients who haven’t been treated before or have non-visceral disease. Then, the MONALEESA-3 study was a trial that took advantage of the FALCON findings and compared treatment with fulvestrant alone versus fulvestrant plus ribociclib [Kisqali] regardless of first- or second-line therapy. That study showed a significant improvement in outcomes with a hazard ratio of around 0.5, which has been seen before.

The PARSIFAL trial, on the other hand, was a direct comparison with palbociclib. Patients received an AI or fulvestrant. The trial did not show a difference in progression-free survival. We are left without knowing what population fulvestrant might be best for, but certainly fulvestrant is a reasonable option in the first- or second-line setting. We have less data regarding what to do in the second line for patients who received fulvestrant up front, but the PARSIFAL and MONALEESA-3 studies showed that [ribociclib and palbociclib] are both reasonable agents to use and could be building blocks for [combinations] with other targeted agents.

How do you anticipate genomic classification will continue to affect the research landscape?

The sub-classification of the breast cancer subtypes is very important in general. In breast cancer, not all patients with luminal A or luminal B [disease] are the same. There may be certain aspects about the different pathways involved in growth and other cellular functions, such as invasion and apoptosis that may vary depending on different gene profiling. Gene profiling is basically a way to categorize cancers, but if we can categorize them in functionally relevant ways, then we are really making advances.

This takes studying large numbers of patients, ideally in the context of a clinical trial where they are being treated similarly or we are comparing 1 treatment with another. Then, we can dissect the different molecular profiles that may predict a benefit. More importantly, we can use that information about the molecular profiles to identify mechanisms of resistance that could inform newer strategies.

What other ongoing research is needed in the

Not all mutations are the same. There may be certain 

 mutations that are generated in certain situations and under certain treatments that we need to understand better. What is really fascinating is trying to understand the functional consequences of 

 mutations, not only in terms of proliferation, but in terms of many other phenotypes that we are interested in targeting, such as metabolic activity, DNA repair, or other hallmarks of cancer. Whether it is invasion, the ability to resist apoptosis, or immunogenicity is critical. Studies in the basic aspects of what 

 mutations do [are important]. [Also, evaluation of] the nitty gritty molecular structure and how the ER interacts with co-activators, co-repressors, and other aspects of the transcriptional machinery that make the ER work [is needed] to understand what 

Of course, we are aware of many other mutational isoforms, such as 

 mutations and growth factor mutations, like exon 20. We need to understand the inner workings of what these mutations cause. When you think about it, cancer is selection of the fittest. Cancer cells do have a higher mutational rate. Many of the mutations that arise out of accident lead to cell death. However, it is those that lead to cell advantage that perpetuate. By understanding the most common driver mutations that arise over time, we can start to develop therapies against each one. Although, there will always be rare mutations that are going to be more difficult to understand and target.

Debu Tripathy, MD, discusses strategies that can be used to overcome ESR1 mutations in estrogen receptor–positive breast cancer. 

Lasofoxifene Emerges as Understanding of ESR1 Mutations Expands in ER+/HER2- Breast Cancer

The ongoing ELAINE-2 trial (NCT04432454), which is evaluating the combination of lasofoxifene and abemaciclib (Verzenio) in patients with 

-mutant, estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer, is building on findings from the ELAINE study, which demonstrated that the oral selective estrogen receptor modulator (SERM) has significant preclinical antitumor activity in 

-mutant models, said Matthew P. Goetz, MD. Positive findings from the trial would not only confirm 

 as an actionable target but demonstrate the viability of sequential CDK4/6 inhibition after progression. 

“I think lasofoxifene is probably the leading SERM to be studied in the setting of 

 mutations,” said Goetz. “The suggestion from the preclinical data is that the combination of lasofoxifene and a CDK4/6 inhibitor should be a reasonable option. The idea of combining abemaciclib or another CDK4/6 inhibitor with lasofoxifene is being tested in the ELAINE-2 study. One would fully expect this to be a well-tolerated and safe regimen, just like when you combine a new CDK4/6 inhibitor with other endocrine therapy partners.”

, Goetz, consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic, discussed ongoing research in the setting of 

-mutant, ER–positive, HER2-negative metastatic breast cancer.

 mutation make you more prone to continue or switch a CDK4/6 inhibitor? 

: Among patients who are progressing on a CDK4/6 inhibitor, one of the major questions that we have is: What are the drivers? What is driving resistance? A number of biomarkers have been identified to be present at the time of progression. These include biomarkers, such as 

 mutations, RB alterations, and certainly cyclin E is a biomarker that suggests that an alternative pathway, including CDK2 may be important. 

 mutations that are developing at the time of progression, we have to ask: Is 

 a driver? If it is a driver, what is the best way to treat that particular patient? Continuing on with the CDK4/6 inhibitor certainly may be a very important treatment strategy. But at this point, it is one that we don’t know the answer to. 

A number of studies are ongoing right now that are really trying to answer the question of: Should you continue a CDK4/6 inhibitor beyond progression? For example, in patients who progress on a CDK4/6 inhibitor, is there a role for switching out the endocrine therapy, and continuing on with the CDK4/6 inhibitor? A number of studies are looking at this question. In the presence of an 

 mutation where there is ligand independent growth of the tumor, continuation of the CDK4/6 inhibitor certainly may be important. We just don’t know the answer to that right now.

How is genomic information currently being used to guide treatment? Is there a preference between using liquid biopsy and tissue biopsy?

It’s a great question. Certainly, genomic information has rapidly become a critical component of how we manage patients with metastatic ER–positive breast cancer. This, of course, is based on the fact that a number of genetic alterations are targetable. For example, we have data with alpelisib [Piqray] in 

 alterations, and we know that this drug has antitumor activity in tumors that that have the PI3 kinase or pathway activated, say through a 

 alteration. We also know from SOLAR-1 that we can assess from the tumor or through ctDNA [circulating tumor DNA]. We also know that there are patients in our clinic where the tumor is not readily accessible. These are, for example, patients with bone only disease. 

Assessing for a genomic alteration through ctDNA analysis is a very attractive way to be able to assess the current state of that particular tumor. This is part of our standard of practice right now to assess for these genomic alterations. We have targets including 

, we have yet to have an FDA-approved drug, but we have hints that using specific drugs may be of value. For example, drugs, such as SERDs [selective estrogen receptor downregulators] or in the case of a SERM, lasofoxifene. 

How do the SERMs compare with SERDs? What distinguishes lasofoxifene from other SERMs?

It’s another great question. We have many oral SERDs that are making their way through clinical trials. One of the ways that these oral SERDs are quite attractive is the fact that they’re able to achieve very good pharmacokinetic concentrations that are associated with excellent ER degradation. The idea here is that ER degradation should be a superior way to treat a tumor that has, in this case, a 

 alteration, and we know that preclinically that indeed is the case. There are many studies demonstrating that these oral SERDs have antitumor activity. 

Lasofoxifene is of course is a SERM. It binds to the ER, but one of the things that we know about lasofoxifene is that at the higher concentrations that are being tested, for example, in the ELAINE study, which is a randomized trial comparing lasofoxifene with fulvestrant [Faslodex], that at the dose, and at the concentrations that are being used in the ELAINE study, that lasofoxifene has been shown preclinically at those concentrations to have substantial antitumor activity in 

Specifically, in work that came out of Dr Jeff Greene’s laboratory comparing, for example, lasofoxifene with fulvestrant, lasofoxifene was superior in terms of inhibiting metastases. 

We have these 2 approaches right now: one of them is using these potent SERDS, and another is utilizing lasofoxifene. Why does lasofoxifene have antitumor activity in this setting? Well, some of the preclinical data really suggest that lasofoxifene maintains its ability to bind, even to the mutated ER, and in that particular setting is able to reduce proliferation, and ligand independent proliferation. This beneficial effect of lasofoxifene is what is being tested in the randomized phase 2 ELAINE study.

Lasofoxifene is also being evaluated in combination with abemaciclib in the ELAINE-2 study. Why was abemaciclib selected as the combination partner?

The most common CDK4/6 inhibitor that is being used probably out in the community right now in the first-line setting is, of course, palbociclib [Ibrance]. Practically, one of the easy things that can be done in this situation is for patients who are progressing on palbociclib is to combine, for example, lasofoxifene with abemaciclib. This is of course, a very attractive regimen that physicians can think about using because 

 mutations are commonly occurring at the time progression on palbociclib and abemaciclib has been shown to have some antitumor activity in the post-palbociclib setting. It’s not FDA approved in that particular setting, but certainly this combination is quite attractive from that standpoint.

Would you say lasofoxifene is the primary player right now or are there other agents to look out for?

The SERMs that have been tested in the endocrine-refractory setting that have shown benefit include the drug endoxifen, which was studied in a randomized phase 2 study. These data were presented at the 2019 San Antonio Breast Cancer Symposium. In that particular study, endoxifen did not lead to a statistically significant improvement in progression-free survival vs tamoxifen. However, there was an interesting analysis in patients who had no prior CDK4/6 inhibitors, and in that setting, endoxifen was markedly better by about 5 months. 

With regard to endoxifen, there are no data or very limited data right now with regard to its role in [patients with] 

 mutations. That is something that will be tested in a randomized phase 2 study, but ELAINE and ELAINE-2 are really the players that we need to emphasize.

What other studies were you most excited to see the results of at the 2020 San Antonio Breast Cancer Symposium? 

In thinking about CDK4/6 inhibitors, there was an update on the monarchE study. The second interim analysis was presented at the 2020 European Society for Medical Oncology Annual Congress and published in the Journal of Clinical Oncology. At SABCS, we saw the primary analysis of invasive disease-free survival as well as data on Ki-67. One of the interesting things that was done in the monarchE study was that there was a prespecified group of patients that were enrolled with very high Ki-67 greater than 20%. We’re going to see some of the data with regard to the potential benefit of abemaciclib in this high group. 

The other abstract that I’m very interested in hearing about is the RxPONDER study, which is a randomized clinical trial in the adjuvant setting for high-risk, ER-positive breast cancer that’s node positive. The randomization was to chemotherapy vs not based on Oncotype Dx recurrence scores. Of course, we have data from TAILORx in the node-negative setting. We’ve been awaiting these data in the node-positive setting for some time, so we’re anxious to see these data as well.

Matthew P. Goetz, MD, discusses ongoing research in the setting of ESR1-mutant, ER–positive, HER2-negative metastatic breast cancer.

ELAINE-2 Trial Could Establish the Actionability of ESR1 in HR+/HER2- Breast Cancer

The introduction of CDK4/6 inhibitors, such as abemaciclib (Verzenio), ribociclib (Kisqali), and palbociclib (Ibrance) has been a significant addition to the hormone receptor (HR)–positive, HER2-negative breast cancer armamentarium, explained Massimo Cristofanilli, MD, who added that current questions regarding subsequent therapy selection can only be answered by testing for resistance mechanisms, such as 

“We need to stress again the importance of molecular testing and make sure that patients participate in clinical trials,” said Cristofanilli. “We desperately need [novel therapies] because we don’t have many available options after fulvestrant [Faslodex]. 

 mutations span across 30% of patients [with estrogen receptor (ER)–positive, HER2-negative breast cancer], so perhaps CDK4/6 inhibitors will be used like trastuzumab [Herceptin] as a backbone for endocrine therapy.”

With regard to novel therapies, the potent selective estrogen receptor modulator (SERM) lasofoxifene is currently being investigated in the phase 2 ELAINE trial (NCT03781063) for use in patients with ER-positive, HER2-negative breast cancer whose tumors harbor an 

In May 2019, the FDA granted a fast track designation to lasofoxifene for use as a treatment for female patients with ER-positive, HER2-negative metastatic 

The goal of the study is to identify a new therapeutic option for patients with ER-positive, HER2-negative metastatic breast cancer with 

 and acquired resistance. Additionally, patients in this space tend to have short-lived or no response to fulvestrant, which is the current standard of care.

, Cristofanilli, a professor of medicine within the Hematology and Oncology Division at the Feinberg School of Medicine at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, discussed the nuances of treating patients with CDK4/6 inhibitors, the ongoing quest to understand mechanisms of resistance, and the potential role of lasofoxifene in the setting of 

-mutant, HR-positive, HER2-negative breast cancer.

After a patient progresses on a CDK4/6 inhibitor, do you recommend continuing or switching CDK4/6 inhibitors?

In the management of patients with metastatic HR-positive disease, the standard of care is to use CDK4/6 inhibitors in combination with an endocrine agent. In the first-line setting, this would be an aromatase inhibitor (AI) and, in the second line, primarily fulvestrant.

Progression on CDK4/6 inhibitors is becoming a major challenge in the management of these patients because we have different situations. Patients will respond for a long time and then, after 1 or 2 years, eventually progress. In these cases, based on the [patients’] molecular profiles, we can decide to use a targeted therapy. We know about 

 mutations, for example, for which alpelisib [Piqray] has been approved. 

Then, there are situations of primary resistance to CDK4/6 inhibitors, which is much more complex. We frequently use chemotherapy very early on for these patients, but it depends on the lack of response in a short period of time, the particular mutation that is driving the resistance, and the site of recurrence. In a patient with bone metastases, we can try endocrine therapy, maybe with a novel agent or a simple agent targeting 

 mutations. In patients who have visual metastases, the standard of care is chemotherapy. 

The pattern of management of these patients varies tremendously. [If patients have an] initial, long response to first-line palbociclib and progression where no specific driver mutation is identified, I would tend to use a different CDK4/6 inhibitor, such as abemaciclib.

mutation influence your treatment selection? How prevalent are

 mutations are probably the most interesting type of mutation that we see in metastatic breast cancer. Luminal breast cancer is very heterogenous. Of course, there is selective pressure from the treatment to develop new clones and new driver mutations. 

 mutations have been discovered in patients who have primarily been exposed to AIs for a period of time; they are markers of resistance to AIs. In general, people believe that this is the most common [reason we see] 

 mutations could be markers of resistance to endocrine therapy. Interestingly, most phase 3 clinical trials approached the approval of CDK4/6 inhibitors [by] evaluating cell-free DNA [cfDNA] for different mutations, including the frequency and onset of 

 mutations were [present in] around 20% to 25% and increased slightly at the end of treatment and at the time of progression. Interestingly, some novel mutations appeared during treatment. This suggests that maybe resistance is no longer due to endocrine therapy. It makes me think that this is more related to fulvestrant. We have not dealt with that yet, meaning we don’t have a novel surge of [these types of agents] to substitute and address the question of whether 

 mutations indicate resistance to the combination or single-agent endocrine therapy. 

 mutation level at baseline, it appeared that [the presence of a mutation] does not reduce the efficacy of palbociclib, for example. Interestingly, more recent data looking at the level of an 

 mutation before treatment with single-agent abemaciclib appeared to show a higher detection rate and increased percentage of 

 mutations compared with the combination. This suggests that if we use a CDK4/6 inhibitor up front, we may reduce the incidence of 

 mutations, thus reducing the specific type of endocrine disease. 

Do you perform genomic testing for patients at each point of progression to look for potential resistance mutations?

The ability to interrogate the tumor, particularly with a type of mutation that we can target is very important. It makes us more willing to test tumors that progress on specific treatments. Clearly, it is not necessary for all our patients to have molecular testing, but when we have a patient who has recurred after a period of time, such as during adjuvant endocrine therapy or after first-line treatment, we must perform a molecular test to detect if a driver [mutation is present].

Of course, the more resistant the tumor becomes, the more important the value of testing becomes. We are talking about the evolution of the disease, so clearly, cfDNA testing is important. The standard of care is to do next-generation sequencing [NGS] in tissue at least once at the time of the patient’s first recurrence. Patients have a long natural history, and the disease evolution is better monitored with a cfDNA test.

How do the results of genomic tests guide subsequent treatment selection?

We learn more and more about the results of testing and how they can be applied [to treatment selection]. We mentioned that, for example, the detection of specific mutations indicate resistance or predict response to specific agents. If a patient has an [

] mutation, for example, they may respond to the TKI neratinib [Nerlynx]. This particular target is [present] in about 5% of patients HR-positive disease, but it is a molecular alteration that patients gain during treatment with endocrine therapy.

Of course, we are pleased that we have an approved drug, alpelisib, and approved testing for patients with 

 mutations. We are still learning how to manage adverse effects [AEs with alpelisib] because [the drug] has a clear role in the management of 

-mutated patients with HR-positive breast cancer in terms of improved outcomes and, even, improved survival.

-targeting agents to replace fulvestrant or to be used after fulvestrant [is ongoing] in a number of clinical trials. In order to be enrolled in these clinical trials, patients have to undergo molecular testing to show that a mutation is present. For this particular group of patients who progress after fulvestrant, it is important to be able to choose a type of treatment that is going to work after molecular testing.

This is just the beginning of what we have learned. For example, we know that particular NGS testing indicates tumor burden with allele frequency detection so we can understand how much disease [a patient has] and how aggressive the tumor is based on the molecular report and the evolution over time. We can detect that at recurrence, even before imaging. This may allow us to make changes in the treatment of some patients.

Also, in some patients, it is important to decide [the optimal] time to start chemotherapy based on the number of mutations that do not have a specific type of targeted therapy [available] that is associated with these molecular features.

Are there any notable differences between the safety profiles of the CDK4/6 inhibitors that may sway you to use one over another in a particular patient?

By now, we know very well how to use the [CDK4/6 inhibitors]. Palbociclib was the first-in-class agent to be approved, so we have a much longer history of monitoring and reporting AEs [with palbociclib]. Clearly, neutropenia is the most important AE. If a patient has a comorbid condition, such that their bone marrow is not able to [handle] palbociclib at multiple dose levels, we have the possibility to choose an alternative [drug].

We have patients who have gastrointestinal conditions, such as diarrhea, for which abemaciclib may not [be the optimal CDK4/6 inhibitor]. The toxicity profiles [of CDK4/6 inhibitors] are very well known.

The lung toxicity described with abemaciclib has also been consistently reported in a small percentage of patients who receive idelalisib [Zydelig].

Besides that, we are trying to figure out what specific characteristics of the tumor allow us to select 1 CDK4/6 inhibitor compared with another. The data have been reviewed in multiple different publications in a retrospective fashion. The efficacy on visceral metastases and primary resistance has an impact on overall survival.

How may the combination of the novel SERM lasofoxifene plus abemaciclib fit into the paradigm? What do we know about the safety profile of the regimen?

Right now, as we mentioned, in patients with 

 mutations, we have an agent that can safely be administered and show efficacy. Having a new agent that can be combined with a CDK4/6 inhibitor is an important way to deal with specific endocrine-resistant [disease] in which 

The combination [of lasofoxifene] with abemaciclib is very intriguing because it can potentially identify the type of patient for which this particular combination will be tested against the standard of care. The safety profile is very consistent with published data. We need to [identify more opportunities for] testing, particularly with regard to the comparison with standard of care.

Perhaps, moving [the combination] very early on [would be beneficial] because most of these patients now progress on adjuvant therapy. We also know that many of these patients will be candidates for abemaciclib in the adjuvant setting. In the future, particularly for patients who develop resistance, it may be that high-risk detection reveals 

 mutations early on and this combination may be used in the adjuvant setting. A long road lies ahead, but we desperately [continue] to search [for answers], and these new data are encouraging. 

Massimo Cristofanilli, MD, highlights the introduction of CDK4/6 inhibitors, such as abemaciclib, ribociclib, and palbociclib, which has been a significant addition to the hormone receptor–positive, HER2-negative breast cancer armamentarium. 

Overcoming CDK4/6 Inhibitor Resistance in ESR1-Mutant HR+/HER2- Breast Cancer

Sarah Sammons, MD, an assistant professor of medicine in the Department of Medicine and member of the Duke Cancer Institute at Duke University School of Medicine, discusses clinical trials examining lasofoxifene in patients with 

The selective estrogen receptor modulator (SERM) lasofoxifene is a compound that appears to show preclinical activity in patients with 

-mutant breast cancer, says Sammons. This agent is currently under investigation in the phase 2 ELAINE trial (NCT03781063), where its activity will be compared with that of fulvestrant (Faslodex) in pre- and postmenopausal patients with locally advanced or metastatic 

Sarah Sammons, MD, discusses clinical trials examining lasofoxifene in patients with ESR1-mutant breast cancer.

Updates in ESR1-Mutant Breast Cancer | Supplements and Featured Publications

Parsing Out Remaining Questions With CDK4/6 Inhibitors in HR+ Breast Cancer

Lasofoxifene Emerges as Understanding of ESR1 Mutations Expands in ER+/HER2- Breast Cancer

ELAINE-2 Trial Could Establish the Actionability of ESR1 in HR+/HER2- Breast Cancer

Overcoming CDK4/6 Inhibitor Resistance in ESR1-Mutant HR+/HER2- Breast Cancer

Dr. Sammons on Research Efforts Examining Lasofoxifene in ESR1-Mutant Breast Cancer