Chelsea LoCascio

CDK4&6 inhibitors have recently moved to the forefront of the treatment landscape when it comes to hormone-positive breast cancer, experts say.

&ldquo;The CDK4&6 inhibitors have been exciting for the last 3 years, and 2015 welcomed the PALOMA-1 data that really took the clinical science of the CDK4&6 dysregulation in cancers and [worked to inhibit] that with the CDK4&6 inhibitor,&rdquo; said Denise A. Yardley, MD.

In an interview with Targeted Oncology, Yardley, a senior investigator of breast cancer research at Sarah Cannon Research Institute, discussed the promise of CDK4&6 inhibitors in estrogen receptor (ER)-positive breast cancer, as well as the potential with immunotherapy agents.

Can you give an overview of the current state of ER-positive breast cancer?

: There are some changes in the management of hormone receptor [HR]-positive, HER2-negative breast cancer. There are all phases of treatment, such as going to early adjuvant breast cancer treatment recommendations and some of the recommendations with regard to extended adjuvant therapy.

Then, there is a changing standard now for the first-line HR-positive, HER2-negative patients with metastatic breast cancer; that really focused on the changing algorithm to incorporate CDK4&6 inhibitors in the first-line setting. Then, we looked at some data of later-line therapy with some of the recent [FDA] approvals of palbociclib [Ibrance] and abemaciclib [Verzenio]in combination with fulvestrant [Faslodex]. Then, from that, the next topic that was natural was looking at hormone resistance, so we really covered and focused a little bit more on different spectrums of hormone resistance.

What are the current recommendations for adjuvant endocrine therapy?

: The current recommendations for adjuvant endocrine therapy are still evolving. It takes a look at the premenopausal patients and the utilization of tamoxifen in that setting. If we look at the trials that are out there with axillary dissection with access min-imized [ADAM] and adjuvant tamoxifen longer against shorter [ATLAS], and then looking at extending the therapy from tamox-ifen from 5 to 10 years, the data are quite consistent. We have had the data there resonate very well throughout many of the trials. The problem is, is it a one-size-fits-all approach?

What we are learning is we&rsquo;re still tailoring it to the patient and their risks, so we are trying to look at modifiers or even incorporate some of the genomic assays that help distinguish that. When we look at the aromatase inhibitors [AIs], the story is a little more muddy than challenging. We have some trials that are positive, like the MA17R study that looked at 10 years of letrozole after a 5-year backbone of tamoxifen. This showed that there was a disease-free survival [DFS] advantage, but again, it encompassed that patients did well in both groups of that trial, with outcomes of 90% disease-free overall survival.&nbsp;

Now, the NSABP B-42 trial did not echo the same results of MA17R, but the design and the statistics were a little different; however, even though DFS was not overall statistically significant, [it showed that] breast cancer-free interval distance recurrence was a significant finding.

In some of the other trials, looking at the DATA trial and the IDEAL trial, in the subsets of the patients who had tumors that were ER-positive, those subsets who had prior chemotherapy for adjuvant therapy or had high-risk disease were groups who do seem to benefit when we look at subgroup analysis. For the AI, the challenge is to discuss that higher[-risk] patient toleranceto ask, what is their risk of disease recurrence&mdash;to tailor that and pair that with the recommendation of extended adjuvant AI therapy.

What else are we seeing with CDK4&6 inhibitors?

: The initial [approval] was palbociclib; you could affect outcomes and show the doubling of the disease control rate or DFS. In February 2015, that opened the door for accelerated approval of palbociclib in that setting.

The confirmatory trial, PALOMA-2, resonated that the signal was real and reproducible; that went on to lead to an approval this year in March 2017. PALOMA-3 took on a different lookstill wanting to test the role of CDK4&6 inhibitors in the patients with HR-positive metastatic breast cancer but [looking] at patients who have been on prior endocrine therapy, failed that, and then went on to receive fulvestrant with the CDK4&6 inhibitor. It showed that, while advantage wasn&rsquo;t as statistically significant as what we saw in the first-line setting, the signal was clearly there and was statistically significant at 5 months. The margin of benefit was a little bit smaller, but there was a later-line therapy group of patients.

The MONALEESA-2 trial resulted with ribociclib [Kisqali]in combination with letrozole, again in that first-line setting. What&rsquo;s so exciting there is that we saw a great benefit in show-ing that doubling of the progression-free survivals has essentially 1 year before patients are experiencing disease progres-sion with the addition of the ribociclib as the CDK4&6 inhibitor.

Abemaciclib is a little bit different as a CDK4&6 inhibitor in that it looked at a different patient population. [It was in] heavily pretreated patients who had prior chemotherapy and endocrine therapies, and those patients received abemaciclib, a CDK4&6 inhibitor as a single agent. Abemaciclib is a little bit different. It&rsquo;s dosed continuously and not on a 3 weeks on/off schedule, such as palbociclib and ribociclib.

It&rsquo;s continuous dosing and twice-daily dosing. As a single agent, we saw a nice signal in a later-line therapy group of patients. Of course, these patients were all CDK4&6-na&iuml;ve patients. They also embarked on a trial with fulvestrant, as well. It showed benefit in a patient who had a prior line of endocrine therapy.

In September 2017, it received FDA approval in endocrine- and chemotherapy-pretreated patients as a single agent and then endocrine-pretreated patients with fulvestrant. The challenge now is looking at the market of CDK4&6 inhibitors. We have 3 that are FDA approved. Are they all a class of drugs or are there nuances that make each unique? That&rsquo;s what we&rsquo;re trying really sort through at this point. If you look at ribociclib, we see that it has a total 100% inhibition of CDK4 and CDK6, which makes it a little dfferent from palbociclib as well as abemaciclib.

The toxicity profile is what you would expectlargely neutropenia. The other interesting part [from preclinical studies] is that ribociclib does cross into the bloodbrain barrier. Now, we&rsquo;ll see how that evolved. We are waiting for other data, too, with ribociclib. It has also been looked at in the first-line setting in combination with tamoxifen. To this point, all of the other trials have only used the AIs or fulvestrant, so now we&rsquo;re actu-ally going to see tamoxifen roll out. A lot of the patients aren&rsquo;t eligible for the AI or can&rsquo;t tolerate it, so we&rsquo;ll get some exciting data as we move forward with that.

They also had a great quality of life that showed that pain control was apparent as a benefit reported by the patients at an 8-week first assessment. As we start learning how these roll out, how patients tolerate them, and what the administration schedule is, we&rsquo;ll figure out abemaciclib, with those continu-ous dosing in different levels of CDK4&6 and some off-target effects with more gastrointestinal [GI] toxicity. It distinguishes itself with a little less neutropenia, but a little bit more GI toxic-ity. All of that will be a way of moving forwardof us exploring the patient populations a little bit more.

Can you talk about hormone resistance and how pathways are being looked at?

: Hormone resistance is an exploding arena in the HR-positive patients. We&rsquo;ve welcomed the data for BOLERO-2 that put everolimus in combination with exemestane as a standard for patients who are failing endocrine therapy or a nonsteroidal AI. That was our first signal that doublet therapy with an endocrine agent backbone in combination with the targeted agent was effcacious and did improve the outcomes and DFS for patients.

The CDK4&6 inhibitors now have rolled out in advanced patients in the second-line setting. Now, what we&rsquo;re learning is what the other patterns in pathways of resistance are. One of the most exciting [aspects] is ESR1 mutations and our ability to recognize them from even circulating tumor DNA. Some [analyses] that have looked at BOLERO-2 looked at the ESR1 prevalence as anywhere from 25% to 40% in AI-pretreated patients.

If you select a patient who failed on an AI, has an ESR1 mutation, and you have a choice of another steroidal, nonsteroidal AI, or fulvestrant, fulvestrant as a selective estrogen receptor degrade [SERD] has resulted in better outcomes from those patients. Understanding ESR1 mutations and being able to test for them is now helping us make better choices for those patients as the next line of endocrine therapy. It&rsquo;s also opened the door now for a variety of oral SERDs, so while fulvestrant is sometimes a little bit more labor intensive because of the injections, now looking at the potential of having an oral SERD in the market for that population of patients is quite interesting.

As we look at adjuvant patients and recommendations of extended AI therapy, we&rsquo;ll have to see the downstream effect of these patients if they relapse. Test them immediately for the consideration of an ESR1 mutation, and perhaps fulvestrant [combined with] a CDK4&6 inhibitor may be the ideal setting for that, so that&rsquo;s what we&rsquo;re looking for. PI3K has been great in terms of the science behind it.

Everolimus has led us to know that you can interrupt the mTOR/PI3/AKT pathway and improve outcomes in patients with HR-positive metastatic breast cancer. However, in the nearly 20 PI3K trials, none of them have really shown a benefit; there is clearly something different about the PI3K.

Then, there&rsquo;s a class of [drugs] looking at the IGFR pathway, and some of those have been hit-or-miss. None have come to the market, but there&rsquo;s a strong signal there if we can find the right way to interrupt that pathway[it could be] that a ligand binder seems to be attacking the receptors associated with a lot of hyperglycemia. That just doesn&rsquo;t seem to be a way to move forward.

Entinostat, which received a breakthrough designation from the FDA, has been a really exciting drug that we&rsquo;ve also worked with and is currently out in a big phase III trial, hopefully for registration. It also seems to have a great signal with immunotherapy; there&rsquo;s a lot of trials that are looking for that in patients, as well. We are partnering with our pharmaceutical industry to find drugs to attack those pathways, and it likely may be triplet drugs. I know we&rsquo;re looking at ribociclib in combination with exemestane and everolimus, an actually very tolerable combination, and early signals seem to be promising.

What potential is there with immunotherapy in this population?

: The immunotherapy potential is something that we still struggle in the HR-positive arena. There have been a lot of trials looking at it, but none that have had a strong resonating signal as with some of the other so allenge for the HR-positive patients; however, we don&rsquo;t know what these tumors are going to look like after CDK4&6 inhibition and failures, as well.

It&rsquo;s something that&rsquo;s continually being looked at. The signal is there. It&rsquo;s been lowa 10% response rate as a single agent in a heavily pretreated group. HR-positive breast cancer is also very heterogenic. Some of the trials now are taking an approach of partnering the immunotherapy with another biologic target. Whether it would be a CDK4&6 or it&rsquo;s going to be an AKT pathway, a MEK inhibitor, or PI3K, all of that are trials that are just now getting their foothold and then we&rsquo;ll have to look for those results.

What else is important to highlight about this evolving field?

: One of the real excitements that has come from looking at the data and now 3 FDA-approved CDK4&6 inhibitors in the metastatic setting is now rolling these into the adjuvant setting. In that setting, we can potentially improve outcomes for more patients. Many of the trials have rolled out in the adjuvant setting looking at different features. We are still trying to identify the high-risk ER-positive adjuvant or early breast cancer patient. One of the trials that is rolling out, EarLEE-1, is looking at patients who either had neoadjuvant therapy or adjuvant therapy and embracing the new prognostic categories that are emerging now through the eighth edition of the American Joint Committee on Cancer [AJCC]. That will roll out for clinicians in January 2018. That&rsquo;s a very interesting way of selecting patients for a trial and being able to select or predict outcomes.

The change in the AJCC is adding to the anatomic pathology that is the tumor, the nodes, or metastasis. Now, the ER or progesterone positivity, the grade of the tumor, and even incorporating some of the multigene assays in coming into a risk category. For the early EarLEE-1 adjuvant trial with ribociclib, which will be given for 2 years in HR-positive preEarLEE1 or postmenopausal patients. They&rsquo;ll be randomized with an endocrine therapy and ribociclib versus endocrine therapy [alone]. Ribociclib is given for 2 years, so we&rsquo;re going to see in a different patient population how that may improve the outcomes.

Abemaciclib is rolled out in the MONARCH 3 trial, and that&rsquo;s looking at abemaciclib in early-stage breast cancer using a different definition and categories of inclusion criteria to select a high-risk patient population. However, we will also roll out with the 2-year plan of abemaciclib versus just standard endocrine therapy in patients who are given an adjuvant endocrine therapy.

Moving forward, seeing how that may totally alter how we treat early-stage breast cancer HR-positive patients, it&rsquo;s going to be exciting, too. Now, we&rsquo;ll still have to wait some time for those signals; however, at least by selecting the higher-risk population and then subsequent trials, we&rsquo;ll get an intermediate group. Hopefully, we&rsquo;ll get a signal or readout quite early from those trials. What we see now is a new standard in first-line HR-positive, HER2-negative metastatic breast cancerperhaps an evolving standard for certain patients with early-stage HR-positive, HER2-negative breast cancer.

It is becoming so challenging in the management of HR-positive breast cancer because, up until a couple of years ago, we really didn&rsquo;t have a host of trials or new data with regard to science or understanding resistance in those patients. All of it was monotherapy single-agent endocrine therapy. Now, the challenge is that the new standard seems to be combination endocrine therapy, so an endocrine therapy agent with a biologic targeted agent.

Articles

Denise A. Yardley, MD,&nbsp;discusses the promise of CDK4&amp;6 inhibitors in estrogen receptor (ER)-positive breast cancer, as well as the potential with immunotherapy agents.&nbsp;

CDK4&6 Inhibitors Revolutionize Hormone-Positive Breast Cancer Care

Advances in genetic testing are transforming the way breast cancer experts understand risk of recurrence and helping with more accurate treatment selection, explains Laura J. van&rsquo;t Veer, PhD.

&ldquo;We have started to use [genetic testing] to inform screening for breast cancer because the logical thinking is, if somebody has an elevated risk, you want to screen [them] more than if somebody has a very low risk to develop breast cancer,&rdquo; said van't Veer. &ldquo;We can assess that by looking into the genetics of a person, whether somebody has a hereditary mutation in a gene as well as looking at other risk factors and combine it in a risk score.&rdquo;

, van't Veer, director of applied genomics at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, discussed determining more accurate methods of treatment for patients with early- and late-stage breast cancer based on advances in genetic testing, specifically the 70-gene prognostic signature.

Can you touch on some of the current guidelines for genetic testing?

If we look [into the] guidelines in genetic testing, for instance, for women who are diagnosed with breast cancer and who have a family history of breast cancer, their recommendation is to get tested if you have 2 first-degree relatives with breast cancer or 1 at a really young age and you&rsquo;re [young]. Those guidelines for genetic testing are quite clear if it also involves family history, but what is becoming more and more a practice is that the information of genetic risk is relevant for every woman, regardless of her family history.

For every woman, at a given age based on her genetic makeup and risk factors, we can give her an estimate of what [chance] she has of the next 5 years of developing breast cancer. That we use to better guide who needs screening by mammography every year.

Perhaps some women can [do it] every other year; some women who have a very high risk need [a mammography] every 6 months. For women under age 40, more than two-thirds have such a low risk that screening doesn't give any benefit. It does more harm because of false negatives and biopsies. You can much better understand who needs what frequency of screening and the age for somebody to start screening.

Where are we now with testing in late-stage or high-risk disease?

Once somebody is diagnosed, there's another way of using the word "risk" just to make that clear. We look into the biology of the breast cancer. We can recognize if that tumor actually would foretell a high risk of recurrence or a low risk of recurrence. There are a couple of genomic tests available, in which you do your test on the tumor material and you assess whether it is a fast-growing tumor or a slow-growing tumor. That would help determine whether therapy by systemic chemotherapy would be good advice.

These tests, such as Oncotype DX, MammaPrint, and PAM50, can all distinguish these subgroups. It depends how they have been tested in clinical trials. MammaPrint is one I&rsquo;ve been working on for a long time. We also set out to understand [what it means if] somebody is clinically high risk, but the tumor is biologically low risk. Can we derive enough evidence that maybe such patients do not benefit from chemotherapy? That was a large clinical trial among 7000 patients, where we showed that those women [who are] clinically high risk and biologically low risk do not benefit substantially from chemotherapy.

It actually does more harm than good. We start to learn more and more how to apply biology for screening and frequency of mammography in a healthy woman. We start to understand by looking into the biology of the tumor. If that tumor displays factors of high risk of recurrence or low risk of recurrence, we use [that] to guide and advise &ldquo;yes&rdquo; or &ldquo;no&rdquo; [to] chemotherapy.

Can you expand on the utility of the 70-gene prognostic signature, or MammaPrint, entails?

[This was] established 15 years ago on patients whom we had the tumor material [from] that was being &ldquo;banked&rdquo; as we call it, so it was saved. We knew after their diagnosis what their disease course had been. Some women had developed a distant recurrence in metastases and other women, for the longest time, had remained disease free, so our scientific question was &ldquo;Can we actually understand why, and can we recognize why some of these tumors have the capacity to metastasize and others do not?&rdquo;

We actually looked at the 25,000 genes that every cell has and tried to find a pattern of activity of genes that would distinguish the low-risk from the high-risk cancers. We found that 70 genes of the total of 25,000, if they are in the "on" status, display the characteristics of an aggressive tumor that is high likelihood to metastasize. If those 70 genes are in the "off" status, then that means that this is a slow-growing tumor that doesn&rsquo;t have much capacity to invade in surrounding tissue and is not at the capacity to metastasize elsewhere in the body. That was the initial finding of those patients who had donated their tumor material.

We waited some 10 years so that we had their follow-up and that gave us this 70-gene prognostic signature, and then subsequently repeated that finding in other series. However, ultimately, 7000 women chose to participate in this MINDACT trial where they got the standard clinical assessment as well as the 70-gene prognostic signature. Based on whether they were low-low risk, high-high, or discordant (high-low, low-high), particularly the discordant group then was randomized to use either the 70-gene prognostic signature or their clinical assessment for further treatment.

That showed that, for women [who are] clinically high risk but the biology is low risk, that they can safely forgo chemotherapy. That actually reduces overtreatment if that would be applied to all women with breast cancer diagnosed in the United States today. There are some 35,000 women per year who could actually forgo chemotherapy or at least can be considered to forgo chemotherapy.

What is your message to community oncologists about genomic testing?

[There are] questions you need to ask yourself. If somebody is diagnosed with breast cancer, the question is &ldquo;What is the best therapy I can give this woman?&rdquo; However, there's also a question of &ldquo;Does every patient need everything I can give her?&rdquo; Understanding if the biology is high risk or low risk will help to guide that decision.

It's going to reduce overtreatment. For every 100 patients with breast cancer, if you would treat 90 with chemotherapy, you know you're overtreating 60 out of the 90; however, we needed better means to recognize who those are. It's understandable why that wasn&rsquo;t done until recently, but now we have better tools and diagnostic tests that are prognostically tested [that] can help to guide that decision.

Are there any remaining challenges in developing, implementing, or administering these tests that you would like to see addressed in the next 5 to 10 years?

The prognostic tests, as they are called&hellip;are now well established; they're in the 2017 ESMO Congress recommendations. It is just realizing that this is a question that can be answered to get it fully used.

Laura J. van&rsquo;t Veer, PhD, discusses&nbsp;determining more accurate methods of treatment for patients with early- and late-stage breast cancer based on advances in genetic testing, specifically the 70-gene prognostic signature.

Expert Discusses Impact of Genetic Testing in Breast Cancer

As research into early-stage estrogen receptor (ER)-positive breast cancer continues to expand, experts are relying more on extended adjuvant hormonal therapy with aromatase inhibitors, but are concerned with the side effects associated with these therapies.

&ldquo;My passion is to really try to figure out how to make the side effects of&nbsp;these therapies more tolerable and how to help women be able to actually have reasonably good and normal quality of life (QoL) while they're taking these therapies, so that we can increase compliance,&rdquo; said Michelle E. Melisko, MD.

, Melisko, a clinical professor of medicine at the University of California, San Francisco (UCSF), discussed a variety of pivotal trials with adjuvant hormonal therapy and other developments in the treatment of patients with ER-positive breast cancer.

Can you give an overview of your presentation?

I spoke about the value of extending adjuvant hormonal therapy beyond 5 years and reviewed the data from clinical trials looking at extending tamoxifen beyond 5 years, tamoxifen followed by aromatase inhibitors, and the most recent data looking at aromatase inhibitors for 5 years versus 10 years.

It's been a very confusing time over the past year, because there have been several large clinical trials that reported out within 6 months of each other that seem to have disparate results. One was a positive trial suggesting&nbsp;that we should continue hormonal therapy, mainly an aromatase inhibitor, beyond 5 years. The second suggested that we shouldn't.&nbsp;But when we take a deeper dive into data, we realize that the results of these trials are very similar, and it simply has to do with the differences in the outcomes or resultsone was statistically significant&nbsp;in favor of extending [therapy] and the other was not.

It has to do with the definitions of the endpoints, the patient population, and what they defined as being a statistically significant outcome. I spoke about that and hopefully it resolved some controversies and help oncologists understand a practical approach that I take to discussing this with patients in making it a very individualized&nbsp;decision. I also spoke a little bit about neoadjuvant endocrine therapy in advance of surgery.

We can give some form of treatment before surgery to improve the chances of a patient having breast-conserving surgery, and we are also able to risk stratify to help us understand which patients are going to have good outcomes after surgery and which won&rsquo;t. In some tumor types, primarily strongly ER-positive cancers, the rates of the cancer going away completelywhat we call pathologic complete response (pCR)&mdash;is very low in strongly ER-positive&nbsp;cancers. Using chemotherapy might not be the optimal approach, so I spoke about some of the data comparing neoadjuvant endocrine therapy with neoadjuvant chemotherapy to help the community of oncologists understand what we at an academic center do to guide our treatment recommendations for women who have&nbsp;these large, but potentially more biologically&nbsp;indolent, cancers.

How has treatment changed over the past couple of years?

At the 2017 ASCO Annual Meeting, there was a presentation about the MA17R study. This was a follow-up of a very well-known trial where patients who originally received&nbsp;5 years of tamoxifen were randomized to receive&nbsp;either placebo or an aromatase inhibitor.

More than 10 years ago, we found out that continuing with an aromatase inhibitor was beneficial. However, this trial looked at the MA17R component, the &ldquo;R&rdquo; being the extension of an aromatase inhibitor beyond those 5 years.&nbsp;There were some women in this trial who had received&nbsp;hormonal therapy for as long as 15 years, and they looked at the added benefit of continuing an aromatase inhibitor for 10 years compared with 5. That trial did meet a statistically significant endpoint&nbsp;of reducing recurrence and improving disease-free survival.

At that time, it was a practice-changing data point. I came home from that meeting telling patients who were coming in, after having taken 4.5 or 5 years of an aromatase inhibitor, to say we now have data that say that they should continue this for 10 years. Fast forward about 6 months to the NSABP B-42 trial, which had a similar&nbsp;design but [included] patients who perhaps had never taken an aromatase inhibitor. They started out taking tamoxifen, took an aromatase inhibitor for 5 years, and then they were randomized to continue it for another 5 years or just stop.

In that trial, there was also a reduction in recurrences, but it did not meet the statistically significant endpoint. One of the big differences that I&rsquo;ll point out in my presentation is that the definition&nbsp;of a recurrence event is different in these 2 trials. One includes the events of other cancers and one doesn't.

Because of these subtle differences, one ended up being a positive study and one didn't. The NSABP B-42 trial did not meet its endpoint of showing that continuation of an aromatase inhibitor was statistically significant. However, when you look at them side by side, look at the hazard ratios, and you look at how much they reduce the risk of a distant recurrence, they both were very similar.

Also, what are the consequences for continuing the hormonal&nbsp;therapythe aromatase inhibitor&mdash;for more than 5 years in terms of cardiac events, atherothrombotic&nbsp;events, or osteoporotic fractures? A lot of patients worry about that. When it comes down to taking a pill for another 5 years, and realizing that it may only be a 1% to&nbsp;2% further reduction risk of recurrence, patients are not going to buy into it.&nbsp;

Do you believe that there is a role for chemotherapy in the neoadjuvant setting?

Absolutely. We have compelling data that are very advantageous to offer treatment before going to surgery for some patients&nbsp;who have large tumors, node-positive tumors, or biologically high-risk cancers. There are a number of different ways that we can actually characterize the tumors as being more biologically high risk through prognostic and predictive markers.

I'm at an institution, UCSF, where we are the leaders in a multicenter, national, and soon-to-be international clinical trial called I-SPY where we look at neoadjuvant chemotherapy in combination with experimental therapies to try to improve the rates of pCR, which we know and believe is associated with better outcomes in certain biological subtypes such as triple-negative breast cancer or HER2-positive breast cancer.

The challenge we face is that, for ER-positive disease or also HER2-negative disease, achieving a pCR is a nice thing, but it happens rarely. Therefore, chemotherapy may not be the best way to get there for those ER-positive cancers, particularly those with low proliferation rates. That's why looking at neoadjuvant endocrine therapy, particularly now in combination with biological therapies such as CDK4/6 inhibitors, may be a better approach for those types of cancers.

What agents coming down the pipeline look promising?

Now, it's not a matter of what's coming down the pipeline. All three CDK4/6 inhibitors are now FDA approved; palbociclib (Ibrance) has been FDA approved now for several years for ER-positive metastatic breast cancer in combination with both aromatase inhibitors and fulvestrant. Within the past year, ribociclib (Kisqali) gained FDA approval and then [recently] abemaciclib (Verzenio) gained FDA approval. These are all drugs that are, at this point, only approved in the metastatic setting for ER-positive disease.

There are multiple trials going on looking at these drugs in women with&hellip;high-risk early-stage breast cancer to see if adding them to hormonal therapy will reduce the risk of recurrence. We don&rsquo;t have any data on that yet. Areas of further exploration are looking at the value of these drugs in combination with HER2-targeted therapies in patients who have ER-positive/HER2-positive metastatic disease and then also trying to define whether we will prove that these drugs have value in the early-stage setting.

If any of these trialsPALLAS and PENELOPE&mdash;end up being positive studies, everyone is going to want to extrapolate that data to lower-risk patients. These medications are not without [adverse] effects, such as fatigue and neutropenia. The question is, &ldquo;How low do you go in terms of absolute benefit to recommend something&nbsp;that is very costly and can also impact QoL?&rdquo;

What was your take-home message for the audience who sat in on your lecture?

It's all about personalized medicine, and there is a lot of fanciness around next-generation sequencing, but we must remember that endocrine therapy is our oldest and most tried-and-true&nbsp;targeted therapy for breast cancer, and recognizing&nbsp;that tailoring your approach to targeting endocrine therapy for each individual patient is important.

Chelsea LoCascio | Authors

Articles

CDK4&6 Inhibitors Revolutionize Hormone-Positive Breast Cancer Care

Expert Discusses Impact of Genetic Testing in Breast Cancer

Expert Discusses QoL Concerns With Extended Adjuvant Hormonal Therapy in ER+ Breast Cancer