Breast cancer is the fifth leading cause of cancer death in the United States, with more than 40,000 estimated deaths in 2017.

Many therapies for patients with breast cancer focus on targeting cancer cell proliferation, with a goal to divert cells to a more senescent phenotype.

Deregulation of the cyclin-dependent kinase (CDK) 4&6retinoblastoma (Rb) axis has been demonstrated to contribute to unrestricted growth that is characteristic of many cancers, including breast cancer. &ldquo;CDKs interact with cyclin D proteins to play an integral role in cell cycle progression, and represent attractive therapeutic targets in many tumors, including breast cancer,&rdquo; noted Conleth G. Murphy, MD, of Bon Secours Hospital, Cork, Ireland, and Maura N. Dickler, MD, of Memorial Sloan Kettering Cancer Center, New York, in The Oncologist.

A hallmark of cancer cells, unrestricted growth is often associated with disordered cell cycle regulation.

The cell cycle includes steps that are highly regulated and coordinated by transient activations of cyclins and CDKs.

Together, these elements form bipartite complexes that phosphorylate proteins and transcription factors, which enable the cell to move through the cell cycle.

CDKs are serine/threonine kinases that affect the G1-S phase transition of the cell cycle, which is mediated by an action on the Rb protein (FIGURE).

Rb and the p107 and p130 proteins have been shown to play a key role in cell cycle regulation through exerting a braking influence on cell proliferation in the early G1 phase.

While hypophosphorylated, the Rb protein sequesters proliferative cellular proteins that are released via CDK4&6&minus;cyclin D1 mediated hyperphosphorylation of Rb. These sequestered proteins include the E2F transcription factors that control gene expression that is essential for moving through the cell cycle from G1 to S phase.

When Rb is hyperphosphorylated, transcription factors that initiate DNA replication are released, leading to activation of dihydrofolate reductase, histone H2A, thymidine kinase, and DNA polymerase alpha.

The CIP/KIP and INK4 protein families mediate negative regulation of CDK4&6&minus;cyclin D1.

The INK4 proteins inhibit D-type cyclin activity through selective interaction with CDK4 and CDK6. This inhibition mechanism involves interaction between the p16- and CDK6-charged binding domains that results in reduced kinase activity and a decreased cyclin-binding surface.

Cyclin D1 is susceptible to extrinsic mitogenic stimulation, which provides a link between the external environment and cell cycle machinery.19 Because of the modulatory control over Rb and the resulting function in promoting cellular proliferation, it has been hypothesized that deregulation of cyclin D1 and CDK4&6 may promote tumorigenesis and tumor maintenance.

Many tumors have been shown to increase cyclin D&minus;dependent activity and to avoid senescence via numerous mechanisms, including p16 inactivation, CDK4 mutation with loss of INK4 binding, CDK4 amplification, overexpression of cyclin D1, or translocation or amplification of CCND1, its encoding gene.

The development and maintenance of certain breast cancers may require cyclin D1, as mice lacking cyclin D1 or CDK4 have demonstrated resistance to implanted breast tumor growth driven by human epidermal growth factor receptor 2 (HER2)/neu.

In breast cancer, multiple mechanisms are involved in frequently reported deregulation of CDK4&6&minus;cyclin D1 activity.26,27 For example, in a cancer genome study of 482 patients with invasive breast cancer, 27.4% exhibited genetic deregulation of the cyclin D1/CDK4&6/p16INK4a pathway.

Approximately half of investigated breast cancer cell lines exhibit cyclin D1 overexpression.

In about 16% of breast cancers, CDK4 may be overexpressed via amplification of the CDK4 gene at 12q13-q14.29 CCND1 amplification has been reported in 38% of HER2-positive breast cancers, 29% of luminal A cancers, and in 58% of luminal B cancers.

Altered function of inhibitors of CDK have also been reported in breast cancer, including p16INK4a, p21WAF1/CIP1, and p15INK4b.

Murine breast cancer models have demonstrated that cyclin D1&minus;CDK4&6 axis activation contributes to a tumorigenic phenotype and is crucial for tumorigenesis in HER2-positive breast cancer.

However, viability and normal mammary development are not adversely affected when CDK2 or CDK4&6 are knocked out.

Cyclin D1 has been shown to induce chromosomal instability via transcriptional regulation of CIN-related genes.

A role for cyclin D1 has also been implicated in cellular migration and invasion, DNA damage-sensing and repair, inhibition of mitochondrial metabolism, and angiogenesis enhancement.

These functions are mostly independent of any CDK4&6 interactions and are not thought to be affected by CDK inhibition. Recently, however, CDK6 was reported to have a kinase-independent angiogenesis function, which suggests an alternative role for CDK6 inhibition in tumor therapy.

Estrogen receptor (ER)positive breast cancers have been shown to be dependent on estrogen signaling for both proliferation and survival.

ER inhibition has also been reported to reduce tumor cell viability and cell cycle arrest in the G1 phase.

Furthermore, ER signaling upregulates cyclin D1 levels, stimulating various signaling pathways that subsequently upregulate CDK4&6 activity.

Acquired resistance and lack of response to hormone-based therapies for ER-positive breast cancers may be mediated by deregulation of alternative pathways, such as HER2 and PI3K/AKT, that may induce cyclin D1&minus;CDK4&6 signaling. Cyclin D1 has also been shown to independently activate ER, with a majority of breast cancers that overexpress cyclin D1 being ER-positive.

Most breast cancers maintain intact or functioning Rb, with loss of Rb expression occurring in just 20% to 35% of breast cancers.

Loss of the Rb protein is more frequently reported in triple-negative breast cancer compared with other subtypes.

The inactivation of Rb contributes to tumor progression via proliferation control loss and conversion to a phenotype that is invasive. Generally, this is associated with poor differentiation and an increased metastatic potential. Without functional Rb, cell-to-cell adhesion is disrupted, facilitating the epithelial&minus;mesenchymal transition, which may contribute to the increased frequency of metastases.

In ER-positive tumors, Rb dysregulation is associated with poor prognosis, whereas it is associated with improved outcomes in ER-negative tumors.

These reported differences in outcomes may be a result of different responses to therapy, as loss of Rb has been demonstrated to increase sensitivity to DNA-damaging agents but leads to continued proliferation with tamoxifen treatment.

CDK4&6 inhibitors contribute to G1 phase cell cycle arrest by preventing the phosphorylation of Rb, which may lead to the inhibition of tumor progression in breast cancer and other cancer types. Despite oncogenic signals that are insensitive to endocrine therapy, CDK4&6 inhibitors effectively prevent cell cycle progression and mitosis.

Patients who have loss of Rb expression do not benefit from CDK4&6 inhibitor treatment due to the downstream position of Rb compared with CDK4&6 in the cell cycle.

The selectivity of palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)3 FDA-approved CDK4&6 inhibitors&mdash;is thought to be related to binding to the specialized adenosine triphosphate (ATP)&minus;binding pocket of CDK4&6 with specific residue reactions in the ATP-binding cleft.

CDK4 and CDK6 are structurally related proteins that have biological and biochemical similarities and are considered functionally equivalent in their ability to phosphorylate Rb.

CDK4 and CDK6 have overlapping functions and share nearly 75% of amino acid identity.

CDK4&6 are expressed in most cell types and can partner with cyclin D1, D2, and D3.

Palbociclib, ribociclib, and abemaciclib bind to the ATP cleft of CDK4 and CDK6. Abemaciclib has been shown to bind more readily to the ATP cleft, forming a hydrogen bond with a conserved catalytic residue, suggesting that it binds less selectively than ribociclib and palbociclib.55 Palbociclib and ribociclib seem to have greater lipophilicity and larger side chains at the binding site compared with abemaciclib, which may reduce interactions with off-target kinase ATP-binding pockets. A study demonstrated that ribociclib exhibited significantly higher selectivity toward CDK4 and CDK6 compared with palbociclib, which interacted with more than twice as many kinases as did ribociclib.

Additionally, a study of palbociclib in molecularly characterized human breast cancer cell lines showed that ER-positive cell lines with luminal features were the most sensitive to palbociclib, whereas basal cell lines were the most resistant to palbociclib.

Promising preclinical evidence demonstrating the potential therapeutic capability of targeting the cyclin D1&minus;CDK4&6&minus;Rb axis resulted in the development of first-generation CDK inhibitors. Flavopiridol (alvocidib), an intravenous pan-CDK inhibitor, was the first to enter clinical trials based on inhibitory activity in vitro against all human tumor cell lines contained in the tumor cell line panel from the National Cancer Institute.

Results of clinical trials investigating flavopiridol monotherapy have been mixed.

Increased antitumor efficacy was reported for the combination of flavopiridol and chemotherapy agents that promote S-phase accumulation.

In a phase I trial of patients with breast cancer and other solid tumors, encouraging results were reported following weekly administration of sequential docetaxel (Taxotere) and flavopiridol.

Complex pharmacokinetics and dose-limiting toxicities have complicated the use of flavopiridol, however. Distal cellular effects associated with flavopiridol treatment include transcriptional suppression, apoptosis, autophagy, and endoplasmic reticulum stress, which have been associated with high rates of dose-limiting toxicities, including hyperglycemia, neutropenia, and cardiac and pulmonary dysfunction.

Based on the low CDK specificity and the narrow therapeutic window, the development of flavopiridol was discontinued.

Seliciclib (roscovitine) as monotherapy demonstrated minimal disease stabilization in phase I studies of patients with solid tumors.

Seliciclib inhibits CDK4&6 poorly, but also inhibits CDK1, CDK2, CDK7, and CDK9.

Second- and third-generation CDK inhibitors have been developed, including compounds with specificity for CDK4 and CDK6. Second-generation inhibitors started to show preferential inhibition of specific CDK subtypes, with initial efforts primarily focused on inhibition of CDK2 due to crystallographic structure availability.

Later, highly selective inhibitors, including palbociclib, ribociclib, and abemaciclib, were evaluated through chemical screening and optimization by adding pyrido[2,3-d] pyrimidin-7-one compounds with a side chain of 2-amino pyridine at the C2 position.

The major CDK inhibitors (palbociclib, ribociclib, and abemaciclib) currently are orally administered and have limited suppression of other CDK activities. These inhibitors have structures analogous to those of flavopiridol, but have different chemical functions.

Cyclin D1 overexpression has been reported in the majority of breast cancers.

Mice lacking cyclin D1 have been shown to be resistant to mammary carcinomas triggered by the oncogene ErbB-2. The crucial role for cyclin D1 in breast cancer formation is the activation of CDK4.

The continued presence of CDK4-associated kinase activity has also been shown to be required for the maintenance of breast tumorigenesis. A study investigating knock-in mice expressing kinase-deficient cyclin D1&minus;CDK4 complexes demonstrated that these mice develop normally; however, these mice demonstrated resistance to mammary carcinomas triggered by ErbB-2.22 &ldquo;These results point to a differential requirement for cyclin D1&minus;CDK4 kinase activity in mammary neoplasia versus in development,&rdquo; noted a team led by Qunyan Yu, MD, of Dana-Farber Cancer Institute, Boston, Massachusetts, in Cancer Cell.

&ldquo;These findings suggest that the pharmacological inhibition of CDK4 kinase might preferentially target breast cancer cells. Our findings will hopefully stimulate therapeutic strategies aiming at blocking CDK4 kinase activity in patients.&rdquo;

GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. World Health Organization/International Agency for Research on Cancer website. globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed November 24, 2017.

Cancer stat facts: female breast cancer. National Cancer Institute/Surveillance, Epidemiology, and End Results Program website. seer.cancer.gov/statfacts/html/breast.html. Accessed November 24, 2017.

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Articles

Clinical Articles

The second most common cancer worldwide, breast cancer remains a significant global burden despite decreased incidence in Western countries.&nbsp;Breast cancer is the fifth leading cause of cancer death in the United States, with more than 40,000 estimated deaths in 2017.

Rationale For CDK4&6 Inhibition in Breast Cancer

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.

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

A trio of cyclin-dependent kinase (CDK) 4&6 inhibitors have continued to revolutionize the field of breast cancer, explains Richard S. Finn, MD, adding that at some point in a patient&rsquo;s course of treatment, a CDK4&6 inhibitorwhether palbociclib (Ibrance), ribociclib (Kisqali), or abemaciclib (Verzenio)&mdash;should be administered.

Palbociclib was approved by the FDA in February 2016 for use in combination with fulvestrant (Faslodex) in pretreated patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, based on results of the phase III PALOMA-3 trial. Palbociclib was initially granted approval by the FDA for use in combination with letrozole as a frontline treatment for postmenopausal women with estrogen receptor (ER)&minus;positive, HER2-negative metastatic breast cancer.Second, the FDA approved ribociclib for use in combination with an aromatase inhibitor (AI) for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer. This decision was based on findings from the phase III MONALEESA-2 trial.

Finally, in September 2017, the FDA approved abemaciclib for use in combination with fulvestrant in women with HR-positive/HER2-negative advanced breast cancer with disease progression following endocrine therapy; the basis for the approval came from the MONARCH 2 trial. Abemaciclib was also approved as a single agent for patients with HR-positive/HER2-negative disease with metastatic disease who have previously received endocrine therapy and chemotherapy. The single-agent indication was considered based on the MONARCH 1 trial.

All 3 of the CDK4&6 inhibitors have demonstrated comparable levels of efficacy, but there are subtle mechanistic and toxicity differences, Finn added.

In an interview with Targeted Oncology, Finn, an associate professor of medicine at the Geffen School of Medicine at the University of California, Los Angeles, covers the evolution of CDK4&6 inhibition in the field of breast cancer and appropriately selecting patients for this type of therapy.

Richard S. Finn, MD,&nbsp;covers the evolution of CDK4&amp;6 inhibition in the field of breast cancer and appropriately selecting patients for this type of therapy.

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