 One of the great things that the pharmaceutical teams have been doing with these studies in the use of CDK 4/6 inhibitors is doing really long-term follow-ups for these patients. That's been very important because it's allowed each of the CDK 4/6 inhibitors abemaciclib, ribociclib, and palbociclib to demonstrate a survival benefit, not just progression-free survival, but an overall survival benefit as well. That's been really powerful because for a long time in the space of ER-positive metastatic breast cancer, there had been a bit of nihilism that we actually couldn't demonstrate a survival benefit because patients might get so many lines of therapy and all these things. These drugs are really important and they do improve overall survival. So, there is credit to the teams for doing all that.

What we saw recently at the 2021 San Antonio Breast Cancer Symposium meeting were long-term follow-ups of the MONARCH 2 and -3 trials of fulvestrant with or without abemaciclib. Those studies continue to show several important things. One is that the regimen is reasonably well tolerated. There are no late toxicity signals that emerged. We spoke a moment ago about the major side effects of abemaciclib, which can include diarrhea and neutropenia, but again, for most patients, this is a manageable set of adverse events. Obviously, the progression-free survival data were well known. What these studies both now show are trends favoring a survival benefit—in some instances, statistically significant survival benefit. I think even more important is clinically compelling data that there's a survival gain for our patients. So, very important long-term follow-up shows no new problems with safety and persistent deep long-term benefits for use of abemaciclib in that setting.

The broad clinical implication is that this class of drugs clearly improves overall survival in metastatic ER-positive breast cancer. These should be the standard of care and they are, and they're widely used and very successful products. In terms of this drug versus the others, there have been very similar reports from the MONALEESA series of trials and from the PALOMA series of trials using ribociclib and palbociclib respectively. So, I think that my own interpretation is that this is a class effect for these drugs, and that all of these drugs have a very similar impact on progression-free and overall survival. Mostly the decision to use them is based on patient tolerability and the desired adverse event profile.

Videos

Expert perspectives on the pooled analysis from MONARCH 2 and MONARCH 3, combining frontline abemaciclib with fulvestrant.

MONARCH 2 and MONARCH 3: Pooled Analysis of Abemaciclib + Fulvestrant

: Ribociclib is a novel CDK4/6 inhibitor that, like the others, has been shown to improve progression-free survival in advanced hormone receptor-positive HER2-negative breast cancer. This drug is dosed 3 weeks on and 1 week off. From its pivotal studies, we've seen that it is generally well-tolerated. Like other CDK4/6 inhibitors it has a class effect—it does cause some bone marrow suppression, mostly leukopenia and neutropenia—but the incidence of neutropenic fever is relatively uncommon. There are also some guidelines to do ECG [electrocardiogram] monitoring at the beginning of treatment with ribociclib, only to monitor for some QTC prolongation that can occur, and in that regard, to be cognizant of other drugs a patient might be on that can prolong the QTC. However, with that being said, this drug is very well tolerated and is broadly used in this space, and that is supported by several phase 3 studies.

MONALEESA-2 was a study that looked at ribociclib in combination with an aromatase inhibitor, either letrozole or anastrozole, and interestingly, MONALEESA-3 was generally looking at a population of patients who had not had a prior CDK inhibitor and who had progressed on an AI [aromatase inhibitor], and that was in combination with fulvestrant. The comparator studies with the other compounds would be PALOMA-3 or MONARCH-2 with palbociclib and abemaciclib respectively. Uniquely in MONALEESA-3, they also had a frontline population. This was a population that got ribociclib and fulvestrant in the frontline setting. Now there's been a lot of interest in using endocrine treatment in the frontline setting even if we go back historically before the introduction of CDK inhibitors. However, studies looking at AIs versus fulvestrant really did not show a significant improvement in outcomes in the general population with the use of fulvestrant. Given that it's intramuscular, a lot of us and patients tend to prefer an oral regimen in that setting. However, we now see that both an AI and ribociclib as well as fulvestrant and ribociclib are yielding significant improvements in overall survival.

These were secondary end points in these studies, and they are very convincing that the use of CDK4/6 inhibitors is pivotal in our patients with ER+ HER2-negative breast cancer. When we look at the subgroups from these studies, we're not able to identify a group that does not get a benefit from the addition of a CDK inhibitor to AI or fulvestrant. When we look at several clinical subgroups such as disease-free interval performance status, age, visceral versus nonvisceral disease, or bone-only disease, there are very consistent benefits. We have not been able to really identify a clinical group of patients that does not benefit from this class. Also, we've been looking for biomarkers, and there have been some molecular profiling studies done from the MONALEESA studies, looking at molecular subtypes of breast cancer such as the luminal A, luminal B, and HER2-enriched. Keep in mind, clinically, when we assess these patients in practice, we're just using estrogen receptor, progesterone receptor, and HER2. However, we do know that there are distinct molecular subtypes that have different prognoses, but they are not necessarily predictive of response. What I mean by that is that regardless of the subtype of breast cancer based on molecular profiling, there's still a consistent benefit to the addition of a CDK inhibitor to endocrine treatment. That we have seen in the recent data coming out of the MONALEESA studies, as well as with the studies with palbociclib and abemaciclib as well.

Highlights from the MONALEESA-2 and -3 trials combining frontline ribociclib with endocrine therapy in patients with HR+/HER2- metastatic breast cancer.

MONALEESA-2 and MONALEESA-3: Frontline Ribociclib + Endocrine Therapy

: One of the secondary end points for most of the CDK4/6 phase 3 registration studies has been to analyze quality of life and delay in the use of chemotherapy. One of the first analyses reported with regard to the PALOMA-3 study, which had a targeted population more at risk, showed a significant improvement in the delay of chemotherapy use in these patients, and subsequently did not show any…of the prior use of CDK4/6 inhibitors on the benefit of subsequent chemotherapy used at the time that the physician felt appropriate. You can imagine that anything between 18 and 24 months delay in chemotherapy use has a significant impact on the quality of life of these patients, irrespective of the chemotherapy, since we know that the majority of chemotherapy major adverse effects are quite different from the toxicity profile of a CDK4/6 inhibitor.

This has been shown as an…analysis of the phase 3 PALOMA-2 and PALOMA-3, which were consistent in these 2 studies, and other studies as well later. The delay in chemotherapy was an important end point, shown later also in the MONALEESA-3 study. Essentially, as I mentioned, this is one of the secondary end points of this phase 3 registration study for CDK4/6. It’s important and significant for women who have been diagnosed with this disease that is now becoming treated more as a chronic condition, with overall survival of 25% to 40% at 5 years, indicating that this patient would remain on this treatment for a longer time. At some point, it will be necessary to introduce chemotherapy, but it will be much later in the natural history of their disease.

There are different conditions with regard to patients with metastatic disease. In these studies, we have looked very carefully, for example, at site of recurrence. Patients with visceral metastases, liver metastases, have the most aggressive type of metastatic disease, even in hormone receptor-positive disease, and use chemotherapy earlier compared to patients with bone-only disease. Irrespective of that, there is an improvement and a delay in chemotherapyalso in patients with visceral metastasis, and with liver metastasis, which is most aggressive and more difficult to treat. We will say across the board, irrespective of the type of recurrence and type of progression and the organ involvement, the combination with a CDK4/6, in this case with PALOMA-2 or PALOMA-3 with Ibrance [palbociclib], was able to delay the use of chemotherapy.

Time-to-chemotherapy results of the PALOMA-2 and -3 trials in HR+/HER2- metastatic breast cancer, which combined frontline palbociclib and endocrine therapy.  

PALOMA-2 and PALOMA-3: Time to Chemotherapy on Palbociclib + Endocrine Therapy

 I think it’s become somewhat of a patient and clinician preference as to whether patients start with an AI [aromatase inhibitor] or fulvestrant. We do have data that suggest that fulvestrant is active after patients have had an aromatase inhibitor. For patients who are progressing on an adjuvant AI, they would probably go to an AI and fulvestrant as their first-line treatment since they’re progressing on AIs. However, I think for most patients who have newly diagnosed advanced disease and who have not had an AI or endocrine treatment within the past year, many of us would favor going with a combined oral regimen. This would be either letrozole or anastrozole in combination with one of the CDK4/6 inhibitors. Again, for a patient who has had adjuvant aromatase inhibitors and has a short disease-free interval, less than a year, or is progressing already on that AI, then a fulvestrant-based CDK regimen would seem to be appropriate.

 The choice between an aromatase inhibitor or fulvestrant in the first-line setting depends on the patient’s prior therapy. If they have been on an aromatase inhibitor recently, or are currently on an aromatase inhibitor as part of their adjuvant treatment program at the time of cancer recurrence or the diagnosis of metastatic disease, then we usually go for fulvestrant. By contrast, if they are several years removed from treatment with an aromatase inhibitor, or if they’ve never had an aromatase inhibitor in the past, then we typically go with the aromatase inhibitor because of the convenience of the oral medication, as opposed to the intramuscular injection that is required for fulvestrant treatment.

We also mentioned briefly a moment ago the 

 mutation status. Increasingly, we are getting genomic sequencing of tumors at the time of recurrence, and that can be done either on a tissue biopsy, which is always a good idea to make sure you’re dealing with a known breast cancer recurrence, and to retest things like estrogen receptor and HER2 markers. But increasingly, we are doing genomic sequencing of those, or we are doing so-called liquid biopsies, where they look for circulating tumor DNA. In those specimens, you can analyze the tumor to see if there is acquisition of an 

 mutation. That’s a common finding in about half the cases that progress or recur on aromatase inhibitor therapy. And in such cancers, our general preference is to use fulvestrant or a SERD [selective estrogen receptor degrader] because we think the outcomes are better with the use of those drugs in the setting of an 

 mutation than with an aromatase inhibitor.

For nearly all patients who have ER [estrogen receptor]-positive metastatic breast cancer, we are including a CDK4/6 inhibitor as part of their first-line treatment in combination with endocrine therapy, be it either an aromatase inhibitor or fulvestrant. We do that because many studies have shown that each of the CDK4/6 inhibitors, when paired with an endocrine backbone, improve the progression-free survival. We also have data from all sorts of studies that it improves overall survival for women with ER-positive metastatic breast cancer. We’re now seeing median overall survival in excess of 5 years for many patients who are getting the combination of endocrine therapy plus a CDK4/6 inhibitor. That’s tremendous progress. 

For most women, the CDK4/6 inhibitors are reasonably well tolerated, but there are few patients who might have adverse effect situations or other particular instances where we might not use a CDK4/6 inhibitor. One would be if there’s a particular concern about neutropenia. One of the adverse effects of CDK4/6 inhibitors is neutropenia. So, for a patient who has recently had surgery, or who has open skin wounds or skin tumor involvement, and you want to get an initial response with endocrine treatment, you might hold off on the CDK4/6 inhibitor for a little while. Some patients have minimal cancer burdens, a tiny lymph node, or a pulmonary nodule, or an isolated bone lesion. And for those patients, there’s always the opportunity to defer a CDK4/6-based regimen to second-line treatment. For many women, they might begin with endocrine therapy alone if they have a minimal cancer burden. Then you might add the CDK4/6 inhibitor later. But just to be clear, for the vast majority of patients, it’s combining a CDK4/6 inhibitor with their standard endocrine therapy.

There are 3 commercially available CDK4/6 inhibitors: abemaciclib, ribociclib, and palbociclib. In the metastatic setting, these drugs all look surprisingly similar in terms of their success rates for improving progression-free and overall survival. Palbociclib and ribociclib are really similar drugs. They are given on a very similar schedule of 3 weeks on and 1 week off, and their major adverse effects include neutropenia. They can also cause some diarrhea and some skin rashes, but those are less common. Abemaciclib is a slightly different product, it’s given twice a day, it’s given continuously, and it has diarrhea as a more common adverse effect than neutropenia. Though, you can see neutropenia with abemaciclib. We tend to use a lot of palbociclib, which was the first drug to market. Our teams have a lot of experience with it, and it’s generally a very well-tolerated drug. We know that the 125-mg dose can be safely lowered to 100 mg if patients have neutropenia without compromising the efficacy of the drug. I’ve got to say for our patients, it’s often a very well-tolerated drug with less diarrhea in particular than is occasionally seen with the abemaciclib. But there isn’t any reason to be dogmatic about choosing one of these drugs over another, and I know that different cancer centers might have preferences for different products.

Shared insight on how best to select frontline therapy, alone or in combination, for patients with HR+/HER2- mBC.

Factors in Selecting Frontline Therapy for HR+/HER2- Metastatic Breast Cancer

 The first thing to say is that estrogen receptor [ER]-positive, HER2-negative breast cancer is the most common kind of both early stage and metastatic breast cancer. Treating patients with this variant or flavor of breast cancer is a really important public health issue, as well of course, as an issue for individual clinical teams, and obviously for patients themselves. We usually begin treatment with anti-estrogen therapies. This can be an aromatase inhibitor, or if the patient has had adjuvant therapy with an aromatase inhibitor, it often is a so-called SERD [selective estrogen receptor degrader], such as fulvestrant. Nowadays, we tend to combine these with targeted treatments.

A typical first-line regimen would be either an aromatase inhibitor or fulvestrant in combination with a CDK4/6 inhibitor, because many studies have now shown that the addition of the CDK4/6 inhibitors will improve progression-free and overall survival. In the second line of treatment, we often continue that combination of endocrine therapy with a targeted drug. There are products like everolimus, which is an mTOR inhibitor that can extend the utility of endocrine therapy. Similarly, for women whose tumors harbor a 

 mutation, there is the option of alpelisib, which is another targeted therapy used in combination with endocrine treatment. A small number of patients will be candidates for multiple lines of endocrine therapy. But after adjuvant treatment and then usually a couple of lines of endocrine treatment in the metastatic setting, most patients whose tumors are resistant to endocrine therapy at that point will need to consider chemotherapy. There are many lines of chemotherapy that we use to control ER-positive hormone therapy-resistant metastatic breast cancer for such patients. That’s what our standard approaches look like circa 2022.

There’s a lot of heterogeneity in the first-line setting because it depends on what the patient has had in the early stage or adjuvant setting. The majority of patients who are diagnosed with metastatic breast cancer have previously been diagnosed with early stage breast cancer and then have had adjuvant treatment. And despite that adjuvant treatment, they have subsequently had a recurrence of the breast cancer. For many women that will mean that they’ve already had, for instance, either tamoxifen or an aromatase inhibitor, or some combination of tamoxifen and aromatase inhibitor. If that’s the case, then we often go with fulvestrant as our endocrine backbone in the first line of therapy, and we would pair that with a CDK4/6 inhibitor. If the patient has truly de novo disease, or if it has been a long time since they were exposed to either tamoxifen or an aromatase inhibitor, we will typically go with an aromatase inhibitor in the first-line setting because of the convenience of the oral medication. Some women are premenopausal at the time of diagnosis of metastatic ER-positive breast cancer. If that’s the case, then one of the other first things we do is suppress ovarian function so they are essentially postmenopausal, and then they are candidates for either an aromatase inhibitor or fulvestrant.

There are many different challenges of managing hormone receptor-positive metastatic breast cancer. One of the common questions is, does a patient need chemotherapy or hormonal therapy initially? Many women who present with metastatic disease will have somewhat limited metastatic disease, bone dominant, or bone-only metastatic disease, or limited sites of disease elsewhere in the body. For most of those women, endocrine therapy should be the initial therapy. A few patients will present with more extensive cancer burdens, particularly including extensive disease in the lung or the liver. Sometimes because of the extent of visceral disease, you have to start with chemotherapy to get control of the cancer, drive down the overall tumor burden, and then switch to a sort of maintenance phase of endocrine therapy, if you will.

The second, larger biological issue is the fundamental problem of resistance to endocrine therapy. We know clinically that many tumors become resistant to endocrine treatment, and we’re learning more about the biology of that resistance mechanism. For women who’ve been on an aromatase inhibitor, a mutation in the estrogen receptor gene called an 

 mutation is a frequent contributor to resistance to aromatase inhibitor therapy. In the setting of an 

 mutation, the tumor cell has acquired the capacity to have the estrogen receptor in the on position, if you will, even though there’s no estrogen present because the patient is on the aromatase inhibitor. Sometimes I describe that to patients as like having a gas pedal stuck to the floor. The car is always accelerating forward, even though you don’t seem to be stepping on the gas. That is a mutation that limits the effectiveness of endocrine therapies, and particularly limits the effectiveness of aromatase inhibitors in the treatment of metastatic breast cancer.

Expert Harold Burstein, MD, PhD, breaks down the treatment armamentarium for patients with HR+/HER2- metastatic breast cancer. 

HR+/HER2- Metastatic Breast Cancer: Treatment Armamentarium 

: Hormone receptor-positive metastatic breast cancer is the most common condition that we as medical oncologists deal with after the patient has a recurrence. As we know, the most common type of breast cancer is hormone receptor-positive disease, and these tumors tend to recur in a predictable way, particularly when they have high-risk conditions including node involvement, large size, and high recurrence score, in the bone, soft tissue, and sometimes in the organs. For these patients, traditionally the treatment has been single-agent androgen therapy. Originally, it was only tamoxifen; subsequently, for postmenopausal women we had different aromatase inhibitors that showed improvement in the progression-free survival, but never showed an improvement in survival. Then Faslodex [fulvestrant], one of the SERDs [selective estrogen receptor degraders] that was used in comparison with aromatase inhibitors in this specific setting, appeared to be superior, particularly in patients with bone disease.

Now in the last 7 years, we had a tremendous improvement in patient outcomes by testing the different CDK4/6 inhibitors. For the first time, we have seen a significant improvement in progression-free survival across the different medical conditions, particularly in patients with bone disease, visceral metastasis, endocrine sensitivity, and endocrine resistance. These have translated to a significant improvement in overall survival in the majority of patients and majority of studies. Interestingly enough, the benefit is seen particularly in patients who have been treated up front, first line, with a combination CDK4/6 and aromatase inhibitor in postmenopausal patients. This has been seen also in a group of patients in the premenopausal setting. It appears that the more sensitive subset of patients are the ones who benefit the most. Finally, an important aspect with regard to the possibility of prolonged survival and quality of life is a delay in the use of chemotherapy. Sometimes this is large number of months, more than 20 months in some of the studies. This obviously represents an unprecedented result compared to what traditionally we had available for these patients.

With regard to hormone receptor-positive metastatic breast cancer, we have an increased understanding of the biology of the disease, particularly with a molecular test, to see mutations that are associated with this disease, one of them being 

 mutations. For the first time, the FDA approved targeting a specific set of mutations in the 

 gene. This is now an available second-line treatment where the drug, alpelisib, has been FDA approved. This treatment is usually used after progression on CDK4/6 inhibitors. This represents a significant proportion of patients because this mutation is present in approximately 30% of patients with metastatic hormone receptor-positive disease. There has been no indication that different variants of 

 mutations have different sensitivities. So across the board, the most common 

 mutations are sensitive to alpelisib. This drug is available to patients whose cancer progresses. The other group of patients most recently is the ER [estrogen receptor]-positive 

 germline mutations. For these patients there is the availability of different PARP inhibitors, olaparib and talazoparib. This is expanding the possibility to treat these patients with a targeted approach based on alterations in germline DNA and not in the somatic mutations.

Massimo Cristofanilli, MD, FACS, provides a historical overview of the HR+/HER2- metastatic breast cancer (mBC) treatment landscape.

Evolving Treatment Landscape of HR+/HER2- Metastatic Breast Cancer 

	Metastatic breast cancer (MBC) is a fatal disease involving the expansion of cancerous cells from the breast to other areas of the body. Treatments for MBC are often limited to palliative care; as a result of MBC is usually fatal. As research continues, factors such as age at diagnosis, hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and site of metastases are currently used to stratify patients into groups with different prognoses and to predict response to systemic treatments. More recently, researchers seek to understand the mechanisms related to tumor dissemination in hopes of therapeutically targeting this process. HRs are expressed in about two-thirds of breast tumors and endocrine therapy is probably the most important systemic therapy for HR-positive breast cancer. Selective estrogen modulators (SERMs) and aromatase inhibitors (AIs) represent the standard options in patients with HR-positive MBC, with selection based on previous exposure and sensitivity in the adjuvant setting. Preclinical models have identified several molecular abnormalities (eg, EGFR and HER-2 overexpression, ESR1 mutations) associated with endocrine resistance, providing rationale for conducting prospective studies. Novel therapeutic agents targeting the PI3KCA/mTOR cyclin-dependent kinases (CDKs) demonstrated the most promising results, with significant impact on the management of patients with endocrine resistance. Future challenges are represented by the testing of sensitive diagnostic tools with the ability to identify predictive markers allowing more personalized therapeutic choice and possibly monitoring.

Breast cancer is the most prevalent female malignancy and the second most common cause of death in developed countries. In 2013 in the United States, an estimated 234,580 women were diagnosed with invasive breast cancer and 40,030 died from it.

 During the last decades, breast cancer survival has increased considerably

 in Western countries due to earlier diagnosis and increasing use of adjuvant and neoadjuvant therapies, but recent statistics suggest that approximately 30% to 70% of patients with primary breast cancer worldwide eventually develop recurrence and die of metastasis every year with an estimated increased mortality of 14%.

 Recent years have produced remarkable changes both in the treatment philosophy of metastatic breast cancer (MBC) and in the available therapies, contributing to improvements in survival rates and quality of life in Western Europe and the United States, with the potential to extend some of these benefits to low and medium income countries worldwide.

Estrogen receptors (ERs) are expressed in about two-thirds of breast tumors, and endocrine therapy is probably the most important systemic therapy for hormone receptor (HR-) positive breast cancer.

 Several prospective studies established the superiority of aromatase inhibitors (AIs) in the management of ER-positive MBC.

 Fulvestrant (Faslodex), a pure estrogen receptor antagonist, demonstrated efficacy comparable to anastrozole and subsequently defined a role and a treatment schedule/ dosage, providing another available therapeutic option.

More recently, a prospective, open label, randomized phase III study evaluated the combination of fulvestrant and anastrozole (Arimidex) compared with single agent anastrozole in postmenopausal women with ER-positive locally advanced or MBC.

 A total of 695 patients were randomly assigned to the two treatment arms. Forty percent of patients were de novo stage IV disease. Moreover, approximately 40% of patients had previously been exposed to tamoxifen and only 30% had received adjuvant chemotherapy. The results demonstrated superiority of the combination arm with a median progression- free survival (PFS) of 15 months (95% confidence interval [CI], 13.2-18.4) compared with 13.5 months for the single agent (95% CI, 12.1-15.1; 

 = .007 stratified log-rank test), suggesting a role for such combination in the management of a selected subset of patients.

Two other studies have evaluated the combination of fulvestrant with an AI in advanced setting.12,13 The Fulvestrant and Anastrozole Combination Therapy (FACT) trial was a multicenter, international, randomized study that enrolled 514 patients treated with either the combination regimen or single agent anastrozole.

 Approximately a third of patients were endocrine therapy naïve (34.4% vs 30.2% anastrozole vs combination respectively). Prior adjuvant chemotherapy exposure was also more frequent in the anastrozole group (49.6% vs 41.9%). There was no statistically significant difference in overall response rate (ORR) (33.6% vs 31.8% for anastrozole vs combination respectively) and median time to progression (TTP) of 10.2 months for anastrozole compared with 10.8 months for anastrozole plus fulvestrant (hazard ratio [HR] = 0.99, 95% CI, 0.81-1.20; P = .91). The Study of Faslodex with or without Arimidex vs Exemestane following progression on non-steroidal Aromatase inhibitors (SoFEA) was a multicenter, phase III randomized controlled trial.

Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250-mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). A total of 723 patients underwent randomization: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4.4 months (95% CI 3.4- 5.4) in patients assigned to fulvestrant plus anastrozole, 4.8 months (3.6-5.5) in those assigned to fulvestrant plus placebo, and 3.4 months (3.0-4.6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (HR = 1.00, 95% CI 0.83-1.21; log-rank 

 = .98), or between those assigned to fulvestrant plus placebo and exemestane (HR = 0.95, 95% CI, 0.79-1.14; log-rank 

In summary, these studies suggest that a combination of fulvestrant and AI should be considered an appropriate choice only for a selected population of de novo stage IV or endocrine-naïve HR-positive postmenopausal patients. Unfortunately, after an initial response to hormonal therapy, most ER-positive tumors develop resistance leading to disease progression.

 Preclinical models have shown that an adaptive upregulation of growth factor signaling is associated with acquired resistance to endocrine therapies, whereas overexpression of human epidermal growth factor receptor 2 (HER2) in ER-positive breast cancer is responsible for de novo resistance to tamoxifen and AIs.

Furthermore, studies on ER biology have highlighted the fundamental role of other signaling pathways in the development of resistance to hormone therapies.

 It has been suggested that overactive growth factor receptor signaling through multiple intracellular pathways may contribute to the evolution of an endocrine resistance phenotype. Manipulation of growth factor signaling networks has emerged as an attractive strategy to delay the onset, or potentially even overcome the resistance to endocrine therapy in breast cancer.

 In this context, a number of clinical trials have tested the use of HER2/neu antagonists, insulin-like growth factor 1 receptor (IGF1R) inhibitors, tyrosine kinase inhibitors (TKIs), multikinase inhibitors, cyclin- dependent inhibitors, mTOR antagonists, and src-inhibitors

 together with hormone therapy. More recently, new ER alpha mutations were described in tumor samples from patients with endocrine-resistant disease, particularly in cases of long-term exposure to antiestrogen therapy.

These studies suggest that the increased routine use of molecular diagnostics platforms in the evaluation of patients with MBC will contribute to improving our understanding of the complex biology of this disease, particularly in ER-positive breast cancer considering the availability of multiple molecularly targeted therapies.

Preclinical data have provided evidence that crosstalk between growth factor receptor and ER pathways may mediate the development of resistance to endocrine therapy in HR-positive disease.

 For example, increased expression of epidermal growth factor receptor (EGFR), human ErbB2 (HER2), and insulin- like growth factor 1 receptors can elicit tamoxifen resistance, as can activation of their downstream signaling pathway components, particularly extracellular signal-regulated kinase and phosphoinositol-3-kinase.

 EGFR overexpression is also predictive of a decreased benefit from tamoxifen,

 and patients with higher EGFR expression are less likely to respond to tamoxifen and have a significantly shorter time to treatment failure.

The combination of endocrine therapy and trastuzumab (Herceptin) or lapatinib (Tykerb) is a first-line therapeutic option in patients with HER2-positive/HR-positive metastatic tumors based of the results of two prospective randomized studies.

The TAnDEM trial was the first randomized phase III study to combine a hormonal agent and trastuzumab, an anti- HER2 antibody, without chemotherapy as treatment for HER2- positive and HR-positive MBC.

 Postmenopausal women were randomly assigned to 1 mg per day of oral anastrozole with or without trastuzumab until progression. Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in all measured endpoints compared with patients receiving anastrozole alone. PFS was 4.8 month versus 2.4 months, and there was a nonsignificant difference in overall survival (OS) of 28.5 months for the combination versus 23.9 months for single agent letrozole. The ORR, consisting of only partial response, was 20% versus 7%, respectively, and the clinical benefit rate (CBR), 43% versus 28%, respectively.

The second study was a multicenter, open-label, randomized phase III trial (EGFR30008) designed to determine the efficacy of lapatinib, a HER2-targeting TKI, in combination with letrozole (Femara) for the treatment of HR-positive, HER2- positive, and HER2-negative advanced breast cancer in postmenopausal women.

 At baseline, the majority of patients included in this study had stage IV disease and received ≥6 months of prior hormone therapy. Patients were randomized in a 1:1 fashion between December 2003 and December 2006 to receive either lapatinib (1500 mg daily) plus letrozole (2.5 mg daily) or letrozole alone (2.5 mg daily). Results showed that the addition of lapatinib to letrozole increased PFS and ORR compared with letrozole alone in HER2-positive disease. PFS was 8.2 months in the letrozole combined with lapatinib arm versus 3 months in the letrozole and placebo arm. OS was 33.3 months versus 32.3 months (unpublished data), respectively, and ORR was 28% versus 15%, respectively. As expected, there was no survival or response benefit in the HER2-negative cohorts.

In HER-2 negative disease several studies have tested the clinical value of EGFR-modulation combined with endocrine therapy. Cristofanilli et al

 evaluated the efficacy and tolerability of anastrozole combined with gefitinib (Iressa) compared with anastrozole plus placebo in postmenopausal women with HR-positive MBC who had not received prior endocrine therapy or chemotherapy or who developed metastatic disease during/after adjuvant tamoxifen. Despite the fact that the study was discontinued after 54% of patient recruitment (94 out of required 174) because of slow enrollment, patients receiving the combination of anastrozole and gefitinib showed a longer PFS, which was the primary endpoint of the study, compared with those receiving anastrozole plus placebo (HR gefitinib/placebo, 0.55; 95% CI, 0.32—0.94; median PFS, 14.7 vs 8.4 months). The post hoc subset analysis of PFS for patients who had received prior endocrine treatment compared with those who were endocrine therapy naïve showed a more pronounced benefit for patients who had not previously received endocrine therapy. Similarly Osborne et al

 reported an improved PFS in patients with newly diagnosed metastatic disease or patients who had relapsed after adjuvant tamoxifen (treatment stopped ≥1 year before study entry) (stratum 1) treated with tamoxifen plus gefitinib. Patients who received tamoxifen plus gefitinib and had recurred during/after adjuvant AI or after failed first-line AI (stratum 2) reported no advantage in clinical benefit.

AZD8931 is an orally bioavailable, reversible, tyrosine kinase, equipotent inhibitor of EGFR, HER2, and HER3 signaling.

 The agent demonstrated anticancer activity in a range of in vitro and in vivo preclinical tumor models, with particular activity in inhibiting signaling driven through ligand stimulation.

The MINT study prospectively tested the hypothesis that adding AZD8931 to anastrozole would delay the development of clinical endocrine resistance in postmenopausal patients with endocrine therapy-naïve advanced breast cancer.

Patients were randomized 1:1:1 to AZD8931 20 mg twice daily in combination with anastrozole 1 mg daily; AZD8931 40 mg twice daily in combination with anastrozole 1 mg daily; or matched AZD8931 placebo twice daily in combination with anastrozole 1 mg daily. Between June 2010 and June 2012, 359 patients were randomized to receive AZD8931 20-mg (n = 118), 40-mg (n = 120), or placebo (n = 121) in combination with anastrozole. At the interim analysis, median PFS in the AZD8931 20 mg, 40 mg, and placebo arms were 10.9, 13.8, and 14.0 months, respectively, suggesting lack of benefit from the combination. Moreover, AZD8931 was associated a significant EGFR-mechanism based toxicity, causing treatment delays and discontinuation. As a consequence, the trial was discontinued for toxicity and lack of efficacy, with impact on the further clinical development of AZD8931. Moreover, the study clearly demonstrated the need to consider endocrine therapy resistance of previous exposure as a more appropriate clinical testing scenario in view of the lack of a defined molecular signature for patient selection.

The phosphoinositide-3-kinase (PI3-kinase)-Akt-mTOR pathway is a major signaling pathway in normal and cancer physiology with high rate of mutational activation of the pathway in breast cancer.

The pathway can be activated by genomic amplification or overexpression of receptor tyrosine kinases, such as HER2, EGFR, and IGF1R. Activating mutations in the catalytic PI3-kinase subunit PIK3CA occur in 36% of breast cancers overall and are especially prevalent in luminal and HER2-amplified breast cancers (29%-45%). Drugs targeting mTOR include rapamycin and its analogues everolimus and temsirolimus, which allosterically inhibit mTORC1 only, and mTOR kinase inhibitors, which inhibit both mTORC1 and mTORC2.

 The randomized phase III BOLERO-2 trial tested everolimus (Afinitor) plus the steroidal AI exemestane (Aromasin) versus placebo plus exemestane in women with metastatic ER-positive/HER2-negative breast cancer that had progressed on prior therapy with nonsteroidal AIs.

 The trial was stopped early after a planned interim data analysis showed that the study had met its prespecified endpoint of PFS. The everolimus arm showed an increase in response rate (7% vs 0.4%) and a significant increase in PFS (10.6 vs 4.1 months by central review). A nonsignificant increase was seen in OS in the everolimus arm, but OS data are immature.

The benefit of everolimus was consistent across subgroups divided by age, prior therapy, and sensitivity to previous hormonal therapy. A recent update analysis of the study confirms the statistically significant advantage in PFS of the combination regimen, clearly supporting this regimen as standard of care in ER-positive patients demonstrating progression after AIs, while the role of mTOR inhibitors in newly recurred disease is under investigation. Additional analysis of this study also demonstrated the efficacy of the combination in patients with more aggressive features of disease such as visceral metastases.

 Moreover, similar benefit has been shown in elderly patients (>70 years of age) but requiring reduced dosage intensity because of toxicity profile.

In contrast, in the recently reported randomized phase III HORIZON trial, the combination of oral temsirolimus and letrozole did not improve response rates or PFS when compared with letrozole plus placebo as first-line treatment for women with locally advanced or metastatic ER-positive breast cancer.

 A key difference between the trial populations is that none of the patients in HORIZON had any prior AI exposure, although approximately 40% had received adjuvant tamoxifen, whereas BOLERO-2 participants essentially all experienced disease progression on prior nonsteroidal AI therapy. This difference is reflected in the response rates seen in the AI plus placebo arms: 27% in HORIZON and 0.4% in BOLERO-2.

	Cell Cycle Modulation and Endocrine Resistance

Dysregulation of cell cycle checkpoints is common in cancer. 39 There are four proliferative cyclin-dependent kinases (CDKs): CDK 1, which predominantly regulates the transition from G2 to M phase, and CDK 2/4/6, which regulate the transition from G1 to S phase. Inactivation of the G1 to S phase checkpoint through several events such as deletion of the retinoblastoma (Rb) protein or cyclin-dependent kinase inhibitor 2A (CDKN2A), CDK 4 point mutation, or cyclin D1 (CCND1) amplification is a characteristic feature of human malignancy.

 Activation of the CDK 4/CDK 6/E2F axis promotes endocrine resistance, and treatment with a CDK 4/6 inhibitor or knockdown of CDK 4 expression abrogates endocrine-resistant cell proliferation.

Moreover, preclinical models suggest a peculiar sensitivity of ER-positive breast cancer cell lines to CDK 4/6 inhibition, indicating a definitive path for clinical investigation.

 Palbociclib (PD-0332991) is an orally bioavailable selective inhibitor of CDK 4/6 that prevents DNA synthesis by blocking progression of the cell cycle from G1 to S phase.

 A randomized phase II study examined postmenopausal women with hormone- sensitive, ER-positive, HER2-negative advanced breast cancer who had not received any prior systemic anticancer therapy for their advanced disease.

 Patients who received palbociclib plus the oral nonsteroidal AI letrozole had significantly longer PFS compared with patients who received letrozole alone (26.1 vs 7.5 months; HR = 0.37; 

 <.001). This promising agent is currently being tested in two phase III trials in combination with letrozole or faslodex (+/- LHRH agonist) respectively.

The increased use of novel molecular diagnostics is changing our understanding of the complexity and heterogeneity of HR-positive disease, allowing a more accurate prediction of sensitivity to therapeutic endocrine manipulations. The identification of genomic abnormalities (eg, ESR1 and CH1 mutations) and activation of molecular pathways regulating cell cycle, proliferation, migration, angiogenesis, and metastasis promoted the evaluation of multiple novel targeted agents in advanced HR-positive breast cancer. In patients with HRpositive (HER2-negative) disease, targeting of the PI3KCA/ mTOR pathway and cell cycle regulators currently appears to be the most promising approach for patients progressing after standard endocrine therapy. Those agents are effective but also associated with significant toxicity and costs, requiring additional efforts to identify specific molecular signatures with the ability to predict the benefit of targeted agents. In fact, significant research questions to be addressed relate to the role of other PI3KCA-modulators in patients with disease recurring after standard AI or after combination regimens (including everolimus). Moreover, the availability of selective inhibitors of CDK 4/6 should suggest the design of strategies focused on a molecular-driven selection allowing more rational choices for these patients.

 Massimo Cristofanilli, MD, FACP, is professor of Medical Oncology, deputy director of Translational Research, and director of the Jefferson Breast Cancer Clinical Program and Center at Thomas Jefferson University in Philadelphia, PA.

 Dr. Cristofanilli reports no relevant conflicts of interest to disclose.

Massimo Cristofanilli, MD, FACP, 1025 Walnut St, Suite 700, Philadelphia, PA 19107

			Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. 

			Lin NU, Thomssen C, Cardoso F, et al. International guidelines for management of metastatic breast cancer (MBC) from the European School of Oncology (ESO)-MBC Task Force: Surveillance, staging, and evaluation of patients with early-stage and metastatic breast cancer. 

			International Agency for Research on Cancer. BLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed February 24, 2014.

			Cortazar P, Justice R, Johnson J, et al. US Food and Drug Administration approval overview in metastatic breast cancer. 

			Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. 

			Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomized trial. 

			Nabholtz JM, Buzdar A, Pollak M, et al; Arimidex Study Group. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. 

			Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. 

			Paridaens RJ, Dirix LY, Beex LV, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. 

			Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. 

			Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer.

			Bergh J, Jonsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. 

			Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormonereceptor- positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial.

			Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. 

			Hiscox S, Morgan L, Barrow D, et al. Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: inhibition by gefitinib (‘Iressa’, ZD1839). 

			Arpino G, Green SJ, Allred DC, et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group study. 

			Giuliano M, Trivedi MV, Schiff R. Bidirectional crosstalk between the estrogen receptor and human epidermal growth factor receptor 2 signaling pathways in breast cancer: molecular basis and clinical implications. 

			Massarweh S, Osborne CK, Creighton CJ, et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. 

			Paul D, Vukelja SJ, Holmes FA, et al. Letrozole plus dasatinib improves progression-free survival (PFS) in hormone receptor-positive, HER2- negative postmenopausal metastatic breast cancer (MBC) patients receiving first-line aromatase inhibitor (AI) therapy. 

			Sanchez CG, Ma CX, Crowder RJ, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer.

			Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. 

			Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormoneresistant metastatic breast cancer. 

			Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-mutations in pretreated advanced estrogen receptor positive breast cancer [Published online January 7, 2014]. 

			Schiff R, Osborne CK. Endocrinology and hormone therapy in breast cancer: new insight into estrogen receptor-alpha function and its implication for endocrine therapy resistance in breast cancer. 

			Nicholson RI, Hutcheson IR, Jones HE, et al. Growth factor signalling in endocrine and anti-growth factor resistant breast cancer. 

			Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study.

			Schwartzberg LS, Franco SX, Florance A, et al. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. 

 2010;15(2):122-129. [published correction appears in Oncologist. 2010;15(3):327.]

			Cristofanilli M, Valero V, Mangalik A, et Al. Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. 

			Osborne CK, Neven P, Dirix LY, et al. Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: a randomized phase II study. 

			Hickinson DM, Klinowska T, Speake G, et al. AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer. 

			Johnston SRD, Basik M, Hegg R, et al. Phase II randomized study of the EGFR, HER2, HER3 signaling inhibitor AZD8931 in combination with anastrozole (A) in women with endocrine therapy (ET) naive advanced breast cancer (MINT). 

			deGraffenried LA, Friedrichs WE, Russell DH, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. 

			Raymond E, Alexandre J, Faivre S, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. 

			Ellard SL, Clemons M, Gelmon KA, et al. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/ metastatic breast cancer: NCIC Clinical Trials Group IND.163. 

			Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. 

			Campone M, Bachelot T, Gnant M, et al. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study. 

			Pritchard KI, Burris HA 3rd, Ito Y, et al. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2- negative, hormone receptor-positive breast cancer in BOLERO-2. 

			Wolff AC, Lazar AA, Bondarenko I, et al. Randomized phase III placebocontrolled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. 

			Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. 

			Knudsen ES, Knudsen KE. Tailoring to RB: tumour suppressor status and therapeutic response. 

			Thangavel C, Dean JL, Ertel A, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. 

			Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. 

			Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. 

			Finn RS, Crown JP, Lang I, et al. Results of a randomized phase 2 study of PD 0332991, a cyclin dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for fÄ±rst-line treatment of ER+/HER2- advanced breast cancer (BC).

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More recently, researchers seek to understand the mechanisms related to tumor dissemination in hopes of therapeutically targeting this process. 

Massimo Cristofanilli, MD, FACP