CDK Inhibitors, Guidelines: Brightest Stars in the Metastatic Breast Cancer Sky

Roxanne Nelson, BSN, RN


March 08, 2017

It is estimated that between 150,000 and 250,000 people in the United States are living with stage IV breast cancer. Global estimates of the burden of metastatic breast cancer are not known. But even if statistics are unavailable, evidence indicates that progress in metastatic breast cancer lags behind that of early-stage breast cancer.[1]

Dr Fatima Cardoso, director of the Breast Cancer Unit at Champalimaud Cancer Centre in Lisbon, Portugal, is a leader in a global initiative[2] to improve the care and treatment of persons with metastatic breast cancer. Roxanne Nelson spoke to Dr Cardoso for Medscape to learn what recent advances have been made in the field of metastatic breast cancer.

CDK Inhibitors Show PFS in ER-Positive Disease

Medscape: What do you feel was the most exciting news over the past year for metastatic breast cancer?

Dr Cardoso: I would have to say that the most important advance has been the confirmation of the value of CDK inhibitors in estrogen receptor (ER)-positive breast cancer. Data from PALOMA-2 were presented at the American Society of Clinical Oncology (ASCO) annual meeting and confirmed the substantial benefit in progression-free survival (PFS) in the first-line setting for palbociclib.[3]

The US Food and Drug Administration FDA had granted conditional approval of palbociclib on the basis on the phase 2 PALOMA-1 data,[4] so it was important to fully validate the approval of the drug, both in the United States and in Europe.

At the annual meeting of the European Society for Medical Oncology (ESMO) this year, we also saw results from the MONALEESA-2 study, which evaluated another CDK inhibitor, ribociclib.[5] The results were very similar to what we saw with the PALOMA-2 study. There was a substantial benefit in PFS and acceptable, manageable toxicity.

This is a class of drugs with toxicity that is easy to manage and tolerate, and it provides a substantial benefit, at least in terms of PFS. We will need to see what the impact will be in overall survival, but I would say that these are the two main studies that can be highlighted for this year.

The CDK inhibitors are the 'stars' for this past year.

There is a third agent in this class of drugs, abemaciclib, and the data were also presented at ESMO.[6] It was a phase 2 study, but it is trending in the same direction. The results are very promising in terms of efficacy and manageable toxicity.

The CDK inhibitors are the "stars" for this past year. We have these three drugs and the results of important studies that were presented at two major meetings. We still need to see what their impact is on overall survival to clearly understand whether they should be considered the new standard of care for all or the majority of ER-positive/HER2-negative advanced breast cancer.

Medscape: Were there any other studies from the past year that you consider important advances?

Dr Cardoso: There were two noteworthy studies involving endocrine therapy. Both were presented at ESMO. The first was the FALCON study, which compared fulvestrant to an aromatase inhibitor in the first-line setting.[7] Fulvestrant had shown promising results in a phase 2 study,[8] but this needed to be reproduced as a phase 3 trial, which was the FALCON study. However, the results were not as strongly positive as we had hoped for. There was only a 3-month benefit to using fulvestrant, as compared to the aromatase inhibitor anastrozole.

The main problem with this study is that it was run exclusively in patients with de novo metastatic disease, and these patients comprise only about 10%-15% of advanced breast cancer patients in the developed world.

Most of our patients have been exposed to endocrine therapy and aromatase inhibitors. If the trial had been run in patients who had previous exposure to endocrine therapy, the benefit most likely would have been higher. So, what I take from this is that fulvestrant is a good first-line option.

The other study presented at ESMO was the BOLERO-4 trial,[9] which was a single-arm, phase 2 study that looked at the use of mTOR inhibitors in the first-line setting. This study shows that we have a drug that works both in first line and second line, at least for a certain subgroup of patients. We urgently need to understand how to select the patients who are the most likely to benefit from each of the options we have.

Another endocrine study was presented at the San Antonio Breast Cancer Symposium (SABCS), known as BELLE-3,[10] which looked at the PI3K inhibitor buparlisib combined with endocrine therapy. The bottom line was that it was a negative study because it extended PFS by only 2 months and the drug was very toxic.

Medscape: In view of these data, where should future research be focused in patients with metastatic ER-positive disease?

We need to understand the best sequence for all available options for the individual patient.

Dr Cardoso: We need to understand the best sequence for all available options for the individual patient. The focus of future research must be to learn the best way of delivering these therapies to our patients. ER-positive breast cancer is the most common subtype of metastatic breast cancer, accounting for about two thirds of all cases. It is essential to identify which patients will benefit the most from each option. For that we need biomarkers.

There have been several studies looking for biomarkers, but unfortunately they were all negative. We currently do not have biomarkers to help guide therapy, and this is a huge unmet need for which research must continue.

We also need to know the effect of each treatment after the others. For example, do mTOR inhibitors work after palbociclib and vice versa?

Less to Note in HER2-Positive and Triple-Negative Disease

Medscape: Was there any new research for patients with HER2-positive disease?

Dr Cardoso: There was not a lot of new information about HER2-positive breast cancer, but it is difficult to have something new every year. There was one study that was presented at SABCS—the phase 2 PERTAIN trial, which looked into the use of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor.[11] The message from this study is that if you decide to use endocrine therapy with an anti-HER2 agent, there is a benefit to doing it with dual blockade because it is clearly better than endocrine therapy alone.

This is one option for some patients with triple-negative breast cancer. But this study does not answer the most difficult question: when to use endocrine therapy or when to use chemotherapy with anti-HER2 therapy. That question is still open. I would like to say that it will be answered very soon, but I'm not sure if anyone will be able to conduct another trial, as these studies are very expensive to run.

Medscape Have we seen any advances this past year for patients with triple-negative disease?

Dr Cardoso: We still don’t have a lot of good news for these patients. There was one study presented at SABCS this year, which was a phase 2 study with the PARP inhibitor veliparib, given to patients with the BRCA1 or BRCA2 mutation.[12] Veliparib was used in combination with chemotherapy, and unfortunately there was almost no benefit plus high toxicity.

At ASCO 2016 there was a discussion of immunotherapy and the role it may have in triple-negative disease, and there will definitely be results to report in the future, as this is an area of great interest and investment.

Consensus Guidelines for Metastatic Breast Cancer

Dr Cardoso: An important milestone affecting all subtypes of metastatic breast cancer was the recent publication of the third International Consensus Guidelines for Advanced Breast Cancer (ABC 3),[13] which was a very important accomplishment. The guidelines are an instrument for education and for advocacy and lobbying. They provide recommendations for basic care of patients with metastatic disease as well as for the treatment of the different breast cancer subtypes. The intention was to provide a global standard of care accessible for all persons with advanced breast cancer.

Medscape: This year and last year, members of MET UP, the metastatic breast cancer patient activist group in the United States, held a demonstration at SABCS, as reported by Medscape, to draw attention to the needs of patients with metastatic breast cancer.

Dr Cardoso: Members of MET UP are asking for more research to be dedicated to metastatic breast cancer, and this is what we have been doing for a long time—first with the ABC Conference and now with the ABC Global Alliance.

More than a decade ago, we created a task force to look into the issues related to metastatic disease and develop specific guidelines, because there really weren’t any available at that time. We also wanted to start identifying specific research needs.

The work evolved, leading to the ABC conference and guidelines. The first conference was in 2011 and it has been a very important work. People have been contacting us and telling us about the impact in their own countries. It’s not just about the guidelines but the fact that we are giving voice to the issues related to metastatic disease.

And this is why we created the ABC Global Alliance—to provide a platform for physicians, pharmaceutical companies, scientists, patients, and advocates to work together to improve the lives of patients with advance breast cancer. Globally, metastatic breast cancer still receives much less attention and dedicated resources than early breast cancer. Most of the money given to research goes to basic research that has very little clinical application, and when money does go to clinical research, it is mostly dedicated to early breast cancer.

When we first began, advocacy groups had few resources for metastatic patients. But now there are at least some resources for metastatic disease in many advocacy groups, and we are starting to see more global resources dedicated to metastatic breast cancer.

Medscape: What do you see as the greatest challenges?

Advocacy is the first step in the majority of countries.

Dr Cardoso: From one country to another, there are huge differences both in healthcare and in the management of advanced breast cancer. Advocacy is the first step in the majority of countries. On the other hand, there have not been a lot of advances, unfortunately. The median overall survival is still about 3 years across all types of breast cancer. In terms of public perception, there is a lack of knowledge and often there are extreme attitudes: People think that because advanced breast cancer is incurable, nothing needs to be done; everyone is going to die. Or they think advanced breast cancer is like early breast cancer and that everything that needed to be done has already been done. The patient is often forgotten in the middle of these extreme views.

We started by developing a global report[14] looking at what has happened in the different fields in the past decade. The report identified many gaps, and we are moving forward to develop a global call to action with measurable objectives that can be achieved in the next 10 years. This call to action and the related projects will be driven by all members of the ABC Global Alliance.

One important goal is to create cancer registries that record recurrences. We have no idea how many metastatic patients there are because registries simply record diagnosis and death, but not recurrence. This is just one example of what can be done, around the world, in the current decade.

Patients are frustrated; they feel that they are powerless. But that is the purpose of the ABC Global Alliance: to face this advanced breast cancer together rather than alone. We have more power when we are together as one strong community.

Fatima Cardoso, MD, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Astellas Medivation, Inc.; AstraZeneca Pharmaceuticals LP; Celgene Corporation; Daiichi Sankyo, Inc.; Eisai Inc.; GE Healthcare; Genentech BioOncology; GlaxoSmithKline; MacroGenics, Inc.; Merck Sharp & Dohme Corp.; Merus B.V.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Pierre Fabre; F. Hoffmann-La Roche Ltd; sanofi-aventis; Teva Pharmaceuticals


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