Global Alliance Addresses Slow Progress in Advanced Breast Cancer

Kate M. O'Rourke


November 27, 2017

Progress With New Drugs

According to Ingrid A. Mayer, MD, leader of the Breast Cancer Research Program at Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, among the most notable advances in MBC in the past 10 years are the ability to genomically profile tumors and the approval of novel HER2-targeted drugs, such as pertuzumab (Perjeta®) and T-DM1 (Kadcyla®), both approved in 2013.[4,5] Dr Mayer said the median survival for patients receiving these HER2-targeted agents is close to 7 years from the time of metastatic diagnosis.

"The ability to genomically profile tumors has opened up new avenues of research," said Dr Mayer. "Every day now, we see novel targeted treatments in clinical trials, which one day may translate into a new treatment that helps get morbidity and mortality from breast cancer down."

More recently, she said, three cyclin-dependent kinase (CDK) 4/6 inhibitors have been approved for hormone receptor (HR)-positive, HER2-negative MBC: palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio™). In 2015, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved palbociclib for HR-positive, HER2-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial therapy in postmenopausal women or in combination with fulvestrant in women who have received prior endocrine therapy.[5] Last spring, the FDA and EMA approved ribociclib in combination with an aromatase inhibitor as initial therapy for postmenopausal women with HR-positive, HER2-negative ABC.[6,7]

More recently, in September, the FDA approved abemaciclib in combination with fulvestrant for women with HR-positive, HER2-negative ABC or MBC with disease progression after endocrine therapy.[8]Abemaciclib was also approved as monotherapy for HR-positive, HER2-negative ABC or MBC with disease progression after endocrine therapy and prior chemotherapy in the metastatic setting. Overall, the side effects associated with CDK4/6 inhibitors are less severe than those experienced with chemotherapy, and in most cases dose delays or reductions result in prompt recovery.[9]

Dr Mayer said the approval of everolimus (Afinitor®) in 2012, for use with exemestane (Aromasin®) to treat postmenopausal women with ABC, was also a step forward.[10]

"For estrogen receptor-positive cancers, the approval of targeted agents, such as the mTOR inhibitor everolimus and the CDK4/6 inhibitors (palbociclib, ribociclib, and most recently abemaciclib), have revolutionized the way we treat estrogen receptor-positive MBC," said Dr Mayer. "Now patients are able to defer the use of chemotherapy for metastatic disease for over 40 months, thanks to the significant impact these strategies have had on progression-free survival (PFS) in this setting," said Dr Mayer.

"The key to success is and will continue to be better, faster, smarter clinical trials."

She pointed out that data from the Surveillance, Epidemiology, and End Results Program shows that mortality rate from breast cancer overall has fallen over the past 10 years. "We have not changed anything in terms of diagnosis and screening for breast cancer, so clearly all of the advances being done are preventing women with early breast cancer from developing metastatic disease, or providing better treatments for MBC," said Dr Mayer. "The key to success is and will continue to be better, faster, smarter clinical trials that would accelerate the availability of new treatments for women with metastatic disease."

Too Much Focus on PFS

Dr Cardoso agreed that the drugs that have really made a difference for patients with MBC are the anti-HER2 agents. "The median overall survival of 2-3 years after a diagnosis of MBC is for all subtypes, but if we look at the HER2 subtype, we have a longer median overall survival," said Dr Cardoso. "These patients can live with metastases for 8, 9, or even 10 years, and this is because we have agents that improve survival, such as trastuzumab, pertuzumab, and T-DM1. For the triple-negative subgroup, unfortunately, we still haven't had any major breakthrough, and certainly the improvement we have seen has not had an impact on survival."

"The advances have been so small and so slow, because we are just aiming for PFS."

Dr Cardoso is hopeful about the novel CDK4/6 inhibitors, but says it remains to be seen whether they will have an impact on overall survival. "The CDK inhibitors have not been shown yet to actually affect survival. If we can find an agent that makes an impact on survival for the most common tumor, luminal, it will make a huge difference," said Dr Cardoso.

Dr Cardoso believes a big barrier to progress in MBC is that clinical trials are too focused on PFS. "Providing a PFS benefit is not enough," said Dr Cardoso. "Clearly, what the best outcome to measure is a hotly debated topic. A lot of my colleagues are content with PFS, but I am not," said Dr Cardoso. "I truly believe that the advances have been so small and so slow because we are just aiming for PFS."

Dr Cardoso has disclosed financial relationships with Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck-Sharp, Merus BV, Mylan, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, and Teva. Dr Mayer has disclosed no relevant financial relationships.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.