Bonanza of New Options for HR+/HER2- Breast Cancer

Javier Cortés, MD, PhD


October 19, 2016

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Hello. Welcome to Medscape Oncology Insights. I am Dr Javier Cortés, head of the breast cancer program at Ramon y Cajal University Hospital in Madrid and Vall d'Hebron Institute of Oncology in Barcelona, Spain. Today I want to highlight several breast cancer studies presented at the 2016 European Society for Medical Oncology (ESMO) meeting in Copenhagen, Denmark.

If I had to summarize this year's meeting, I would say that this has been the endocrine-positive, HER2-negative breast cancer meeting. This year, I have not seen many interesting data for triple-negative breast cancer or HER2-positive breast cancer, except for some interesting data regarding new biosimilar compounds.

Red-Letter Meeting for HR-Positive, HER2-Negative Patients

For patients with estrogen-receptor (ER)-positive/HER2-negative breast cancer, however, we have seen very interesting and positive results. For patients who have metastatic ER-positive/HER2-negative disease and who do not need a quick response, usually we should offer treatment with endocrine-based therapy. We know that palbociclib, a new cyclin D kinase (CDK) 4/6 inhibitor, combined with fulvestrant in endocrine-resistant patients or with letrozole in endocrine-sensitive patients, clearly improves outcomes, with impressive median time to progression of 24 months in the first-line setting.

This year we have learned more about these compounds. Dr Richard Finn discussed some data about the biomarker analysis in the PALOMA-2 study.[1] Unfortunately, we again were not able to observe which patients benefited more or less from palbociclib-based therapy. All patients seemed to have similar benefit. Of note, the great majority of samples in this study were taken from primary tumors, sometimes many years ago.

We had two very interesting trials: The FALCON trial[2] compared first-line treatment with fulvestrant and treatment with anastrozole, and MONALEESA-2[3] compared the second CDK4/ 6 inhibitor, ribociclib, in combination with letrozole, or letrozole plus placebo.


[FALCON was a randomized, placebo-controlled, phase 3 pivotal trial that compared anastrozole vs fulvestrant in women with ER- and/or progesterone receptor-positive locally advanced or metastatic breast cancer.] In this trial, patients could not have received previous treatment with endocrine therapy in any setting. Thus, patients who had received endocrine therapy in the neoadjuvant and/or the adjuvant setting were excluded regardless of the disease-free interval of time. All patients in this study were sensitive to endocrine therapy.

Fulvestrant could be a good standard of care in the future for those patients without B-cell metastasis.

Fulvestrant improved progression-free survival significantly more than anastrozole. Of interest, a subgroup analysis showed that in patients with B-cell metastasis, this benefit was less clear, but in patients without B-cell metastasis, the progression-free survival benefit was tremendous, in favor of fulvestrant.

From my point of view, fulvestrant could be a good standard of care in the future for those patients without B-cell metastasis who have not received previous endocrine therapy.


We have also very interesting results from MONALEESA-2.

Dr Gabriel Hortobagyi presented results of MONALEESA-2 during the Presidential Session. The study was simultaneously published online in the New England Journal of Medicine.[4] The results of this study were amazing. [This trial compared the CDK4/6 inhibitor ribociclib plus letrozole vs letrozole plus placebo in women with hormone receptor-positive, HER2-negative recurrent or metastatic breast cancer.] In this study, patients could have received previous endocrine therapy in the neoadjuvant or adjuvant setting with a nonsteroidal aromatase inhibitor, but the disease-free interval between the end of endocrine therapy and appearance of metastasis had to be at least 1 year. Patients could not have received endocrine therapy in the metastatic setting.

The primary endpoint was progression-free survival and it was impressive, with a hazard ratio of 0.56 in favor of ribociclib-based therapy. No unexpected adverse events were observed; a febrile neutropenia or leukopenia was the most important adverse event. Surprisingly, some patients also had a grade 3 transaminitis, but the majority of cases were reversible.

Without a doubt, CDK 4/6 inhibitor-based therapy should be the standard of care for patients with B-cell metastasis.

Thus, we have several interesting options in the first-line setting: the combination of letrozole plus palbociclib or ribociclib, and fulvestrant. Which of these should be used? The answer will depend on many issues, but I believe it is quite reasonable to consider fulvestrant for patients without B-cell metastasis who have not received previous endocrine therapy. It is also reasonable to treat these patients with CDK 4/6 inhibitor-based therapy. Without a doubt, CDK 4/6 inhibitor-based therapy should be the standard of care for patients with B-cell metastasis.

mTOR Inhibition in Endocrine-Sensitive Patients and New Compound for BRCA Mutations


BOLERO-4[5] was a single-cohort, nonrandomized phase 2 trial with 202 patients receiving the combination of letrozole plus everolimus, the oral mTOR inhibitor. This was in a first-line setting, and all patients were sensitive for endocrine therapy. It is interesting to note that at least in particular models we have observed, the activation of this PI3K/AKT/mTOR-signaling pathway is important in tumor cells of patients who have previously received endocrine therapy. This may have important consequences, which is why everolimus is registered only for endocrine-resistant patients.

Nevertheless, in BOLERO-4, patients were endocrine sensitive and the data were quite interesting. The overall response rate exceeded 40%, and the median time to progression had not been reached at the median follow-up of 17.5 months. Grade 3 stomatitis was reported at a rate of 6.5%, but that can be managed easily; corticosteroid-based mouthwashes could also be used prophylactically.

New Option for Women With BRCA2 Mutations

We also had some interesting data[6] regarding a new compound against BRCA tumors, called lurbinectedin. To summarize, this drug seems to work very well in patients with mutations in BRCA2. For BRCA1-mutated patients, olaparib and other PARP inhibitors could play an important role.

These are the most interesting data presented at ESMO 2016, and I believe that they are practice-changing. In many areas of the world, palbociclib and ribociclib are not yet available. But why not use fulvestrant for some of our patients if we have the opportunity? I hope that in the coming months and years, we will have all of these compounds available for our patients.

Thank you all for joining me for this edition of Medscape Oncology Insights. This is Javier Cortés, reporting from ESMO 2016 in Copenhagen, Denmark.


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