Expert: Evolution of Management of Breast Cancer has "Undergone Profound Changes"

Gabriel Hortobagyi, MD, FACP, professor and chair emeritus of the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center discusses the changes in breast cancer management over the past decade.

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Q: How have you seen the treatment paradigm for HR+/HER2- breast cancer shift over the last decade or so?

Gabriel Hortobagyi: There has been a major change and major improvement, I should say, in the treatment profile of the HR+ HER2- breast cancers, especially in the metastatic setting, but also translating gradually into the primary setting. In the metastatic setting until about 2016, when the first targeted therapy was approved for this indication, the standard of care was endocrine monotherapy in a sequential pattern. With the approval of everolimus, an mTOR inhibitor, in 2016, based on the Bolero-2 trial, which I had the honor of chairing, that changed and gradually, we shifted from endocrine monotherapy to combination endocrine therapy at least in second and third line. With the approval of the 3 CDK4/6 inhibitors currently on the market, that was dramatically changed because now the standard of care in the metastatic setting for HR+ HER2- breast cancer is a combination of endocrine therapy with a CDK4/6 inhibitor, today that being ribociclib or abemaciclib.

Now since then, additional agents have been approved, [one for] those with a PI3 kinase mutations[one] for those with the PI3 kinase AKTP10 pathway abnormalities, elecestrant for those with ESR1 mutations, so it has become much more complicated, but to the benefit of our patients, and both disease control and duration of survival have improved as a result with a relatively well tolerated modification of the regimen. So today, the median survival for this group of patients exceeds 5 years routinely. Of course, there are many additional forms of combination endocrine therapy and other therapeutics that are coming down through clinical trials that will add to the new standard of care.

Q: How have the tools for stratifying patients and determining optimal treatment plans evolved?

Gabriel Hortobagyi: The treatment of patients with HR+, HER2- breast cancer has continued to evolve, and now we have multiple lines of therapy in the metastatic setting that is very well established. The selection of treatments depends on a variety of patients and prior treatment dependent factors as well as biomarkers. So obviously, all of these patients have tumors that express their hormonal receptors, and that is the minimum requirement. The first line treatment for those who have not seen a CDK4/6 inhibitor ever or within the past 12 months is endocrine therapy, usually an aromatase inhibitor with the CDK4/6 inhibitor, either ribociclib or abemaciclib. In the second line, we actually need some additional biomarkers such as PI3 kinase status or the status of that signaling pathway ESR1 characterization to rule out or rule in mutations and depending on that, then we will select different treatments. Something that we have not discussed is that we have also had the benefit of the development of antibody drug conjugates and some of the HR+, HER2- breast cancers now qualify for the new classification of HR+, HER2-Low and have substantial activity in that group of patients so they add one more option for treatment selection. It has become a little bit more complicated to select treatment, but these various factors allow us to personalize therapy to each patient's need and minimize side effects on treatment that do not work for that particular group of patients.

In the adjuvant setting, the selection is a somewhat more limited because several of these drugs are have not been approved as yet for their used in the curative management of breast cancer. But certainly, CDK4/6 inhibitors, specifically abemaciclib, has been approved for that, and other treatments are now undergoing evaluation in the adjuvant setting, with some with greater, somewhat lesser success. So soon, we will have multiple options, and in addition to stage and nodal status and menopausal status, we will use other biomarkers that will be of importance in selecting patients. One biomarker that I have not mentioned, but it's important in a small minority of patients is BRCA mutations, and of course, PARP inhibitors, specifically olaparib is relevant to the management of a small segment of patients with HR+, HER2- breast cancer in the adjuvant setting too.

Q: As treatments for breast cancer are getting more and more specific (ex. HER2-low), where do you see the future of breast cancer management going?

Gabriel Hortobagyi: The evolution of the management of both primary and metastatic breast cancer has undergone profound changes over the past 10 years, and while the addition of combination endocrine therapies such as those with CDK4/6 inhibitors, mTOR inhibitors, AKT inhibitors, PI3 kinase inhibitors, selective estrogen receptor down regulators, has added substantially. A recent addition to this has been the introduction of immune oncology, which has had a significant impact in the new adjuvant therapy of some of these patients, and certainly in the metastatic setting too. I think we have now several lines of investigation that will continue to contribute to the complexity and hopefully the efficacy and safety of the treatment approaches to both primary and metastatic breast cancer.