Debu Tripathy, MD
Although existing therapies are prolonging progression-free survival (PFS), the debate as to what frontline endocrine therapy to use and whether to partner it with a CDK 4/6 inhibitor in patients with hormone receptor (HR)-positive breast cancer continues to evolve, explained Debu Tripathy, MD.
“If we cross some of the significant biological barriers and figure out why patients develop resistance to these drugs, we can push [the PFS] out further and maybe obviate the need for the more toxic therapies altogether.”
In an interview during the 2018 OncLive®
State of the Science Summit™ on Breast Cancer, Tripathy, professor and chairman, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, tracked the evolution of treatment of patients with metastatic HR-positive breast cancer.
OncLive: How has the management of advanced HR-positive breast cancer evolved?
This an area that has evolved a lot in the last few years. The most important thing about treating patients with metastatic HR-positive breast cancer is to confirm the histology at the time of initial diagnosis. You want to make sure that the patient truly has breast cancer metastasis depending on where the easiest lesion to biopsy is. That may be in the lung, the liver, or sometimes in the bone. It’s also important to check the estrogen, progesterone, and HER2 receptors since that can sometimes change from what the primary tumor was. Of course, it also serves as a confirmatory diagnosis for patients who present with metastatic breast cancer.
Over the last several decades, the pendulum has shifted to treating patients with metastatic breast cancer according to receptor subtype. For patients with HR-positive, HER2-negative breast cancers, the general paradigm for treatment is to use endocrine therapy first. As recently as 1 decade ago, chemotherapy was the first treatment that patients would get.
We now know that if we start with endocrine therapy for most cases, patients will have a better quality of life (QOL). Though randomized studies have been few and far between, the ones that have been done suggest that survival is the same and some data show that survival is better. From a QOL standpoint, we certainly feel that endocrine therapy is the best initial treatment for most patients.
There are exceptions to this. In patients with rapidly progressive cancer or extensive visceral burden, we will sometimes start with chemotherapy. If they achieve a response, then we convert them to maintenance hormonal or endocrine therapy.
Over the last 5 to 7 years, there has been a shift in how we approach patients with HR-positive breast cancer, primarily because of what we learned from patients who become resistant to endocrine therapy. The first set of discoveries revolve around growth factor receptor pathways, which seem to be overactive in patients with refractory disease. On this basis, several trials have been done to target various growth factor receptor pathways.
The mTOR inhibitor everolimus (Afinitor) was the first one to be approved in 2012 in partnership with second-line endocrine therapy with fulvestrant (Faslodex). That has now become a standard of care. More recently, treatment with CDK inhibitors has been paired with both first- and second-line therapy.
Initially, tamoxifen was our treatment of choice for patients with any type of HR-positive breast cancer. Aromatase inhibitors (AIs) were introduced later. The AIs, when compared with tamoxifen in the trials done in the 1990s, showed that they were about equally effective. Some of the studies showed that AIs were slightly better, but the one big difference was the risk of thrombosis. Thrombosis is elevated in patients with metastatic breast cancer. That was not a problem with the AIs, so this became the first-line therapy.
The other important observation was that in premenopausal patients, medical suppression of the ovaries with gonadotropin-releasing hormone analogues was found to be better when added to tamoxifen than tamoxifen alone. For most premenopausal patients, it became customary to use either surgical or medical ovarian suppression.
Even in the era of biological therapies where we're combining CDK4/6 inhibitors and mTOR inhibitors with endocrine therapy, it is customary to use ovarian suppression in premenopausal patients along with AIs or fulvestrant.
The question of what the best endocrine therapy is in the first-line is still evolving. Is it AIs or is it fulvestrant? Fulvestrant has traditionally been used in the second-line setting as the estrogen-receptor (ER) downregulator. Comparative trials for this were hampered by the fact that we were initially not using the appropriate dose of fulvestrant. When it became clear that the 500-mg monthly dose was the more appropriate dose and showed a survival advantage over the 250-mg dose, there was a renewed interest in comparing this with AI therapy.