The Evolution of Treatment Approaches for ER+ MBC

Komal Jhaveri, MD, FACP:We have really come a very, very long way for treatment of [estrogen receptor] (ER)-positive breast cancer. And what we have learned is that endocrine therapy is a very effective treatment strategy. Until 2000, we learned that for postmenopausal women specifically, aromatase inhibitors are thought to be a very active class of agents. Because when we compare aromatase inhibitors with tamoxifen, specifically in postmenopausal women, we found that there was an improvement in the time to progression or progression-free survival, and therefore that became a standard of care in the first-line metastatic setting for these women.

Since then we’ve now also seen data from trials such as the FIRST trial, which was a phase II trial, and also the FALCON trial, which is a phase III trial, looking at fulvestrant [Faslodex] in the first-line setting when compared [with] anastrozole [Arimidex].

And more recently, since 2012, I think our efforts have all been driven to our understanding the mechanisms of endocrine resistance and trying to overcome that. Because what we’ve learned is, it’s not that the endocrine therapies are not effective and that they don’t work. They do work. But ultimately, after a few years, all these women now are progressing.

So our focus has been to define combination strategies, and we now have combination therapies, including mTOR inhibitor, or everolimus [Zortress], with aromatase inhibitors that are approved based on the BOLERO-2 trial. And we also have a new class of exciting agents called the CDK4/6 inhibitors that are also now approved both in the first- and second-line setting for these women and have changed the treatment landscape for ER-positive metastatic disease.

When we think about treating breast cancer, particularly breast cancer that is ER-positive,HER2-negative, and we think about what we used to do back in the day, say 20 years ago, we only had choices like tamoxifen, which…was approved in 1998 for metastatic disease. And now we have various choices, and in fact we have choices [that] are specific for premenopausal women and postmenopausal women.

For example, when we think about a premenopausal woman historically, what we have learned based on the meta-analyses from the Dutch group is that when you combine ovarian suppression with tamoxifen, there is a statistically significant improvement in both progression-free survival and overall survival, and that’s what we do in clinic with these women.

When we think about postmenopausal women, we have data from so many trials that looked at aromatase inhibitors, and [we] compared them [with] tamoxifen and showed superior efficacy for aromatase inhibitors with respect to time-to-progression and progression-free survival in the first-line setting.

But then we also have trials such as FALCON trial that looked at fulvestrant when compared [with] anastrozole in the first-line setting and showed a significant improvement in [PFS], but these were women who were de novo metastatic patients. So these women were not treated with prior endocrine therapy.

So we were doing all of these various approaches for our women until 2015, when the very first agent, which was palbociclib, a CDK4/6 inhibitor, got approved in combination with an aromatase inhibitor in the first-line setting and showed improvement in [PFS] in the orders of about 28 months based on the longest follow-up data that we have, compared [with] aromatase inhibitors alone.

Since then we’ve also had multiple other agents, including ribociclib [Kisqali] [and] abemaciclib [Verzenio], which also in combination with aromatase inhibitors have shown a similar improvement in [PFS]. And so based on the data when we see a class effect with unprecedented improvement in [PFS] in the first-line setting, certainly our first-line choice for patients with ER+ metastatic disease has become a combination of the CDK4/6 inhibitor with aromatase inhibitors.

Transcript edited for clarity.

A 65-Year-Old Woman With Metastatic ER+/PR+ Breast Cancer

December 2013

• A 65-year-old woman was examined by her gynecologist after discovering a right-sided lump in her upper inner breast; she reported feeling exhausted lately, requiring frequent rest
• PE showed a grape-sized right palpable mass at 3 o’clock
• Diagnostic ultrasound showed a spiculated and hypoechoic mass measuring 26 x 23 x 21 mm; imaging in the left breast was unremarkable
• Core biopsy showed high-grade infiltrating ductal carcinoma
  • Hormone receptor status: ER+/ PR+
  • HER2,IHC 1+
• She underwent lumpectomy and axillary lymph node dissection that revealed a 2.3-cm infiltrating ductal carcinoma, 4 of 12 nodes were positive for disease
• CT of the chest, abdomen, and pelvis showed that the disease had spread to her bones and biopsy confirmed metastatic disease
• ECOG 1
• She was started on ribociclib + fulvestrant