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Tripathy Discusses Developments in HR+ Breast Cancer

Caroline Seymour
Published: Tuesday, Aug 14, 2018

The FALCON trial directly compared anastrozole with fulvestrant and showed a slight superiority of fulvestrant in terms of progression-free survival (PFS). In fact, in patients who did not have visceral disease—had bone-only or soft tissue disease—the outcome was significantly better. The important thing about this study is that it was done in patients who had not previously received endocrine therapy, including in the adjuvant setting. Most of the patients were de novo or hadn't had adjuvant therapy. That is one caveat about that trial; it is now raising the question of whether fulvestrant should be the partner with some of the biological drugs, such as CDK4/6 inhibitors.

The MONALEESA-3 trial looked at fulvestrant and the CDK4/6 inhibitor ribociclib (Kisqali) in first- or second-line therapy. The trial showed that, in the first-line setting, the PFS was very favorable; it was among the longest PFS we've seen. There wasn't a head-to-head comparison of fulvestrant to an AI in this trial. It suggests that maybe fulvestrant and CDK4/6 inhibitors may be an optimal first-line therapy. There is still some controversy there.

For the most part, we're using endocrine-based therapies initially. While there is some controversy as to what endocrine therapy might be best and who should receive CDK4/6 inhibitors; it's important to remember there is no difference in overall survival yet. The trials weren't designed to look at that. The bottom line is we have much fewer toxic alternatives now. With the advent of biological therapies, the PFS is being pushed out.

One of the important things is preserving QOL and delaying the time patients may need to go on to chemotherapy if they're refractory to endocrine biotherapies. As more biological therapies come to the forefront, we’re hoping that we can delay the time that patients may need chemotherapy. If we cross the significant biological barriers and figure out why patients develop resistance to these drugs, we could push it out further and obviate the need for the more toxic therapies altogether. 

How have the TAILORx results informed management of the disease and affected chemotherapy's relevance in the treatment paradigm?

Shifting to early-stage breast cancer, endocrine therapy is clearly important for patients who have HR-positive disease. One of the big questions is, “Who needs chemotherapy and how much do they benefit from it?” This is particularly true in lower-risk cancers, specifically patients who have node-negative disease.

In the past, there was a series of clinical trials that compared endocrine therapy alone—primarily tamoxifen—with the addition of chemotherapy. They showed a small benefit of 3% to 5% in disease-free survival. The National Institutes of Health issued a call for all patients to receive chemotherapy, even with node-negative and HR-positive breast cancers. We knew all along that many of these patients didn't need these therapies, but we couldn't identify who they were.

When gene-profiling technology became available in the late 1990s and early 2000s, we thought we could apply this technology to decipher who needed chemotherapy and who didn't. Fortunately, there were tissue resources from adjuvant trials comparing hormonal therapy alone with hormonal therapy plus chemotherapy. [These patients] had 10 to 15 years of follow-up.

When those tissues were subject to gene profiling and the classifiers were constructed and validated on other data sets, it became clear that these signatures were in fact prognostic. Oncotype DX, MammaPrint, and several others have shown that these classifiers can identify high- and low-risk patients. Moreover, the data suggested that patients with low scores also had a low benefit from the addition of chemotherapy. Not only did they have a good prognosis, but the impact of chemotherapy was marginal. This was an important step forward in allowing us to treat fewer patients with chemotherapy.

When these tests came online, there was a clear drop in the number of patients getting chemotherapy. According to the projections, we weren't necessarily sacrificing outcomes in these patients. However, a prospective randomized trial needed to be done not only to confirm the general premise but also to start looking at subsets and set the thresholds for where we should and shouldn't recommend chemotherapy.

The TAILORx study was the largest randomized breast cancer trial ever done; it enrolled close to 10,000 patients. Of those, patients with intermediate-risk scores were randomized to receive endocrine therapy only or endocrine therapy with chemotherapy. They revised the cut points so that there was a better sense that we weren't inappropriately undertreating patients. The low-risk group was treated with endocrine therapy. [Patients with] high scores were treated with chemotherapy followed by endocrine therapy. We know that the patients with low scores had an excellent outcome.


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Community Practice Connections™: 1st Annual Paris Breast Cancer Conference™Dec 31, 20181.5
35th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Clinical Vignette SeriesJan 31, 20192.0
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