Denise Yardley, MD
The de-escalation of therapy has been a continuing theme in much of the breast cancer treatment landscape over the last year. Multiple trials from the 2018 ASCO Annual Meeting addressed this, as well as provided options for physicians who want to move away from chemotherapy, according to Denise A. Yardley, MD.
On the other end of the spectrum, the first results from the phase III placebo-controlled D-CARE study were unexpected, Yardley said. Findings showed that in patients with early breast cancer undergoing locoregional and standard system adjuvant therapy, denosumab did not reduce breast cancer recurrence.3
Additionally, results with the PARP inhibitor talazoparib from the EMBRACA trial presented at the 2017 San Antonio Breast Cancer Symposium have sparked interest, Yardley said. Talazoparib reduced the risk of disease progression or death by 46% versus chemotherapy in patients with BRCA
-positive advanced breast cancer.4
This led to the FDA granting a priority review designation for the PARP inhibitor in patients with HER2-negative locally advanced or metastatic breast cancer with germline BRCA
In an interview during the 2018 OncLive®
State of the Science Summit™ on A Summer of Progress: Updates from ASCO 2018, Yardley, senior investigator of breast cancer research, Sarah Cannon Research Institute, weighed in on the recent data reported in breast cancer.
OncLive: Can you please provide an overview of your breast cancer presentation?
: I reviewed updates from the 2018 ASCO Annual Meeting. It is quite exciting because nearly every topic that was pivotal in the presentation revolved around different strategies of treatment that weren't our standard backbone of chemotherapy. We are looking at de-escalating therapy—really trying to tailor it and make it very specific to the risk of recurrence for patient—we are trying to improve outcomes with different strategies, and trying to take away chemotherapy from patients who will not benefit from it.
PERSEPHONE and TAILORx were 2 standout studies from the 2018 ASCO Annual Meeting. Could you give some background on those trials?
PERSEPHONE was very exciting, and we are potentially looking at a new standard. We recognize that the HER2-positive breast cancer trials, up until this point, all have an empirical 12 months of trastuzumab therapy. Therefore, when we saw the data several years ago of giving a 9-week course of trastuzumab that showed great benefit, that question became, “Does 12 months stand for all patients, or could we do a little less?” It is interesting because there is a cost associated with the administration and there is cardiac toxicity, so PERSEPHONE addressed the 6 months versus 12 months [of trastuzumab] in a noninferior style. What they could show is that they are noninferior.
Now, when we look at the subgroups who did benefit with 12 months, those were patients who had prior taxane therapy, concurrent therapy, or those who were node negative or HR negative. It is not a practice-changing trial for myself personally, but it gives us a comfort level when there is a patient who may encounter a comorbid condition, can no longer travel for treatment, or lose their intravenous access and do not want to get another port put in. There are certain segments of patients where 6 months will be beneficial.
TAILORx is an exciting trial. We have been waiting for that intermediate-risk group, which is about 70% of the 10,000 women. What is so exciting about that is that it helps us feel comfortable about foregoing chemotherapy for patients with early-stage breast cancer. This was a node-negative population that was HR positive, and that is the group that we struggle with and do not want to overtreat. TAILORx is timely and built upon what we knew about the biology of HR-positive breast cancer that it is on that pathway of estrogen receptor. It showed that the majority of those patients did not benefit from the addition of chemotherapy in terms of disease-free survival (DFS).
It also gave a moment to pause and reflect on subgroups. The patients under the age of 50 with a Oncotype score of 16 to 20 had some benefit, so it is definitely a worthwhile discussion. Those who had a score of 21 to 25 had a little bit of benefit as well with the addition of chemotherapy as well. This gave us an opportunity to sit down and have a great discussion about risks and benefits and incorporate the patient in that decision.
Were there any other exciting abstracts in breast cancer in 2018?
The data with denosumab was very interesting. We participated in the D-CARE trial and were a little surprised that it didn't show a benefit in either primary endpoints of bone metastases–free survival or DFS. The very next presentation was from our Austrian colleagues from the ABCSG-18 trial, which already showed a benefit in 2014 in reduction of fractures. We saw that with both of the trials. Now, we have data on for the secondary endpoint of the trial that showed DFS benefit. At 8 years, there is about a 3% benefit in DFS, which was not seen in the D-CARE trial.
The other interesting part was looking at some of the side effects. The D-CARE trial, which had a very intensive denosumab administration schedule for the first few months, did have a high rate [of side effects]. The longer patients were on the trial, the higher the incidence of some side effects like osteonecrosis of the jaw (ONJ) were.
That has always been a discussion point with patients when we talk about denosumab. In the Austrian group, they had some dental events, but no ONJ. They also did not see the atypical femur fractures either. Their schedule was every 6 months, which is something that we utilize as standard of care with patients who are on long-term aromatase inhibitors. Looking at that partnership of data, I am comfortable with a 6-month schedule with aromatase inhibitor therapy. This provided us good data, as it helps bone health—it just didn’t change DFS in the D-CARE trial.
What will the role of biosimilars will be in breast cancer?
Biosimilars are just a moving target right now. We are all trying to figure out how that is going to play into practice. Our own institution has had many trials come our way, but we haven't really been picking up and participating. We understand the need and how they add to and benefit the community, but our group is pretty much a diehard for the standard.
Can you speak to any recent data with PARP inhibitors in breast cancer?
The trial that really resonated with me was the talazoparib trial, which had 20 patients. What was so pivotal was that this was the first trial of an adjuvant targeted therapy in early-stage BRCA
-mutant patients. It showed that with just a pill, 53% of the patients could expect to achieve a complete pathologic response in the absence of chemotherapy. If you included the residual cancer burden, that was 63%. It was exciting to see another step away from chemotherapy and replacing it with a targeted therapy for a very direct effect.
We will learn how to manage the hematologic toxicities. There was a fair amount of anemia, with 29 transfusions among those patients. That is something we are not quite used to. When I talk to patients about therapies, I need to remind them that drugs other than chemotherapy have side effects too. Immunotherapy, mTOR inhibitors, PI3K inhibitors—we are learning about different toxicities. That was the same with this PARP inhibitor trial.
Is there anything else that you would like to add?
The RESPECT trial addressed the HER2 population, and what was interesting is that it was the first trial really focused on elderly patients. Patients had to be between 70 and 80 years old with HER2-positive breast cancer. They randomized patients to 12 months of monotherapy with trastuzumab or trastuzumab with chemotherapy. It did not meet its primary endpoint, but what we saw were few events in both arms. There were 18 recurrent events at 3 years in the trastuzumab arm, and 12 that got chemotherapy plus trastuzumab. It signals that these patients are doing well with HER2-targeted therapy. When we look at some of the differences, one of the key messages was that the elderly patients did well with standard of care chemotherapy plus trastuzumab. This gives us great confidence to move forward and offer standard chemotherapy.
On the other hand, we have patients who may get a dose of chemotherapy, may not want chemotherapy, but the differences were small. Meaning, trastuzumab monotherapy may be an option for those who do not want to move forward with chemotherapy. The expectations are close to a 3-year DFS of 89%, which is good with just trastuzumab alone. Again, this makes us feel more comfortable when we are stepping away from our standard of chemotherapy, and just offering HER2-targeted therapy.
- Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2018;36(suppl; abstr 506).
- Sparano JA, Gray RJ, Wood WC, et al. TAILORx: phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. J Clin Oncol. 2018;36(suppl; abstr LBA1).
- Coleman RE, Finkelstein D, Barrios CH, et al. Adjuvant denosumab in early breast cancer: First results from the international multicenter randomized phase III placebo controlled D-CARE study. J Clin Oncol. 2018;36(suppl; abstr 501).
- Litton JK, Rugo HS, Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-07.