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Clinicians discuss results of MA.17R trial, role of extended hormone therapy
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Extending aromatase inhibitor treatment with letrozole from 5 years to 10 years significantly improved DFS in postmenopausal women with early-stage breast cancer, according to results of the phase 3 MA.17R trial presented during the plenary session of the ASCO Annual Meeting.
In addition, continued aromatase inhibitor treatment did not appear to compromise overall quality of life, according to an analysis of patient-reported outcomes.
HemOnc Today spoke with clinicians from leading institutions about the implications of the double blind, randomized controlled MA.17R trial, which included data from 1,918 women with early-stage breast cancer randomly assigned to letrozole or placebo for 5 years. All women had previously received 5 years of aromatase inhibitor therapy, either as initial treatment or after tamoxifen. Median follow-up was 6.3 years.
The researchers observed a total of 165 recurrences (letrozole, n = 67; placebo, n = 98). Distant recurrences occurred in 42 women assigned letrozole and 53 women assigned placebo.
Ninety-five percent of women assigned letrozole achieved 5-year DFS compared with 91% of women assigned placebo. These data equated to a 34% reduced risk for recurrence (HR = 0.66; P = .01).
The annual contralateral breast cancer incidence rate was 0.21% among women assigned letrozole compared with 0.49% among women assigned placebo. These data represented a 58% reduction in the risk for contralateral breast cancer (HR = 0.42; P = .007).
The clinicians HemOnc Today spoke with offered a range of opinions on the trial. Some said the study results have the potential to be practice-changing, while others called for additional research.
Results of MA.17R trial ‘clearly recommend’ extending therapy
About 70% of patients with breast cancer have ER–positive disease. Anti-estrogen therapy is an extremely important part of treatment for breast cancer. At this point, in postmenopausal patients, the most appropriate treatment is an aromatase inhibitor, because many randomized trials have shown that aromatase inhibitors are superior to tamoxifen. We’ve been debating and discussing the duration of aromatase inhibitor therapy in the clinic and in the real world for a long time, whether it should be 5 years or 10 years. We know that for anti-estrogen treatment with tamoxifen, 10 years is better than 5 years. However, the question about duration remains for postmenopausal patients, where we mainly use aromatase inhibitors, which are stopped after 5 years.
The MA.17R trial took about 2,000 patients who had been treated with 5 years of letrozole and randomly reassigned them to 5 more years of letrozole or placebo. The primary endpoint of the trial, DFS, was achieved, and overall survival was similar in both groups. The improvement in DFS was mainly due to a reduction in contralateral breast cancer.
The good news is that the side effects were not that different. Overall, patients tolerated the treatment well. Osteopenia and osteoporosis were common side effects, but there was no clinically significant difference between the two groups of patients.
However, there are many limitations of this study. NSABP B-42 is a prospective randomized trial that is ongoing and will give us a definitive answer. While we wait for that data, we can come to several conclusions to help our patients:
- In high-risk patients, prolonged anti-estrogen therapy with an aromatase inhibitor is beneficial, and it should be discussed.
- Overall long-term toxicity related to treatment with an aromatase inhibitor is manageable.
- In low-risk patients, it is important to carefully discuss risk versus any added benefit from extended use of an aromatase inhibitor beyond 5 years.
Jame Abraham, MD
Director, Breast Oncology Program
Cleveland Clinic
Disclosure: Abraham reports no relevant financial disclosures.
Careful patient selection will identify best candidates for extended treatment
This is an important study that looked at the use of extended adjuvant letrozole in postmenopausal women with early-stage breast cancer. Women who had either completed 5 years of upfront aromatase inhibitor therapy or 5 years of an aromatase inhibitor following tamoxifen were randomized to receive an additional 5 years of letrozole. Thus, 80% of those randomized to receive more endocrine blockade had already completed as many as 10 years of anti-estrogen therapy.
Importantly, most of the benefit in DFS appeared to be related to a reduction in new primary contralateral breast cancers as opposed to prevention of a distant recurrence. That’s an important thing to be aware of. Additionally, the follow-up was relatively short, so we don’t see an overall survival benefit yet. It may take some time to see those curves separate.
The questions that are going to come up in clinics will be from women who are nearing the end of their 5 years of aromatase inhibitor therapy. Should I continue? What’s the risk of continuing? What’s the benefit of continuing? It’s going to be an important conversation to have with these women. If women are tolerating the therapy well, and there aren’t concerns about bone density, then it’s reasonable to be thinking about 10 years of an aromatase inhibitor as opposed to 5 years. Women who had a small node-negative tumor need to be aware of the absolute versus relative risk reduction and use that information to decide whether extended therapy is a strategy they want to pursue.
Keerthi Gogineni, MD, MSHP
Assistant Professor, Department of Hematology and Medical Oncology
Emory University School of Medicine
Disclosure: Gogineni reports no relevant financial disclosures.
Extended therapy shows benefit, but more research is needed
This session reviewed an important development in early-stage breast cancer.
HR–positive cancers account for about two-thirds of early-stage breast cancers. We typically use hormone therapy to lower the risk of the cancer returning or spreading after treatment. It’s been known over the years, through many randomized trials, that the risk of recurrence is lowered by about 50% and the risk of death is lowered by about a third with the use of hormone therapy. These studies date back to the early 1970s.
Over time, it’s become clear that patients develop later recurrences. The duration of hormone therapy has been tested, comparing 1 to 2 years of tamoxifen to 5 years of tamoxifen, and has shown that longer duration is better. Most recently, there have been trials showing an improvement in 10 years compared with 5 years. This has always made sense, knowing the natural history of breast cancers recurring late.
The MA.17 trial was initially designed to look at the addition of the aromatase inhibitor letrozole following 5 years of tamoxifen. Patients were randomly assigned to placebo or an additional 5 years of letrozole after 5 years of tamoxifen.
The study was positive. It showed an approximately 5% to 6% reduction in recurrences, and, in longer-term follow-up, has also shown improvement in mortality. This, of course, led to the approval of aromatase inhibitors in this setting. All of these data were presented more than 10 years ago. Following that study, a second randomization was instituted for the patients who had completed 5 years of letrozole and they were randomly reassigned to another 5 years of letrozole or placebo. The first results of that study showed a further improvement in DFS from 90% to approximately 94% to 95% with an additional 5 years of letrozole.
Now, most of that benefit was a reduction in second primary cancers. Only 1% to 2% of the benefit was in metastatic recurrences, so we have to keep that in mind. The bottom line is that longer aromatase inhibitor therapy — 10 years vs. 5 years — is better, but the benefit is small enough that it might be reasonable to consider this in higher-risk patients, maybe patients with positive nodes. Also, some of the molecular profiles that are being used to estimate risk at the beginning of therapeutic decision-making may also be useful in making decisions about longer-term therapies. There is still some controversy as to which of the diagnostic assays may be best at this, so it will require further research.
Debu Tripathy, MD
Chair, Breast Medical Oncology
The University of Texas MD Anderson Cancer Center
Editorial board member, HemOnc Today
Disclosure: Tripathy reports no relevant financial disclosures.
Better molecular predictors, early eradication of tumor can suppress late recurrences
As medical oncologists, we worry most about late recurrences. The presentation by Paul E. Goss, MD, PhD, FRCPC, FRCP(UK), director of breast cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, clearly demonstrated that women who extended their aromatase inhibitor beyond the first 5 years had reduced recurrences. However, there was still a significant number of women taking extended aromatase inhibitor therapy who had recurrences. Furthermore, the number of women spared a late recurrence was relatively small — 42 women assigned letrozole compared with 53 women assigned placebo. To me, this suggests that we still have a long way to go in understanding how best to suppress these late recurrences.
I can think of two ways we could help our patients make a decision. The first goal would be to develop a much better molecular predictor of late recurrence. There are several profiles that had been identified. Many of them are commercially available; some of them have to be modified to address the specific question of late recurrence.
A better predictor of risk for our patients who finish 5 years of aromatase inhibitor therapy would allow us to say, “Your risk of recurrence now is very small, so the benefit of the therapy is very small.” Alternately, the predictor could identify a subset of women who may have a substantial risk of recurrence and might benefit the most.
I think the molecular predictors will be one way we can move forward, but we have to remind ourselves that the molecular predictors will have a very tough road ahead to make them useful, in the sense that they were taken in the woman’s primary breast cancer, before she had received any kind of adjuvant therapy — particularly endocrine therapy. We’re asking the question 5 years later. Are those cells that were taken from the primary tumor really predictive of residual dormant cells that may be left or not? That’s an active research question.
The second major way to approach the issue of whether you need extended endocrine therapy is to completely eliminate the tumor during the first 5 years. Most of the trials that have been presented on extended endocrine therapy were targeting endocrine agents alone. The initial trials — including the MA.17 trial — included women who completed 5 years of tamoxifen, a selective endocrine receptor modulator, followed by 5 years of an aromatase inhibitor, an estrogen deprivation strategy.
In the past 3 or 4 years, we’ve learned that we can target other signaling pathways that impinge on estrogen receptor function to improve outcome. We have all used the mTORC1 inhibitor everolimus, which is approved for the treatment of metastatic disease. It does not directly target the estrogen receptor’s ability to bind estradiol, but it is an effective agent when used in combination with an aromatase inhibitor.
Many of us have also used the CDK 4/6 inhibitor palbociclib. Palbociclib (Ibrance, Pfizer) can be used in combination with both selective estrogen receptor modulators, such as fulvestrant and estrogen deprivation strategies, like the aromatase inhibitors. So if we could move those agents forward — and that is being tested in multiple clinical trials of adjuvant therapy — perhaps we can completely eliminate the risk of late recurrence by eliminating the risk of any recurrence from years 0 to 5. It’s a bit of a moving target, but I certainly think it proves that strategies to target estrogen receptor function in breast cancer could help us resolve the question of whether women need any therapy after year 5. I was very impressed by the talk by C. Kent Osborne, MD, given during the Gianni Bonadonna Breast Cancer Award lecture at the ASCO Annual Meeting, in which he outlined potential strategies and ways to move forward with targeting the estrogen receptor for the treatment of breast cancer.
One of the themes of the ASCO Annual Meeting was immunotherapy for cancer. While further targeting ER function may help eliminate any residual tumor, it is also possible that targeting other signaling pathways, such as CDK4/6, may actually make more cells dormant by suppressing their progression through the cell cycle. While targeting immunotherapy to ER–positive tumors may be difficult, it’s one of the things we should think about.
Today, the conventional wisdom is that ER–positive tumors are not that immunogenic. However, we have many, many antibodies that have been developed in breast cancer that either have failed to show a therapeutic benefit on their own or had a limited therapeutic benefit. These antibodies could be used as immune-targeting agents. In particular, we understand the principle of antibody-dependent, cell-mediated cytotoxicity, or ADCC — an antibody’s ability to bind a receptor and then attract natural killer cells to eliminate the tumor. This could be exploited in ER–positive breast cancer without having to identify immunogenic mutations or immunogenic antigens.
I realize that’s a little bit of a pipe dream, but certainly the concept of eliminating disease in years 0 to 5 would address the question of whether women need extended endocrine therapy — because we’re using extended endocrine therapy to try to eliminate any tumor that’s residual after the first 5 years. Treatment with extended endocrine therapy is very clearly becoming the standard of care, but I think we all have to recognize the benefits are fairly small and there are long-term toxicities. We need to continue to improve and not say this is state-of-the-art and as far as we’re going to go.
Douglas Yee, MD
Professor of Medicine and Pharmacology
Director, Masonic Cancer Center
John H. Kersey Chair in Cancer Research
University of Minnesota
Editorial board member, HemOnc Today
Disclosure: Yee reports no relevant financial disclosures.
References:
Goss PE, et al. Abstract LBA1. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Lemieux J, et al. Abstract LBA506. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.