Steven E. Vogl, MD
At the 2017 San Antonio Breast Cancer Symposium (SABCS), Michael Gnant, MD, FACS, of the Medical University of Vienna presented the 9-year median follow-up of a trial looking at the length of extended aromatase inhibitor therapy. At least four other recently presented or published trials have addressed this issue, but none in exactly the way the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-16 did, and none of them had sufficient length of follow-up to allow definitive conclusions to be drawn.
Before this trial was reported, we knew an aromatase inhibitor after 5 years of tamoxifen sharply reduced disease-free survival events. The key trial showing this (the National Cancer Institute of Canada Clinical Trials Group study MA.17) unblinded the trial and crossed over many members of the control group after just 2.5 years of median follow-up because the first analysis showed a major effect.1 The 17% of MA.17 patients who were premenopausal at diagnosis (but later lost their ovarian function while on tamoxifen) obtained most of the benefit: a 74% reduction in disease-free survival events compared with those postmenopausal at diagnosis, who had just a 33% reduction in disease-free survival events.2 MA.17 mandated 5 years of aromatase inhibitors (letrozole in this trial) therapy to those assigned to it but never established the second 2.5 years was needed. The early unblinding did not even allow a thorough evaluation of the toxicity of the second 2.5 years. ABCSG offers a partial answer to the issue of aromatase inhibitor duration.
This was a randomized prospective trial of 3,469 evaluable women postmenopausal at study entry, with a median age of 65 and 32% younger than age 60. At diagnosis, presumably few were premenopausal, 72% had tumors ≤ 2 cm, 66% had negative axillary nodes, 19% had grade 3 primaries, and 77% of primaries stained for both estrogen and progesterone receptors. Treatments for 80% included postoperative radiation; 51% had 5 years (± 1) of adjuvant tamoxifen, 42% had both tamoxifen and an aromatase inhibitor, and about 7% had anastrozole (an aromatase inhibitor) alone. Patients were assigned at entry to receive either 2 or 5 years of anastrozole, so the first 2 years of therapy were the same for both arms.
The median follow-up was 106 months from randomization and 82 months (6.8 years) from treatment divergence. About 21% of patients stopped anastrozole in the first 2 years without a disease-free survival event, and 33% assigned to 5 years stopped early without a disease-free survival event. These are typical rates of noncompliance in such studies.
There was no detectable benefit noted in terms of disease-free or overall survival with anastrozole given beyond 2 years. If one starts looking for a difference after those assigned to 2 years of anastrozole stopped (since no difference would be expected while the treatment arms are identical), 8-year disease-free survival is about 75% in each arm and overall survival is about 84% in each arm. If one limits the evaluation strictly to adherent patients in an exploratory analysis, 8-year disease-free survival is still about 76% in each arm. Fractures, however, were increased in years 3 to 5 after randomization from 4.5% among those assigned to stop therapy to 7% among those assigned to continue therapy (the latter rate would likely be even higher had everyone assigned to 5 years of anastrozole actually continued treatment).
No Information on Women Premenopausal at Diagnosis
In MA.17, these women reduced their disease-free survival events by 74% if they took an aromatase inhibitor after 5 years of tamoxifen. Because of the size of the benefit, one would like to be sure none of it is lost by shortening the duration of aromatase inhibitor therapy. Dr. Gnant reports that there were few to none of these women in ABCSG-16 (personal communication, January 8, 2018). We therefore still do not know how long to give these women an aromatase inhibitor after 5 years of tamoxifen.
Results from MA.17 make clear that the development of an apparently localized breast cancer in the setting of high estrogen levels makes these cancers particularly sensitive to the profound estrogen suppression induced by an aromatase inhibitor after menopause. MA.17R suggests there is little benefit to extending the aromatase inhibitor beyond 5 years when begun after 5 years of tamoxifen across all ages at diagnosis but offers no information on up to 5 years of extended aromatase inhibitor for any age group.3
Should This Have Been a Noninferiority Study?
Alas, because MA.17 was closed early and the control patients informed they had been given placebo and encouraged to cross over to letrozole after a median follow-up of 2.5 years, one cannot assert that 5 years of therapy with an aromatase inhibitor after 5 years of tamoxifen is the established standard. Five years was the intended duration of therapy in MA.17 for the experimental group, but the early closure means only about 2.5 years were shown to be superior to no further therapy. The shorter-duration arm of ABCSG-16 is close enough to 2.5 years to be considered the control or established therapy. Since shorter therapies are less toxic, more convenient, and less expensive, one may reasonably ask whether longer therapies be required to prove themselves superior! The latter clearly was not the case in ABCSG-16!
We Can Prevent Fractures From Aromatase Inhibitor Therapy
Denosumab (Xgeva) at 60 mg subcutaneously every 6 months was shown in ABCSG-18 to halve the rate of fractures from 5 years of anastrozole from 16% to 8%. This study was published in 2016—long after the last patient entered ABCSG-16 in 2010.4 It makes sense that denosumab at this dose should be offered whenever an aromatase inhibitor is given for an extended period, whether for 2 years, 5 years, or longer. The excess fractures from an additional 3 years of aromatase inhibitor in ABCSG-16 are a problem, but not as big a problem now as they were when ABCSG-16 was conducted!
Does Prolonged Aromatase Inhibitor Prevent New Primary Breast Cancers?
In MA.17R it did—about half the 4% disease-free survival benefit noted by year 17 from diagnosis was a result of a 2% reduction in new contralateral primaries from letrozole given between years 10 and 15 after diagnosis. In the Dutch IDEAL study, this benefit of extended aromatase inhibitor was particularly notable in women younger than age 55 at entry.5 NSABP B-42 confirmed a reduction in contralateral breast cancers from 5 years of extended aromatase inhibitor.6 In ABCSG-18, a relatively small study with few contralateral cancers, no reduction in these contralateral breast cancers was observed with 3 more years of aromatase inhibitor therapy. If a patient is particularly concerned about preventing contralateral primaries, has no difficulty with arthralgias or progressive osteoporosis, and can afford denosumab to prevent fractures, I would not let the absence of a benefit in this endpoint in ABCSG-16 (a fairly small study) dissuade me from offering longer aromatase inhibitor therapy that probably prevents new primary breast cancers based on the other trials.
In lower-risk populations, endocrine breast cancer prevention has never been shown to improve either the duration or the quality of life.— Steven E. Vogl, MD
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We lack information, though, on whether extended aromatase inhibitor therapy prevents new breast cancers in those with the highest risks of new cancers in retained breasts, the women with high-penetrance mutations. Among those with BRCA1/2, we have observational data that tamoxifen halves the rate of new breast cancer development, even though most BRCA1 cancers lack hormone receptors!7 Breast cancer prevention with hormonal drugs is particularly attractive in this population, since it may spare many women from early bilateral mastectomies. In lower-risk populations, endocrine breast cancer prevention has never been shown to improve either the duration or the quality of life. This is probably why it has been undertaken so rarely in North American practice.
How Does ABCSG-16 Change Practice Now?
Very few postmenopausal women at diagnosis now receive 5 years of tamoxifen unless they are intolerant of aromatase inhibitors. Many, though, start with tamoxifen and switch to an aromatase inhibitor after 2.5 to 3 years, as was done in BIG 1-98 and TEAM, where the switch therapies were about as effective as 5 years of an aromatase inhibitor. Tamoxifen alone, though, was inferior for the 5-year disease-free survival endpoint in BIG 1-98. Starting with tamoxifen allows evidence-based therapy to continue for 7.5 to 8 years. This is attractive since MA.17, ATLAS, and aTTom suggested that longer endocrine therapy is better. ABCSG-16 tells us that we can assure women who were postmenopausal at diagnosis and reach the 5-year mark in such a switch strategy that 2 more years of an aromatase inhibitor is very likely to be enough, saving them 3 years of an aromatase inhibitor and 3 years of denosumab (the annual retail cost of the latter is currently about $2,000 in the United States). ■
At Microphone 1 is an occasional column written by Steven E. Vogl, MD, of the Bronx, New York. When he’s not in his clinic, Dr. Vogl can generally be found at major oncology meetings and often at the microphone, where he stands ready with critical questions for presenters of new data. The opinions expressed in this column reflect those of the author and do not necessarily reflect the opinions of ASCO or The ASCO Post.
DISCLOSURE: Dr. Vogl reported no conflicts of interest.
1. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262-1271, 2005.
2. Goss PE, Ingle JN, Martino S, et al: Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol 24:355-361, 2013.
3. Goss PE, Ingle JN, Pritchard KI, et al: Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med 375:209-219, 2016.
4. Gnant M, Pfeiler G, Dubsky PC, et al: Adjuvant denosumab in breast cancer (ABCSG-18): A multicentre, randomized, double-blind, placebo-controlled trial. Lancet Oncol 386:433-443, 2015.
5. Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, et al: Optimal duration of extended adjuvant endocrine therapy for early breast cancer: Results of the IDEAL trial (BOOG 2006-05). J Natl Cancer Inst 110:10.1093/jnci/djx134, 2018.
6. Mamounas EP, Bandos H, Lembersky BC, et al: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy with letrozole in postmenopausal women with hormone-receptor (+) breast cancer who have completed previous adjuvant tx with an aromatase inhibitor: Results from NRG Oncology/NSABP B-42. 2016 San Antonio Breast Cancer Symposium. Abstract S1-05.
7. Phillips KA, Milne RL, Rookus MA, et al: Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol 31:3091-3099, 2013.
Michael Gnant, MD, FACS
Postmenopausal women with hormone receptor–positive breast cancer who took the aromatase inhibitor anastrozole for 2 years after an initial 5 years of adjuvant endocrine therapy received an equal benefit to those who took the drug for 5 additional years. The trial...!-->!-->