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Extended hormone therapy prolongs DFS, maintains quality of life
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CHICAGO — 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 trial MA.17R trial presented during the plenary session of the ASCO Annual Meeting.
Further, continued aromatase inhibitor treatment did not appear to compromise overall quality of life, according to an analysis of patient-reported outcomes from the trial.
“Estrogen receptor–positive breast cancer is a chronic and relapsing form of cancer,” 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, said during a press conference. “MA.17R asks the question of whether extending aromatase inhibitor therapy from 5 years to 10 years further improves outcomes.”
Postmenopausal women with hormone receptor–positive early-stage breast cancer are usually treated with 5 years of upfront aromatase inhibitor therapy, or with aromatase inhibitors after 2 to 5 years of tamoxifen.
Goss and colleagues evaluated whether extending aromatase inhibitor therapy from 5 years to 10 years could further reduce the risk for breast cancer recurrence.
Benefits of additional therapy
The double blind, randomized controlled MA.17R trial included data from 1,918 women with early-stage breast cancer, whom the researchers randomly assigned to letrozole or placebo for 5 years.
All women enrolled in the trial had previously received 5 years of aromatase inhibitor therapy, either as initial treatment or after tamoxifen.
DFS served as the primary endpoint.
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 95%, compared with 91% of women assigned placebo. These data equated to a 34% reduced risk for recurrence (HR = 0.66; P = .01).
One hundred deaths occurred on each arm. The 5-year OS rate was 93% for the letrozole arm and 94% for placebo (HR = 0.97).
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 researchers did not observe a significant worsening of bone health between groups. A total of 133 bone fractures occurred among women assigned letrozole, compared with 88 in the placebo arm. One hundred and nine cases of new osteoporosis occurred in the letrozole arm compared with 54 in the placebo arm.
Further, researchers did not observe any new emergent symptoms or toxicities.
“MA.17R is the first study to show a benefit of extending aromatase inhibitor therapy beyond 5 years,” Goss said. “Unlike many anticancer therapies, aromatase inhibitors are readily accessible around the world, and therefore our results will further improve the outcome of many women with breast cancer.”
Patient-reported outcomes
There were no significant differences in overall quality of life or menopause-specific quality of life between the letrozole and placebo arms, according to an analysis of patient-reported data conducted by Julie Lemieux, MD, MSc, of the Centre Hospitalier Universitaire de Québec, and colleagues.
“Aromatase inhibitors decrease estrogen to very low levels in menopaused women,” Lemieux said during the press conference. “Estrogen deprivation can lead to side effects, such as arthralgia, hot flashes and sexual symptoms, such as vaginal dryness.”
Because of these effects, quality of life served as a key secondary endpoint of the trial.
Lemieux and colleagues measured quality of life using the SF-36 questionnaire and the menopause-specific quality of life (MENQOL) survey administered at baseline and every 12 months for up to 5 years. They calculated mean score changes between 12 months and 36 months.
Certain treatment centers required adherence to surveys; at other centers, participation in quality-of-life surveys was optional.
A total of 1,428 patients completed the baseline surveys, and the overall study population had a compliance rate greater than 85%.
Baseline SF-36 summary scores were close to the population norm of 50 and similar in both arms for physical functioning (letrozole, 47.5; placebo, 47.9) and mental functioning (letrozole, 55.5; placebo, 54.8). No significant mean changes occurred over time for physical or mental functioning.
Of the eight remaining subscales of the SF-36 survey, the researchers observed a difference in the role-function physical subscale domain (mean difference, 3.2; P = .009). However, Lemieux noted that this difference did not reach the minimum level of clinical importance, which was 5 points.
Preliminary results suggested that patients randomly assigned to letrozole reported worse vasomotor symptoms (12 months, P = .02; 36 months, P = .03) and sexual functioning (12 months, P = .01; 36 months, P = .01).
However, updated data presented during the press conference showed no difference between the two groups in any of the four domains of the MENQOL questionnaire: vasometer symptoms, psychosocial functioning, physical functioning and sexual functioning.
Lemieux identified limitations of this analysis, including the fact that the population was highly selected. All women studied had tolerated 5 years of aromatase inhibitor therapy, with 70% having also previously received tamoxifen.
“In women who already tolerated 5 years of aromatase inhibitors, extending letrozole did not worsen their global- or menopause-specific quality of life compared with placebo,” Lemieux said. “It is very reassuring for those women who want a longer duration of adjuvant endocrine therapy that they can expect a preserved quality of life.” – by Cameron Kelsall
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.
Disclosure: Goss and Lemieux report no relevant financial disclosures. Please see the abstracts for a list of all other researchers’ relevant financial disclosures.
Perspective
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Debu Tripathy, MD
The use of an extended hormonal therapy is a concept that has been entertained for a long time as it is clear that patients with hormone responsive disease continue to recur at a relatively constant rate for up to 15 to 20 years after their diagnosis. There are now data that show 10 vs. 5 years of tamoxifen is superior from the ATLAS and aTTom trials, but information on more than 5 years of an aromatase inhibitor (AI) is lacking.
MA.17R is the first study to report results on patients who have already completed 5 years of the AI letrozole and then re-randomly assigned them to placebo or another 5 years of letrozole. Most of the patients had already received 5 years of tamoxifen — that was the original design of the study before they added the second randomization — but there were a few patients who did not receive tamoxifen but who did get letrozole for 5 years, who were then randomly assigned to another 5 years of letrozole or placebo.
The study was a positive study; it showed overall fewer invasive recurrences. About 91% of the patients did well without recurrences in the placebo arm compared to 95% with 5 added years of letrozole, but many were local recurrences or contralateral breast cancers. The difference in metastatic recurrences was only about 1% and there was no difference in OS or deaths from breast cancer.
What do we take away from this and how is this practice changing? We can say that extended letrozole does improve the risk for recurrence. However, it has not yet shown to improve survival in the overall population. It could be that in higher-risk patients — patients who have positive nodes or other high-risk features — the benefits will be larger.
We have to counterbalance this benefit against the increasing fracture rate. These drugs do cause osteoporosis and slightly increase risk for fracture, although in the MA.17R trial, the bulk of these were in the wrist and not major weight bearing/high morbidity sites. It is possible that not all the patients were monitored and treated appropriately for preventing fractures. We now know that antiresorptive agents, like bisphosphonates and denosumab, can lower the fracture risk, and this relatively new knowledge may not have been applied uniformly in the trial. This is a caveat we are going to have to be aware of and discuss with patients.
The quality-of-life study showed that in just about all domains, there was no difference between the arms, except in the role of function-physical subscale. Patients in the extended arm did have more joint pain, a known side effect of the aromatase inhibitors and a higher fracture rate as mentioned earlier. But, the other side effects were pretty well matched. It is important to recognize that this population of patients had all taken prior AI and then agreed to participate in the trial, so this may underestimate what would be seen in routine practice.
Different patients have different perceptions of being on a medication, especially one that has side effects. But, even when they do not have side effects, compliance is an issue. So, extended treatment is a personalized decision. Patients need to be aware of what benefits they are getting for their specific situation and preferences. Physicians should make every attempt to try to quantify it to the best extent possible, at least with the data that are available from this trial.
Many of the aromatase inhibitors are now generic, so the cost is not as much of an issue, but even generic drugs can cost money. Some patients have copays of $20 to $50 or more a month, so cost is important to discuss with patients. Fortunately, these prices are not in the range of other biological drugs.
The bottom line is this trial is practice changing, and for selected patients, we may be recommending extended, 10 years of adjuvant aromatase inhibitor therapy and requisite monitoring.
References:
Davies C, et al. Lancet. 2013;doi:10.1016/S0140-6736(12)61963-1.
Gray RG, et al. Abstract 5. Presented at: ASCO Annual Meeting, May 31-June 4, 2013; Chicago.
Perspective
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Julie M. Vose, MD, MBA, FASCO
This abstract will be very beneficial around the world, as this medication is available in so many countries and has a proven effect of decreasing recurrence, as well as decreasing contralateral breast cancer. That is another important preventative factor.
It is also really important that we consider doing quality-of-life analyses or patient-reported outcomes in all of our studies. We must consider what patients are going through and that they can tolerate additional treatments. Even when there is a small benefit, we want to make sure that there are not also excess toxicities.
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Lajos Pusztai, MD, DPhil
This is a practice-changing study. There are background data that suggested tamoxifen for 10 years would lead to better outcomes than 5 years, with similar data for 10 years of an aromatase inhibitor compared with 5 years after 5 years of tamoxifen. The big question that lingered is whether 5 years of aromatase inhibitor therapy is enough. This is the first study which is actually consistent with other similarly designed studies testing different combinations of extended endocrine therapy, and it showed an improvement that is very important.
The quality-of-life data support the importance of the findings, but in many ways, they are not unexpected. Women who continue therapy for 10 years obviously had to be doing well; otherwise, they would cease therapy. In that respect, we are looking at a self-selected population. Practicing oncologists who administer these drugs know that there is a fairly large population of women who tolerate them extremely well, with little to no adverse events.
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