Only 2 Years of Extended Anastrozole Needed in Breast Cancer

Liam Davenport

December 08, 2017

SAN ANTONIO ----  Postmenopausal women with hormone receptor–positive breast cancer who have already taken endocrine therapy for 5 years can proceed with just 2 more years, rather than another 5 years, of additional therapy with the aromatase inhibitor (AI) anastrozole (Arimidex, AstraZeneca), an Austrian study concludes.

The 2- and 5-year regimens gave the same reduction in relapse risk but had less adverse effect on bone health, potentially protecting women from fractures.

The results come from  the ABCSG-16 trial, a randomized controlled trial of almost 3500 women reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017.

Dr Michael Gnant

Lead investigator, Michael Gnant, MD, director and chairman of the Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria, said in a release: "There is simply no rationale to keep most patients on extended AI for longer than two years."

"This result can help save a lot of unnecessary side effects for many women around the world," he said, adding: "I believe that these trial results should be implemented into daily practice at once."

I believe that these trial results should be implemented into daily practice at once. Dr Michael Gnant

Presenting his findings, Dr Gnant began by highlighting that hormone receptor–positive breast cancer has a significant long-term risk for relapse and that more than 50% of relapses occur after the first 5 years of follow-up.

There has consequently been a tendency to extend the duration of adjuvant hormone therapy. The results of several studies exploring how best to extend therapy have shown that after 5 years of tamoxifen, there is a clear benefit from extended adjuvant therapy with AIs, although the picture is less clear after initial AI treatment.

Dr Gnant said, "So, the question remains: If we extended adjuvant aromatase inhibitors, for how long do we have to treat?"

The researchers therefore undertook the ABCSG-16 trial, in which 3484 postmenopausal women with hormone receptor–positive stage I to III breast cancer from 75 centers in Austria were randomly assigned to 2 years or 5 years of anastrazole, 1 mg/day.

All the women had already undergone 4 to 6 years of endocrine therapy with tamoxifen, an AI, or an AI after tamoxifen following initial surgery with or without radiotherapy.

The median age of the women was 64 years. The tumor size was less than 2 cm in most (72%) cases, and 31% of patents had node-positive disease.

Eighty percent of women had undergone breast-conserving surgery, and 29% had received additional (neo)adjuvant chemotherapy. In the first 5 years after local therapy, 51% of women had been given tamoxifen only, while 49% had received an AI.

Dr Gnant described the trial population as "what I would call a typical or average postmenopausal luminal breast cancer cohort, as we see in the US or in European countries."

By the cutoff date of June 30, 2016, the researchers had found that 757 patients were disease-free: 377 (22%) from the 2-year anastrozole group and 380 (22%) from the 5-year anastrozole group.

The team calculated that after a median follow-up period of 106.2 months, there was no significant difference in the proportion of women with disease-free survival, at 71.1% in the 2-year therapy group and 70.3% among patients treated for 5 years, at a hazard ratio of 1.007 (P = .925).

Furthermore, in no subgroups did treatment duration significantly affect disease-free survival, even after stratification of the patients by age, tumor stage, nodal status, histologic grade, hormone receptor status, previous hormone therapy, or previous chemotherapy.

Overall survival also did not differ between the 2-year and 5-year treatment group, with 10-year overall survival rates of 85.3% and 84.9%, respectively (hazard ratio, 1.007; P = .947).

Dr Gnant noted that treatment adherence in the trial was consistent with what would be expected for patients who had already received endocrine therapy for 5 years before randomization, with a "relatively constant rate of patients dropping off standard aromatase inhibitor therapy over time."

He added: "Interestingly, those patients who also received chemotherapy or more aromatase inhibitors in the first 5 years were more likely to be compliant; probably this can be explained by a perception of a higher relapse risk in these subgroups."

Dr Gnant pointed out that an exploratory analysis in only patients who were "perfectly adherent" also showed that disease-free survival did not differ between the 2-year and 5-year groups, "so I think this further supports the validity of the overall message of the trial."

Crucially, the team did find a difference in adverse events between the two treatment groups, with a nonsignificant trend toward a higher rate of fractures among patients given anastrozole for 5 years vs those treated for just 2 years, at a hazard ratio of 1.353 (P = .053), based on a rate of 6.3% vs 4.7% at the 5-year follow-up.

Speaking at a press conference, Dr Gnant said, "While not providing outcome benefits, the extension of treatment to 5 additional years leads to increased side effects, including more fractures, and should thus be avoided."

"We can conclude that, after 5 years of standard endocrine treatment, 2 additional years of aromatase inhibitors are sufficient as extended therapy," he said.

In the future, specific molecular characteristics may be found to identify patients who would benefit from prolonged adjuvant therapy. "But, for now, we can conclude that 7 years are good enough for almost every patient with luminal breast cancer," he said.

Negative Study, Positive News

Dr Gnant commented that "for us as clinical scientists, a negative trial is always disappointing, [but] I think the clinical take-home message can help to avoid unnecessary side effects for many, many women."

SABCS co-director Carlos L. Arteaga, MD, who is director of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, Texas, and moderated the press conference, agreed, saying: "Negative study, positive news."

He added that he would have no problem putting the findings into practice, and he expressed a hope that there will be more de-escalation studies, particularly as AIs are now being combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.

Dr Arteaga said, "I think we should do better than just extending, extending, extending [therapy]. We have to come up with better ideas."

He told Medscape Medical News: "I think, for the last few years, we have realized that, for a long time, we have treated too many women for too long, and the reason is because we can afford the standards of care."

"But the fact of the matter is, just in a minority of women those interventions make a difference. We are in a time of maturity [in the field], so let's give it a try, let's de-escalate."

Dr Arteaga sounded a note of caution, however, emphasizing that de-escalation must be backed up by randomized studies.

"In the process of de-escalating, we may be depriving some women, so we have to be very careful and do studies like the one you heard today," he said.

The study was funded by AstraZeneca. Dr Gnant has received honoraria, travel or accommodations funding, and research funding from AstraZeneca.

San Antonio Breast Cancer Symposium (SABCS) 2017. Abstract GS3-01. Presented December 7, 2017. 

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