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More Data Show Small Benefit From Extended Endocrine Therapy


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Richard Gray, MSc

Richard Gray, MSc

Two studies presented at the 2018 San Antonio Breast Cancer Symposium validated a small benefit of extending adjuvant aromatase inhibitor therapy beyond thestandard 5 years for postmenopausal women with hormone receptor–positive breast cancer. In a meta-analysis of 24,912 patients from 12 randomized trials, performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), the risk of recurrence was reduced by 33% when an aromatase inhibitor was given for 5 additional years after tamoxifen but by just 19% when it followed treatment with an aromatase inhibitor.1 In a Japanese study, treatment with the same aromatase inhibitor for 10 years led to significant improvement in disease-free and distant disease–free survival.2 In both studies, the benefit increased with increasing numbers of positive lymph nodes.

EBCTCG Meta-analysis

The EBCTCG data were presented by Richard Gray, MSc, of the University of Oxford, UK. He explained that the studies compared 3 years with 5 years of an aromatase inhibitor vs no further treatment after 5 or more years of endocrine therapy.1 There were 7,500 women

treated with 5 years of tamoxifen alone, 4,800 treated with 5 years of an aromatase inhibitor alone, and 12,600 treated with 5 to 10 years of tamoxifen followed by an aromatase inhibitor.

Extended Aromatase Inhibitor Therapy

  • Two trials at the 2018 San Antonio Breast Cancer Symposium validated earlier studies, showing a statistically significant—though perhaps clinically insignificant—benefit of extending an aromatase inhibitor beyond 5 years in patients with early, hormone receptor–positive breast cancer.
  • In a meta-analysis by the EBCTCG, the overall risk of recurrence was reduced by 33% when an aromatase inhibitor was given for 5 additional years after tamoxifen but by just 19% when it followed treatment with an aromatase inhibitor.
  • In the Japanese AERAS trial, which evaluated the continuation of the same aromatase inhibitor, the 5-year disease-free survival rate was 91.9% with continued therapy vs 84.4% with 5 years of an aromatase inhibitor; survival was no different, at about 99% in both arms.
  • In both studies, the benefit was greatest in women with positive lymph nodes, and toxicity was increased with continued endocrine therapy.
  • Many experts suggest considering extended endocrine therapy for women deemed at high risk for recurrence but not for the majority of patients.

In the overall analysis, extended endocrine therapy led to a 24% reduction in the risk of any recurrence (9.5% vs 7.0%; P < .00001), a 15% reduction in the risk of distant recurrence (6.1% vs 5.1%; P = .004), and a nonsignificant reduction in breast cancer mortality (3.1% vs 2.8%; P = .09).

The benefits of extended therapy differed according to the type of prior therapy, with a larger reduction in the risk of recurrence when the aromatase inhibitor was preceded by tamoxifen, as follows:

  • Extended aromatase inhibitor therapy after approximately 5 years of tamoxifen: a 33% risk reduction for any recurrence, with a 5-year gain of 3.6% (P < .00001); a 23% reduction in the risk of distant recurrence, with a 5-year gain of 1.5% (P = .008); and a 23% reduction in breast cancer mortality, with a 5-year gain of 0.8% (P = .05)
  • Extended aromatase inhibitor therapy after 5 years of an aromatase inhibitor alone: a 24% risk reduction for any recurrence, with a 5-year gain of 1.2% (P = .02); a 22% risk reduction in distant recurrences, with a 5-year gain of 0.3% (P = .09): and a 1% risk reduction in breast cancer mortality, with a 5-year loss of 0.2% (P = .97)
  • Extended aromatase inhibitor after 5 to 10 years of tamoxifen, then an aromatase inhibitor: a 16% risk reduction for any recurrence, with a 5-year gain of 2.1% (P = .002); an 8% reduction in the risk of distant recurrence, with a 5-year gain of 1.0% (P = .29); and a 7% reduction in breast cancer mortality, with a 5-year gain of 0.2% (P = .45).

The impact of extended aromatase inhibitors on recurrence risk clearly depends on the type of prior endocrine therapy, he said. Among women treated with prior tamoxifen, the risk reduction was larger, 33% (P < .00001), as compared with women who received an aromatase inhibitor for at least part of their initial endocrine therapy (19%; P = .00010).

The meta-analysis provides a reliable summary of the available evidence to inform clinicians on the efficacy of extending aromatase inhibitor therapy compared with stopping it after about 5 years.
— Richard Gray, MSc

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Here are the key messages, according to Dr. Gray: Extended aromatase inhibitor therapy reduces the risk of recurrence by almost 35% in women who have received about 5 years of tamoxifen and “more modestly” by about 20% in those who received an aromatase inhibitor with or without prior tamoxifen. Risk reduction is apparent in the first 2 years after prior tamoxifen but not until the third year after prior aromatase inhibitor therapy. The absolute benefits increase as more nodes are involved. The occurrence of bone fractures also increased by 24% with extended endocrine therapy.

He suggested that “10 more years are needed to assess the effects of extending aromatase inhibitors on breast cancer mortality.” Nevertheless, he maintained that the meta-analysis provides “a reliable summary of the available evidence to inform clinicians on the efficacy of extending aromatase inhibitor therapy compared with stopping it after about 5 years.” Dr. Gray suggested that tumor size and nodal status should guide the use of extended therapy.

AERAS Trial

Although most studies have evaluated the efficacy of adding an aromatase inhibitor after 5 years of tamoxifen or an aromatase inhibitor, the prospective AERAS study investigated the benefit of continuing the same aromatase inhibitor for 5 years and for 10 years. The hypothesis was that 10 years of treatment may reduce the risk of recurrence, said Shoichiro Ohtani, MD, PhD, of Hiroshima City Hiroshima Citizens Hospital, Japan.2


I would recommend that patients with node-positive disease continue an aromatase inhibitor for 10 years.
— Shoichiro Ohtani, MD, PhD

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The study enrolled 1,683 women who had received approximately 5 years of adjuvant anastrozole; women who had received tamoxifen and then anastrozole for at least 2 years were also allowed. Patients were randomly assigned to stop treatment or continue it for 5 more years. Overall, 75% of the “stop” group and 70% of the “continue” group completed 5 years of study treatment and were followed for a median of 4.9 years.

The 5-year disease-free survival rate was 91.9% for the continue group and 84.4% for the stop group (hazard ratio [HR] = 0.548; P = .0004), and the distant disease–free survival was 97.2% and 94.3%, respectively (HR = 0.514; P = .0077). Overall survival, however, was 99% in both arms, with just 7 deaths during follow-up (4 in the extended anastrozole arm and 3 in the stop group).

Local recurrences were observed in 1.8% of the continue group and 3.8% of the stop group. Distant recurrences were observed in 2.7% and 5.6%, and second primaries were noted in 1.5% and 4.3%, respectively.

All subgroups benefited from extended endocrine therapy. However, this benefit did come at the cost of more bone fractures in the continue group (2.8% vs 1.1%), osteoporosis (33% vs 28%), arthralgia (19.2% vs 11.7%), joint stiffness (11.7% vs 4.9%), and hot flashes (6.7% vs 3.1%). Grade ≥ 3 adverse events, however, were uncommon.

Weighing the benefits and risk of 10 years of endocrine therapy, Dr. Ohtani concluded, “I would recommend that patients with node-positive disease continue an aromatase inhibitor for 10 years.” 

DISCLOSURE: Dr. Gray reported no conflicts of interest. Dr. Ohtani has financial relationships with Chugai, AstraZeneca, Pfizer, and Eisai.

REFERENCES

1. Gray R, Early Breast Cancer Trialists’ Collaborative Group: Effects of prolonging adjuvant aromatase inhibitor therapy beyond 5 years on recurrence and cause-specific mortality: An EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women. 2018 San Antonio Breast Cancer Symposium. Abstract GS3-03. Presented December 6, 2018.

2. Ohtani S, Iijima K, Higaki K, et al: A prospective randomized multi-center open-label phase III trial of extending aromatase-inhibitor adjuvant therapy to 10 years: Results from 1,697 postmenopausal women in the N-SAS BC 05 trial: Arimidex extended adjuvant randomized study (AERAS). 2018 San Antonio Breast Cancer Symposium. Abstract GS3-04. Presented December 6, 2018.


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