10-Year Adjuvant AI Use Supported In Hormone Receptor-Positive Early Breast Cancer

Extended treatment with letrozole improves outcomes relative to placebo after 5 years of letrozole in postmenopausal women with early breast cancer

medwireNews: Postmenopausal women with hormone receptor-positive early breast cancer who have taken an aromatase inhibitor (AI) as adjuvant therapy for around 5 years can benefit from extending treatment for a further 5 years, suggest the results of a placebo-controlled trial.

The researchers report improvements in disease-free survival (DFS) and incidence of contralateral breast cancer with the AI letrozole, but overall survival (OS) was not prolonged compared with placebo.

The MA.17R trial recruited 1918 postmenopausal women who had previously received adjuvant AI therapy for a median of 5 years and randomly assigned them to receive either letrozole 2.5 mg/day or placebo for another 5 years.

Extended treatment with letrozole significantly reduced the risk of disease recurrence or occurrence of contralateral breast cancer by 34% compared with placebo. The 5-year DFS rate was 95% for the 959-letrozole treated patients and 91% for the 959 women given placebo.

The annual incidence of contralateral breast cancer was also significantly lower with letrozole than placebo, with rates of 0.21% versus 0.49% per year, giving a hazard ratio of 0.42.

However, after a median follow-up of 6.3 years, the 5-year OS rates were comparable between the treatment arms, a finding that the authors of a linked editorial do not find surprising.

Rowan Chlebowski and Matthew Budoff, both from Harbor–UCLA Medical Center in Torrance, California, USA, write: “The participants, who in most cases underwent randomization approximately 10 years after the time of diagnosis, have passed the peak risk of recurrence and a considerable proportion of their remaining risk as well.

“In any event, avoiding a new diagnosis of invasive breast cancer is a benefit in itself.”

Researcher Paul Goss, from Massachusetts General Hospital Cancer Center in Boston, USA, and colleagues found a significant increase in bone-related adverse events in the letrozole group relative to the placebo group, with significantly higher incidence of bone pain (18 vs 14%), fracture (14 vs 9%) and new-onset osteoporosis (11 vs 6%).

The arms were comparable with respect to the incidence of other toxicities, except for increase in alkaline phosphatase and alanine aminotransferase levels.

The team believes that “[u]ltimately, the decision of whether a patient should receive prolonged therapy with an aromatase inhibitor will depend largely on the extent of its effect on her in terms of toxic effects and quality of life, the extent to which bone mineral density is maintained, as indicated by sequential scans, and the patient’s individual risk of disease recurrence.”

The research was simultaneously published in The New England Journal of Medicine and presented at the annual meeting of the American Society of Clinical Oncology in Chicago, Illinois, USA.

Ian Smith, from the Royal Marsden NHS Foundation Trust in London, UK, who discussed the MA.17R results, notes that the small but significant increase in DFS has been achieved without major toxicity after very prolonged use.

But he explains that the reduction in contralateral breast cancer contributes significantly to this benefit so that there is only a nonsignificant 1.1% improvement in distant recurrence.

Emphasizing that it is important to identify the patients who are at risk of late recurrence as “they are the ones we want to target” for extended therapy, Ian Smith noted that distant recurrence may take up to 20 years even in patients with high-grade or node-positive patients, and that recurrence is still found in those with the lowest risk.

“We need to develop an algorithm based on both clinical and genomic parameters for risk of late relapse, so that the great majority of patients who don’t need prolonged therapy can be identified”, the discussant concluded. 

References

Goss PE, Ingle JN, Pritchard NJ, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med 2016; Advance online publication 5 June. doi: 10.1056/NEJMoa1604700

Chlebowski RT, Budoff MJ. Changing adjuvant breast cancer therapy with a signal for prevention. N Engl J Med 2016; Advance online publication 5 June. doi: 10.1056/NEJMe1606031

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