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The long-term risk of distant recurrence for women with early breast cancer has declined significantly, a decades-long analysis of clinical trial data showed, largely a result of patients enrolling with lower-risk disease along with improved adjuvant therapy.

In women with estrogen receptor (ER)-positive disease scheduled for at least 5 years of endocrine therapy, the 10-year rate of distant recurrence declined from 20.5% for those enrolled in trials in 1990-1999 to 15.4% in 2000-2004 and 11.7% in 2005-2009.

For ER-negative disease, rates declined from 29.7% in 1990-1999 to 21.5% and 18.2%, respectively, according to a report from Early Breast Cancer Trialists' Collaborative Group published in .

"Our data suggest that for women with estrogen receptor-positive disease diagnosed after 2000 who have at least 5 years of endocrine therapy planned, the risk of distant recurrence persists but is about a tenth lower than equivalent women in our previous report," the authors wrote. "By contrast, for those with estrogen receptor-negative disease, the majority of recurrences occurred in the first 5 years after diagnosis."

They cited a number of possible explanations for the decline in distant recurrences, including that the proportion of patients with node-negative disease in trials has increased over time, better tumor staging, and improvements in adjuvant treatment -- such as more-effective endocrine therapy (e.g., aromatase inhibitors), or for longer durations, and the introduction of adjuvant trastuzumab (Herceptin) for HER2-positive disease.

The analysis estimated that 80.5% of the improvement for ER-positive disease and 89.8% of the improvement for ER-negative disease was explained by changes in patient and tumor characteristics and improved treatments. After adjusting for the number of positive nodes, tumor size and grade, patient age, and treatment, the 10-year distant recurrence rate was reduced by up to 32% after 2000 among patients with ER-positive disease and by up to 21% among those with ER-negative disease:

• ER-positive disease 2000-2004: RR 0.77 (95% CI 0.75-0.79)
• ER-positive disease 2005-2009: RR 0.68 (95% CI 0.65-0.71)
• ER-negative disease 2000-2004: RR 0.82 (95% CI 0.79-0.85)
• ER-negative disease 2005-2009: RR 0.79 (95% CI 0.74-0.83)

In a , Paolo Tarantino, MD, of the University of Milan, and Sara Tolaney, MD, MPH, of the Dana-Farber Cancer Institute in Boston, said the results are a reminder of the importance of cancer research, "with efforts to achieve earlier diagnosis and better treatment of breast cancer progressively converging to reduce rates of recurrence in patients."

"These results offer crucial data to inform discussions with patients in clinical practice, allowing better estimates of the absolute risk reduction associated with each therapeutic intervention," they added.

The analysis from the included 155,746 women newly diagnosed with breast cancer in 151 randomized trials conducted from 1990 and 2009 -- 114,811 with ER-positive disease scheduled to receive at least 5 years of endocrine therapy, and 40,935 women with ER-negative disease.

Women were eligible if they were younger than 75 years at diagnosis and had a tumor diameter of 50 mm or less, fewer than 10 positive axillary lymph nodes, and no evidence of distant metastases at entry.

Women with ER-positive disease were older than those with ER-negative disease (median 55 vs 50 years). A quarter of women with ER-positive disease and 37% of those with ER-negative disease were diagnosed before 2000; tumor characteristics by year of diagnosis showed a significant trend towards lower risk tumors in more recent years.

Based on nodal status, the 10-year distant recurrence risk among patients with ER-positive disease from 1990-1999 to 2000-2009, decreased as follows:

• 0 positive nodes: 10.1% to 7.3%, respectively
• 1 to 3 positive nodes: 19.9% to 14.7%
• 4 to 9 positive nodes: 39.6% to 28.5%

For ER-negative disease, rates decreased as follows:

• 0 positive nodes: 18.3% to 11.9%
• 1 to 3 positive nodes: 31.9% to 22.1%
• 4 to 9 positive nodes: 47.8% to 36.5%

"Several recent treatment advances are expected to further improve outcomes for patients with breast cancer," said Tarantino and Tolaney, noting benefits seen with the use of neoadjuvant or adjuvant targeted therapies in HER2-positive disease, perioperative immunotherapy for triple-negative breast cancer, adjuvant olaparib (Lynparza) in BRCA-associated breast cancer, and adjuvant CDK4/6 inhibitors for high-risk ER-positive breast cancer.

"Thus, in the context of modern clinical practice, recurrence might be even less common than what was observed in the present analysis," they wrote.

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