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Genetic Testing May Improve Selection of Women With Estrogen Receptor–Positive Breast Cancer for 10 vs 5 Years of Hormonal Therapy

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Key Points

  • Recurrence rates were highest in the first 5 years for women with HER2-positive breast cancer, and were highest between 5 and 10 years for women with HER2-negative breast cancer.
  • Women with HER2-negative, estrogen-sensitive tumors had increased recurrence rates after 5 years, which coincided with the cessation of adjuvant hormonal therapy.

Genetic analyses of results from 1,125 postmenopausal women being treated for estrogen-responsive breast cancer have shown that some of them are more likely than others to have a late recurrence of their cancer and might benefit from 10 years of hormone therapy rather than 5 years. Women who had HER2-negative, estrogen receptor–positive tumors had more than double the risk of their cancer recurring between 5 and 10 years after surgery and after 5 years of adjuvant hormone therapy, reported Mitch Dowsett, FMedSci, PhD, BSc, at a press conference at the European Breast Cancer Conference.

“Our data suggest that these patients, who are those that appear to benefit most from the current standard 5 years of endocrine treatment, may also benefit from adjuvant hormone treatment that extends beyond that 5 years,” said Dr. Dowsett, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London. The work is a collaboration between his team and that of Jack Cuzick, PhD, FMedSci, FRCP(hon), at the Wolfson Institute of Preventive Medicine, Queen Mary University of London.

Oncotype DX Score

The findings are the latest to come from the ATAC trial, a double-blind phase III clinical trial that randomly assigned postmenopausal women with early, estrogen receptor–positive breast cancer to receive anastrozole, tamoxifen, or a combination of the two.

The investigators used data from the Oncotype DX 21-gene recurrence score to analyze the genetic makeup and to predict the likelihood of cancer recurring within 10 years in these women. The Oncotype DX result is a single score made up of 5 control genes and 16 informative genes, some of which are considered as groups rather than individual genes. One of these groups, the E-module, consists of four genes related to estrogen signaling, including the estrogen receptor itself, said Dr. Dowsett.

The researchers had previously shown that prediction of recurrence by Oncotype DX was poorer in the second 5 years after a patient’s diagnosis than in the first 5 years. To find out the reason for this, they determined the relationship between the expression of the individual genes and gene modules and early (up to 5 years) and late (between 5 and 10 years) recurrence rates in women with estrogen receptor–positive, HER2-negative breast cancer.

Gene Expression and Recurrence Rates

They assessed the gene expression and recurrence rates in 1,125 women in the ATAC trial, who had an average of 10 years of follow-up. Nearly 90% of the women were HER2-negative, and there were 215 recurrences during the 10 years.

Recurrence rates were highest in the first 5 years for women with HER2-positive breast cancer, compared with the subsequent 5 years. For women with HER2-negative breast cancer, the recurrence rates were higher between 5 and 10 years.

“When we looked at the women with HER2-negative breast cancer and defined them according to their E-module score, which indicated how sensitive to estrogen their tumors were, we found that there was a striking difference,” said Dr. Dowsett. “Among women with tumors most sensitive to estrogen, with a high E-module score, the recurrence rate more than doubled from 5.7% in the first 5 years to 13.6% in the subsequent 5 years. However, if they had a low E-module score, there was little difference in recurrence rates between the first 5 years and the next 5 years: 10.3% vs 12.3%.”

The researchers say that their results show that, despite similar overall recurrence rates for patients with estrogen receptor–positive tumors between the first 5 years and the next 5 years, there were important differences between groups of tumors with different gene-expression profiles.  

“Importantly, HER2-negative tumors that are very sensitive to estrogen are usually considered to be relatively low risk, yet these were the tumors that showed an increase in recurrence after 5 years, which coincided with the cessation of adjuvant hormonal therapy,” said Dr. Dowsett. “It is commonly thought that the reduction in recurrence achieved by 5 years of endocrine therapy ‘carries-over’ into the 5 years. Our results suggest this effect may differ markedly between different groups of estrogen receptor–positive tumors. We need to do more detailed analyses on large numbers of tumors to find out if this is the case.”

He said the results also suggested a way in which methods of predicting recurrence using genetic signatures may be improved. “Better predictors of recurrence than the Oncotype DX and others currently being used should be possible based on the different recurrence rates of different groups of tumors and their different sensitivity to endocrine therapy.” He and his colleagues are already working to see if they can achieve this.

Next Steps

“We are already testing over 900 tumors from the ATAC trial to see if we can identify the estrogen-sensitive tumors better than by the genes in the Oncotype DX test. This will allow us to see whether, using the knowledge from this work, we can indeed create better predictors of recurrence both for the first 5 years and subsequent years after diagnosis,” he said.

The findings could change clinical practice: Women with HER2-negative, high estrogen-signaling breast cancer might be considered for adjuvant hormone therapy that is extended to 10 years. However, the results need to be confirmed in other sets of tumors first.

Dr. Cuzick added, “It has long been known that women with estrogen receptor–positive cancers have a higher late recurrence rate than those with estrogen receptor–negative negative tumors. This work makes clear that even within estrogen receptor–positive cancers, the level of expression is important. Further work is needed to see if genetic expression profiles are better at doing this than more conventional quantitative immunohistochemistry.”

The study was funded by AstraZeneca, Breakthrough Breast Cancer, Royal Marsden NIHR Biomedical Research Centre, Institute of Cancer Research, and Cancer Research UK.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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