Results from the British aTTom trial, presented during the 49th Annual Meeting of the American Society of Clinical Oncology, shows that 10 years of adjuvant treatment with tamoxifen (Nolvadex?, Istubal?, Valodex?; AstraZeneca) provides women with estrogen-receptor-positive (ER+) breast cancer greater protection against late recurrence and death from breast cancer than does the current standard of only five years of tamoxifen. The study was, in part, supported by Cancer Research UKand the UK Medical Research Council.

The study showed that while side effects also increased with longer tamoxifen use, the overall benefits greatly outweigh the risk of continuing therapy. The findings from aTTom, a Phase III randomized study, complement and confirm the results of the recently published international Adjuvant Tamoxifen ? Longer Against Shorter or ATLAS study.[1, 2, 3]

ATLAS trial
In the ATLAS study, researchers randomized approximately 6,800 women who had been on tamoxifen for five years to either continue taking it for another five years or to stop. The goal was to see if another five years of tamoxifen treatment further reduced the risk of recurrence in years five to 10 and beyond. The results of the trial showed that
women who take 10 years of tamoxifen had less risk of breast cancer recurrence than women who stop after 5 years. An important conclusions from this trial is that most of this risk reduction occurred in years 10 and beyond.


Women with early-stage breast cancer who took tamoxifen for 10 years following treatment for their primary cancer, had roughly 25% lower rates of breast cancer recurrence and death compared to those who took the drug for five years, as currently recommended.


Prevention of cancer recurrence after surgery
Hundreds of thousands of women worldwide take tamoxifen to prevent cancer recurrence after surgery for early-stage breast cancer. To date, tamoxifen is only effective in women with hormone-sensitive (ER-positive) tumors and most women start taking tamoxifen immediately after completing their initial surgery or chemotherapy.

Prior studies have shown that 5 years of tamoxifen reduces breast cancer death rates by about a third over a 15-year period following diagnosis. This study shows that 10 years of tamoxifen reduces breast cancer recurrence and death rates by an additional 25%, from year 10 onwards, compared to 5 years of tamoxifen therapy. The researchers estimate that, compared to taking no tamoxifen, 10 years of tamoxifen reduces breast cancer death rate by a third in the first 10 years after diagnosis and by half subsequently.

?Five years of adjuvant tamoxifen is already an excellent treatment but we thought that longer treatment might be even better because women with ER-positive breast cancer can have recurrences long after treatment is completed. Until now, though, there have been doubts whether continuing tamoxifen beyond five years is worthwhile,? said lead study author Richard G. Gray, MA, MSc (Photo), a professor of medical statistics at the University of Oxford in Oxford, United Kingdom. ?This study and its international counterpart ATLAS confirm that there is definitely a survival benefit from longer tamoxifen treatment and many doctors will likely recommend continuing tamoxifen for an extra five years.?

UK Trial
Between 1991 and 2005, 6,953 women in the United Kingdom who had been taking tamoxifen for 5 years were randomly assigned to continue treatment with tamoxifen for another 5 years or to stop immediately.

The women were contacted yearly to assess treatment compliance, recurrence, hospital admissions and death rates. Compliance was good with about 75% of women in the 10-year group continuing to take tamoxifen.

Fewer breast cancer recurrences
With 5,000 women followed for more than 10 years after randomization, and some as long as 20 years,fewer breast cancer recurrences were seen in the 10-year tamoxifen group than in the 5-year group (16.7 % vs. 19.3%). Longer treatment also reduced the risk of dying from breast cancer. The treatment allocation had little effect on either recurrence rates or death rates during the period 5-9 years
after diagnosis. After that, however (i.e., during the second decade after diagnosis), the women who had been allocated to continue tamoxifen treatment had a 25 percent lower recurrence rate and a 23% lower breast cancer mortality rate than the women who had been allocated to stop after only 5 years.

Practice changing results
“This landmark trial confirms recent findings of the ATLAS trial showing that extending therapy with tamoxifen to 10 years significantly lowers breast cancer recurrences and mortality. These results are therefore practice changing for premenopausal women with hormone receptor positive breast cancer and especially relevant for women who are at high risk of recurrence,” noted Sylvia Adams, MD, breast cancer expert and ASCO spokesperson.

Daniel Rea, MD, a clinical lead researcher based at the University of Birmingham, noted: ?These results are important as they establish that giving tamoxifen for longer than the current standard of five years significantly cuts the risk of breast cancer returning. Doctors are now likely to recommend continuing tamoxifen for an extra five years and this will result in many fewer breast cancer recurrences and breast cancer deaths worldwide. Tamoxifen is cheap and widely available so this could have an immediate impact.?

Adverse events
?Five years of tamoxifen is already an excellent treatment but there have been concerns that giving it for longer might not produce extra benefits and could even be harmful,” Gray noted.

Women taking tamoxifen can experience side effects similar to menopausal symptoms, such as night sweats and hot flashes. Rare but serious side effects of tamoxifen include increased risk of endometrial cancer (cancer of the lining of the uterus), blood clots and stroke. No excess incidence of stroke was observed with 10 years of tamoxifen therapy, though endometrial cancer risk was higher in this arm.

Endometrial cancer is often detected early, when it is usually curable; the researchers estimated that for every endometrial cancer death that occurs as a side effect of long-term tamoxifen, there would be 30 deaths from breast cancer prevented. Therefore, the benefits of continuing tamoxifen to 10 years greatly outweigh the risks, Gray explained.

Long-term effects
Researchers are planning to follow women in this and the ATLAS study for at least five more years to see if there is additional long-term benefit. A retrospective analysis of combined data from aTTom, ATLASand three smaller trials will be conducted to determine if there are subgroups of women that benefit the most from longer tamoxifen treatment. Ongoing clinical trials are comparing 5-year and 10-year use of aromatase inhibitors to see if longer use leads to more benefit as has been seen with tamoxifen.

References:
[1] Davies C, Pan H , Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Alencar VH, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oest
rogen receptor-positivecancer: ATLAS, a randomised trial. Lancet. 2012 Dec 5. pii: S0140-6736(12)61963-1. doi: 10.1016/S0140-6736(12)61963-1. [Epub ahead of print][Abstract]
[2]Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.Lancet. 2011 Aug 27;378(9793):771-84. Epub 2011 Jul 28.
[3] Hofland P. ATLAS Study: Extending Adjuvant Tamoxifen Treatment Improves Survival and Reduces Risk for Late Breast Cancer Recurrence; Greatest Additional Benefit Observed in 2nd Decade After Initial Diagnosis. OncoZine, December 2012, 5. [Full Article]

For more information:
Abstract #5: aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 in 6,953 women with early breast cancer.
Plenary Session Study
Author: Richard G. Gray, MA, MSc, University of Oxford, Oxford, United Kingdom
Date: Sunday, June 2, 2013, 3:50 ? 4:05 PM CDT
Location: Room: N Hall B1m

Photo:Richard G. Gray, MA, MSc, a professor of medical statistics at the University of Oxford in Oxford, United Kingdom.Photo Courtesy: ? ASCO/Silas Crews

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