Ten years of tamoxifen ups cancer survival rates

'Breast cancer deaths halved if patients given "wonder drug" tamoxifen for 10 years, not five,' reports the Daily Mail.

This headline is based on a study of the effectiveness and side effects of extended tamoxifen treatment in women with early-stage oestrogen-sensitive breast cancer.

As the name suggests, oestrogen-sensitive (ER) breast cancers are growths of cancerous cells that are stimulated by the hormone oestrogen. Tamoxifen is used to block the effects of oestrogen on these ER cancers.

Tamoxifen is commonly offered alongside other breast cancer treatments and it is usually recommended that treatment with the drug continues for five years after other treatments have ended. This is because research has found that a long-term course of tamoxifen can reduce the risk of breast cancer returning (recurrence) and can also help prevent breast cancer deaths.

The researchers thought that extended treatment for 10 years may offer further benefits. They did in fact find that cancer recurrence was lower in women receiving 10 years of treatment compared with women getting the standard five years of treatment.

Much of this added benefit occurred 10 years or more after the initial cancer diagnosis. This may be of particular significance to younger women with early-onset breast cancer, where the potential impact of the recurrence of cancer in terms of life expectancy may be more of a concern.

Overall, this large study suggests that extended tamoxifen treatment may be more effective for some women than the current standard of treatment. Further studies are underway to measure both the long-term benefits and risks of this treatment option more precisely.

Where did the story come from?

The study was carried out by researchers from the University of Oxford and other institutions throughout the world, and was funded by Cancer Research UK, the UK Medical Research Council, the US Army, EU-Biomed and AstraZeneca UK (a manufacturer of tamoxifen).

While the funding by a pharmaceutical company may represent a potential conflict of interest, the researchers stressed that the "study was designed, conducted, analysed, interpreted and reported by the investigators independently of all funding bodies".

The study was published in the peer-reviewed medical journal The Lancet.

Generally, the media reported the story accurately. While the Daily Mail somewhat simplistically referred to tamoxifen as a "wonder drug", they did make the important point that long-term use of  tamoxifen is associated with risks as well as benefits, such as a slight increase in the risk of developing endometrial or uterine cancer.

Helpfully, all of the stories included the fact that tamoxifen is only effective for ER-positive breast cancers.

What kind of research was this?

This was a randomised controlled trial that compared outcomes (cancer recurrence and mortality) for two groups of women:

• women treated with a five-year course of tamoxifen
• women treated with a 10-year course of tamoxifen

Previous research on women with ER-positive breasr cancer has shown that women who receive tamoxifen for five years have a lower risk of the cancer recurring than those who have no treatment.

Tamoxifen has also been found to reduce the risk of dying of breast cancer during the first ten years following cancer diagnosis.

The researchers thought that this benefit may be even greater with longer treatment.

What did the research involve?

To assess the effectiveness of extended (10-year) versus standard (five-year) treatment, the researchers enrolled women with breast cancer who were currently receiving tamoxifen as part of their treatment. They randomly assigned the women to either discontinue treatment at five years, per standard practice, or continue treatment for another five years.

All of the women had early stage disease and received therapy that their doctors believed had completely removed the cancerous cells from the breast tissue. This meant that at the beginning of the trial, all of the women were free of known disease.

The researchers followed-up the women and compared the rates of cancer recurrence and deaths between the two groups.

They also examined side effects associated with the drug treatment in the five- and 10-year treatment groups.

Other than the length of treatment with tamoxifen, the women continued treatment as usual with their regular doctor. The researchers collected information each year on treatment status, breast cancer recurrence, any new cancers (including endometrial cancer, which is a known side effect of tamoxifen treatment), and deaths during the previous year.

The ER status of these women varied: 6,048 women either had ER-negative cancer or their ER status was unknown. 

These women were included in the analysis of tamoxifen side effects, but not in the main recurrence and mortality analysis.

This means that recurrence and mortality results should only be interpreted as relating to women with ER-positive cancer, not all breast cancer cases.

The trial's follow-up period was 15 years after breast cancer diagnosis.

What were the basic results?

In the 10-year treatment group, during the follow-up period there were:

• 617 recurrences
• 331 breast cancer deaths

In the five-year group there were:

• 711 recurrences
• 397 breast cancer deaths

In their primary analyses of the 6,846 women with ER-positive breast cancer, the researchers found that treatment for 10 years resulted in lower rates of cancer recurrence and mortality than treatment for five years. However, this effect was only significant after 10 years of follow-up. The researchers found that:

• there were no significant differences in breast cancer recurrence between the two groups after five to nine years of follow-up (rate ratio (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02)
• there were no significant differences in deaths due to breast cancer between the two groups after five to nine years of follow-up (RR 0.970, 95% CI 0.79 to 1.18)
• after 10 or more years follow-up, there was a 25% reduction in the rate of breast cancer recurrence among women treated for 10 versus five years (RR 0.75, 95% CI 0.62 to 0.90)
• after 10 or more years follow-up, there was a 29% reduction in the rate of death due to breast cancer among women treated for 10 versus five years (RR 0.71, 95% CI 0.58 to 0.88)

When comparing treatment side effects reported by 12,894 women with an ER-status breast cancer, the researchers found that compared with women treated for five years, those receiving extended tamoxifen treatment had:

• no significant difference in death due to reasons other than breast cancer (RR 0.99, 95% CI 0.89 to 1.10) or stroke (RR 1.06, 95% CI 0.83 to 1.36)
• an 87% higher rate of hospitalisation or death due to pulmonary embolism (RR 1.87, 95% CI 1.13 to 3.07)
• a 74% higher rate of hospitalisation or death due to endometrial cancer (RR 1.74, 95% CI 1.30 to 2.34)
• a 24% lower risk of ischaemic heart disease (RR 0.76, 95% CI 0.60 to 0.95)

Overall, the cumulative risk of dying of breast cancer between five and 14 years after first diagnosis was 12.2% in the extended treatment group versus 15.0% in the standard treatment group, a reduction in absolute risk of 2.8% (or a reduction in breast cancer mortality of 28 per 1,000 women). 

On the harms side, during the same follow-up period the cumulative risk of developing endometrial cancer was 3.1% in the extended group versus 1.6% in the standard group. The mortality risk of these new endometrial cancers were 0.4% in the extended and 0.2% in the standard groups, with an absolute risk increase of 0.2% (or an increase in endometrial cancer mortality of two per 1,000 women).

How did the researchers interpret the results?

The researchers concluded that, "For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at five years produces a further reduction in recurrence and mortality, particularly after 10 years," and that these results "suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis."

Conclusion

This study suggests that extended treatment with tamoxifen can bring further benefits to women with ER-positive breast cancer at the expense of an increased chance of pulmonary embolism and endometrial cancer.

The balance appears to favour the benefit of treatment, with an absolute reduction in breast cancer mortality of 2.8% compared with an absolute increase in endometrial cancer mortality of 0.2%.

This trial has several strengths, including the large study size, the long-term follow-up, and the similar follow-up in each treatment group.

The effectiveness results should only be considered to apply to the specific group of women included in the study – women with early-stage ER-positive breast cancer that has responded to initial treatment, leaving them free of disease after initial treatment.

The authors report that previous studies show that side effects seen after five years of tamoxifen treatment include endometrial cancer (cancer of the lining of the uterus) and thromboembolic disease (diseases involving blood clots).

This study shows that these risks are higher in women treated with tamoxifen for 10 years than women who have received five years of treatment.

The researchers say that the increased risk of death due to new cases of endometrial cancer is "greatly outweighed in ER-positive disease by the decrease in breast cancer mortality".

Despite the promising results of this study, it is unlikely that its publication will lead to an overnight change in how early stage ER-positive breast cancer is treated by doctors. Cancer researchers tend to err on the side of caution and most of them would want more detailed information gleaned from further studies about the potential benefits and risks of long-term tamoxifen treatment before any changes are made to the way women with breast cancer are treated.