A “‘breast cancer wonder drug’ increases the risk of developing another form of breast cancer by 440%”, according to today's newspapers. The Daily Mail 's story on tamoxifen says that these secondary cancers are much more dangerous as there are no drugs that specifically target them.
The body’s hormones, such as oestrogen, are involved in the development of some types of breast cancer, so drugs such as tamoxifen are used to block the effects of these hormones. This well-designed study has found that tamoxifen treatment does reduce the risk of new cancers that respond to oestrogen, but also increases the risk of going on to develop the rarer, oestrogen receptor negative (ER-) cancers, which do not respond to the hormone.
It should be noted that while there was a large increase in the chances of developing an ER- cancer, it is still rare and the overall risk remains low. The increased risk only occurred in women who took the drug for more than five years.
Overall, tamoxifen has clear benefits in treating breast cancer, but the implications of these new data will be an important element to consider when weighing up the use of tamoxifen.
Where did the story come from?
This research was carried out by Christopher Li and colleagues at Fred Hutchinson Cancer Research Center in Seattle and funded by The National Cancer Institute in the US. The study into adjuvant hormone therapy was published in the peer-reviewed medical journal Cancer Research.
What kind of scientific study was this?
Women who have recovered from breast cancer are said to have a substantially increased risk of developing a new breast cancer in the other breast. While hormone therapy is believed to reduce this risk, there are some early data to suggest that it may increase the risk of certain types of tumour, called oestrogen receptor-negative (ER-) tumours. Tamoxifen is a hormone therapy drug given for tumours that respond to oestrogen, called hormone receptor positive (ER+) tumours.
To look into the role of hormone therapy in secondary cancers, this case control study compared 367 women initially diagnosed with an invasive ER+ breast cancer and then later diagnosed with a new cancer in the other breast. These women were then matched with 728 women in the control group who had been diagnosed with only a single breast cancer.
The cases were drawn from a potential 17,628 women aged 40 to 79 who had been diagnosed with a first breast cancer in the Seattle region of the US between 1990 and 2005. The researchers excluded women with stage IIIC or IV primary breast cancer, as these cases were more likely to recur and have lower survival rates.
All women had been included in the study because they had ER+ tumours and the researchers were interested in the exposure of tamoxifen, which was used to treat them. All case subjects had developed invasive cancer in their second breast at least six months after treatment for cancer in their first breast. Control subjects were matched by age, year of diagnosis, county of residence at first diagnosis, race/ethnicity and which stage the first breast cancer was at. To be included they also had to have survived until the date on which their matched case subject was diagnosed with breast cancer in their second breast.
Study participants were contacted by telephone and interviewed regarding hormonal therapy for breast cancer, other treatments, breast cancer risk factors, reproductive and past medical history, family history and sociodemographic details. Medical records were also consulted for detailed information on treatment history and all drugs taken, including information on doses, frequency, start and end dates and adverse effects.
The researchers used statistical analyses to examine the associations between hormonal therapy given for breast cancer and the risk of developing ER+ and ER- cancers in the other breast. In their analysis the researchers favoured medically recorded data over self-reported data.
What were the results of the study?
Radiotherapy and chemotherapy were received equally between case and control subjects. Cases were both more likely than controls to have been diagnosed when their breast cancer was at a more advanced stage and to have a positive family history of breast cancer. Of the women who had developed a new cancer in the other breast, 303 of these were ER+ cancers and 52 were ER- cancers.
Women who had received treatment with tamoxifen or another type of hormonal therapy had an overall reduced risk of developing a new primary cancer in the other breast (OR 0.6; 95% CI 0.5 to 0.8). However, this reduction in risk was confined to those who had been treated for longer than one year, and this overall drop in risk was attributable to reduction in risk of ER+ tumours. Compared with women not treated with hormonal therapy, women treated with tamoxifen for five or more years had a reduced risk of ER+ cancer in the other breast (OR 0.4; 95% CI 0.3 to 0.7), but also a 4.4 times increased risk of developing an ER- cancer (OR 4.4, 95% CI 1.03 to 19.0). Tamoxifen use for less than five years was not associated with ER- cancer in the other breast.
What interpretations did the researchers draw from these results?
The researchers conclude that although hormonal therapy for breast cancer has clear benefits, the relatively uncommon outcome of developing an ER- cancer in the other breast may need to be considered as one of its risks. They say that this is of clinical concern given the poorer prognosis of ER- cancers compared with ER+ types.
What does the NHS Knowledge Service make of this study?
The risk of developing a new cancer in their second breast is said to be between two and six times greater in women who have recovered from breast cancer. Various studies have demonstrated that tamoxifen decreases the risk of cancer recurrence and of new ER+ cancer in the other breast, although it has suggested that the risk of ER- cancer may actually increase.
This is a valuable and well designed study, which has found that tamoxifen treatment reduced the risk of new ER+ cancer but increased the risk of the rarer ER- cancer.
It should be noted that the large 4.4 times increase in risk of ER- cancer (the 440% increased risk reported in news headlines) was restricted to women who had received tamoxifen treatment for five or more years. As ER- breast cancer is relatively uncommon, only 14 of the 358 women treated for this duration then developed ER- cancer, meaning that although it was a large increase in risk the absolute numbers are still quite low. On the basis of the study there would still only be 39 cases per 1,000 women taking tamoxifen for five years.
Other points to note include that:
- When calculating risk figures from such a small number of cases there is likely to be some inaccuracy. As the outcome of developing new ER- breast cancer is quite rare, a much larger sample size would provide more confident results.
- There was no significant association between use of tamoxifen for less than five years and risk of ER- cancer.
- Risk figures were adjusted to account only for the use of radiation therapy. There may be other confounding clinical factors affecting risk of new breast cancer that have not been assessed (although the researchers did take care to identify from the women a large amount of medical data and detail of their treatments).
- Most members of the study had used tamoxifen, so use of other types of hormone therapy cannot be reliably assessed. Further research will be needed to see if other increasingly used hormonal therapies carry similar risk.
As the authors say, this issue is of clinical and public health importance given the frequent use of tamoxifen therapy for breast cancer, the growing number of female survivors and the significant morbidity and mortality associated with a new ER- cancer developing in the other breast. This will be another important consideration when weighing up the risk and benefits of using tamoxifen treatment.