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Tamoxifen: What Difference Does It Really Make?

A new study about tamoxifen efficacy was reported last weekend by ABC News with this headline: Breast Cancer: Tamoxifen Saves Lives but Some Women Go Without It. This particular story featured a photo of and interview with someone I know and respect, Alicia Staley, an activist, blogger, breast cancer survivor, and founder of The Staley Foundation. So, imagine how I felt doing what I always do when I see a news headline about breast cancer research. Which is that I become immediately suspicious of the hype, and the percentages quoted in the article, and attempt to find the original study.

The original study was published on July 29th by The Lancet at this link: The Efficacy of Tamoxifen. However, if you want to get behind the headlines, you have to read the entire study, which you can see here: Longterm Tamoxifen Efficacy, An Analysis of Randomised Trials. The study was funded by Cancer Research UK, the British Heart Foundation, and the Medical Research Council, and was undertaken by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), a collective of researchers whose stated mission has for many years been to review research literature about early breast cancer and its treatment. The EBCTCG describes their mission as follows:

Systematic reviews of the effects of health care attempt to bring together all relevant evidence on a particular intervention or treatment, so that people choosing between different interventions are more informed and can make better decisions.

In other words, my kind of people.

The ABC News story reported these findings from the study:

Taking a [tamoxifen] pill a day for five years reduced annual breast-cancer mortality by 30 percent for 15 years, the study found. And recurrence rates fell 47 percent in the first four years after treatment, and 32 percent over the next five years, according to the study.

You're supposed to say, "Wow!" and be impressed. And it is impressive. And we've basically known this for quite some time. However...

Behind the hype: relative versus absolute.

What the study in fact did was to review some twenty-plus previous studies of tamoxifen efficacy, involving some 54,000 women, divided generally into the usual groups -- those who took tamoxifen and those in the control groups who did not -- and analyzed all the statistical findings. Both node-negative and node-positive women were included in each group, i.e., women who did and did not have breast cancer in their lymph nodes. It also included women who did and did not receive chemotherapy. This indicates indirectly that women with Stages I, II & III cancers were included. Trials for women with ductal carcinoma were excluded. The data was then analyzed for three time periods: from 0-4 years after initial diagnosis; from 5-9 years after diagnosis; and for 10 or more years after diagnosis. Finally, overall statistics were computed for all the participants in the 20+ studies reviewed.

It has been known for some years now that the women who are likely to benefit the most from tamoxifen, as well as other adjuvant oral chemotherapy such as aromatase inhibitors, are those whose breast cancer tumors contain receptors that are positive for estrogen (ER+). These are tumors that in effect feed on estrogen, among other things. So, keeping estrogen away from breast tissue would, it would seem logical, help prevent tumors from recurring or would at least slow them down. That is what tamoxifen does, by blocking the receptors in breast tissue that take up estrogen.

The study included participants who had every type of tumor receptivity, and separated participants into groups according to the specific hormone receptivity of their tumors. It's important to bear in mind how the word 'recurrence' is used in this study. Usually, a breast cancer recurrence is a return of symptoms in the same breast in which the original tumor appeared. A new occurrence of breast cancer in the other breast is not considered a recurrence, but a new event, and it may not be the same kind of breast cancer that was originally diagnosed in the first breast. In this study, however, first recurrence data included the occurrence of any breast cancer, whether is was local, in the opposite breast or distant.

If we focus on the data analyzed for women with strongly ER positive breast cancer, the type that should benefit most from tamoxifen, we find the following. This group included women with ER+ cancers, with and without PR+ receptivity, including 44% who had node positive breast cancer, 56% who did not, and 51% who received chemotherapy. Ultimately, those in the tamoxifen group took the drug for five years.

  1. For all ER+ women, there were in years 0-4, a rate of 3.74% who had recurrences among those who took tamoxifen, compared to a rate of 6.71% in the group that did not.  Which means that there were 2.97% fewer recurrences in the group that took tamoxifen, for a relative decrease of 44.2% in rate of recurrence with tamoxifen.
  2. For all ER+ women, in years 5-9, 2.62% had recurrences while taking tamoxifen compared to 3.46% among those who did not, a decrease of 0.84% in the number of recurrences with tamoxifen, and a relative decrease of 24.3% in the rate of recurrence.
  3. This also means that 96.3% of women taking tamoxifen in years 0-4 did not have recurrences, and neither did 93.3% of the women who did not take it.
  4. In years 5-9, 97.4% of women taking tamoxifen did not have recurrences, and neither did 96.5% of the women who did not.
  5. ER+ women who took tamoxifen for 1-2 years had nearly as great a reduction in recurrence in years 0-4 as those who took it for it for five years.

The reality of the small absolute percentages is something to keep in mind when an oncologist is flogging you with statistics, a practice I call 'statistical terrorism.' If you are one of those women among the single-digit percentages who are unlucky enough to have a recurrence, it certainly matters greatly that you are not among that lucky 90+ percentage of women who don't. But it's frightening enough to have breast cancer without having statistics thrown at us that are taken out of context. A statistic that is often quote to women advised to take tamoxifen is that it will cut their recurrence risk in half. In reality, that half may only represent a single digit decrease.

But does it save lives?

Now to examine the data for breast cancer mortality. Once again, to zero in on those one would expect to benefit most from tamoxifen, we can look at the analysis of mortality done among all women with strongly ER+ tumors. Breast cancer mortality was calculated by starting with the total death rate among all of the study participants, and subtracting the death rate for those women who never had a recurrence of breast cancer, who presumably died of other causes. All of these rates and percentages are technically projected, based on taking tamoxifen for five years, but the projections are based on the hard data of comparing mortality rates with recurrence rates.

  1. In years 0-4 after initial diagnosis of breast cancer, 1.79% of ER+ women taking tamoxifen died of breast cancer, compared to 2.46% of women who did not take tamoxifen and also died of breast cancer. This represents a difference of 0.67% in the number of breast cancer deaths between the two groups, or a decrease in the breast cancer mortality rate of 27.2% associated with taking tamoxifen in these years.
  2. In years 5-9, 2.25% of ER+ women who took tamoxifen for five years died of breast cancer, compared to 3.23% of women who did not take tamoxifen, for a difference of 0.98% in the number of breast cancer deaths between these two groups. The decrease in the rate of breast cancer mortality associated with five years of tamoxifen use was 30.3% in these years.
  3. In years 10-14, 1.54% of ER+ women who took tamoxifen for five years died of breast cancer, compared to 2.28% among those who did not take it. There were 0.74% more deaths by breast cancer in the latter group, and the decrease in the breast cancer mortality rate associated with five years of tamoxifen use was 32.5%.
  4. For ER+ women who were 15 years or more from their initial diagnosis, the mortality rate was 1.48% in the tamoxifen group, 1.89% in the control group, a difference of 0.41% in the number of breast cancer deaths, or a 21.7% relative decrease in mortality associated with five years of tamoxifen use.
  5. ER+ women who took tamoxifen for only 1-2 years experienced a continued decrease in mortality after five years from initial diagnosis.

The study also compared the rates of recurrence and mortality for women with ER+ tumors under age 45 at diagnosis, and those between 55 and 69 at diagnosis, and found comparable statistics. This analysis can be found in Figure 6. of the full study.

Will it save my life?

Once again, take a hard look at those numbers. Taking tamoxifen for five years after being diagnosed with ER+ breast cancer saved the lives of less than 1% more women across the period of fifteen years studied compared to those women who did not take it. It's a small number, a measley number in fact, but because of the astounding incidence of breast cancer, it still represents a lot of lives. But perhaps not enough of them.  At this writing, I have not been able to obtain statistics for how many women this less-than-1%-more represents among all the women who die every year of breast cancer. Nor is there space in this post to discuss the side effects of tamoxifen, and the mortality rates for women who died of uterine cancer or blood clots that may have been caused by tamoxifen, although there is some analysis of the available data in the study.

My purpose here is to place things into some kind of perspective. The actual numbers reported in this study certainly call into question the assumptions that are used to determine recurrence risk, and are then quoted to us by our doctors. When doctors use relative percentages, not absolute percentages, they are doing us a disservice by omitting the perspective we need to make informed decisions about treatment. Quality of life can be severely affected by the estrogen deprivation brought about by hormone therapy, but discussion by oncologists of side effects and their impact on quality of life is often cursory at best, generally incomplete, and sometimes omitted entirely.

Back to my friend Alicia Staley, who was interviewed as part of the ABC News report. Staley was diagnosed with ER+ breast cancer at age 33. She took tamoxifen for two-and-a-half years, according to the report, but the side effects were having such a profoundly negative impact on her quality of life that she had to stop taking it. Six months later, she had a recurrence. Would she have had one if she had continued taking it? Naturally, she went round and round about her decision to stop it. But as the above data indicate, some women who take tamoxifen have recurrences anyway. Staley concluded that perhaps the tamoxifen bought her some time, enabling her to make a better and more definitive decision about what treatment to have when she did have a recurrence, without having to question herself had she never taken tamoxifen at all.

It's a tough choice, but to echo the mission of EBCTCG, it's important to have complete information about any treatment before deciding whether it's the right one for you.  And you can't get that from a glance at the average news headline or an incomplete discussion with your doctor.


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