Tamoxifen Efficacy Revisited: Behind The Hype

PLEASE NOTE: Inaccuracies in my interpretation of the statistics in study referred to in this post were brought to my attention by one of the commenters below. After doing a lot of digging and head-scratching, I have decided to leave the original text, but have added strike-throughs over data that I wrongly interpreted, and further comments in purple text. The result is data that are more difficult to understand. The figures and graphs I referred to in the study show calculations for recurrence rates that are not simple rates of recurrence by incidence, but rather represent cumulative recurrence occurring over time.  The percentages I quoted originally cannot be read, therefore, as the simple rate of recurrence per number of women.  Rather, they represent the rates of recurrence per woman-year.  As nearly as I can explain that, it means the percentage rate of recurrence per woman across a year.  The rates that are shown in the graphs and figures in the study text plot the cumulative rate of recurrence, not the number of incidences of recurrence. And if that makes you wonder how it all applies to you as an individual, you are not alone.

Sometimes, I honestly feel as though I’ve unwittingly taken on the role of the unofficial Wet Blanket of Breast Cancer Research Statistics. I’m sure my college undergrad stats professor would be proud of me, however, for not taking statistical hype at face value. She was for many years a statistical analyst for the Framingham Heart Study, so she knew a thing or three about statistical hype.

This time, some of the hype came with a personal connection. The site for ABC News published a story 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 percentages quoted in the article, and attempt to find the original study.

I’d like to say somewhat tangentially that I want to thank the publishers of The Lancet very, very much for allowing me to register as a non-paying but interested stakeholder, which allows me to have access to their published studies in PDF form. Not every research journal does this, although quite a few of them do. And for we cash-poor cancer survivors and bloggers, who usually do not make a red cent from our efforts, it is a boon not to have to pay an average of $31.50 for the privilege of viewing a complete study online for 24 hours. The research reported by ABC News was published yesterday by The Lancet at this link: The Efficacy of Tamoxifen. You can view the summary without being registered. 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. In the previous review linked to their name above, 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, meaning that study participants were included whether they had breast cancer in their lymph nodes or not. It also included women who did and did not receive chemotherapy. This indicates indirectly that women who had early, small-tumor invasive breast cancers were included, along with those who had larger or more advanced tumors. 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+). This means 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. If we look more closely at one of these groups, the ER/PR+ group, meaning women whose tumors are receptive to both estrogen and progesterone, we find a detailed analysis. For the first four years after initial breast cancer diagnosis, the data yielded the following:

  • Of the 16,701 women taking tamoxifen, there were 570 recurrences in this time period, or a recurrence rate of 3.41% per woman-yearThese numbers are listed under a recurrence graph in Figure 1, for women with ER+/PR+tumors, but represent a calculation of percentage by woman-year, which is not a simple rate of recurrence per number of women, as they appeared to be when I first read them.  The recurrence rates shown on the graph are calculated as the cumulate rate of recurrence over the number of years shown along the bottom of the graph, based on the total number of women in this group, indicated at the top as 7,378.
  • Of the 15,432 women who did not take it, there were 926 recurrences per in this period, or a recurrence rate of 6.0% per woman-yearSee the previous comment.
  • The difference between these rates of recurrence is 2.59%.  This calculation, thank heaven, does not change.
  • This means that there were relatively 43.1% fewer recurrences in the ER/PR+ group taking tamoxifen in the first four years after initial breast cancer diagnosis and treatment than there were in the group who did not take it.  Still relative, still the same.
  • Out of the entire group of 32,133 women, there were 1,496 cumulative breast cancer recurrences in the first four years, for a cumulative recurrence rate within years 0-4 of about 20.3%.
  • If the control group of 15,432 women had instead taken tamoxifen, and responded as well as the tamoxifen group did, then it can be estimated that only 526 women in the control group would have had a recurrence, preventing some 400 women, 400 recurrences, or another 2.59% of them, from having a recurrence may have been prevented in the first four years.

It’s important to remember that these are statistics for breast cancer recurrence, not mortality. It’s also 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.

Looking at the same group of ER/PR+ women, the statistics for years 5-9 after initial diagnosis are as follows:

  • Of the 12,248 women on tamoxifen for these years, there were 303 recurrences during this period, for a recurrence rate of 2.47% per woman-yearSame deal as the previous section.
  • Of the 10,295 women not on tamoxifen for this period, there were 360 recurrences, for a rate of 3.5% per woman-year.
  • The difference between these two rates of recurrence was 1.03% per woman-year, which means that there were 29.4% fewer recurrences in the group that took tamoxifen compared to the group that did not, for years 5-9.
  • If the control group had taken tamoxifen and experienced a similar decrease in recurrence rate, then only 254 of these women would have had a recurrence, which would have meant 106 fewer recurrences in these 10,295 women, may have occurred, or a recurrence rate that was 1.03% better per year, as it was in the group that took tamoxifen.

Similar data were calculated for all women with ER positive breast cancer, whether PR+ or not, including 44% who had node positive breast cancer, 56% who did not, and 51% who received chemotherapy.

  • For all ER+ women, there were in years 0-4, a recurrence rate of 3.74% per women-year occurred 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 per woman-year in the group that took tamoxifen, for a relative decrease of 44.2% in rate of recurrence with tamoxifen.
  • For all ER+ women, in years 5-9, a recurrence rate of 2.62% had recurrences per woman-year occurred among those while taking tamoxifen compared to 3.46% per women-year 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.

Below is the graph from Figure 5 of the study, showing the 100% ER+ group from which these figures above were taken.  The text at the top about recurrence rate calculation is mine.  The colored lines were added by me to mark off the time periods that were used in the study to generate the recurrence rates per woman-year shown below the graph.  For about fifteen minutes, I actually understood how to calculate cumulative recurrence risks myself, and the numbers outlined in aqua are the cumulative rates at the end of Years 0-4, which, thank heaven, match the plot points on the graph.  I just couldn’t face doing it again for Years 5-9, so I used estimates, taken from the plot points intersecting the green lines, in my edited numbers above.

At this point, it should be noted that among all women who had ER+ tumors, by year 4 there was a cumulative recurrence rate of 14.1% among women taking tamoxifen, which means that 85.9% 96.3% of women taking tamoxifen in years 0-4 did not have recurrences, and neither did 75.7% 93.3% of the women who did not take it. In years 5-9, about 78% 97.4% of women taking tamoxifen did not have recurrences, and neither did about 62% 96.5% of the women who did not. 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 relative statistics thrown at us that are taken out of context. Yes, I know. To my regular readers, I readily admit that I sound like a broken record. Or a broken mp3 audio file.

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, I looked 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.

  • In years 0-4 after initial diagnosis of breast cancer, 1.79% of women per woman-year taking tamoxifen died of breast cancer, compared to 2.46% of women per woman-year who did not take tamoxifen and also died of breast cancer. This represents a difference of 0.67% in the yearly rate of breast cancer deaths per woman-year between the two groups, or a decrease in the breast cancer mortality rate of 27.2% associated with taking tamoxifen in Years 0-4 these years. The cumulative mortality rates at the beginning of Year 5 are plotted on the graph, and were calculated to be 8.6% among women who took tamoxifen and 11.9% in women who did not, which represents a 27.7% estimated decrease in mortality by the beginning of Year 5.
  • In years 5-9, 2.25% of women per woman-year who took tamoxifen for five years died of breast cancer, compared to 3.23% of women per woman-year who did not take tamoxifen, for a yearly difference of 0.98% per woman-year in the number of breast cancer deaths between these two groups. The average yearly decrease in the cumulative rate of breast cancer mortality associated with five years of tamoxifen use was 30.3% in these years.
  • In years 10-14, 1.54% of 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 At Year 15, the end of the study period, the cumulative decrease in the breast cancer mortality rate associated with five years of tamoxifen use was projected to be 32.5% about 28% for this group, for a cumulative gain in the number of lives saved of 9.2%.
  • For 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.

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

Will it save my life?

Once again, one needs to keep in mind that taking tamoxifen for five years after being diagnosed with ER+ breast cancer was projected to have saved the lives of less than 1% more women in each woman-year calculated across the period of fifteen years studied compared to those women who did not take it.  But the cumulative gain at the end of 15 years was 9.2%. It’s still a small number, a measley number in fact, across a span of 15 years, 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% percentage 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, but there is some analysis of the available data on this in the study.

My purpose here is to place things into some kind of perspective. 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. And in the current climate of sound-byte, quick-and-dirty journalism, it seems almost pointless to plead with those who get paid to report on research to do a more thorough job.

Now, if I could only get someone to pay me for doing it…

…especially after forcing my brain around the concept of cumulative risk.  I’m sure I probably still got some of the interpretation wrong, but I wanted at least to make the attempt to clarify the data I quoted here, especially since I am aware that parts of this post have been cut and pasted hither and yon, and perhaps used in a manner I did not intend.  While I am perhaps more in awe now of the efforts of the EBCTCG, I am also moved to make a plea to all researchers to report their findings in plain language.  And I would like to thank the splendid individual in the Epidemiology Section of the New Mexico Department of Health who wrote an explanation of the difference between incidence rate and cumulative incidence that I could actually understand, albeit briefly. I certainly won’t be giving a lecture on the subject anytime soon.


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This entry was written by Kathi, posted on Saturday, July 30, 2011 at 07:07 pm, filed under Chemotherapy-IV & Oral, Research and tagged , , , , , , . Bookmark the permalink . Post a comment below or leave a trackback: Trackback URL.

22 Responses to “Tamoxifen Efficacy Revisited: Behind The Hype”

  1. Fabulous analysis! Bravo!

  2. Aw, heck, Ann. It was too hot to mow the lawn today anyway. 😉

  3. Thank you! This is exactly what I try to explain to people, but I am not as smart as you. 🙂

  4. Yes, thank you. Like you, I’d like to see data on node negative versus node positive women.

    I had pure DCIS (no nodes) and I do not plan to take Tamoxifen. One of the reasons is that the potential SEs bother me (both the silent ones like strokes and the non-silent ones like headaches). Another reason is that it doesn’t seem worthwhile to cut in half a percentage that’s pretty small in the first place.

    Fortunately my MO isn’t pushing it and say’s it’s completely up to me.

  5. Arlyn, I’ve discovered that there are also side effects to reading research studies — headaches, eye strain, calculator fatigue — but I’m going to lie down shortly and get rid of them. 😉

    Cycle-path, there is actually quite a lot of data in this study. I could write a half-dozen posts about all of it. I have to hand it to the EBCTCG. They analyzed the data every which way till Sunday, and discuss all sorts of implications for treatment. EBCTCG is dah bomb. But you still have to do some sifting and sorting.

  6. Great analysis Kathi! Greatly appreciated and will help many.

  7. God, you’re smart! Thanks for breaking it down for us, KK! xo

  8. Kathi, I am so impressed that you are using Saturday time to analyze breast cancer research and then taking the time to share it with others! What a lot of data to wade through and I hope your eyes and head are better today!

    I agree that once again the news seems hyped. I guess there is such a strong draw to present *great* news when it comes to cancer. But I’m a little more tempered in this case. I do think tamoxifen has probably been the single best thing we have gotten in breast cancer over the last several decades (except perhaps herceptin, but don’t have long-term data yet). And this meta-analysis did show us some good things – that the benefit is real over the very long term, so maybe the drug isn’t simply delaying recurrences, and the side effects were not so much of a problem for women under 55. Considering that the pill is now generic and fairly low cost, what irks me is the marketing of the AIs as superior by big Pharma. But that’s another topic…

    Thanks for the great post!

  9. I think I busted a few neurons on this…!

    There are really more blog posts that I should write about this study, or as an adjunct to it. The whole ‘relative vs. absolute’ stats thing bugs the heck out of me. What interests me now, among other things, is that I think a lot of us have been quoted recurrence risk percentages that don’t seem to jive with the data presented here. We’ve been quoted, in general, much higher recurrence risks when being advised about adjuvant hormone therapy, which makes me want to do some more digging.

    Laura, I believe arimidex had gone generic, so it’s less costly. But I also think that, in general, the side effects of all of these drugs that may not be life-threatening per se, but relate to quality of life, have not been well-researched and tend to get minimized. Estrogen ends up being treated as though it is the enemy, when cancer is the enemy. There are so many problems that arise from shutting off all the body’s sources of estrogen, I really hope someone is looking for more precise ways of targeting ER+ breast tissue and not annihilating the rest of our bodies in the process. And yes, I do wonder how many of these studies have been sponsored by Astra Zeneca & other pharma companies who make these drugs.

    I feel like I want to interview a pathologist, too, in order to look at how the tissue is analyzed in the lab & what current assumptions are used to determine individual recurrence risk. I have this feeling that the data being used for that is often outdated by now. Hmm…

  10. Kathi, it is interesting with armidex and femara going generic, how the studies now feature aromasin.

    I treat a lot of men with prostate cancer, and when lupron was a money maker for the urologists, they all got it, and now that it’s now: they reviewed the data which only showed benefit for men with more aggressive disease and higher PSA’s and the side effects were considered significant enough to limit its use.

    Why isn’t estrogen deprivation given the same close look as testosterone?

    When the study came out that aromasin was superior to tamoxifen for prevention of breast cancer in high risk women, I wanted to scream…

    Thanks for another wonderful article.

  11. Judy, very interesting regarding side effects of lupron and prostate CA. I have been often tempted to write a post about this very subject — why is estrogen deprivation treated so blithely? I have felt for a long time that there’s something unseemly and sexist about it.

    Coonie, thank you for thinking I’m brilliant!! Nice to know someone does. 🙂 I’m stubborn, that’s for sure, and I had wicked smaht parents. Helped a lot!

  12. Great goooga mooooga KAK!!! I always knew you were smart, but you’re BRILLIANT!!! Thank you SO MUCH for taking the time to break this down for us mere mortals to understand:) I want to be like you when I grow up:)

    Big hugs Sistah!!!

  13. Kathi,

    Excellent posting and very informative, too. After chemo and radiation, I was on Aromasin for about a year and a half — until I was almost crippled by intense bone pain. I had to stop. My oncologist is wonderful, but a second-opinion guy tried to intimidate me with stats from the Internet (he brought the printouts).

    Newly diagnosed, I left his office crying. Luckily my current onc saved the day!!

  14. I wish I could pay you!!! Would you accept very deepest gratitude in lieu of payment? I am ER+ and was on Tamoxifen for 3 years before coming off the drug (with the agreement of my oncologist) as I wanted to try for a baby. Sadly that hasn’t worked out the way I had hoped..but I am still off Tamoxifen (and still trying to conceive). Every so often my conscience pricks me about staying off the drug but for me it is a calculated risk and one I am willing to take.

  15. When I first learned about Tamoxifen, my gut instinct was to run away, screaming. Doctors and other patients said, “Why wouldn’t you want to cut your risk in half?” And I kept asking, “But…half of WHAT?” So, understanding that the side effects could kill me, I turned down the drug and have been going solo on the whole estrogen thing. But, being a DCIS Gal gives me that ability to just walk away if I want.

    Then I met this amazing radiologist (who is writing a book about breast cancer and, basically, how not to panic) who introduced me to relative and absolute risk. Holy cow! He opened up a whole new world for me.

    My sister’s doctor offered her Tamoxifen as a preventative. I gave her the list of side effects and she said, “No thanks!”

    The sad thing is that we know too many women for whom the cancer was so aggressive, well, they didn’t stand a chance. Not knowing what category we fall into until it’s too late doesn’t help us to make these treatment decisions.

  16. You are so right about the need for complete and accurate information before beginning any treatment and sometimes this is next to impossible to get. It’s a challenge to look deeper than the simplistic headlines. As the old saying goes, if it sounds too good to be true, it probably is. That might hold true here as well. As always, thanks for doing such a tremendous job with researching this stuff.

  17. […] Kathi has been delving in behind the headlines on Tamoxifen and doing some breath-taking analysis of the stats – check out her post Tamoxifen Efficacy Revisited: Behind the Hype. […]

  18. Kathi,

    I admire your effort to understand the Lancet report, but you have completely misinterpreted some of the data and are spreading erroneous information. The stats you are quoting are for women-years — a statistical technique — not interpretable to mean that’s the percentage of women who recurred over the time period in question.

    PLEASE take a look at the charts in the Lancet report for the overall recurrence risk and risk reduction with tamoxifen.

    Of the group you reference (ER+ women, including 44% who had node positive breast cancer, and 51% who received chemotherapy) 46 percent of those who did NOT take tamoxifen had a recurrence of breast cancer within 15 years, compared with 33 percent who DID take tamoxifen. In that same group, 33 percent of those who did NOT take tamoxifen died of breast cancer within 15 years, compared to 24 percent who DID take tamoxifen.

    Your statement: “it should be noted that among all women who had ER+ tumors, 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.” is just flat-out WRONG, I’m sorry to say.

    Again, look at the charts! In years 0-4, 25 percent of those women had a recurrence compared to about 12 percent on tamoxifen. You are misinterpreting the use of “women-years” in the Lancet study.

    For the sake of breast cancer patients everywhere (I’m one of them, of course) I beg you to correct your entry above.

    Thanks,

    Rebecca

  19. Thank you for writing, Rebecca! I really appreciate your taking the trouble to write. And I definitely do not want to spread inaccurate information. I will look again at the study & correct my post as needed. I may need a few days to get to it, but I most certainly will.

  20. Thanks, Kathi! Someone is cutting and pasting your blog post (above) all over a big BC discussion site, which is how I found you. Great blog, by the way! But this person seems to be using it to suggest that people not take Tamoxifen. In my opinion, women can take ithe drug or leave it, according to their beliefs and desires, but they should be aware of the facts and their recurrence risk and how Tamoxifen might affect it.

  21. Makes my brain ache. At the end of the day, though, I’m resigned to taking Tamoxifen regardless of convoluted or contradictory statistics, because if not I must ask what my other options are, pharmeceutical or otherwise, and am at a loss…

  22. I hear you, emily. Wish it weren’t true. Too many of us are at loss, especially those with metastatic disease. Hugs.

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