This article is a response to that written by Professor Susan Davis for InSight+ on 9 September 2019.

I HAVE spent several decades studying and managing the impact of hormones on the breast and breast cancer; Professor Susan Davis has spent the same time studying and treating women with reproductive hormone dysfunction. How can we be so far apart in our interpretation of the recent seminal Lancet article on breast cancer risk and menopausal hormone therapy (MHT)?

I will try and explain and suggest a way that we can come into alignment.

First, a potted history of MHT:

The recent Lancet article is from Sir Richard Peto’s group at Oxford – a group that changed the direction of how we view so many diseases, especially breast cancer. Here are some highlights from the latest article:

  • meta-analysis of prospective individual data for 108 647 post-menopausal women who developed breast cancer between 1992 and 2018;
  • 51% had used MHT;
  • the mean age of commencement of MHT was 50 years old;
  • the mean usage of MHT at the time of diagnosis was, for current users, 10 years, and for past users, 7 years;
  • the risk was greatest for continuous oestrogen-progestin even with short term usage; and
  • oestrogen-only MHT, irrespective of oral or transdermal administration, also increased risk.

The article also demonstrates a few important points:

  • cMHT is worse than oestrogen-only therapy (much higher risk than the WHI data showed);
  • even 1–4 years of usage of cMHT caused a 60% increase in breast cancer (relative risk, 1.60; 95% CI, 1.52–1.69); and
  • even after cessation, there is a significant residual risk proportional to length of usage.

The following is the absolute increase in risk:

Five years usage:

  • continuous cMHT — 1 in 50 develop BCa;
  • intermittent cMHT — 1 in 70 develop BCa;
  • oestrogen only MHT — 1 in 200 develop BCa

10 years usage:

  • continuous cMHT — 1 in 25 develop BCa;
  • intermittent cMHT — 1 in 35 develop BCa;
  • oestrogen only MHT — 1 in 100 develop BCa.

The article also demonstrated that:

  • all types of MHT, except vaginal oestrogen, increased the risk, including tibolone, with a relative risk of 1.57; and
  • the WHI trial gave MHT to older women of average age 63 years. The Lancet article found similar lower relative risks as the WHI trial in the 60–69 years group – much lower than the risk in those starting MHT at a younger age.

The final statement of the article is particularly concerning from a public health perspective:

“In western countries there have been about 20 million breast cancers diagnosed since 1990, of which about 1 million would have been caused by MHT use.”

There are several elements of Professor Davis’ comments with which I disagree:

“If obesity were a drug, we would be recommending people did not use it.”

In relation to the above statement, the Lancet data are not just a simple rehash of a meta-analysis and should not be relegated to that single take-home message. I do not believe Professor Davis has argued persuasively against the quality of the data, which show:

  • a higher risk in cMHT;
  • risk in oestrogen-only MHT;
  • risk of tibolone usage;
  • risk is of earlier onset than previously thought;
  • significant risk after cessation of therapy;
  • no risk of vaginal oestrogen usage; and
  • validation of the higher incidence of lobular carcinoma – the “occult malignancy” breast specialists dislike.

“As prescribing practices have changed significantly over the past decade, further research is needed to determine the impact of currently recommended regimens.”

There are no WHI-like trials to support the assertion that the switch to newer MHT results in less breast cancer. Is this history repeating itself? Are we initiating new therapies purporting to be better but without RCTs? One of the new cMHTs uses oral CEE and the only change is in the uterine protective agent.

“It is vital to consider this to be a unidimensional study.”

This is not disputed, but it is a huge trial adding to the knowledge in our understanding about the most commonly diagnosed cancer in Australia.

“What they fail to highlight is that, for young women, MHT increases their breast cancer risk to approximately what it would have been if they had not gone through an early menopause.”

The Lancet authors did not fail to take this into consideration. To limit biases, the main analyses were restricted to prospective studies, allowed for early menopause decreasing breast cancer risk and bringing forward the age when MHT is started, and adjusted for various other potential confounding factors (as other correlates of breast cancer risk might also affect the type or timing of MHT use).

“The reported data were observational.”

These are data from women within clinical trials, and even they were observational, this is no longer an epitaph of dead data.

The 21st Century Cures Act, which passed the US Congress in 2016, places additional focus on the use of real world evidence data to support regulatory decision making, including approval of new indications for approved drugs. The US Congress defined “real world evidence” as data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than traditional clinical trials.

The hope is to avoid large expensive RCTs by using smaller RCTs with adaptive design and Bayesian statistics, and then real world evidence data for validation. This year, for example, a CDK 4/6 inhibitor for male breast cancer was registered, without a large clinical trial, using very sophisticated analysis of electronic health records data. It was the first time the Food and Drug Administration had given this type of approval and has led to large pharmaceutical companies looking to buy electronic health record companies to progress drug development.

On the other hand, I believe Professor Davis would agree that there are many women suffering severe menopausal symptoms unnecessarily, either because their doctor will not prescribe MHT, or because the woman is too scared to take the therapy. Many turn to expensive, potentially dangerous therapies in desperation. Over the past 30 years, we have not done a good job in dealing with breast cancer risk and MHT.

So, how can we use this change in direction?

A subset analysis of the WHI study demonstrated that in those whose breast density increased while taking MHT, there was a proportionate increase in risk of developing breast cancer. Conversely, in the tamoxifen prevention study, those who had a reduction in breast density in the tamoxifen arm were those who had the greatest reduction in breast cancer risk.

Therefore, real world evidence could cross-reference a potential surrogate marker of breast cancer risk (mammographic breast density) to MHT type and usage. This may give us the answers we need without waiting for a change in breast cancer incidence and more argument over data veracity or applicability.

However, it is a slow road. Breast Screen Australia does not give women information about their individual breast density, whereas Breast Screen WA does. There are likely many women taking MHT who are having screening mammograms that show their breast density has gone up and neither they nor their GP are aware of this fact.

Automated mammographic reading software that removes observer bias is available; it gives a continuous variable output and is relatively inexpensive. If this were introduced in a uniform way across the country, it may help coalface clinicians navigate this difficult area.

I agree with Professor Davis that the new forms of MHT do not seem to elicit the same toxicity in the breast as the older MHTs. I base this on an understanding of the complex intracrinology of the breast, real world evidence, and some RCTs that show there is a paucity of effect of these new therapies on mammographic breast density.

Our assertions have not been sufficient to convince medical practitioners and women that these new therapies are safe. Disagreement between an experienced breast cancer specialist and researcher like myself and Professor Davis, the President of the International Menopause Society, does not improve that situation.

In the end, my disagreement with Professor Davis boils down to two things:

  • real world evidence — the data presented in the Lancet article are extremely valuable and concur with what most researchers in hormone-dependant breast cancer thought was happening. We have not listened sufficiently to epidemiologists in the past, much to our chagrin; and
  • Professor Davis’ final assertion that “future research is needed”. If that research is RCTs, it is not going to happen, so let’s change direction. Link mammographic breast density to MHT usage – these are data that are or could be collected at Breast Screen – and breast cancer incidence. This is obtainable and results could be rapid.

Dr Stephen Birrell is an Adjunct Academic to the Dame Roma Mitchell Research Laboratories at the Department of Medicine, University of Adelaide. He was previously the Director of the Breast Cancer Unit at Flinders Medical Centre. He is a Founding Member of the PacRim Hormone Dependant Cancers Research Group. He is Founder and Chief Medical Officer of Havah Therapeutics and Wellend Health.

 Dr Birrell is a major shareholder in Havah Therapeutics and Wellend Health. He has received grants and speaking honoraria from AstraZeneca Global, Pfizer, Besins Healthcare, Novartis and Roche.

 

The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.


Poll

Real world evidence should be given equal weight as that from RCTs
  • Strongly agree (55%, 21 Votes)
  • Agree (21%, 8 Votes)
  • Disagree (13%, 5 Votes)
  • Neutral (5%, 2 Votes)
  • Strongly disagree (5%, 2 Votes)

Total Voters: 38

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6 thoughts on “Breast cancer and MHT: time for real world evidence

  1. Peter Bradley says:

    Sadly, once again in discussion of this subject, all the attention appears to be directed at the ‘incidence’ of breast Ca, and called ‘risk’, but as we all know, no-one dies of the breast primary, it is the metastases that are life threatening. One could say therefore, a better term than risk might be incidence, which is less ‘negative’..!

    So, why is there usually so little discussion of the ultimate mortality comparison between the treated and control groups in any of these studies, which is the real ‘risk’ factor – ie death from… Actually, if memory serves, WHI did do this, and the ultimate mortality in the treated cohort was favourable, compared to those who had never had MHT. (Personally I still prefer the term HRT, but that’s just me, I guess).

    I’m one of those who tends to like thinking outside the square. Accepting that most of these tumours are hormone dependent, I think it not inappropriate to consider the analogy of a nurtured garden as opposed to a neglected one, so the weeds then grow fast when watered, seen early, and plucked out. As opposed to slow growth when not, so the latter seeds early, as opposed to being plucked out earlier. One wonders if breast Ca incidence is not more a case of earlier detection, therefore removal and therefore better chance of cure, as opposed to one slow growing, not detected early, so spread had occurred before treated. This earlier detection not being just because of receiving more ‘hormonal fertiliser’, but because women on HRT are seen more often for the Rx, but also tend to have breast checks and mammograms more regularly for the same reason.

    It would be so much more helpful if the author above had also compared the mortality statistics, and not just incidence, of the trials he quotes, assuming the studies continues long enough to do so. If not, then they are indeed flawed studies, are they not..? As surely ultimate mortality or survival are extremely valid findings in this issue..?

  2. Stephen Birrell says:

    Thank you for your comments. Due to the nature of my remit to respond to Prof Davis I focused on incidence-point taken about risk.
    However I would direct you to another Lancet article that has just come out that addresses mortality and MHT https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32033-1/fulltext.
    They found both for oestrogen-only and for oestrogen-progestagen preparations, women who had been current users at recruitment had significant excess breast cancer mortality risks (p<0·0001). These were greater the longer the duration of MHT use had been at recruitment.
    Also it has been pointed out by many authors that MHT increases mammographic breast density thus reducing the sensitivity of mammography and increases interval cancer rates.
    It is not just mortality that is the problem with breast cancer -it is a very morbid disease and extracts a large cost on the individual as well as the community

  3. Anonymous says:

    Very interesting and useful article and I will certainly be looking at women patients with increasing breat density on mammogram screening more closely.

  4. Virginia.clay@lcgproject.com says:

    Thank you. That was very clear.

  5. Anonymous says:

    I have had breast cancer on and off for over 30 years. In all that time I have been with Professor Birrell. We have been through a lot together trying various medications and trials. I doubt I would be here if not for him. I am 81 years of age and feel very honoured to have Professor Birrell with me on my journey and I thank him profusely for his guidance.

  6. Karen Edwards says:

    I too thank Prof. Stephen Birrell for me being here today as I developed triple negative breast cancer in 2008 and have been under his care for the past 11 years.
    My children were very young when I became sick and my goal was to see them grow up. Prof. Birrell has given me that chance and I will be forever grateful to him for the rest of my life.

    Thank you Karen Edwards.

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