Dr. Jeremy Braybrooke is a consultant medical oncologist and clinical lead for oncology at University Hospitals Bristol, as well as a senior clinical research fellow at the University of Oxford. Rosie Bradley is a medical statistician in the Clinical Trial Service Unit at the University of Oxford.
At the 2021 San Antonio Breast Cancer Symposium, Rosie presented the results of their meta-analysis of four studies looking at effectiveness of aromatase inhibitors compared to tamoxifen in pre-menopausal women diagnosed with early-stage, hormone receptor-positive disease.
Listen to the episode to hear them explain:
- the results of the study, showing that an aromatase inhibitor and ovarian suppression reduced recurrence risk more than tamoxifen, but didn’t lead to better overall survival
- the side effects of aromatase inhibitors and tamoxifen
- how Dr. Braybrooke is advising his pre-menopausal patients diagnosed with early-stage, hormone receptor-positive disease
Running time: 14:19
Show Full Transcript
Jamie DePolo: Hello. Thanks for listening. I’m very excited to tell you that we have two guests on the podcast today. Dr. Jeremy Braybrooke is a consultant medical oncologist and clinical lead for oncology at University Hospitals Bristol, as well as a senior clinical research fellow at the University of Oxford. Rosie Bradley is a medical statistician in the Clinical Trial Service Unit at the University of Oxford.
At the 2021 San Antonio Breast Cancer Symposium, the results of their study on the effectiveness of aromatase inhibitors compared to tamoxifen in pre-menopausal women diagnosed with early-stage, hormone receptor-positive disease were presented. They join us to talk to us about the results and what they mean for pre-menopausal women diagnosed with this type of breast cancer. Dr. Braybrooke and Ms. Bradley, welcome to the podcast.
Dr. Jeremy Braybrooke: Thank you.
Rosie Bradley: Thank you.
Jamie DePolo: To start, just in case anyone isn’t aware, can you explain why tamoxifen is mainly used in pre-menopausal women and why researchers want to see if aromatase inhibitors can work in women who haven’t gone through menopause yet?
Dr. Jeremy Braybrooke: Of course. Tamoxifen and aromatase inhibitors are both considered very effective treatments for hormone receptor-positive breast cancer. Tamoxifen works well for both pre- and post-menopausal women and is what we call a selective estrogen receptor modulator.
In post-menopausal women, the ovaries stop producing estrogen, and there’s a separate pathway called the aromatase pathway that converts other hormones into estrogen, and that’s the pathway that the aromatase inhibitors target and effectively switch off. The reason the aromatase inhibitors on their own therefore don’t work in pre-menopausal women is that most of their estrogen is being produced by the ovaries, and the aromatase inhibitors have no effect on the ovaries if they’re still functioning.
Jamie DePolo: Thank you. Thank you. Rosie, could you please summarize the study and the results for us?
Rosie Bradley: Of course. So, just leading on from what Jeremy said, so on behalf on the Early Breast Cancer Trialists’ Collaborative Group, we undertook an individual patient-level meta analysis of four trials, which randomized pre-menopausal women who have ER-positive, early-stage breast cancer and were treated with ovarian suppression randomized to either AI or tamoxifen. Our aim was to investigate whether these pre-menopausal women treated with ovarian suppression could benefit from aromatase inhibitors.
So, from these four trials there are just over 7,000 women. The four trials were ABCSG-12, TEXT, SOFT, and an Italian trial called HOBOE. ABCSG-12 randomized to three years of treatment, where the other trials randomized to five years of treatment. We collected data on baseline characteristics — so tumor characteristics and patient characteristics — date, site of any recurrence and second primary cancers, and date and cause of death. Primary outcomes were timed to breast cancer recurrence and what caused mortality.
From those four trials that we pulled together for our meta analysis, we had a median follow up of about eight years. The proportional rate of recurrence averaged 20% lower for women allocated to AI compared to tamoxifen, and the main benefit from AI was seen in those first few years — so years naught to four — whether treatments differed. And then there was no further loss of benefit or no further benefit seen in years five to nine and then very little follow up beyond year 10. We did see a reduction in distant recurrence during the time period, but there was no difference in breast cancer mortality or overall survival so far.
Jamie DePolo: Thank you. So, I kind of want to pick up on that last point. So, we have, you said, about a 20% lower risk of recurrence in women who were treated with an aromatase inhibitor and ovarian suppression compared to women treated with tamoxifen, but we don’t have an improvement in overall survival or breast cancer survival. So why do we think this is?
Rosie Bradley: So, as I mentioned, we’ve only got around eight years median follow up for these trials, and we know to see differences or to assess the effect on mortality we really need longer-term follow up. So, we are seeing that difference in distant recurrence so far. We would expect that to translate into effect on breast cancer mortality, but as I stressed that we really need that longer-term follow up to fully assess the effects.
Jamie DePolo: Okay. Thank you. Now there was a study that was published by the Journal of The National Cancer Institute just last month, in November, and it showed that early-stage, hormone receptor-positive disease could indeed come back 10 to 30, and I think even longer than 30 years. I think there was one 32-year recurrence after diagnosis. So, Dr. Braybrooke, would you mind putting your study sort of in the context of that study? What does that mean?
Dr. Jeremy Braybrooke: Yes. Absolutely. I mean, the study you refer to was the large Danish registry study, and I think it’s been known for some time that there is the long-term risk of late recurrences for people with hormone receptor-positive breast cancer, including some work that our group published in the New England Journal of Medicine in 2017. One of my colleagues, Hangchao Pan, did a very large analysis showing that after five years of endocrine treatment there was a study on continued risk of breast cancer recurrence even out to 20 years, and this Danish registry study certainly builds on that and shows that for some people that risk seems to carry on, as you say, even out to 30 years and potentially beyond.
And it’s one of the puzzles with hormone receptor-positive breast cancers, what’s happening during that very extended period of time and why the cells suddenly reactivate. The presumption is that it is a reactivation of dormant cells. Where we put that into the context of this study is quite complicated because this study was looking at a maximum of five years of endocrine treatment within the randomizations, and all the people were randomized tamoxifen or aromatase inhibitors and ovarian function suppression. What we know from other analyses is that actually extending endocrine treatment beyond five years seems to give additional benefit, but of course, that then needs to be bound against risk and against side effects.
What both the New England Journal study and the recent JNCI study have shown is that the risk does seem to relate to your stage of cancer at the time of initial diagnosis. So even many years later, that risk seems to be greater if you have a bigger tumor, if you have more heavily node-positive disease. So that’s probably where it starts to influence our earlier decision-making as to which treatment may be the best for each individual patient. Sorry, that’s quite a long, complicated answer.
Jamie DePolo: No. No. That’s fine because, you know, our site is primarily in that people have been diagnosed, as well as their caregivers, and sometimes the results make the headlines and they seem to be conflicting or they don’t make sense together. So, I am grateful to you for explaining that together so that people can understand.
I also do want to pick up on what you said about side effects. So, we know that aromatase inhibitors can cause joint pain, dramatically decrease quality of life for some people who take them. I believe I saw a study that said that about 26% of people prescribed them stop taking them early because of side effects. So, given all that and given that we don’t have an improvement in overall survival yet, can we say yet whether it’s worth it or is it an individual situation where each woman has to kind of balance the side effects versus the reduction of risk, the reduction in risk of distant recurrence, but kind of knowing maybe there’s no overall survival benefit?
Dr. Jeremy Braybrooke: I think, as Rosie said, it probably is too early to know whether there is an overall survival benefit or not, and we’ve seen in many other trials of hormone treatment that actually you do need the 10, 15 year-plus follow up before you see a change in overall survival. I think the fact that we’re seeing a difference in distant recurrence, we would expect that to translate into an overall survival difference, but what that absolute value will be we don’t know.
I think it’s really important, the concept of the side effects and how people manage that. These are long-term treatments. People are taking them for at least five years, probably 10 years, and therefore they’ve got to be manageable so that they can get on with their lives and hopefully not be too debilitated by the side effects.
All endocrine treatment has side effects, and there is a great deal of individual variation in how people tolerate those endocrine treatments, both in terms of tamoxifen and aromatase inhibitors. The side effects can vary between those different drugs, and it’s the balance of those day-to-day side effects, but also perhaps some of the difference in longer-term risks. So, we know that, for example, aromatase inhibitors are more associated with osteoporosis and an increased risk of bone fractures, whereas long-term use of tamoxifen can be more associated with risk of uterine cancer. So, we have to balance those up, and it does become very much an individual discussion between the physicians and the patients.
Within the context of our study, I think it’s particularly important for pre-menopausal women, what the effect of ovarian suppression has on them and their day-to-day function as well, because you’re inducing a rapid, early menopause often in very young women with a long life expectancy ahead of them. Certainly, as a clinician, I spent a lot of my time having those conversations and those discussions trying to balance potentially the most effective treatment, but also with something that is manageable. And different women will have different perceptions of what’s most important to them, and absolutely we have to consider that as well in those discussions.
Jamie DePolo: Okay. Thank you. Now have the results of your study, have they changed at all how you talk to your patients about this? Has it given you any new insights or any new sort of options?
Dr. Jeremy Braybrooke: I think what our study has done has built on the evidence that was already there. So, the four trials that we’ve pooled in this meta analysis have all previously been published and we have results from those, but sometimes with individual trials it can be quite confusing to see what the clear message is and sometimes those individual trials will show conflicting results.
So, I think for me, this analysis helps me with those conversations with my pre-menopausal patients. So those who we think are at high enough a risk to consider ovarian function suppression in place of something such as just tamoxifen on its own, then having the conversation, well, if we’re going to do ovarian function suppression, is that better combined with an aromatase inhibitor rather than tamoxifen? And I think this study shows that, yes, that probably is true, but also not to underplay the fact that people will get significant benefit if they had ovarian suppression with tamoxifen and many people will get very good benefit from tamoxifen on its own. So, you sometimes have to sort of think carefully and try the different treatments and see what impact that has on each individual woman and look at what ways you can try and offset some of the side effects and how to make it manageable.
Jamie DePolo: Dr. Braybrooke, Rosie, thank you both so much for joining us today and explaining this study. It’s been very helpful.
Dr. Jeremy Braybrooke: Thank you.
Rosie Bradley: Thank you.
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