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Volume 102 Issue 18 Interview Transcript

Adam Weiss: Welcome to the JNCI Podcast, a production of the Journal of the National Cancer Institute. I’m Adam Weiss. Huge numbers of women take hormones either before, during or after menopause. Most take them to deal with their menopause symptoms, but some took them to reduce the risk of certain diseases at least until recent studies show that they may do more harm than good. This hormone therapy has been used for decades, but it wasn’t until fairly recently that these drugs were rigorously tested to see what effects, positive or negative, they had on health. Surprisingly, one class of hormone therapy drugs was linked to a significant increase in common types of lung cancer. My guest today found that link, and he just published a new paper in JNCI looking at the connections between these drugs and lung cancer. Doctor Rowan Chlebowski is a medical oncologist at the Los Angeles Biomedical Research Institute at the Harbor UCLA Medical Center, and he’s joining me on the phone from his office. Welcome to the JNCI Podcast.

Rowan Chlebowski: I’m happy to be here.

Adam Weiss: So this paper is a follow-up to the women’s health initiative study which found links between hormone therapy, breast cancer and heart disease, and it’s also a follow-up to another paper you published recently showing that estrogen plus progestin increased the risk of certain lung cancers. Can you tell us what you were looking at in both pap

Rowan Chlebowski: Yeah, we did two studies, one with estrogen plus progestin. That is in women who have an attacked uterus, because a study shortly before this started in 1993 showed that women who got estrogen alone who had a uterus, about a third of them would have proliferative changes in the endometrium which would be maybe early steps on the way to endometrial cancer, uh, just after one year, so one had to add the progestin to protect the uterus against the estrogen effects.

Adam Weiss: So, when you were adding this hormone, it was missing at that point. It seemed to be causing other problems, but people weren’t sure.

Rowan Chlebowski: That’s right, yes, and so what this study was is it involved 10,739 post-menopausal women between the ages of 50 and 79 years, so that, when we got done, we’d be able to tell, uh, all women of every age whether they should be taking this medication or not, and this was a drug that had been taken by about 95 percent of women that were using menopausal hormone therapy in the United States, so it was a very commonly used drug, and this particular study, the estrogen only study, when we reported all the results, it was kind of neutral with respect to overall health benefits. It might’ve caused a little bit of reduction and started closer to menopause in heart disease, but didn’t have any great benefits.

Adam Weiss: But a study you just recently published did find a link between some of these drugs and lung cancer. How did you discover that?

Rowan Chlebowski: One thing that happened is, after we continued to follow these patients, we had a report from the estrogen plus progestin trial, that once we stopped the therapy, which was after five and a half years, it looked like there was more cancer mortality in the women who had previously been on the hormones, and so that caused us to look first into the estrogen plus progestin group to see what was the cause of this mortality. We have reported that estrogen plus progestin had a trend towards a few more lung cancers which wasn't significant, but actually had a statistically significant substantial increase in lung cancer mortality of 71 percent, and that was really a big issue especially in current and past smokers. In the United States, about 15 percent of women are current smokers and 35 percent of post-menopausal women are past smokers. Well, in that combined estrogen plus progestin group of current smokers, one in 100 would have an otherwise avoidable death from lung cancer by using estrogen plus progestin for about five and a half years. If they were a past smoker, they had about one in 200 having a chance of an otherwise avoidable death from lung cancer, so those are really remarkably high numbers, and so the related question, of course, would be, do we see the same problem arising in women who were taking estrogen only in the other trial, and that’s what we looked at in this study.

Adam Weiss: So, in the paper that you’re here to talk about today, you looked at people taking estrogen only which is standard for anyone on these drugs who’s had a hysterectomy?

Rowan Chlebowski: Right, you know, and, like I said, the set-up for that was that, in the estrogen plus progestin study, there was a statistically significant increase in lung cancer mortality which was substantial, and so that raised the question whether we would see the same thing with estrogen only in this separate trial.

Adam Weiss: And, from reading the paper, it seems like you didn’t. It seemed like estrogen only was safer than the two hormones combined.

Rowan Chlebowski: Yeah, that’s correct. There really was no significant increase in incidents, and the risk of death from lung cancer was almost identical in the women given estrogen alone compared to the women given placebo after 7.9 years of follow-up, so it was a strikingly different result, and actually in the manuscript, the difference in survival from lung cancer in the two separate studies, estrogen alone and estrogen plus progestin, was significantly different, so we saw a negative effect on lung cancer survival in the estrogen plus progestin trial, and we saw no significant effect on lung cancer survival in the estrogen alone trial.

Adam Weiss: So do we have any idea why this is the case? I’ve heard of hormone receptors and breast cancer, and that kind of makes sense, but do lung cancers have the same thing? Why would lung cancer react badly to some hormones and not to others?

Rowan Chlebowski: Well, there’s been a number of lung cancers end up having hormone receptors, but there’s a couple of issues, one of which is one of the reasons we think this was working the way it did with the estrogen plus progestin is that estrogen plus progestin are potent antigen stimulators. You know, when you think of the endometrium and menstrual cycle, the endometrium lining of the uterus has to proliferate and get big to get ready for, you know, purported pregnancy coming, and then it has to do it over again in a month, and so, to get that from nothing to this thick endometrium, you need a lot of antigens to stimulation.

Adam Weiss: So, basically, it’s a hormone that helps stuff grow really fast which is not always a good thing when you talk about cancer.

Rowan Chlebowski: Yeah, so it helps the vascucher grow, and so, of course, with our great interest in antigens inhibition for cancer treatment suggest that maybe estrogen plus progestin could negatively impact a broader array of cancers, not just breast cancer working through estrogen kind of receptors, so that’s one thing. I guess the other part of it is that certain lung cancers express estrogen receptor beta of which is not commonly measured in breast cancer, and those lung cancers that overexpress this estrogen receptor beta are more likely to have favorable characteristics and more likely to respond to different cancer therapies than lung cancers that don’t express this estrogen receptor beta, so suggesting that there are really unknown relationships between hormone receptor status, lung cancer, lung cancer histology and lung cancer prognosis.

Adam Weiss: So could this study then teach us something kind of fundamental about lung cancer and not just inform people whether or not they should take these various hormones for menopause?

Rowan Chlebowski: Yeah, I think it would, because where we see a difference between estrogen and estrogen plus progestin on lung cancer incidence, it could point to different kinds of pre-clinical studies that someone might want to conduct on either lung cancer pre-clinical models or animal models to see if they can identify therapeutic strategies for lung cancer, and some of tho

Adam Weiss: So you said at the beginning that one of your goals in looking at this was to better inform how to use these therapies with people. If you take the results that you got, are we at a point now where you can say use this kind of drug in this case, don’t use this kind of drug in this other case, or is more study needed?

Rowan Chlebowski:
In terms of defining where are we after the current reports of the Women’s Health Initiative with respect to clinical practice, I think we’re pretty far along in terms of defining safety and a reasonable role for estrogen only therapy for women who had a prior hysterectomy. That is a minority of women, but, for those women, it looks like estrogen only can safely be taken for five or six years with probably an anticipation of actually some clinical benefit in terms of perhaps reduction in breast cancer, perhaps reduction in coronary heart disease, but at least no net adverse effects, so those women would be able to have the benefit of climacteric symptom management, which would be hot flashes, night sweats, would generate some favorable effect on bone. That information is pretty solid. Again, we don’t know the long-term consequences of continuing, but, since many women’s symptoms go away after a few years, that might be enough, so that is reassuring information.

Rowan Chlebowski: On the other hand, the information on estrogen plus progestin leaves a cloud, really. After five and a half years of therapy, there was a net harm. There’s a new question that, if you start the hormone therapy closer to menopause, there might not be so much cardiovascular risk or at least coronary heart disease risk with estrogen plus progestin, and I should mention the other cancer effect is the breast cancer, and, actually, we have just reported that estrogen plus progestin actually increases breast cancer mortality, as well, so, taken together with our lung cancer results, estrogen plus progestin used for about five and a half years increased death from the two leading causes of cancer death in women, and, because estrogen plus progestin interfered with breast cancer diagnosis, it kind of makes the breast denser, so the cancers were there, but were not able to be detected, so that meant they were able to grow and get to be a larger stage.

Rowan Chlebowski: A safe interval for breast cancer risk for estrogen plus progestin use then cannot be defined, so it really raises a question of how severe one’s climacteric symptoms there has to be before one would be interested in using combined estrogen plus progestin, so there will be a debate about this issue now, but I believe that the effects of the menopausal hormone therapy on cancer has not gotten sufficient attention in the past, so maybe this summarizes estrogen alone for about five or six years for women with climacteric symptoms seems to be safe and effective. Estrogen plus progestin really can’t be given a clear safety signal for any duration largely related to the potential adverse effects on very common cancers occurring in women.

Adam Weiss:
Well, it really sounds like this research will be a big factor in clinical practice from now on. Doctor Chlebowski, thank you so much for taking the time to share it with us.

Rowan Chlebowski: Okay. Great.

Adam Weiss: And thank you for listening to the JNCI Podcast. For more interviews, audio summaries of JNCI issues and more information about today’s topic, visit jnci.oxfordjournals.org. To get in touch with us, send an e-mail to podcasts@oxfordjournals.org or follow us on Twitter. We’re at jnci_now. If you liked this episode, please share it with your colleagues and friends. I’m Adam Weiss. Thanks again for listening.