The following is the edited transcript and figures from a webinar presentation made by Dr. Heather Wakelee, medical oncologist and Associate Professor at Stanford Cancer Center, on Never-Smokers and Gender Differences in Lung Cancer.

Let's move to biological differences of risk of lung cancer between men and women.

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In the table above, this gets right at the question of whether there's an increase risk of smoking for women versus men. This is some of the data that we have from some of the larger trials, very different types of studies, some were case-control studies where if someone developed lung cancer the investigators would find similar people who matched in every way except that they didn't have cancer, and then others were cohort studies, in which a large cohort, a defined population, was followed closely over time.

When you look at that, as far as whether there's an increased risk of smoking causing lung cancer in women versus men, it's really not clear. Some of the earlier trials say yes, and then many of them say no, including the largest one, which came out in 2008. We're left not really knowing, with the question still open for debate. We have some hypotheses as to why women may have higher risk, because of certain genes that have differently expressed in women versus men, but I really don't think we can say one way or the other about that.

When you talk about what's different between women versus men, obviously hormones come to mind, and there are certain female hormones like estrogen that have been implicated in lung cancer. So estrogen receptor beta, which is one of the receptors for estrogen, is found in lung tissue as well as the reproductive organs but nowhere else, so that makes it a potential culprit just by association.

This estrogen receptor-beta is found in lung cancer cells, and if you give estrogen to lung cancer cells growing in a dish, that can make them grow. So that also got people very suspicious about an estrogen role. And estrogen also interacts with epidermal growth factor receptor (EGFR) and many other genes involved in cell growth. So this is intriguing: it's not a definite linkage between estrogen and lung cancer, but it certainly makes us wonder about that, and there's a lot of ongoing research.

When we look at that, we also understand that some women have higher levels of estrogen, obviously pre-menopausal women and then post-menopausal women who are taking estrogen or estrogen and progesterone are going to have higher hormone levels. So there've been a lot of studies done for women taking female hormone therapy after menopause, is there an increased risk of getting lung cancer.

And when we look at all the data that's come out and we get into some of the larger trials, some have said yes, some have said no. Most have shown either no effect, or, if anything, a decreased risk of lung cancer for women taking female hormone therapy -- so we don't have a clear answer. There's nothing here clearly saying that taking hormones increases a woman's risk of getting lung cancer.

There was, however, one study published in 2006 that looked at women who already had lung cancer who were taking hormone therapy. It showed that the women continually take hormone therapy after the diagnosis perhaps didn't do as well. So it's a bit of a confusing story, and the next few slides go through an even larger trial that looked at that.

This is the Women's Health Initiative, a study looking at estrogen plus progesterone, or estrogen alone for women who were post-menopausal. It was initially designed as a placebo-controlled trial, where half the women got the drugs, half the women received placebo. They were treated for five years: this is almost 17,000 patients on the estrogen plus progesterone, and really the study was designed to look for a reduction in cardio-vascular disease.

Unfortunately, the study was halted when it was found that the overall risk to health was higher from getting that combined estrogen and progesterone. So if you look at that "global index" above, these are hazard ratios. So with the hazard ratio, if your number is greater than one, it means that the intervention is worse than the placebo, and if it's less than one then the intervention is helpful.

When you look at the global index, essentially looking at all outcomes, 1.15 is indicating that the estrogen plus progesterone was worse than being on placebo. This obviously is 17,000 people being followed with a randomized treatment of either placebo or the hormones so the best place to really look for all kinds of cancers. This showed very clearly that breast cancer was increased, and now we've done some work with looking at the lung cancer from the study.

So in this Women's Health Initiative, looking at the estrogen plus progesterone cohort, we looked at non-small cell lung cancer in terms of the incidence, meaning people just getting the disease, and also the survival after the diagnosis. If you look at the incidence, on the left in the figure above, the total numbers weren't that high. It was 96 people getting estrogen plus progesterone who developed lung cancer, versus 72 people getting placebo, out of almost 17,000 people on this study. The hazard ratio was 1.28, indicating a potential increase in incidence from the hormones, but it didn't reach the statistical significance. The P value is 0.12, meaning that there is a more than 10% chance that this difference is due to chance alone, so we can't say definitely whether there was an increased risk of getting lung cancer, but the results were trending in that direction.

The panel on the right in the figure above is looking at survival after lung cancer was diagnosed. In those patients who got lung cancer, the 96 who were getting combined treatment, estrogen and progesterone and the 72 who were on the placebo arm, once they were diagnosed, the group who were on the hormone therapy, whether they were continuing on it or stopped, they had a higher risk of dying from their lung cancer. The hazard ratio here is 1.59, essentially a 60% increased risk of dying from their disease. This P value was statistically significant, so this is something we believed: that if you are taking the combined estrogen/progesterone, they had a higher risk of dying at a given time point from lung cancer.

In trying to figure that out, we looked at the differences in the lung cancer that developed in those getting the hormones versus those not getting hormones, and what came out of that is that those getting hormones were more often found to have stage IV, widely spread disease by the time they were diagnosed, and were also more likely to have a very what we call poorly differentiated, or more aggressive looking type of lung cancer.

So maybe that's why, even though there wasn't a really much higher number getting lung cancer, those who got it who were getting hormones, their cancer was more aggressive and, unfortunately, more likely to kill them. That's a current theory, and this is specifically for those people on combined estrogen and progesterone.

We more recently have analyzed the estrogen alone on the Women's Health Initiative. We know that if you had estrogen alone and you had a uterus, that increases your risk of endometrial cancer, but women who had a hysterectomy, who didn't have a uterus, were able to get estrogen alone.

This is a little bit of a smaller subset, and patients then either got combined estrogen alone or placebo. Here, the global index wasn't so bad, it wasn't clear that estrogen alone was really all that harmful, and when we looked at many other factors, it also wasn't as clear. So even for breast cancer, not as harmful as really the estrogen with progesterone that's a real significant problem, and the same thing held out with lung cancer.

The figure above is looking at the incidence, whether there were more cases of lung cancer. Here, again, there was a trend -- maybe taking estrogen slightly increased the risk for getting lung cancer -- but it was not significantly significant at all, with a hazard ratio not significant, at 1.17. So we cannot say from this study that taking estrogen increases anyone's risk of getting lung cancer.

When we look at the deaths from lung cancer (above), unlike the situation when we looked at estrogen plus progesterone versus placebo, which was significantly higher with hormone therapy, when we look at estrogen alone, it's really not. So that gets us to question whether all that data looking at the role of estrogen among cancer is really the culprit,or maybe it's the progesterone part of the female hormones and so a lot more research needs to be done here.

There was one other important study worth noting, which looked at estradiol levels in lung cancer patients who were on the trial being treated with a novel drug. What they showed was that it wasn't the age but rather the estradiol levels that matter: the people who had high estradiol levels did not do as well as those with lower ones. It was interesting too, they looked at estradiol levels in men, and men with higher estradiol levels also did poorly. So this is something pointing towards it being estrogen and not progesterone. In the end, I think we're still left with a lot of questions on what role the female hormones play in lung cancer.

Next: differences in treatment outcomes by gender