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.

There has been a lot of historical data showing that women with lung cancer do better than men with lung cancer, and we don't really know why, but this has been seen over and over again. These are some earlier trials; one was looking at the registry data (SEER) showing that women with lung cancer did better than men, and another trial done at the Mayo Institute showing that again women do better than men by a small percentage, but a definite statistically significant improvement.

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Looking at that in a little bit more depth, here is an analysis of that registry data looking at older patients, at least 65 years old, who had early stage lung cancer -- so stage I or II -- and they looked at whether they had surgery, or chemotherapy and radiation, or no treatment at all. Then they looked at the lung cancer survival and also overall survival and broke it up into men versus women.

What they showed was that women did better -- so if you looked at everybody getting surgery, the women getting surgery did better than the men did getting surgery. If you looked at chemotherapy/radiation, the women getting chemotherapy/radiation did better than the men getting chemotherapy/radiation, and if you looked at those who opted to get no treatment at all, the women still did better than men. They also, of course, looked at smoking to see if that might be what they're looking at, and there were no differences. The differences by sex and smoking couldn't explain the survival differences.

The figure above is a graphic display showing that if you had surgery you did the best: those are the blue lines, but women did better than men. If you had chemo/radiation, it was a little bit better than doing nothing, and again the women did better than men; and the same if you did nothing. Not the best outcomes, but women were doing a little bit better than men.

The figure above is looking at people who had metastatic, stage IV lung cancer, looking at very different chemo options and showing that in this trial, whatever chemo you got, people did about the same. And we use that information to look at how did the men on that study do versus the women. Since everybody was doing the same on average, no matter what chemo you got, it allowed us to do that. We saw that both men and women had the same likelihood of having a shrinkage of their tumor with chemotherapy, 19% for both, but when we looked at survival we were able to show that women actually lived longer than men.

The women are in blue, the men are in yellow, and again everybody's getting exactly the same chemo. but for reasons we don't understand women did better than men.

Investigators from the Southwest Oncology Group also looked at pooled data from six lung cancer trials to compare results between women and men. They found that women and men had the same patient characteristics, except some weight loss differences that were more prevalent in men. Their toxicity from the chemo was about the same, but again there was this significant difference in survival, where women were doing better than men: living longer, even though they were getting the same treatment. However, they took it another step and they showed that there was a difference by age, and that the youngest women actually were not doing well. It was the older women, women at least 60 years old who were doing really well, and women under 60 not clearly doing better than men, raising the question of whether menopausal status is an important variable. This age difference makes some sense if we're talking about this potential of estrogen and progesterone fueling lung cancer. It doesn't make sense that women would do better than men, except it's only the women who don't have high estrogen and progesterone who are doing okay

We also looked at the ECOG data, evaluating the same ECOG 1594 trial we just discussed, which was just different chemotherapy choices. And then we added data from another trial where people on the control arm received carboplatin and paclitaxel chemotherapy. We did the same analysis, taking the men versus the women and then looking at the different age groups.

This is a little bit of a busy table, but in the first column it's men versus women: you have the under 45 and so women who are under 45 unfortunately had a rather disappointing survival time. It's a small number of people, so this is not a definite answer by any means, but it's intriguing and they were actually doing worse than the men who were young, the under 45 group.

When you look at those in the middle ranges, ages 45 to 59, the women are doing a little bit better than they were when they were at the younger ages and now doing a little bit better than the men.

And when you look at those over 60, we see the striking differences. If you look at the numbers, most of the women on these trials were over 60, and they were the ones doing quite well. They had a survival of almost a year on average, and it's important to remember, of course, that many people live longer than a year. These are averages, and I always tell my patients not to look directly at these numbers, since they apply to populations and not specific individuals. Many people live longer, obviously some people don't do as well; that's how we get to these averages.

But on average, the women over 60 were living quite a number of months longer than the men over 60, so that's looking at it in columns. If we look at it in rows, if you look at the women there's a very interesting association of longer survival with increasing age in women, and that did reach statistical significance.

In contrast, when looking at the men, the younger men were actually doing better than the older men but not statistically so. It's a very interesting finding -- it's small numbers, so it's just a hypothesis, but it's quite intriguing.

Now let's turn to chemo with antiangiogenesis. Avastin (bevacizumab) is an antibody to vascular endothelial growth factor (VEGF). VEGF is important for growing new blood vessels, and in order for a cancer to grow, you have to grow new blood vessels, so treatments have been designed to block that. Avastin is the only antiangiogenic drug approved in lung cancer right now, and in the ECOG 4599 trial, patients received either standard chemo or chemo plus Avastin, and those getting the Avastin lived a couple of months longer on average.

But what was very confusing was that for women, even though the Avastin significantly improved how likely it was that their tumor shrunk (that's that response rate (RR) at the bottom), significantly improved the progression-free survival (PFS) (and again that includes a hazard ratio, which is favorable if it's less than one). But when we looked at survival for women, there was no overall survival benefit with the Avastin -- that has a hazard ratio of 0.96, which essentially means no real difference between getting the drug or not, while for men it was very striking at .69. So this is very confusing as to why the Avastin seemed to be working for women and shrinking the tumors but wasn't helping them live longer.

When that's been looked at further, they couldn't figure out any differences. There was no difference in what treatment people were getting later, so once women had progression, there was no evidence that after progression treatment was different for women than for men. We also decided to do that same sort of analysis looking at women by different ages to see if there was any difference, and survival was calculated for each group of men versus women, and age equal to or greater than 60 or less than 60.

When we look at the results broken down by both patient sex and age, we see that among people who were greater than or equal to sixty years old, for women on the control arm, women just getting chemo the survival was almost fourteen months, which is great. For women who were older who were getting Avastin with chemo it was still really good, at 12.8 months, but it doesn't look like the Avastin was adding to the survival for those women who were over sixty.

But when we look at men who were over sixty, the median survival with chemo alone was about eight and a half months -- again these are all averages -- but when you added Avastin, that improved to 11 months. So it appears that Avastin was helping older men live longer but really wasn't making a big impact for the older women.

But when we look at the people under 60 it's a very different story. Here, for the women just getting chemo, median survival was about 11 months, albeit not looking at a large number of people. But when we added Avastin to chemo, the numbers went way up -- it went up four and a half months.

This was really quite interesting: the Avastin seemed to be helping these younger women but not the older women. When we look at the men who were younger, we see median survival numbers of 9.3 months vs 12.4 months, about the same order of magnitude improvement whether men were under 60 or over 60. So age had no impact for the men but a big impact for the women.

Why do women live longer? We really don't know. It could be that they metabolize drugs differently and may therefore have a better response to the chemotherapy for that reason. But as I've shown you, there really wasn't any response difference: it's just the survival difference, so we don't have a good answer. It could be there're just variations in the natural history of the disease by sex. We don't know why. Could be the hormonal factors that as I talked about? It's very confusing. There could be the DNA repair capacity, which has to do with how well someone is able to recover from chemotherapy, or a lot of other undetermined factors.

Overall, though, older women overall seem to do better than men with lung cancer, but younger women with lung cancer may not, and this could be hormonal -- we don't know yet. But we are starting to notice these sex differences, and most lung cancer trials do now pay attention to potential differences in outcomes by patient sex, which should help provide more answers, and there's a lot of work and basic science laboratories looking at the estrogen and progesterone and other potential differences between men versus women.