We have rarely divided cancers along the lines of sex, except for the obvious ones like breast, prostate, testicular, ovarian, etc., but there is growing evidence to begin to consider patient sex in the field of lung cancer. (As a semantic point for the delicate souls out there who will wonder why I use the word “sex” throughout this post (but notice my restraint in not putting it in bold), it isn’t an attempt to broaden interest by turning OncTalk into an adults only website: the term gender applies to whether a person identifies themselves as male or female as a sociological variable, but patient sex is the biological, genetic and non-transferable assignment). We’ll start to explore some of what we’re learning, and I understand that some very intriguing information on sex-based differences will be presented at the American Society for Clinical Oncology Annual Conference in early June. I’ll give you those updates when they’re publicly available.

First, there’s the issue of the changing patterns of lung cancer. A review of a large database of cancer patients (free full article here) revealed that younger patients with lung cancer (<50) are more likely to be women, and that women disproportionately develop adenocarcinomas and small cell lung cancer, with a relative dearth of squamous cell carcinomas. This suggests that there are differences in the risk factors that can lead to lung cancer in men vs. women. In addition, I’ve described in a previous post some work by Dr. Heather Wakelee at Stanford that shows a disproportionate number of women who are life-long never-smokers in multiple case series.

Obviously, when we see biological differences between the sexes, an important question is whether hormonal differences may be responsible. Estrogen is directly involved with the development of breast and ovarian cancer, but it now also appears that estrogen is involved with lung cancer as well. Unlike breast and lung cancer, Unlike breast cancer, where there is an estrogen receptor commonly expressed that is known as ER-alpha, lung cancer commonly expresses ER-beta, and it is not more commonly expressed in lung tumors of women than men, suggesting that ER-beta levels may not be modulated by estrogen levels in the body. Lung tissue normally expresses this ER-beta receptor, more than any other tissues in the body outside of the reproductive tract. When ER-beta on lung tissue is activated in lab models (test tubes with cells or mouse models of cancer), cells grow and divide, so this leads us to think that perhaps blocking ER could be helpful. Moreover, ER interacts with EGFR, a setting in which sex-based differences have been well-described, leading some investigators to initiate studies in which both hormonal function and EGFR are targeted at the same time. More on that later.

There have been some mixed results on the correlation of estrogen exposure with risk of lung cancer and then outcomes in women who have lung cancer. Taioli and Wynder (reference here) showed that women who experienced early menopause had about a 70% reduction in risk of developing lung cancer, and that there is a markedly increased risk of developing adenocarcinomas among smoking women who had been on hormone replacement therapy (HRT). Another study (abstract here) looked at a large population of women in Sweden and found that estrogen replacement was associated with a modestly higher risk of women developing lung cancer, although the women on estrogen were also more likely to have smoked. However, other studies have reported that women on HRT do not appear to be at higher risk (abstract here) and may even have a decreased risk for developing lung cancer(abstract here).

A trial in breast cancer that included women treated for early stage disease, in which half of the patients received tamoxifen, which activates estrogen receptors, had an increased risk of developing different cancers later, most commonly lung cancer (abstract here).

One study was just reported by Dr. Ganti and colleagues (abstract here) that evaluated the survival of women who were diagnosed with lung cancer as a function of HRT exposure (minimum 6 weeks). In this report, the investigators reviewed the medical records of 498 women with lung cancer (NSCLC or SCLC, any stage) and found that there were some key differences. Women who had been on HRT were overall younger (median age 63 vs. 68 for those who hadn’t been on HRT), but more importantly that women on HRT had a significantly worse survival than women who had not been on HRT (median survival 79 vs. 39 months, p = 0.02):

(click to enlarge)

As was seen by Taioli previously, the apparently detrimental effects of HRT were much more pronounced among women who smoked.

Overall, then, there are some discrepant results, but a majority of the literature suggests a potentially harmful effect of hormone therapy in women in terms of risk of developing lung cancer and outcomes in the setting of identified lung cancer. Next we’ll cover the differences by patient sex in responses to therapy.