HR+ NSCLC More Common in Women; EGFR, KRAS More Common in HR+ NSCLC


Women have a higher likelihood of having hormone receptor (HR+) non-small cell lung cancer (NSCLC) than men, and mutations of EGFR and KRAS were more common in HR+ NSCLC in a recent study.

Women were more likely to have hormone receptor–positive (HR+) non–small cell lung cancer (NSCLC) than men, and EGFR and KRAS mutations were more commonly seen in cases of HR+ NSCLC in a study published in Frontiers in Oncology.

Lung cancer incidence in the US has been on a downtick, but a larger decline has been seen in men despite similar lowering of tobacco use between men and women. There have been multiple proposed theories, including exogenous estrogen exposure, the study authors noted.

human eyeball with lashes stock photo | © Alamy

human eyeball with lashes stock photo | © Alamy

First, this study aimed to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of NSCLC.

Cigarette smoking is a main risk factor for lung cancer, which is the most common cause of cancer-related deaths in the United States. General incidence of lung cancer has been decreasing across men and women mostly because of the decrease in smoking, but there has been only a small decline of lung cancer in women compared with men.

A total of 3256 NSCLC tumor samples presented for molecular profiling between 2013 to 2018 were retrospectively classified and evaluated for HR expression. HR+ was defined as 1% or more nuclear staining of estrogen receptor-alpha (ER-a) or a progesterone receptor (PR) by immunohistochemistry. Next-generation sequencing (NGS) was performed by Illumina MiSeq hot spot 47 gene panel (n = 2753) and Illumina NextSeq 592 gene panel (n = 503). Significance was determined by an adjusted P value (Q value) where a value less than .05 was considered statistically significant.

In 18.3% of NSCLC cases, HR+ was identified, and it more commonly occurred in women compared with men (19.6% vs 11.4%; P < .0001; Q < .0001). EGFR mutations more commonly happened in HR+ NSCLC than HR- NSCLC (20.2% vs 14.6%; P = .002; Q = .007). Generally, men with EGFR mutations were impacted by HR status, with a higher prevalence in HR+ NSCLC, and these differences weren’t seen in women. But, in women aged 45 years or less, there was a trend toward a higher prevalence of HR+ NSCLC (25.25% vs 11.32%; Q = .0942), and 10 out of 25 (40.0%) of HR+ cases in young women were EGFR mutated. KRAS mutations and ALK+ IHC expression happened more in HR+ NSCLC, and TP53 mutations happened more in HR- NSCLC.

Also, the researchers determined that more studies are needed to understand the role of estrogen better in older men, but it has been shown that those with high serum levels of free b-estradiol had significantly worse survival than those with lower b-estradiol among male patients with advanced NSCLC, so hormone therapy that targets b-estradiol may benefit older men.

The present study showed that HR+ NSCLC and HR+/EGFR-mutated NSCLC are more commonly found in young women. Men showed a greater prevalence of PR+ overall.

Additionally, the study showed that TP53 mutations were negatively correlated with hormone receptor presence. This could be in part due to the fact that estrogen receptor–positive tumors were more likely to be EFGR-mutated, and this subtype is less commonly associated with TP53 mutations.

“Preclinical studies have examined ER and EGFR simultaneously and have found that estrogen through its receptor can stimulate lung cancer cell proliferation, resistance to cell death, angiogenesis, and metastasis,” wrote the researchers.

There is deficient epidemiological evidence, however, and more observational research is needed to address the association between hormone replacement therapy (HRT) and the incidence of NSCLC.

Since the data displayed higher prevalence of HR+ with EGFR mutations in older age patients with NSCLC, future studies aimed at determining response to TKIs based on aromatase levels and specific ER receptor expression is needed. Researchers also said it might be worth investigating the specific role of ER+ with EGFR Exon 20 insertions.

Additionally, more studies with stricter inclusion criteria for HR+ are needed to see if there is advantage to targeting HR in subgroups with EGFR and KRAS mutations.

One limitation of this study was that there was a large variation in detection rates, and the IHC panel only analyzed ER- but not ER-b.

As an increasing majority of NSCLC has ER-a expression, new therapies in breast cancer targeting ESR1 mutations might hold promise in future studies in HR+ NSCLC. “Thus, additional clinical trials with more selective inclusion parameters and investigation of new TKIs and estrogen modulator combinations should be investigated in HR+ NSCLC,” concluded the researchers.


Hsu R, Chen D, Xia B, et al. Impact of gender and mutational differences in hormone receptor expressing non-small cell lung cancer. Front Oncol. Published online August 28, 2023. doi: 10.3389/fonc.2023.1215524

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