Estrogen in the development of esophageal and gastric adenocarcinoma

The aim of this thesis was to address the hypothesis that estrogen protects women against the development of esophageal and gastric adenocarcinoma (AC). These two cancers show a striking but totally unexplained male predominance in their incidence. There are 6-7 men for every woman affected by esophageal AC, while the male: female ratio in gastric AC is 2-3:1.

In the first study, we investigated whether hormone replacement therapy (HRT) with estrogen protects postmenopausal women against esophageal and gastric AC. We conducted a nested case-control study, in which cases and controls came from a cohort of postmenopausal women in the United Kingdom. Prospectively recorded data from the General Practice Research Database were used. Women on HRT had a significantly decreased risk of gastric AC (odds ratio (OR) 0.48, 95% confidence interval (CI) 0.29-0.79), an association that seemed stronger for non-cardia than for cardia gastric AC (OR 0.34, 95% CI 0.14-0.78). HRT use was not linked with a decreased risk of esophageal AC (OR 1.17, 95% CI 0.41-3.32).

In the second study, we prospectively assessed the risk of esophageal and gastric AC in women who had been treated for breast cancer with the anti-estrogen drug tamoxifen. Our large population-based cohort of postmenopausal women was identified from the Swedish Cancer Register. Among 138 885 cohort members contributing to more than 1 million person-years of follow-up, we found a non-significantly increased risk of esophageal AC in those exposed to tamoxifen (standardized incidence ratio (SIR) 1.60, 95% CI 0.83-3.08). No association was observed in the unexposed. No increased risk of cardia AC was identified, irrespective of exposure to tamoxifen. The risk of non-cardia gastric AC was increased in the tamoxifen-exposed cohort (SIR 1.27, 95% CI 1.03-1.57), and it was almost doubled (SIR 1.86, 95% CI 1.10-3.14) in the period of longest latency (10-14 years) after breast cancer diagnosis. We concluded that there might be a link between tamoxifen and risk of non-cardia gastric AC.

In the third and fourth studies the potential influence of endogenous estrogen and of tamoxifen exposure on the risk of the intestinal type of gastric AC was addressed. Immunohistochemical laboratory work was conducted in order to assess the expression of estrogen receptors (ERs). In both studies we used data from the Swedish Cancer Register and we identified patients with gastric cancer diagnosed in the county of Stockholm.

In the third study we categorized gastric AC cases into three groups according to their endogenous estrogen exposure: 1) women aged <50 years (“exposed women”), 2) men <50 years (“unexposed men”) and 3) women >70 years (“unexposed women”). Compared to “exposed women”, the intestinal type of gastric AC was over 4 and 9 times more common among “unexposed men” (OR 4.7; 95% CI 2.2-10.3) and “unexposed women” (OR 9.1; 95% CI 4.3-19.6), respectively. No differences in ER expression were found between the three groups. A loss of ERbeta and a gain of ERalpha in the tumor cells compared to non-tumor cells was observed. ERbeta cx was identified for the first time in gastric tissue.

In the fourth study we identified all women with a breast cancer diagnosis who subsequently developed gastric AC. The intestinal type of gastric AC was not more frequent among tamoxifen users (27%) than among non- users (34%) (p=0.601). There were no material differences between the two groups regarding distribution of ERs in intestinal AC specimens. Tamoxifen users seemed to have a shorter latency between breast cancer and gastric AC diagnoses.

In conclusion, this thesis supports the hypothesis that estrogen may protect women against development of gastric AC, while we did not find evidence for this in esophageal AC. The mechanism underlying this protection is not yet clear, but it may be mediated by ERs. For the first time the existence of estrogen receptor beta cx in gastric tissue is reported.

List of scientific papers

I. Lindblad M, García Rodríguez LA, Chandanos E, Lagergren J (2006). Hormone replacement therapy and risks of oesophageal and gastric adenocarcinomas. Br J Cancer. 94(1): 136-41
https://pubmed.ncbi.nlm.nih.gov/16404367

II. Chandanos E, Lindblad M, Jia C, Rubio CA, Ye W, Lagergren J (2006). Tamoxifen exposure and risk of oesophageal and gastric adenocarcinoma: a population-based cohort study of breast cancer patients in Sweden. Br J Cancer. 95(1): 118-22. Epub 2006 Jun 6
https://pubmed.ncbi.nlm.nih.gov/16755290

III. Chandanos E, Rubio CA, Lindblad M, Jia C, Tsolakis AV, Warner M , Gustafsson JÅ, Lagergren J (2007). Endogenous estrogen exposure in relation to distribution of histological type and estrogen receptors of gastric adenocarcinoma. [Submitted]

IV. Chandanos E, Lindblad M, Rubio CA, Jia C, Warner M, Gustafsson JÅ, Lagergren J (2007). Tamoxifen exposure in relation to distribution of histological type and estrogen receptors of gastric adenocarcinoma. [Submitted]