A recent study from Jun Ho Yi and In-Gu Do reveals anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer

Their etrospective study showed that in a total of 932 patients with GC who had received curative resection followed by adjuvant chemoradiation, 40 patients (4.3%) were ER-α positive by IHC. ER-αexpression was associated with diffuse-type cancer and a poorer clinical outcome. Their in vitro study demonstrated that E2 enhances proliferation of an ER-α-positive GC cell line and that both fulvestrant and paclitaxel inhibited its proliferation; this result was not observed in ER-α-negative GC cells. Combination of fulvestrant and paclitaxel may show synergism. Both fulvestrant and paclitaxel enhanced E-cadherin expression, a crucial factor in diffuse-type carcinogenesis; this effect was mediated via the ER-α pathway.

The carcinogenic role of estrogen in breast and ovarian cancers is well understood, and in breast cancer, estrogen-directed therapy is a mainstream treatment. It has been suggested that E2 may play a role in the carcinogenesis of tissues other than female reproductive organs, including in lung, thyroid, or gall bladder cancers. It has also been suggested that estrogen is involved in development of non-small cell lung cancer, especially in adenocarcinoma of non-smoking women, and that there is functional cross-signaling between EGFR-ER pathways. Several in vitro studies have shown that combination treatment with fulvestrant enhances the anti-tumor efficacy of gefitinib and vandetanib.

Since the late 1980′s, estrogen and ER have been suspected to play roles in GC Owing to the male predominance of GC and the fact that males who were treated with estrogen for prostate cancer showed a reduced risk of GC, some investigators assumed that estrogen plays a preventive role against GC. However, as older menopause and null parity are associated with an increased risk of development of GC in women, in the same way as breast cancer, some investigators have regarded estrogen as pro-carcinogenic for GC. One population-based cohort study has reported that endogenous estrogen exposure was associated with a lower frequency of intestinal-type cancers and a higher frequency of diffuse-type cancers, giving rise to the idea that the role of estrogen may vary with GC histology.

In contrast to estrogen, the clinical implications of ER, especially the α subtype, have been relatively consistent for a long time. As described in the Introduction, approximately 20% of GC patients are positive for ER-α, and it is associated with poorly differentiated histology and a poor prognosis. In the present study, however, they found that less than 5% of patients were ER-α-positive. This may have resulted from our use of the usual ER-α IHC method for breast cancer, which differs in antibody concentration, incubation time, and temperature from the method employed by the former studies. As no validated ER-α IHC protocol or interpretation guidelines exist for GC, further study is needed. From a histological perspective, they also found that ER-α was significantly associated with diffuse-type GC. While 4 of 279 patients (1.4%) with intestinal-type cancer showed ER-α expression, 34 of 595 patients (5.7%) with diffuse-type cancer and 2 of 36 (5.6%) with mixed-type cancer showed ER-α expression; multivariate analysis of the results showed that the differences were significant. In regard to survival, patients with ER-α expression showed shorter median DFS than patients without ER-α expression (55.6 months vs. 143.2 months, P = 0.044); again, ER-α expression was shown to be associated with poor DFS following multivariate analysis.

In the in vitro analysis, ER-α expression, examined by protein and mRNA expression, was found to be associated with E2-dependent growth and inhibition. In SNU-216 cells, an ER-α positive cell line, E2 led to cellular proliferation which was suppressed by fulvestrant; these results were not observed in SNU-620 cells, an ER-α negative cell line. Kameda et al. have also shown that E2 induces proliferation of KATO-III and NCI-N87 cells, which was suppressed by fulvestrant and ER-α siRNA. They further analyzed the impact of paclitaxel in this setting. Keeping further analysis, including clinical trials in mind, they chose to use paclitaxel because it has been demonstrated to produce a synergistic impact with fulvestrant in breast cancer models, and because it is widely used as a standard treatment for metastatic GC patients, with a 4-week administration schedule that is compatible with that of fulvestrant. Although we could not draw any conclusions from the colony-forming assay, the combination of fulvestrant and paclitaxel showed synergistic effects in the viability assay. This synergism is concordant with their known modes of action; paclitaxel is a microtubule-stabilizing agent, and E2 enhances cell motility by destabilizing microtubules via deacetylation of α-tubulin, thereby causing paclitaxel resistance.

Absent or aberrant expression of E-cadherin is pivotal in both familial and sporadic forms of diffuse gastric carcinogenesis, probably via methylation of the promoter of the E-cadherin gene. Park et al. showed that ER-α regulates E-cadherin levels in ovarian cancer cell lines, and a study by Oesterreich found that ER-α and corepressors bind to the E-cadherin promoter and that overexpression of corepressors down-regulated E-cadherin in breast cancer cell lines. In the present study, suppressing ER-α with fulvestrant and siRNA resulted in increased E-cadherin levels. Because E-cadherin loss is not only involved in carcinogenesis but also in cancer invasion and metastasis, they hypothesize that restoring E-cadherin may have a beneficial influence on disease course. One of the motives that initiated this analysis was that they observed a considerable number of patients with diffuse-type GC. In their cohort, 65.4% were diffuse-type GC and in Asian trial, it is a quite common finding that diffuse-type GC being more predominant than intestinal-type. It becomes dramatically remarkable by an international AVAGAST trial, in which diffuse-type cancer predominated in Asian population while intestinal-type cancer predominates in European population. They think that there is an ethnic difference regarding the Lauren’s classification and probably the incidence of ER expressing GC.

The present study has several limitations. Regarding the retrospective analysis, patients with metastatic disease were not included. If ER-α and its correlated E-cadherin are associated with tumor progression, patients with metastatic disease may show more frequent ER-α expression. The population of the current study is all Asians and interestingly, most studies dealing with this issue came from East Asia. Although there is one study dealing with this issue in Western population, ethnic difference should be investigated in the future. Also, as described above, their IHC method requires further validation. Although poorly differentiated histology was associated with more frequent ER-α expression (5.4%), the fact that the remaining 94.6% of the patients did not show ER-α expression warrants further investigation to elucidate the pathogenesis of this disease. For the in vitro analysis, they used the methods described in Kameda’s study. Thus, fixed concentrations of E2 and fulvestrant were used throughout the analyses. However, E2 acts via 2 pathways: via the estrogen receptor (the genomic pathway) and via transcriptional cross-talk (the non-genomic pathway). They have only focused on the genomic pathway; the role of the non-genomic pathway should be clarified by further studies. At last, efficacy of paclitaxel in this subset should be investigated, as this agent demonstrated complete inhibition of cellular proliferation in colony-forming assay.

The present study implies that some portion of GC patients express ER-α and that they have distinct clinicopathologic features. Whether ER-α is simply another prognostic factor, or whether it may act as a therapeutic target, similar to HER-2, in GC patients require further investigation, including prospective clinical trials.

Reference:

Jun Ho Yi, Jiryeon Jang and In-Gu Do, Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer, Scientific Reports, 4, Article number:7592 ︱doi:10.1038/srep07592