Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor–Positive Breast Cancer

Abstract

A B S T R A C T PurposeSeveral mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and MethodsWe performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. ResultsIn B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P Ͻ .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. ConclusionThese data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

Immunohistochemical Phenotype of Breast Cancer during 25-Year Follow-up of the Royal Marsden Tamoxifen Prevention Trial

“…In contrast, in the post-8-year period of follow-up, any differences would be expected to be representative of the intrinsic phenotype of cancers that survived initiation or promotion during treatment or were initiated posttreatment The major findings in this study are that the reduction in the incidence of breast cancer continues to be only in ER-positive disease even beyond 8 years and those ER-positive tumors tend to also have lower ER levels than that in the placebo population. These effects are similar to those reported by Kim and colleagues (7), although in that article, the data were from women having received a median of only 4.5 years of randomized therapy (15). Our findings provide evidence against ERnegative cancers arising from ER-positive precursors because by now we should be seeing a reduction in ER-negative cancers.…”

Phase II Study of Bolus 5-Fluorouracil and Leucovorin Combined with Weekly Paclitaxel as First-Line Therapy for Advanced Gastric Cancer

“…The median OS in our study was slightly longer than those in previous phase II/III studies for 5-FU or S-1 combined with taxane, although the median PFS was comparable [25,30,31,32]. The longer OS in the present study may be related to the better performance status of patients enrolled as compared with that in other studies.…”

“…For example, tumors associated with obstruction of the pylorus or cardia or with peritoneal dissemination as a common characteristic of diffuse-type GC cause dysphagia, nausea, vomiting and intestinal obstruction, often precluding the administration of oral anticancer drugs. Recently, the non-inferiority of leucovorin-modulated weekly bolus 5-FU regimen in comparison with S-1 [29] and good anti-tumor activity of S-1 plus docetaxel [30] in advanced GC patients have been reported in phase III trials. Unfortunately, there are no data directly comparing the anti-tumor activity of 5-FU plus taxane (paclitaxel or docetaxel) with that of S-1 plus taxane.…”

Estrogen Receptor Expression in 21-Gene Recurrence Score Predicts Increased Late Recurrence for Estrogen-Positive/HER2-Negative Breast Cancer

“…The only other publication of the impact of individual genes and gene modules in the OncotypeDx considered the predictive value of the individual genes and the gene modules for benefit Clinical Cancer Researchfrom adjuvant tamoxifen in the NSABP B14 trial (20). In that report, the RS overall had borderline significance (P ¼ 0.06) for a higher score to indicate relatively poor benefit but higher scores in the estrogen module were indicative of significantly reduced recurrence with tamoxifen (P interaction ¼ 0.008).…”

“…This may be because IHC measures of ER do not show linearity with mRNA levels (20). Modern ER IHCs show compressed ranges for ER expression in ER þ tumors and therefore less distinct separation between different levels of ER expression than is achieved by mRNA estimates (21).…”