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DREAM, a Possible Answer to the Estrogen Paradox of the Women’s Health Initiative Trial

ABSTRACT: Estrogen is thought to cause proliferation of all estrogen receptor positive (ER+) breast cancers. Paradoxically, in the Women’s Health Initiative Trial, estrogen-only hormone replacement therapy reduced the incidence and mortality of low grade, ER+, HER2- breast cancer. We gave estradiol to 19 post-menopausal women with newly diagnosed low-grade, ER+, HER2- breast cancer in a prospective window of opportunity clinical trial and examined the changes in proliferation and gene expression before and after estradiol treatment. Ki67 decreased in 13/19 (68%) patients and 8/13 (62%) showed a decrease in Risk of Recurrence Score. We chose three prototypical estrogen responders (greatest decrease in ROR) and non-responders (no/minimal change in ROR) and applied a differential gene expression analysis to develop pre-treatment (PRESTO-30core) and post-treatment (PRESTO-45surg) gene expression profiles. The PRESTO-30core predicted adjuvant benefit in a published series of tamoxifen, the partial estrogen agonist. Of the 45 genes in the PRESTO-45surg, thirty contain the Cell cycle genes Homology Region (CHR) motif that binds the class B multi-vulva complex (MuvB) a member of the DREAM (Dimerization partner, retinoblastoma-like proteins, E2F, MuvB) complex responsible for reversible cell cycle arrest or quiescence. There was also near uniform suppression (89%) of the remaining DREAM genes consistent with estrogen induced activation of the DREAM complex to mediate cell cycle block after a short course of estrogens. To our knowledge, this is the first report to show hormonal modulation of DREAM genes and suggest involvement of DREAM pathway associated quiescence in endocrine responsive post-menopausal ER+ breast cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139688 | GEO | 2021/12/27

REPOSITORIES: GEO

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Project description:Introduction: The I-SPY 1 TRIAL was designed to evaluate complete pathologic response and tumor volume change, measured by magnetic resonance imaging (MRI), stratified by molecular subtypes and link response to 3-year recurrence free survival (RFS).Methods: Eligible patients had T =3 cm and received neoadjuvant chemotherapy with AC plus optional taxane. Serial MRI, biopsy, and blood draws were conducted over the course of treatment, and a database of multiple molecular profiles was assembled.Results: A total of 221 patients were eligible for analysis: median tumor size was 6.0 cm and median age was 49 years. The I-SPY 1 TRIAL patients had tumors with aggressive biology: 45% were estrogen receptor (ER) negative, 31% Her2+; and 91% high risk by the Netherlands Cancer Institute (NKI) 70-gene profile. After a median of 3.9 years, RFS was 77%. HR/HER2 status improved predictability of RFS with the greatest difference between HR+/HER2- and triple-negative disease (hazard ratio 0.39). Wound healing signature activation, p53 mutation, and Risk of Relapse (ROR) score were highly correlated and also significantly improved the accuracy of RFS predictions when added to stage. The rate of pathologic complete response (pCR) varied considerably from a low of 0-2% (NKI low risk, luminal A) to a high of 43-61% (17q Amplified, HER2 enriched, HR-/HER2+). Both pCR and the more refined residual cancer burden (RCB) were significant predictors of RFS for all patients and even more predictive when analyzed within biomarker subsets. Good risk (NKI low, ROR-S low risk, Wound Healing quiescent, p53 wild type) signatures were associated with significantly higher 3-year RFS than poor risk expression signatures (ROR-S high risk, Wound Healing Activated, p53 mutation, NKI high risk).Conclusion: Importantly, in this set of biologically poor prognosis tumors, pCR predicts for better outcome, especially when analyzed within breast cancer subsets. Keywords: reference x sample reference x sample

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DREAM, a Possible Answer to the Estrogen Paradox of the Women’s Health Initiative Trial

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