The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers

Cancer Cell, Год журнала: 2018, Номер 34(3), С. 427 - 438.e6

Опубликована: Сен. 1, 2018

Язык: Английский

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Metastatic heterogeneity of breast cancer: Molecular mechanism and potential therapeutic targets

Seminars in Cancer Biology, Год журнала: 2019, Номер 60, С. 14 - 27

Опубликована: Авг. 14, 2019

Язык: Английский

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Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial

The Lancet Oncology, Год журнала: 2017, Номер 18(7), С. 904 - 916

Опубликована: Май 31, 2017

Язык: Английский

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Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment

Pharmacology & Therapeutics, Год журнала: 2017, Номер 186, С. 1 - 24

Опубликована: Дек. 28, 2017

Breast cancer is the most frequently diagnosed in women, with estrogen receptor positive (ER+) breast making up approximately 75% of all cancers diagnosed. Given dependence on active ER signaling these tumors, predominant treatment strategy has been to inhibit various aspects this pathway including directly antagonizing use selective modulators (SERMs) and degraders (SERDs). Interestingly, for growth often retained even after progression through several lines antiestrogen therapy, a bonafide biomarker subtype driving continued research development novel ER-targeted therapeutics treat patient population. This, combined continuous discovery mechanisms underlying endocrine resistance, resulting continually evolving landscape ER+ cancer. This review discusses antagonists investigated cancer, outlining their pharmacological tissue-specific action as well specified within setting. In addition, resistance SERMs SERDs, combination therapy strategies, ongoing drugs are also reviewed context changing clinical Lastly, role SERDs non-breast indications discussed.

Язык: Английский

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Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer

Nature Communications, Год журнала: 2018, Номер 9(1)

Опубликована: Фев. 23, 2018

Abstract CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of heterogeneity is unknown. Here we use plasma samples from patients randomized phase III PALOMA-3 study inhibitor palbociclib and fulvestrant cancer show that relative change PIK3CA ctDNA after 15 days treatment strongly predicts PFS on (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy shown to be frequently sub clonal, dynamics offering limited prediction clinical outcome. These results suggest a robust biomarker inhibitors, demonstrating divergent clones treatment.

Язык: Английский

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Epigenetic mechanisms in breast cancer therapy and resistance

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Март 19, 2021

The majority of breast cancers express the estrogen receptor (ERα) and agents targeting this pathway represent main treatment modality. Endocrine therapy has proven successful in hormone-responsive cancer since its early adoption 1940s as an ablative therapy. Unfortunately, therapeutic resistance arises, leading to disease recurrence relapse. Recent studies increased our understanding how changes chromatin landscape deregulation epigenetic factors orchestrate resistant phenotype. Here, we will discuss epigenome is integral determinant hormone response why are promising targets for overcoming clinical resistance.

Язык: Английский

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SETER/PR: a robust 18-gene predictor for sensitivity to endocrine therapy for metastatic breast cancer

npj Breast Cancer, Год журнала: 2019, Номер 5(1)

Опубликована: Май 30, 2019

Abstract There is a clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2−) breast cancer endocrine therapy, targeted RNA sequencing (RNAseq) offers diagnostic potential measure both transcriptional activity functional mutation. We developed the SET ER/PR index gene expression microarray probe sets that were correlated with receptors ( ESR1 PGR ) robust preanalytical analytical influences. tested in biopsies metastastic HR+/HER2− against treatment outcomes 140 patients. Then we customized assay 18 informative, 10 reference transcripts, sequence ligand-binding domain (LBD) using droplet-based RNAseq, residual from 53 Higher samples predicted longer PFS OS when patients received therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 0.955, p = 0.035; OS: 0.315, 0.157 0.631, 0.001). Mutated LBD was detected 8/53 (15%) metastases, involving 1−98% transcripts (all had high index). A signature based on good performance facilitated our customization an accurate RNAseq phenotype genotype ER-related transcription. Elevated associated prolonged cancer, especially absence mutated transcript.

Язык: Английский

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Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations

Cancer Cell, Год журнала: 2018, Номер 33(2), С. 173 - 186.e5

Опубликована: Фев. 1, 2018

Язык: Английский

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ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

Breast Cancer Research, Год журнала: 2021, Номер 23(1)

Опубликована: Авг. 15, 2021

In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone therapy, estrogen deprivation by aromatase inhibition. How these affect tumor sensitivity established and novel therapies active areas research. These include receptor-targeting agents, such as selective receptor modulators, covalent antagonists, degraders (including tamoxifen, fulvestrant, agents), combination therapies, endocrine therapy plus CDK4/6, PI3K, or mTORC1 this review, we summarize existing knowledge surrounding mechanisms action roles in We then analyze recent literature on how outcomes therapies. For tamoxifen relative vitro but do not clearly lead patients, making agents category promising. Regarding nullify any inhibitor component combination. Thus, combinations using alternatives inhibition, where non-endocrine is efficacious monotherapy, still effective against mutations. results emphasize importance investigating combinatorial resistance, challenging efforts are. also discuss future directions open questions, studying differences among distinct mutations, asking adjust clinical decisions based molecular surveillance testing, developing that

Язык: Английский

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ESR1 mutations in breast cancer

Cancer, Год журнала: 2019, Номер 125(21), С. 3714 - 3728

Опубликована: Июль 18, 2019

The acquisition of ligand‐independent ESR1 mutations during aromatase inhibitor therapy in metastatic estrogen receptor (ER)‐positive breast cancer is a common mechanism hormonal resistance. Preclinical and clinical studies have demonstrated that can preexist primary tumors be enriched metastasis. Furthermore, express unique transcriptional profile favors tumor progression, suggesting selected may influence Several groups used sensitive detection methods using patient liquid biopsies to track or truncal somatic predict treatment outcome some these techniques eventually guide sequential options patients. Further development standardization mutation tracking circulating DNA ongoing. Clinically, patients with derive benefit when treated fulvestrant CDK4/6‐targeted therapies, but the more potent selective ER degraders and/or new targeted biotherapies are needed overcome endocrine‐resistant phenotype mutant–bearing tumors. In this review, we discuss mechanisms resistance dissemination as well for tracking, newly discovered potential therapeutic targets, implications treating

Язык: Английский

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