TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor–Positive Breast Cancer

Jeselsohn, Rinath; Barry, William T.; Migliaccio, Ilenia; Biagioni, Chiara; Jin, Zhao; Tribolet-Hardy, Jonas de; Guarducci, Cristina; Bonechi, Martina; Laing, Naomi; Winer, Eric P.; Brown, Myles; Leo, Angelo Di; Malorni, Luca

doi:10.1158/1078-0432.ccr-16-0148

Cited by 27 publications

(38 citation statements)

References 54 publications

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“…TFAP2C is a regulator of ER transcriptional activity and luminal differentiation (Cyr et al, 2015). Moreover, we recently showed that TFAP2C expression was highly associated with decreased progression free survival in metastatic ER + breast cancer (Jeselsohn et al, 2016). To validate that TFAP2C is a ER-mutant transcriptional target and an essential gene for mutant cell growth in HD conditions, we first confirmed mutant induced upregulation of TFAP2C mRNA and protein levels (Figure S5B-S5C).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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“…Through its role as a pioneer factor for oestrogen receptor, higher levels of FOXA1 protein may increase cellular sensitivity to oestrogen. While FOXA1 expression has been linked with positive clinical outcome 27–29 , high levels of FOXA1 have recently been associated with poor outcome, metastasis, decreased response to fulvestrant, and endocrine resistance 26,30,31 . Identification of FOXA1 alterations in patients undergoing hormone therapy may thus be important for recognizing mechanisms for resistance to therapy and tumour progression.…”

Section: Discussionmentioning

confidence: 99%

Recurrent and functional regulatory mutations in breast cancer

Rheinbay

Parasuraman

Grimsby

et al. 2017

Nature

282

294

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Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.

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“…In the TransCONFIRM substudy, genome-wide transcrip-tomic analysis was conducted on primary tumor samples from 134 patients with Affymetrix microarrays (Santa Clara, CA, USA). 68 High expression of most genes in the EGF-signaling pathway and FOXA1 transcription-factor network strongly predicted decreased PFS. An exploratory multivariate Cox analysis identified a set of 37 genes, among them the known regulator of ER activity TFAP2C , whose expression was independently associated with PFS.…”

Section: Efficacy Studies For Fulvestrant As Monotherapy or In Combinmentioning

confidence: 98%

Section: Efficacy Studies For Fulvestrant As Monotherapy or In Combinmentioning

confidence: 99%

Clinical utility of fulvestrant in the treatment of breast cancer: a report on the emerging clinical evidence

Rocca¹,

Maltoni²,

Bravaccini³

et al. 2018

CMAR

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Fulvestrant is the first selective estrogen receptor (ER) downregulator available in clinical practice. It is a pure antiestrogen with no agonistic effects, leading to degradation of ER alpha, with activity in tamoxifen-resistant breast cancer (BC) models. Pharmacokinetic and pharmacodynamic studies and several postmarketing clinical trials led to the definition of the optimal dose at 500 mg intramuscularly on days 1, 15, and 29 and then every 28 days. Targeting ER alpha, fulvestrant is a cornerstone of treatment in luminal BCs, whose growth is largely driven by the ER pathway. In endocrine therapy-naïve patients with hormone receptor-positive, HER2− advanced BC (ABC), fulvestrant yielded significantly longer progression-free survival compared to anastrozole in the Phase III FALCON study. Due to its mechanism of action and pharmacokinetic properties, fulvestrant is an ideal backbone for combination therapies. Preclinical studies have shown synergism with drugs acting on signaling pathways involved in the development of endocrine resistance, among which the cyclin D/cyclin-dependent kinase 4-6/retinoblastoma pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, contributing to overcoming or delaying endocrine resistance. In the Phase III PALOMA-3 trial, a combination of the cyclin-dependent kinase 4/6 inhibitor palbociclib with fulvestrant significantly improved progression-free survival over fulvestrant alone in women with hormone receptor positive, HER2− ABC progressing during prior endocrine therapy. This led to approval of the combination in this clinical setting. Similar results were obtained with abemaciclib and ribociclib. Combination with pan-PI3K inhibitors, though showing some efficacy, was hampered by the toxicity of these agents, and studies in combinations with more selective inhibitors of the α-catalytic subunit of PI3K are ongoing. Fulvestrant has shown partial activity also in patients with tumors harboring mutations of the ESR1 gene. It is thus a key drug in the treatment of ABC, whose role in combination with new targeted agents is still evolving.

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TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor–Positive Breast Cancer

Cited by 27 publications

References 54 publications

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

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

Recurrent and functional regulatory mutations in breast cancer

Clinical utility of fulvestrant in the treatment of breast cancer: a report on the emerging clinical evidence

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