The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers

Razavi, Pedram; Chang, Matthew T.; Xu, Guotai; Bandlamudi, Chaitanya; Ross, Dara S.; Vasan, Neil; Cai, Yanyan; Bielski, Craig M.; Donoghue, Mark T.A.; Jonsson, Philip; Penson, A.; Shen, Ronglai; Pareja, Fresia; Kundra, Ritika; Middha, Sumit; Cheng, Michael L.; Zehir, Ahmet; Kandoth, Cyriac; Patel, Ruchi; Huberman, Kety; Smyth, Lillian M.; Jhaveri, Komal; Modi, Shanu; Traina, Tiffany A.; Dang, Chau T.; Zhang, Wen; Weigelt, Britta; Li, Bob T.; Ladanyi, Marc; Hyman, David M.; Schultz, Nikolaus; Robson, Mark E.; Hudis, Clifford A.; Brogi, Edi; Viale, Agnès; Norton, Larry; Dickler, Maura N.; Berger, Michael F.; Iacobuzio‐Donahue, Christine A.; Chandarlapaty, Sarat; Scaltriti, Maurizio; Reis‐Filho, Jorge S.; Solit, David B.; Taylor, Barry S.; Baselga, José

doi:10.1016/j.ccell.2018.08.008

Cited by 669 publications

(753 citation statements)

References 66 publications

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“…Pan‐cancer analysis (Zehir et al , ) reveals that primary tumours with MET amplification have higher overall survival rate (11.83 months) compared to metastatic tumours (9.88 months). However, MET amplification appears at a very low percentage in different breast cancer data sets both in primary (TCGA BRCA (0.4%), (Pereira et al , ) (1.5%), (Razavi et al , ) (0.1%)) and metastatic tumours (2.3%) (Lefebvre et al , ), MBC project 2018 (1.3%), (0.2%) (Zehir et al , ), (0.15%) (Razavi et al , ). Future studies addressing the relationship between aneuploidy and MET under different oncogenic drivers could underline the importance of MET inhibitors as prognostic markers in the treatment of this disease.…”

Section: Discussionmentioning

confidence: 99%

Acquisition of chromosome instability is a mechanism to evade oncogene addiction

et al. 2020

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Chromosome instability (CIN) has been associated with therapeutic resistance in many cancers. However, whether tumours become genomically unstable as an evolutionary mechanism to overcome the bottleneck exerted by therapy is not clear. Using a CIN model of Kras‐driven breast cancer, we demonstrate that aneuploid tumours acquire genetic modifications that facilitate the development of resistance to targeted therapy faster than euploid tumours. We further show that the few initially chromosomally stable cancers that manage to persist during treatment do so concomitantly with the acquisition of CIN. Whole‐genome sequencing analysis revealed that the most predominant genetic alteration in resistant tumours, originated from either euploid or aneuploid primary tumours, was an amplification on chromosome 6 containing the cMet oncogene. We further show that these tumours are dependent on cMet since its pharmacological inhibition leads to reduced growth and increased cell death. Our results highlight that irrespective of the initial CIN levels, cancer genomes are dynamic and the acquisition of a certain level of CIN, either induced or spontaneous, is a mechanism to circumvent oncogene addiction.

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Section: Discussionmentioning

confidence: 99%

Acquisition of chromosome instability is a mechanism to evade oncogene addiction

et al. 2020

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“…Culturing breast cancer cells with WT ESR1 for the long term in hormone-depleted media resulted in gradual acquisition of the Y537C mutation in MCF-7 cells and the Y537S mutation in SUM44 cells. 4 More recently, Li et al 24 confirmed a role for the IGF-1R pathway using similar mutant models. The Y537C mutation was not identified in the parental MCF-7 cells, suggesting that these mutations can either preexist or be acquired depending on the cell line background.…”

Section: Biology Of Esr1 Mutations In Preclinical Studiesmentioning

confidence: 92%

“…4 Using this mutational profiling technology, ESR1 mutation status was analyzed in archival samples from a cohort of 929 breast cancer patients who were treated at Memorial Sloan Kettering Cancer Center. 4 Using this mutational profiling technology, ESR1 mutation status was analyzed in archival samples from a cohort of 929 breast cancer patients who were treated at Memorial Sloan Kettering Cancer Center.…”

Section: Ngs Detection Of Esr1 Mutations In Patient Biopsiesmentioning

confidence: 99%

“…Several mechanisms of de novo and acquired endocrine therapy (ET) resistance have been described, including loss of ER expression, ER crosstalk with growth factor receptors, subclonal genomic alterations of tumor suppressors or drivers, and acquisition of ESR1 fusions or activating ESR1 missense mutations. [2][3][4] Current clinical strategies to effectively treat and prevent recurrence of ER-positive breast cancer is with ETs, which target the ER through hormone deprivation or antagonistic binding of the receptor. ET cures about half of patients in the nonmetastatic setting, and clinical benefit is seen in about 30% of metastatic patients.…”

Section: Introductionmentioning

confidence: 99%

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ESR1 mutations in breast cancer

Dustin

Fuqua

2019

Cancer

156

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

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“…An increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and ER transcriptional machinery have been found in patients previously exposed to hormonal therapy [65]. Activating mutations of ERBB2 and loss-of-function mutations were also more frequent in endocrine resistance tumors.…”

Section: Tracking Tumor Evolution In Breast Carcinomasmentioning

confidence: 99%

Ancillary Tests in Breast Cytology: A Practical Guide

Beça

Schmitt

2019

Acta Cytologica

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Utilization of fine-needle aspiration biopsy (FNAB) cytology for the diagnosis of diseases of the breast has been met with both excitement and uncertainty during the last couple of decades. Presently, FNAB for the diagnosis of primary and metastatic breast lesions is on the rise again. This is probably due to its fast turnaround time, cost efficiency, and minimal invasiveness, characteristics of this sampling modality which are particularly crucial for patients requiring frequent repeat biopsy in the setting of metastatic lesions. In this article, we will briefly review the main modern applications of FNAB of the breast when coupled with contemporary ancillary techniques. Such contemporary ancillary techniques range from classic immunocytochemistry (ICC) to the most modern molecular techniques, particularly next-generation sequencing. Coupled with contemporary ICC and molecular methods, FNAB of the breast can be used for several applications. The applications reviewed in this article include the primary diagnosis of a breast lesion, the identification of the breast as a primary source of a metastatic lesion, the evaluation of breast prognostic/predictive markers, and the tracking of tumor evolution. In our opinion, FNAB of the breast is an ideal sampling method, sharing many of the advantages of truly liquid and of tissue biopsies. Ultimately, we aim at demystifying the complexity of many of the challenges traditionally associated with the application of ancillary techniques to FNAB of the breast and provide insights into some of the most cutting-edge and clinically useful application scenarios.

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The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers

Cited by 669 publications

References 66 publications

Acquisition of chromosome instability is a mechanism to evade oncogene addiction

Acquisition of chromosome instability is a mechanism to evade oncogene addiction

ESR1 mutations in breast cancer

Ancillary Tests in Breast Cytology: A Practical Guide

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