scholarly journals PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer

2019 ◽  
Author(s):  
Angélica Santiago-Gómez ◽  
Ilaria Dragoni ◽  
Roisin NicAmhlaoibh ◽  
Elisabeth Trivier ◽  
Verity Sabin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Disease Progression ◽  
Poor Prognosis ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
P21 Activated Kinase

AbstractDespite the effectiveness of endocrine therapies to treat estrogen receptor-positive (ER+) breast tumours, two thirds of patients will eventually relapse due tode novoor acquired resistance to these agents. Cancer Stem-like Cells (CSCs), a rare cell population within the tumour, accumulate after anti-estrogen treatments and are likely to contribute to their failure. Here we studied the role of p21-activated kinase 4 (PAK4) as a promising target to overcome endocrine resistance and disease progression in ER+ breast cancers. PAK4 predicts for resistance to tamoxifen and poor prognosis in 2 independent cohorts of ER+ tumours. We observed that PAK4 strongly correlates with CSC activity in metastatic patient-derived samples irrespective of breast cancer subtype. However, PAK4-driven mammosphere-forming CSC activity increases alongside progression only in ER+ metastatic samples. PAK4 activity increases in ER+ models during acquired resistance to endocrine therapies. Targeting PAK4 with either CRT PAKi, a small molecule inhibitor of PAK4, or with specific siRNAs abrogates CSC activity/self-renewal in clinical samples and endocrine-resistant cells. Together, our findings establish that PAK4 regulates stemness during disease progression and that its inhibition reverses endocrine resistance in ER+ breast cancers.HighlightsPAK4 predicts for failure of endocrine therapies and poor prognosisPAK4 drives stemness and progression in ER+ metastatic breast cancerTargeting PAK4 abrogates breast CSC activity and restores sensitivity to endocrine treatmentsTargeting PAK4 will improve outcome of ER+ breast cancer patientsList of Abbreviations that appeared in abstractCancer Stem-like Cells (CSCs)p21-activated kinase 4 (PAK4)Estrogen Receptor (ER)

scholarly journals Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Lauren Darrigues ◽  
Jean-Yves Pierga ◽  
Alice Bernard-Tessier ◽  
Ivan Bièche ◽  
Amanda Bartolini Silveira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Disease Progression ◽  
Somatic Mutations ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Prognostic Impact ◽  
Radiological Evaluation ◽  
Tumor Dna

Abstract Background Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2−) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency. Methods ER+ HER2− MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes. Results Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (NPIK3CA = 21, NTP53 = 2, NAKT1 = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5–32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4–18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested. Conclusion Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.

The effect of trastuzumab therapy on clinical benefit from fulvestrant treatment for metastatic estrogen receptor-positive breast cancer patients.

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 155-155
Author(s):  
Mahmoud Charif ◽  
Elyse E. Lower ◽  
Diane Kennedy ◽  
Harriet Kumar ◽  
Shugufta Khan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Clinical Benefit ◽  
Primary Tumor ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Primary Tumors ◽  
Duration Of Therapy ◽  
Her 2

155 Background: Overexpression of HER2/neu is associated with tamoxifen resistance in breast cancer (Osborne CK et al. J Natl Canc Inst 2003; 95:353-361). However pts may present with both estrogen receptor (ER) and HER2/neu + tumors. The benefit of adding fulvestrant to trastuzumab is unclear. The objective of the study was to determine the effect of trastuzumab on fulvestrant therapy. Methods: This was an IRB approved record review of patients (pts) from three medical oncologists with biopsy-proven ER+ metastatic breast cancer treated with fulvestrant who also had their primary tumor tested for HER2/neu. Demographic data collected included age at diagnosis, type and stage of cancer, original and metastatic ER, progesterone receptor (PR), and HER-2/neu biomarkers, and site(s) of metastasis, and primary local and systemic treatment. All pts with HER-2/neu + primary tumors received trastuzumab. The duration of fulvestrant therapy was calculated. Time to clinical disease progression on fulvestrant was measured as a surrogate for duration of clinical benefit. Results: Eighty-five metastatic ER+ fulvestrant treated breast cancer pts with known primary tumor HER2/neu status were identified and the duration of therapy calculated. All eleven (13%) pts with documented HER2/neu + primary tumors received trastuzumab. The duration of therapy for HER2/neu + pts (772 (51-1911) days (median (range)) was longer than HER2/neu negative pts (360 (60-2,739) days, p=0.059). The median duration of fulvestrant therapy was 425 days. Pts with HER2/neu + tumors were more likely to be treated beyond the median fulvestrant therapy with an odds ratio of 6.2 (1.26 to 30.92 95% confidence interval, p=0.0249). Conclusions: Trastuzumab plus fulvestrant therapy was associated with a more prolonged clinical response than fulvestrant alone in pts with metastatic breast cancer. This synergism may be due to the effect of trastuzumab inhibiting the activation of transcriptional coactivator MED1, a recently discovered key crosstalk point between HER2/neu and ER signaling pathways in mediating endocrine resistance (Cancer Res 2012;72(21):5625;PLoS One 2013; 8:e70641).

A Review of Trastuzumab-Based Therapy in Patients with HER2-positive Metastatic Breast Cancer

2009 ◽  
Vol 1 ◽  
pp. CMT.S35
Author(s):  
David N. Church ◽  
Chris G.A. Price
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibody ◽  
Metastatic Breast Cancer ◽  
Poor Prognosis ◽  
Chemotherapy Regimen ◽  
Metastatic Breast ◽  
Preclinical Studies ◽  
Breast Cancers ◽  
Her2 Receptor ◽  
Her2 Positive

The ERBB2 or HER2 receptor is overexpressed in 25% of breast cancers and is associated with poor prognosis. Trastuzumab, a monoclonal antibody targeting HER2 has been demonstrated to improve survival when combined with chemotherapy for the treatment of HER2 overexpressing metastatic breast cancer (MBC). Further studies have endeavoured to clarify the optimum chemotherapy regimen in combination with trastuzumab for MBC and its use together with novel biological agents. This review summarises these data together with preclinical studies exploring the mechanism of trastuzumab action and causes of drug resistance. The frequent incidence of brain metastases in patients on trastuzumab is highlighted, and data on the continuation of trastuzumab following CNS and non-CNS progression reviewed.

scholarly journals Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2397
Author(s):  
Eylem Kulkoyluoglu Cotul ◽  
Qianying Zuo ◽  
Ashlie Santaliz-Casiano ◽  
Ozan Berk Imir ◽  
Ayca Nazli Mogol ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metabolic Pathways ◽  
Nuclear Export ◽  
Tumor Regression ◽  
Critical Role ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Metabolic Phenotype ◽  
Breast Cancers

The majority of breast cancer specific deaths in women with estrogen receptor positive (ER+) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER+ tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER+ breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD+. PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER+ metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.

scholarly journals Are We Ready to Use ESR1 Mutations in Clinical Practice

Breast Care ◽  
2017 ◽  
Vol 12 (5) ◽  
pp. 309-313 ◽  
Author(s):  
Rinath Jeselsohn
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Aromatase Inhibitors ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Breast Cancers ◽  
Poor Overall Survival ◽  
Treatment Naïve ◽  
Esr1 Mutations

The recurrent ligand-binding domain ESR1 mutations are an important mechanism of endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. These mutations evolve under the selective pressure of endocrine treatments and are rarely found in treatment-naïve ER+ breast cancers. Preclinical studies showed that these mutations lead to ligand-independent activity facilitating resistance to aromatase inhibitors and relative resistance to tamoxifen and fulvestrant. Retrospective analyses of ESR1 mutations in baseline plasma circulating tumor DNA from clinical trials suggest that these mutations are prognostic of poor overall survival and predictive of resistance to aromatase inhibitors in metastatic disease. Larger datasets and prospective studies to confirm these results are lacking. In addition, response to other standard treatments for metastatic breast cancer in the presence of the ESR1 mutations is unknown, and studies to determine the optimal treatment combinations for patients with ESR1 mutations are also needed.

scholarly journals Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kanako Hagio ◽  
Toraji Amano ◽  
Hideyuki Hayashi ◽  
Takashi Takeshita ◽  
Tomohiro Oshino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Targeted Sequencing ◽  
Breast Cancer Patients ◽  
Somatic Gene ◽  
Estrogen Receptor Positive ◽  
Gene Alterations

AbstractClinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients’ prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

scholarly journals The SERM/SERD Bazedoxifene Disrupts ESR1 Helix 12 to Overcome Acquired Hormone Resistance in Breast Cancer Cells

2018 ◽  
Author(s):  
Sean W. Fanning ◽  
Rinath Jeselsohn ◽  
Venkatasubramanian Dharmarajan ◽  
Christopher G. Mayne ◽  
Mostafa Karimi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Hormone Replacement ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Breast Cancers ◽  
Helix 12

AbstractAcquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in theESR1(estrogen receptor alpha (ERα) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER+ breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We find BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show that BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.SignificanceBazedoxifene (BZA) is a potent orally available antiestrogen that is clinically approved for use in hormone replacement therapy (DUAVEE). We explore the efficacy of BZA to inhibit activating somatic mutants of ERα that can arise in metastatic breast cancers after prolonged exposure to aromatase inhibitors or tamoxifen therapy. Breast cancer cell line, biophysical, and structural data show that BZA disrupts helix 12 of the ERα ligand binding domain to achieve improved potency against Y537S and D538G somatic mutants compared to 4-hydroxytamoxifen.

Leveraging Antiprogestins in the Treatment of Metastatic Breast Cancer

Endocrinology ◽  
2021 ◽  
Author(s):  
Sailaja Kamaraju ◽  
Amy M Fowler ◽  
Elizabeth Weil ◽  
Kari B Wisinski ◽  
Thu H Truong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Endocrine Therapy ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Mtor Inhibitors ◽  
Mammary Tissue

Abstract Although incurable, the prognosis for patients with metastatic breast cancer (MBC) has considerably improved with the approvals of multiple targeted and cytotoxic therapies. For hormone receptor-positive (HR+), i.e., estrogen receptor and progesterone receptor positive (ER+/PgR+) and Human Epidermal Growth Factor Receptor-2 negative (i.e.,ERBB2 gene non-amplified or HER2-) MBC, current approved treatment options include palliative endocrine therapy (ET), Cyclin-Dependent Kinase (CDK 4/6) inhibitors, mTOR inhibitors, and PI3 kinase inhibitors. Most treatments target ER+ disease regardless of PgR status. Although the presence of PgR is crucial for ER+ cell proliferation in both normal and malignant mammary tissue, currently, no approved treatments specifically target PgR. Recent literature has demonstrated, the potential of antiprogestins in the treatment of MBC both in preclinical and clinical studies.Antiprogestins, including selective PgR modulators (SPRMs) that act as PgR antagonists, are a promising class of therapeutics for overcoming endocrine resistance in patients who develop activating estrogen receptor 1 (ESR1) and phosphatidylinositol 3-kinase (PI3K) gene mutations after prior endocrine therapy. Herein, we summarize the role of PgR and antiprogestins in the treatment of MBC. Other aspects on the use of functional imaging, clinical trials incorporating novel antiprogestins and potential treatment combinations to overcome endocrine resistance will be briefly discussed.

scholarly journals O28: M6A DEMETHYLASE FTO A POTENTIAL TARGET IN BRAIN METASTATIC BREAST CANCER

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
S Keelan ◽  
S Charmsaz ◽  
S Purcell ◽  
D Varešlija ◽  
S Cocchiglia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastasis ◽  
Disease Progression ◽  
Therapeutic Target ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Potential Therapeutic Target ◽  
Rna Methylation ◽  
Pharmacological Inhibition

Abstract Introduction Brain metastasis (BrM) occurs in 10-30% of patients with advanced breast cancer (BC). BrM is increasing in incidence and confers a poor prognosis. We aimed to investigate the contribution of global epi-transcriptomic alterations in N6-methyladenosine (m6A) RNA-methylation as a therapeutic target in brain metastatic breast cancer. Method In preliminary studies we have demonstrated m6A demethylase – FTO as the main contributor to the progression of ER+ breast cancer. Furthermore an association between FTO and reduced disease-free-survival (n=870, p=0.018) was observed. Here we conducted an epigenetic inhibitor screen using two therapeutic agents, ethyl-ester-meclofenamic acid (MA2) and FB23-2 on matched 2D cell line, 3D organoid cultures and patient-derived xenografts (PDX) explant models of brain metastasis. Result Upon integration of mapped global RNA methylation landscape with matched proteomic analysis, we observed genome-wide RNA hypo-methylation of key pluripotency genes, including SOX2 and KLF4, as key players underlying tumour progression to the brain.  Genetic and pharmacological inhibition of FTO in novel ex vivo models of BrM significantly reduced protein expression levels of KLF4 and SOX2. Moreover, pharmacological inhibition of FTO with MA2 and FB23-2, inhibited cell proliferation in endocrine-resistant BC and patient BrM cells. We translate our findings to the clinic by demonstrating the efficacy of anti-FTO therapies in several unique PDX and 3D organoid BrM models. Conclusion Our results reveal epi-transcriptional remodelling events as a key mechanism in BrM. This study establishes an early role for targeting RNA methylation in the management of disease progression and presents FTO as a potential therapeutic target in BrM. Take-home message This study establishes an early role for targeting RNA methylation in the management of disease progression and presents FTO as a potential therapeutic target in brain metastatic breast cancer.

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