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).

Concordance of Genomic Variants in Matched Primary Breast Cancer, Metastatic Tumor, and Circulating Tumor DNA: The MIRROR Study

2019 ◽  
pp. 1-16 ◽  
Author(s):  
Fernando Moreno ◽  
Javier Gayarre ◽  
Sara López-Tarruella ◽  
María del Monte-Millán ◽  
Antonio C. Picornell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Primary Tumor ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Circulating Tumor Dna ◽  
Primary Tumors ◽  
Genomic Variants ◽  
Ctdna Analysis ◽  
Tumor Dna

PURPOSE Genetic heterogeneity between primary tumors and their metastatic lesions has been documented in several breast cancer studies. However, the selection of therapy for patients with metastatic breast cancer and the search for biomarkers for targeted therapy are often based on findings from the primary tumor, mainly because of the difficulty of distant metastasis core biopsies. New methods for monitoring genomic changes in metastatic breast cancer are needed (ie, circulating tumor DNA [ctDNA] genomic analysis). The objectives of this study were to assess the concordance of genomic variants between primary and metastatic tumor tissues and the sensitivity of plasma ctDNA analysis to identify variants detected in tumor biopsies. PATIENTS AND METHODS Next-generation sequencing technology was used to assess the genomic mutation profile of a panel of 54 cancer genes in matched samples of primary tumor, metastatic tumor, and plasma from 40 patients with metastatic breast cancer. RESULTS Using Ion Torrent technology (ThermoFisher Scientific, Waltham, MA), we identified 110 variants that were common to the primary and metastatic tumors. ctDNA analysis had a sensitivity of 0.972 in detecting variants present in both primary and metastatic tissues. In addition, we identified 13 variants in metastatic tissue and ctDNA not present in primary tumor. CONCLUSION We identified genomic variants present in metastatic biopsies and plasma ctDNA that were not present in the primary tumor. Deep sequencing of plasma ctDNA detected most DNA variants previously identified in matched primary and metastatic tissues. ctDNA might aid in therapy selection and in the search for biomarkers for drug development in metastatic breast cancer.

Genomic of circulating tumor cells in metastatic breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1002-1002 ◽  
Author(s):  
J. M. Reuben ◽  
B. N. Lee ◽  
C. Li ◽  
K. R. Broglio ◽  
V. Valero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Cells ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Notch 1 ◽  
Primary Tumors ◽  
Metastatic Site ◽  
Her 2 ◽  
Pre Treatment

1002 Background: Metastatic breast cancer (MBC) is an incurable condition and palliative treatments are selected by considering pre-treatment prognostic and predictive factors. Recently, we reported the detection of CTCs to be predictive of prognosis and treatment efficacy and reasoned they might also be used to assess biological characteristics of the patient’s tumor to improve on treatment selection. Methods: Twenty patients with newly diagnosed MBC were enrolled in a prospective clinical trial designed to assess the baseline value of CTCs, evaluate the expression of selected genes in CTCs, and compare the expression of same biomarkers in the primary tumor (PT) and/or metastatic site (MS), as determined by standard IHC and FISH. CTCs were assessed by CellSearch, and subjected to real-time PCR (qPCR) for the expression of transcripts for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER-2), notch-1, and mammaglobin (MGB) using commercial primers. Results: Sixteen of patients had =1CTCs. With respect to biomarkers of PT, 17 were ER+, 11 PR+, and 3 HER-2 amplified. Among the 15 patients with MS, the biomarkers were as follows: 9 ER+, 7 PR+, and 2 HER-2 amplified. There were significant associations between the primary and metastatic tumors with respect to the presence of ER (χ2 = 6.516, P = 0.0107), PR (χ2 = 5.529, P = 0.0187), and HER-2 (χ2 = 3.938, P = 0.0472). The qPCR of CTCs detected transcripts: ER in 3 patients (15%); PR in none (0%); MGB and HER-2 in 2 (10%) and 11 patients (55%), respectively. Notch-1 transcripts were detected in 13 patients (65%). CTCs with detectable transcripts of HER-2 were more likely to co-express notch-1 transcripts (χ2 = 4.295, P = 0.038). Of the 4 samples without detectable CTCs, one was HER-2 positive, and three had notch- 1 transcripts. Conclusions: This study demonstrated a significant concordance in biomarkers expression between the tumor cells of the primary tumors and the metastatic site. Furthermore, it suggests that CTCs differ significantly from those tumor cells with regards to the expression of hormone-receptor and HER-2 status. Thus, CTCs may represent a unique and heterogeneous cell population which phenotype and “homing” properties should be further investigated. [Table: see text]

Clinical algorithm to predict who may benefit from CDK4/6 inhibitors in patients (p) with estrogen receptor positive and HER-2 negative (ER+/Her2-) metastatic breast cancer (MBC).

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e13060-e13060
Author(s):  
Eudald Felip-Falgàs ◽  
Iris Teruel ◽  
Juan José García Mosquera ◽  
Carlos Erasun ◽  
Vanesa Quiroga Garcia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Clinical Algorithm ◽  
Estrogen Receptor Positive ◽  
Her 2

scholarly journals Biglycan (BGN) is differentially expressed in metastatic breast cancer, both in metastases to the brain and to the lymph nodes.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Primary Tumor ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Clinical Problem ◽  
Differentially Expressed ◽  
Down Regulation ◽  
Primary Tumors ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes to discover genes associated with brain metastasis in patients with metastatic breast cancer. We found that biglycan, encoded by BGN, was among the genes whose expression was most different in the brain metastases of with patients with metastatic breast cancer as compared to primary tumors of the breast. Interestingly, biglycan was also among the genes most differentially expressed transcriptome-wide when comparing primary tumors of the breast to normal breast tissue. We observed significant down-regulation of biglycan in metastasis to the brain. Molecular functions and down-regulation of BGN may be important for metastasis of primary tumor-derived cancer cells the brain in humans with metastatic breast cancer, and suggests a role for changes in biglycan expression during a spectrum of transformation from benign tissue of the breast, primary tumor and finally to metastasis of the brain.

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 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.

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