scholarly journals Comparison of Estrogen and Progesterone Receptor Antibody Reagents Using Proficiency Testing Data

2017 ◽  
Vol 141 (10) ◽  
pp. 1402-1412 ◽  
Author(s):  
Megan L. Troxell ◽  
Thomas Long ◽  
Jason L. Hornick ◽  
Abiy B. Ambaye ◽  
Kristin C. Jensen
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Proficiency Testing ◽  
Immunohistochemical Analysis ◽  
Predictive Testing ◽  
Standard Of Care ◽  
Tissue Microarrays ◽  
Current Standard ◽  
Testing Data ◽  
Positive Results

Context.— Immunohistochemical analysis of estrogen receptor (ER) and progesterone receptor (PgR) expression in breast cancer is the current standard of care and directly determines therapy. In 2010 the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) published guidelines for ER and PgR predictive testing, encompassing preanalytic, analytic, postanalytic factors; antibody validation; and proficiency testing. Objective.— To compare the performance of different antibody reagents for ER and PgR immunohistochemical analysis by using CAP proficiency testing data. Design.— The CAP PM2 survey uses tissue microarrays of ten 2-mm cores per slide. We analyzed survey data from 80 ER and 80 PgR cores by antibody clone from more than 1200 laboratories. Results.— Laboratories used the ER antibodies SP1 (72%), 6F11 (17%), 1D5 (3%), and the PgR antibodies 1E2 (61%), 16 (12%), PgR-636 (13%), PgR-1294 (8%) in 2015. While 63 of 80 ER cores (79%) were scored similarly using each of the 3 antibodies, there were significant differences for others, with SP1 yielding more positive interpretations. Four cores were scored as ER negative by more than half of the laboratories using 1D5 or 6F11, while SP1 produced positive results in more than 70% of laboratories using that antibody. Despite the greater variety of PgR antibody reagents and greater PgR tumor heterogeneity, 61 of 80 cores (76%) were scored similarly across the 4 PgR antibodies. Conclusions.— Accurate ER and PgR testing in breast cancer is crucial for appropriate treatment. The CAP proficiency testing data demonstrate differences in staining results by ER clone, with SP1 yielding more positive results.

scholarly journals Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER-positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper

2018 ◽  
Vol 10 ◽  
pp. 175883591880961 ◽  
Author(s):  
Nicolò Matteo Luca Battisti ◽  
Nienke De Glas ◽  
Mina S. Sedrak ◽  
Kah Poh Loh ◽  
Gabor Liposits ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Older Adults ◽  
Older Patients ◽  
Geriatric Oncology ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Cyclin Dependent Kinase ◽  
Current Standard ◽  
Oncology Review ◽  
Er Positive

The current standard of care for the management of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer has been redefined by the introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Although adults aged 65 years and older account for the majority of patients with breast cancer, limited data are available about the age-specific dosing, tolerability, and benefit of CDK4/6 inhibitors in this growing population. Older adults are under-represented in clinical trials and as a result, clinicians are forced to extrapolate from findings in younger and healthier patients when making treatment decisions for older patients. In this article, we review the limited age-specific evidence on the efficacy, toxicity, and quality of life (QoL) outcomes associated with the use of CDK4/6 inhibitors in older adults. We also describe ongoing trials evaluating CDK4/6 inhibitors in the older population and highlight that only a minority of adjuvant and metastatic trials of CDK4/6 inhibitors in the general breast cancer population includes geriatric assessments. Finally, we propose potential strategies to help guide decision making for fit and unfit older patients based on disease endocrine sensitivity, the need for rapid response and geriatric assessment.

scholarly journals Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 89 ◽  
Author(s):  
Nishant Gandhi ◽  
Gokul Das
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor Alpha ◽  
Cancer Metabolism ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Current Standard ◽  
Therapeutic Implications ◽  
Altered Metabolism

Current standard-of-care (SOC) therapy for breast cancer includes targeted therapies such as endocrine therapy for estrogen receptor-alpha (ERα) positive; anti-HER2 monoclonal antibodies for human epidermal growth factor receptor-2 (HER2)-enriched; and general chemotherapy for triple negative breast cancer (TNBC) subtypes. These therapies frequently fail due to acquired or inherent resistance. Altered metabolism has been recognized as one of the major mechanisms underlying therapeutic resistance. There are several cues that dictate metabolic reprogramming that also account for the tumors’ metabolic plasticity. For metabolic therapy to be efficacious there is a need to understand the metabolic underpinnings of the different subtypes of breast cancer as well as the role the SOC treatments play in targeting the metabolic phenotype. Understanding the mechanism will allow us to identify potential therapeutic vulnerabilities. There are some very interesting questions being tackled by researchers today as they pertain to altered metabolism in breast cancer. What are the metabolic differences between the different subtypes of breast cancer? Do cancer cells have a metabolic pathway preference based on the site and stage of metastasis? How do the cell-intrinsic and -extrinsic cues dictate the metabolic phenotype? How do the nucleus and mitochondria coordinately regulate metabolism? How does sensitivity or resistance to SOC affect metabolic reprogramming and vice-versa? This review addresses these issues along with the latest updates in the field of breast cancer metabolism.

scholarly journals Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Current Treatment Standards and Future Perspectives

Breast Care ◽  
2020 ◽  
Vol 15 (6) ◽  
pp. 570-578
Author(s):  
Clemens Dormann
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Second Line ◽  
Current Standard ◽  
Epidermal Growth ◽  
Positive Breast Cancer

<b><i>Background:</i></b> The basis of improved systemic therapy for inoperable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is formed by HER2-targeting monoclonal antibodies. Dual HER2 blockade with pertuzumab and trastuzumab in combination with docetaxel in previously untreated patients, and trastuzumab emtansine (T-DM1, an antibody-drug conjugate [ADC] consisting of trastuzumab, a linker and a cytotoxic payload) after prior trastuzumab therapy have demonstrated progression-free survival (PFS) and overall survival (OS) superior to what was achieved with the previous treatment routine. Therefore, pertuzumab and trastuzumab with chemotherapy (preferably with a taxane) and T-DM1 are considered the current standard of care in the first- and second-line settings, respectively. For later lines of therapy, no uniformly recognized standard of care has been defined. Accepted options include treatment with trastuzumab beyond progression, in combination with a broad variety of single-agent chemotherapies used sequentially, or lapatinib (an HER2-targeting tyrosine kinase inhibitor [TKI]) in combination with either trastuzu­mab or capecitabine. However, most of these options have not been formally tested in patients receiving the current standard of care therapy for metastatic disease. <b><i>Summary:</i></b> In patients previously treated with today’s standard of care, including a significant subgroup with untreated or progressing brain metastases, the combination of tucatinib, a novel HER2-targeting TKI, with trastuzumab and capecitabine, demonstrates a clinically meaningful improvement in PFS and OS when compared to placebo with trastuzumab and capecitabine. Neratinib, another HER2 TKI, in combination with capecitabine, compared to lapatinib and capecitabine, as well as margetuximab, an HER2-directed monoclonal antibody with a fragment c (Fc) domain engineered to enhance immune activation, compared to trastuzumab, both combined with the investigator’s choice of chemotherapy, showed a statistically significantly longer PFS. However, not all patients in the respective trials had received pertuzumab and T-DM1 prior to enrollment and, so far, no improvement in OS has been demonstrated. After a median of 6 prior lines of therapy, trastuzumab deruxtecan (T-DXd), a novel ADC, showed a meaningful overall response and PFS. Although the safety profile was generally manageable, treatment-related interstitial lung disease (ILD) might pose a challenge in routine practice. Pyrotinib, another HER2 TKI, was evaluated in combination with capecitabine in patients after prior exposure to trastuzumab when pertuzumab and T-DM1 were not available. In this setting, PFS was better than with lapatinib and capecitabine. <b><i>Key Messages:</i></b> In 2020, pertuzumab and trastuzumab with taxane-based chemotherapy in the first line, and T-DM1 in the second line, remain the standard of care. Tucatinib, neratinib, margetuximab, and T-DXd expand the armamentarium for treatment beyond the second line. Pyrotinib might be another option, especially for patients, who do not have access to pertuzumab and T-DM1.

scholarly journals Automated Tumour Recognition and Digital Pathology Scoring Unravels New Role for PD-L1 in Predicting Good Outcome in ER-/HER2+ Breast Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Matthew P. Humphries ◽  
Sean Hynes ◽  
Victoria Bingham ◽  
Delphine Cougot ◽  
Jacqueline James ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Significance ◽  
Digital Pathology ◽  
Scoring Systems ◽  
Standard Of Care ◽  
Inflammatory Cells ◽  
Predictive Biomarker ◽  
Current Standard ◽  
Her2 Breast Cancer ◽  
Biomarker Quantitation

The role of PD-L1 as a prognostic and predictive biomarker is an area of great interest. However, there is a lack of consensus on how to deliver PD-L1 as a clinical biomarker. At the heart of this conundrum is the subjective scoring of PD-L1 IHC in most studies to date. Current standard scoring systems involve separation of epithelial and inflammatory cells and find clinical significance in different percentages of expression, e.g., above or below 1%. Clearly, an objective, reproducible and accurate approach to PD-L1 scoring would bring a degree of necessary consistency to this landscape. Using a systematic comparison of technologies and the application of QuPath, a digital pathology platform, we show that high PD-L1 expression is associated with improved clinical outcome in Triple Negative breast cancer in the context of standard of care (SoC) chemotherapy, consistent with previous findings. In addition, we demonstrate for the first time that high PD-L1 expression is also associated with better outcome in ER- disease as a whole including HER2+ breast cancer. We demonstrate the influence of antibody choice on quantification and clinical impact with the Ventana antibody (SP142) providing the most robust assay in our hands. Through sampling different regions of the tumour, we show that tumour rich regions display the greatest range of PD-L1 expression and this has the most clinical significance compared to stroma and lymphoid rich areas. Furthermore, we observe that both inflammatory and epithelial PD-L1 expression are associated with improved survival in the context of chemotherapy. Moreover, as seen with PD-L1 inhibitor studies, a low threshold of PD-L1 expression stratifies patient outcome. This emphasises the importance of using digital pathology and precise biomarker quantitation to achieve accurate and reproducible scores that can discriminate low PD-L1 expression.

A Phase II Add-on Study of Vorinostat (VOR) in Higher Risk Myelodysplastic Syndrome with Failure of Hypomethylating Agents (HMA): The GFM Azavor Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2900-2900
Author(s):  
Thomas Prebet ◽  
Jacques Delaunay ◽  
Eric Wattel ◽  
Thorsten Braun ◽  
Pascale Cony-Makhoul ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rate ◽  
Standard Of Care ◽  
Median Number ◽  
Current Standard ◽  
Stage Design ◽  
Early Evaluation ◽  
Positive Results

Abstract Background: Azacitidine (AZA) is the current standard of care for patients treated for higher risk MDS, but 40-50% patients do not respond and most responders eventually relapse. Median survival after AZA failure is only 5 months and no standard of care is defined for this population. Preclinical studies and positive results of phase I-II trials support a synergistic effect of the histone deacetylase (HDAC) vorinostat (VOR) and AZA in terms of response, although no survival advantage of the combination has as yet been demonstrated. We hypothesized that adding VOR to AZA in patients with primary or secondary AZA resistance could rescue response and prolong survival. Methods: inclusion criteria inGFM AZAVOR study (NCT 01748240) were: 1/IPSS int 2 or high risk MDS at the time of initiation of AZA 2/treatment with at least 6 cycles of AZA and either failure to achieve any response or loss of response (per IWG2006 criteria) 3/a maximum of 3 months between AZA failure and inclusion with no other treatment in between. Patients received VOR 300mg bid from day 3 to day 9 of each cycle. AZA was given at standard 75mg/m2/d day 1 to 7 or at the maximum previously tolerated dose in case of dose reduction. Patients were evaluated after 6 cycles and responding patients treated until progression. The trial used a two-stage design, and accrual was to be stopped if less than 3 responses were seen in the first 14 evaluable patients. Results 21 patients were included between march 2013 and September 2014. Nineteen patients were treated (1 patient died and 1 progressed before treatment). Median age was 72 years. All pts had higher risk MDS and had received a median of 6 cycles of AZA before entering the trial. The median number of AZA+ VOR cycles administered was 3 (range: 1-12). No unexpected SAEs were seen, and the most common AEs were infection, thrombocytopenia, GI toxicities, and fatigue. After 6 cycles of treatment, only 2 patients (11%) achieved response (1 erythroid hematological improvement, 1 partial remission), , which, per protocol, triggered the stop of accrual. At last follow-up, 18 patients were off study and one patient was still on treatment. Nine patients stopped treatment because of progression (42%), 4 stopped treatment for lack of response (21%), 2 stopped treatment because of intolerance (11%), 1 patient stopped at his request (5%), and 1 patient died of complications of cytopenias while on treatment (5%). Median overall survival was 13 months. Conclusion This is the first report of an add-on study in high risk MDS, a strategy that may be useful for the early evaluation of drugs for which synergy with AZA is expected. Our results show that the proposed regimen of AZA +VOR can be used safely. However, the observed response rate was not above the "background" response rate expected from AZA alone continuation in a comparable patient population, indicating that the addition of VOR cannot reverse resistance to AZA. Disclosures Prebet: CELGENE: Research Funding. Off Label Use: lenalidomide. Wattel:Janssen: Consultancy, Honoraria, Research Funding; PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Vey:Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria.

A Dickens Tale of the Treatment of Advanced Breast Cancer: The Past, the Present, and the Future

2012 ◽  
pp. 28-38 ◽  
Author(s):  
George W. Sledge ◽  
Fatima Cardoso ◽  
Eric P. Winer ◽  
Martine J. Piccart
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Scientific Discovery ◽  
Metastatic Breast ◽  
Standard Of Care ◽  
Chemotherapeutic Agents ◽  
Targeted Therapeutics ◽  
Current Standard ◽  
The Past ◽  
Incurable Disease

Overview: Metastatic breast cancer (MBC), a usually incurable disease, continues to vex physicians and patients. Recent decades have seen great improvements in the treatment of MBC, based on the availability of novel targeted therapeutics and more standard chemotherapeutic agents. This article describes the goals of therapy for MBC, the progress made against MBC in recent decades, the current standard of care, and the ongoing efforts of basic and translational researchers to transfer the fruits of modern scientific discovery to patients in the clinic.

Active c-Src has prognostic and therapeutic value in ER-negative breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10063-10063
Author(s):  
A. Arnaout ◽  
L. Yang ◽  
C. Holloway ◽  
N. Steven ◽  
P. Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Significance ◽  
Immunohistochemical Analysis ◽  
Tissue Microarrays ◽  
Distant Recurrence ◽  
Breast Cancers ◽  
Nonreceptor Tyrosine Kinase ◽  
Human Breast Carcinomas ◽  
Er Positive ◽  
Er Status

10063 Background: Approximately 33% of newly diagnosed breast cancers lack ER and these tend to have a worse prognosis as compared to ER-positive breast cancers. Therapeutic options are limited as they are not responsive to antihormonal therapy and often develop resistance to chemotherapies. We have recently shown that activation of the nonreceptor tyrosine kinase protein c-Src leads to the accelerated ER degradation in ER-negative breast cancers. This study performs an immunohistochemical analysis of activated c-Src in a large cohort of primary human breast carcinomas to a) assess its prognostic significance and b) correlate its relationship to the ER status of breast cancers. Methods: A total of 916 patients with breast cancer diagnosed between 1987 and 1997 had clinicopathological data and paraffin-embedded tumor tissues for the study. Tissue microarrays were constructed. A four point scoring system based on immunostaining intensity was used to grade the levels of active phosphorylated c-Src. Grading was done by one pathologist. Statistical analysis was used to assess the prognostic significance of activated c-Src and its relationship to other prognostic variables. Results: Median follow-up was 7.31 years. Active c-Src grade was inversely correlated with ER status (p=0.004) and predicted for treatment with chemotherapy (p=0.002) and lack of treatment with Tamoxifen (p=0.007). Patients with greater levels of c-Src tended to be younger (p=0.004) and had higher Bloom Richardson scores for their tumors (p=0.004). Higher levels of c-Src also predicted for for shorter timing to distant recurrence (p=0.01) and shorter timing to death (p=0.04). There was a trend towards a shorter timing to regional recurrence with higher levels of c-Src but the relationship was not statistically significant (p=0.08). Conclusion: This study supports the hypothesis that the presence of active, phosphorylated c-Src contributes to the development of ER-negative status in breast cancers. The presence of c-Src also is associated with other poor prognostic factors and contributes to a worse prognostic outcome. This study suggests that c-Src inhibitors may be a novel therapeutic strategy for the treatment of ER-negative breast cancers. No significant financial relationships to disclose.

scholarly journals Deep learning trained on H&E tumor ROIs predicts HER2 status and Trastuzumab treatment response in HER2+ breast cancer

2021 ◽  
Author(s):  
saman farahmand ◽  
Aileen Fernandez ◽  
Fahad Shabbir Ahmed ◽  
David Rimm ◽  
Jeffrey H Chuang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Response ◽  
Cross Validation ◽  
Area Under The Curve ◽  
Standard Of Care ◽  
Her2 Status ◽  
Current Standard ◽  
Her2 Positive ◽  
Trastuzumab Therapy ◽  
Her2 Breast Cancer

The current standard of care for many patients with HER2-positive breast cancer is neoadjuvant chemotherapy in combination with anti-HER2 agents, based on HER2 amplification as detected by in situ hybridization (ISH) or protein immunohistochemistry (IHC). However, hematoxylin & eosin (H&E) tumor stains are more commonly available, and accurate prediction of HER2 status and anti-HER2 treatment response from H&E would reduce costs and increase the speed of treatment selection. Computational algorithms for H&E have been effective in predicting a variety of cancer features and clinical outcomes, including moderate success in predicting HER2 status. In this work, we present a novel convolutional neural network (CNN) approach able to predict HER2 status with increased accuracy over prior methods. We trained a CNN classifier on 188 H&E whole slide images (WSIs) manually annotated for tumor regions of interest (ROIs) by our pathology team. Our classifier achieved an area under the curve (AUC) of 0.90 in cross-validation of slide-level HER2 status and 0.81 on an independent TCGA test set. Within slides, we observed strong agreement between pathologist annotated ROIs and blinded computational predictions of tumor regions / HER2 status. Moreover, we trained our classifier on pre-treatment samples from 187 HER2+ patients that subsequently received trastuzumab therapy. Our classifier achieved an AUC of 0.80 in a five-fold cross validation. Our work provides an H&E-based algorithm that can predict HER2 status and trastuzumab response in breast cancer at an accuracy that is better than IHC and may benefit clinical evaluations.

scholarly journals Lost but Not Least—Novel Insights into Progesterone Receptor Loss in Estrogen Receptor-Positive Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4755
Author(s):  
Michał Kunc ◽  
Marta Popęda ◽  
Wojciech Biernat ◽  
Elżbieta Senkus
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Progesterone Receptor ◽  
Neoadjuvant Treatment ◽  
Predictive Biomarkers ◽  
Immunohistochemical Analysis ◽  
Estrogen Receptor Α ◽  
Local Relapse ◽  
Copy Number Loss ◽  
Double Positive

Estrogen receptor α (ERα) and progesterone receptor (PgR) are crucial prognostic and predictive biomarkers that are usually co-expressed in breast cancer (BC). However, 12–24% of BCs present ERα(+)/PgR(−) phenotype at immunohistochemical evaluation. In fact, BC may either show primary PgR(−) status (in chemonaïve tumor sample), lose PgR expression during neoadjuvant treatment, or acquire PgR(−) phenotype in local relapse or metastasis. The loss of PgR expression in ERα(+) breast cancer may signify resistance to endocrine therapy and poorer outcomes. On the other hand, ERα(+)/PgR(−) BCs may have a better response to neoadjuvant chemotherapy than double-positive tumors. Loss of PgR expression may be a result of pre-transcriptional alterations (copy number loss, mutation, epigenetic modifications), decreased transcription of the PGR gene (e.g. by microRNAs), and post-translational modifications (e.g. phosphorylation, sumoylation). Various processes involved in the down-regulation of PgR have distinct consequences on the biology of cancer cells. Occasionally, negative PgR status detected by immunohistochemical analysis is paradoxically associated with enhanced transcriptional activity of PgR that might be inhibited by antiprogestin treatment. Identification of the mechanism of PgR loss in each patient seems challenging, yet it may provide important information on the biology of the tumor and predict its responsiveness to the therapy.

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