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.

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 Glucocorticoid Receptor Expression Predicts Good Outcome in response to Taxane-Free, Anthracycline-Based Therapy in Triple Negative Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Ahmed Elkashif ◽  
Victoria Bingham ◽  
Paula Haddock ◽  
Matthew P. Humphries ◽  
Stephen McQuaid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucocorticoid Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Standard Of Care ◽  
Predictive Biomarker ◽  
Receptor Expression ◽  
Breast Cancers ◽  
Current Standard ◽  
Poor Outcome

Triple negative breast cancer (TNBC) is a poor outcome subset of breast cancers characterised by the lack of expression of ER α, PR, and HER2 amplification. It is a heterogeneous group of cancers which fail to derive benefit from modern, more targeted treatments such as Tamoxifen and Herceptin. Current standard of care (SoC) is cytotoxic chemotherapy, which is effective for some patients, with other patients deriving little/no benefit and lacking alternative treatments. This study has identified the glucocorticoid receptor (GR) as a potential predictive biomarker of response to anthracycline-based chemotherapy in triple negative breast cancer (TNBC). GR gene expression levels in patient samples were analysed through publicly available microarray datasets as well as protein expression through immunohistochemistry (IHC) and correlated with clinical/pathological outcomes, including survival. While the results confirmed previous observations that high GR expression is associated with poor outcome in response to taxane-based chemotherapy, this study shows for the first time that high GR expression is associated with improved outcomes in the context of anthracycline-based chemotherapy. GR therefore has the potential to be used as a predictive biomarker to guide treatment choices and ensure that patients derive the greatest benefit from first line treatment, avoiding unnecessary costs, side effects, and disease progression.

scholarly journals RADI-13. Systemic Therapy Type and Timing Effects on Radiation Necrosis Risk in HER2+ Breast Cancer Brain Metastases Patients Treated with Stereotactic Radiosurgery

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii20-iii20
Author(s):  
Christine Park ◽  
Evan Buckley ◽  
Amanda Van Swearingen ◽  
Will Giles ◽  
James Herndon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stereotactic Radiosurgery ◽  
Systemic Therapy ◽  
Radiation Necrosis ◽  
Standard Of Care ◽  
Current Standard ◽  
Her2 Breast Cancer ◽  
Breast Cancer Brain Metastasis ◽  
The Impact ◽  
Systemic Therapies

Abstract Background Current standard of care options for HER2+ breast cancer brain metastasis (BCBrM) include radiation therapy, brain permeable systemic therapies, and in select cases, neurosurgical resection. There is a concern that HER2-directed systemic therapies when administered concurrently with stereotactic radiosurgery (SRS) may increase the risk of radiation necrosis (RN). This study explores the impact of timing and type of systemic therapies on the development of RN in patients treated with SRS for HER2+ BCBrM. Methods This was a single-institution, retrospective study including patients ≥18 years of age with HER2+ BCBrM who received SRS between 2013 and 2018 with at least 12-month post-SRS follow-up. Presence of RN was determined at one-year post-SRS. Demographics, radiotherapy parameters, and timing (“during” defined as four weeks before/after SRS) and type of systemic therapy were evaluated. Results Among 46 patients with HER2+ BCBrM who received SRS, 28 (60.9%) developed RN and 18 (39.1%) did not. Age (mean 53.3 vs 50.4 years, respectively), radiotherapy parameters (dose, fraction, CTV, GTV, CI, V12Gy, all p>0.05), and receipt of any type of systemic therapy during SRS (60.7% vs 55.6%, p = 0.97) did not differ between patients who did or did not develop RN. However, patients who developed RN more commonly received more than one line of HER2-directed therapy independent of SRS timing compared to those who did not develop RN (75.0% vs 44.4%, p = 0.08). In fact, a significantly higher proportion of those who developed RN received more than one line of HER2-directed therapy during a given SRS treatment compared to those did not develop RN (35.7% vs 5.6%, p<0.05). Conclusions Patients with HER2+ BCBrM who receive multiple lines of HER2-directed therapy during SRS for BCBrM may be at higher risk of RN. Collectively, this data supports a practice of holding HER2-directed therapy during treatment with SRS if medically acceptable.

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.

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.

The relationship between treatment intensity and characteristics of patients with early-stage breast cancer.

2020 ◽  
Vol 38 (29_suppl) ◽  
pp. 125-125
Author(s):  
Jeffrey Franks ◽  
Nicole Caston ◽  
Courtney Williams ◽  
Andres Azuero ◽  
Monica S. Aswani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
High Intensity ◽  
Early Stage ◽  
Standard Of Care ◽  
Early Stage Breast Cancer ◽  
Treatment Intensity ◽  
Low Intensity ◽  
Her2 Breast Cancer ◽  
To Receive

125 Background: Clinical trials are used to generate standard-of-care, yet often do not reflect patient populations treated in real-world settings. Elderly patients or patients of color who are often underrepresented in trials, which may impact what types of treatments are prescribed. This study examines how patient characteristics are associated with treatment intensity in early stage breast cancer. Methods: This retrospective cross-sectional study included women with a stage I-III breast cancer from American Society of Clinical Oncology’s CancerLinQ database treated by chemotherapy from 2005-2019. Seven standard-of-care regimens were characterized by intensity. For patients with ER+/- HER2- breast cancer, low-intensity regimens were Taxol and Cyclophosphamide or Adriamycin and Cyclophosphamide; while Taxol, Adriamycin, and Cyclophosphamide was considered high intensity. For patients with HER2+ breast cancer, the low intensity regimen was Taxol and Herceptin; while Adriamycin and Cyclophosphamide followed by Taxol and Herceptin; Taxol, Carboplatin, and Herceptin; or Taxol, Carboplatin, Herceptin, and Pertuzumab were considered high intensity. A model estimating the likelihood of intensity was calculated using log-binomial regression, in order to produce relative risks. The models were adjusted for patient demographics and cancer stage. Results: Of 24,383 patients, 51% had ER+HER2-, 20% ER-HER2-, and 29% HER2+ breast cancer. Most patients were White (60%), age 40-69 (80%), had stage II breast cancer (39%), and received higher intensity treatment (65%). Adjusted for the other covariates, patient who were Black were more likely to receive high-intensity treatment than patients who were White (61% vs 58%; RR 1.05, 95%CI 1.02-1.06. Additionally, older adults were more likely to receive low-intensity treatment, with 42% of patients over 70 receiving low intensity treatment, and 29% of patients between the ages 40 and 69 received low intensity treatment (RR 1.5, 95% CI 1.44 -1.54). Conclusions: Differences in treatment intensity were observed for patients with differing demographic characteristics. Further research is needed to determine lack of representation in clinical trials impacts on prescribing patterns, regimen intensity, and survival.

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