The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (﻿TNBC﻿) is low1–5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6–13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1–PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK–STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types. A pick-the-winner clinical trial design in patients with metastatic triple-negative breast cancer shows that immune induction with doxorubicin or cisplatin may improve clinical responses to PD-1 blockade and induce a more favorable tumor microenvironment.

Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.5406

The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice

While immunotherapy has become an increasingly attractive strategy in patients with urothelial bladder cancer, the need for a biomarker to identify patients whose cancer is the most likely to respond has never been more crucial. This review systematically evaluates evidence regarding PD-L1 as a predictive biomarker of response to anti-PD(L)1 monoclonal antibodies in patients with urothelial bladder carcinoma, and discusses its current limits in routine clinical practice. We performed a critical review of PubMed/Medline according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective clinical trials evaluating anti-PD(L)1 monoclonal antibodies in urothelial bladder carcinoma together with retrospective studies evaluating PD-L1 expression in patients with bladder cancer were included. Evidence data related to PD-L1 as a predictive biomarker of response to immune checkpoint blockade monotherapy across clinical trials are detailed in this review. The different companion diagnostic assays, and the methods for PD-L1 scoring in urothelial bladder carcinoma are reported. Additionally, the issues related to the implementation of PD-L1 testing in clinical practice are discussed. PD-(L)1 monoclonal antibodies atezolizumab and pembrolizumab are restricted to patients with PD-L1 positive status in the first-line setting in patients with advanced or metastatic urothelial bladder carcinoma who are ineligible to cisplatin-based chemotherapy. Importantly, the use of anti-PD(L)1 mAb in the other clinical settings is not based on PD-L1 status, but rather on patients’ clinical characteristics. Further identification of biomarkers with high negative predictive value will also be of utmost importance to identify patients who may not respond to such immunotherapies.

PD-L1 testing in urothelial bladder cancer: essentials of clinical practice

Carcinoma in situ (CIS) is believed to be a precursor of muscle-invasive carcinomas that may arise from these flat high-grade, superficial urothelial lesions. CIS accounts for approximately 10% of all bladder tumors. Therapeutic options for urothelial CIS are limited, and in order to inhibit disease progression and recurrence, current guidelines recommend transurethral resection (TURBT) followed by intravesical administration of Bacillus of Calmette-Guerin (BCG). Approximately 30–40% of patients fail the BCG therapy with recurrence and progression of disease. In the present study, we examined the expression of PD-L1 both in neoplastic epithelial cells and in stromal inflammatory cells in patients with diagnosis of CIS primary responders and not responders to BCG therapy, in order to verify if the PD-L1 expression could identify patients resistant to BCG treatment. Moreover, we analyzed on the same cases the immunoreactivities of anti-PD-L1 MoAbs such as SP263, C23, and SP142. Our results have showed that PD-L1 expression in tumor cells and in immune cell compartment is higher in BCG-unresponsive group than in BCG responders, but only the PD-L1 22C3 expression in tumor cells seems to be associated with recurrence of disease (p = 0.035; OR 0.1204; CI 95% from 0.0147 to 1.023). Hence, our data suggest that the PD-L1 22C3 expression could help to identify CIS that fail the BCG therapy, supporting the hypothesis that enhanced levels of intratumoral PD-L1 22C3 expressed by the tumor cells may explain the failure of BCG immunotherapy.

PD-L1 expression in bladder primary in situ urothelial carcinoma: evaluation in BCG-unresponsive patients and BCG responders.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with limited treatment options. Recently, there has been a growing interest in immunotherapy with immune checkpoint inhibitors (ICIs) in TNBC, leading to extensive preclinical and clinical research. This review summarizes the current state of knowledge on ICIs efficacy and their predictive markers in TNBC and highlights the areas where the data are still limited. Currently, the only approved ICI-based regimen for TNBC is pembrolizumab with chemotherapy. Its advantage over chemotherapy alone was confirmed for non-metastatic TNBC regardless of programmed death-ligand 1 (PD-L1) expression (KEYNOTE-522) and for metastatic, PD-L1-positive TNBC (KEYNOTE-355). Pembrolizumab’s efficacy was also evaluated in monotherapy, or in combination with niraparib and radiation therapy, showing potential efficacy and acceptable safety profile in phase 2 clinical trials. Atezolizumab + nab-paclitaxel increased the overall survival (OS) over placebo + nab-paclitaxel in early TNBC, regardless of PD-L1 status (IMpassion031). In IMpassion130 (untreated, advanced TNBC), the OS improvement was not statistically significant in the intention-to-treat population but clinically meaningful in the PD-L1 positive cohort. The durvalumab–anthracycline combination showed an increased response durability over placebo anthracycline in early TNBC (GeparNuevo). Several phase 1 clinical trials also showed a potential efficacy of atezolizumab and avelumab monotherapy in metastatic TNBC. ICIs appear to be applicable in both neoadjuvant and adjuvant settings, and are both pretreated and previously untreated patients. Further research is necessary to determine the most beneficial drug combinations and optimize patient selection. It is essential to identify the predictive markers for ICIs and factors affecting their expression.

https://journals.sagepub.com/doi/pdf/10.1177/11795549221099869

Current State of Knowledge on the Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer Treatment: Approaches, Efficacy, and Challenges

In this collaborative study by the Russian Society of Clinical Oncology and the Russian Society of Pathology, we assessed the concordance among three validated, commercially available PD-L1 immunohistochemistry assays for patients with urothelial cancer Tumors from 100 urothelial cancer patients were stained with the antibody clones 22C3 (Agilent), SP142 (Ventana Medical Systems), and SP263 (Ventana Medical Systems), which are used in clinical trials of second-line therapy with checkpoint inhibitors Four trained pathologists independently evaluated the percentages of tumor cells (TC) and tumor-infiltrating immune cells (IC) that were stained at any intensity by each of the antibodies The test-specific cutoffs for the proportions of stained cells in a positive sample were pre-specified as TC + IC ≥ 10% or TC ≥ 10% for 22C3, IC ≥ 5% for SP142, and TC ≥ 25% or IC ≥ 25% for SP263 Three hundred immunohistochemistry slides were scored The percentages of PD-L1 staining in the three assays without using any cutoff were higher in the IC than in the TC (55% versus 24% for 22C3, 45% versus 8% for SP142, and 72% versus 27% for SP263, respectively) The Pearson correlation coefficients for anti-PD-L1 staining in the IC were 05, 069, and 085 with 22C3/SP142, 22C3/SP263, and SP142/SP263, respectively The Pearson correlation coefficients for PD-L1 staining in the TC were 093, 099, and 091 for the same pairs Among the patients who were negative for PD-L1 staining by one test, 91–100% were also negative by the other tests Among the patients who were positive by one test, 43–100% were also positive by the other tests Our data indicate that repeated testing can be avoided as a patient with urothelial cancer who is classified as negative for PD-L1 expression by one of the three single tests using the corresponding cutoff rule is highly likely (91–100%) to be classified as negative by either of the other tests

RUSSCO-RSP comparative study of immunohistochemistry diagnostic assays for PD-L1 expression in urothelial bladder cancer.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Alexey Petrov

Author Tools

Chat about Author

Papers

RUSSCO-RSP comparative study of immunohistochemistry diagnostic assays for PD-L1 expression in urothelial bladder cancer.