scholarly journals Predictive Biomarkers for Immune Checkpoint Inhibitors in Metastatic Breast Cancer

2020 ◽  
Author(s):  
Abirami Sivapiragasam ◽  
Prashanth Ashok Kumar ◽  
Ethan S. Sokol ◽  
Lee A. Albacker ◽  
Jonathan K. Killian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Metastatic Breast ◽  
Predictive Biomarkers

scholarly journals Efficacy and predictive factors of immune checkpoint inhibitors in metastatic breast cancer: a systematic review and meta-analysis

2020 ◽  
Vol 12 ◽  
pp. 175883592094092 ◽  
Author(s):  
Yutian Zou ◽  
Xuxiazi Zou ◽  
Shaoquan Zheng ◽  
Hailin Tang ◽  
Lijuan Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Metastatic Breast ◽  
Cd8 T Cell ◽  
First Line ◽  
Grade 3

Background: Immune checkpoint inhibitors (ICIs) have shown encouraging treatment efficacy for metastatic breast cancer in several clinical trials. However, response only occurred in a small population. Evidence predicting response and survival of patients with metastatic breast cancer following ICI treatment with existing biomarkers has not been well summarized. This review aimed to summarize the efficacy and predictive factors of immune checkpoint therapy in metastatic breast cancer, which is critical for clinical practice. Methods: PubMed, Embase, Cochrane Library, Web of Science, www.clinicaltrials.gov , and meeting abstracts were comprehensively searched to identify clinical trials. The outcomes were objective response rate (ORR), treatment-related adverse events (trAEs), immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS). Results: In this review, 27 studies with 1746 patients were included for quantitative synthesis. The pooled ORR was 19% [95% confidence interval (CI) = 12–27%]. Programmed death-ligand 1 (PD-L1)-positive patients had a higher response rate [odds ratio (OR) = 1.44, p = 0.01]. First-line immunotherapy had a better ORR than second-line immunotherapy (OR = 2.00, p = 0.02). Tumor-infiltrating lymphocytes (TILs) ⩾5% (OR = 2.53, p = 0.002) and high infiltrated CD8+ T-cell level (OR = 4.33, p = 0.006) were ideal predictors of immune checkpoint therapy response. Liver metastasis indicated poor response (OR = 0.19, p = 0.009). However, the difference was non-significant in ORR based on age, performance status score, lymph node metastasis, and lactate dehydrogenase (LDH) level. In addition, the PD-L1-positive subgroup had a better 1-year PFS (OR = 1.55, p = 0.04) and 2-year OS (OR = 2.28, p = 0.02) following ICI treatment. The pooled incidence during ICI therapy of grade 3–4 trAEs was 25% (95% CI = 16–34%), whereas for grade 3–4 irAEs it was 15% (95% CI = 11–19%). Conclusions: Metastatic breast cancer had modest response to ICI therapy. PD-L1-positive, first-line immunotherapy, non-liver metastasis, and high TIL and CD8+ T-cell infiltrating levels could predict better response to ICI treatment. Patients with PD-L1-positive tumor could gain more survival benefits from immune checkpoint therapy.

scholarly journals Tumor-Infiltrating Lymphocytes and Breast Cancer: Are Immune Checkpoint Inhibitors Ready for Prime Time in Breast Cancer?

2016 ◽  
Vol 33 (4) ◽  
pp. 237-246 ◽  
Author(s):  
Ana Cvetanović ◽  
Slađana Filipović ◽  
Nikola Živković ◽  
Miloš Kostić ◽  
Svetislav Vrbić ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Tumors ◽  
Prime Time ◽  
Infiltrating Lymphocytes

SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. The relevance of TILs cannot be ignored but needs to be properly evaluated in larger prospective studies which must encompass the parameters set out in previous studies. The use of TILs as prognostic biomarkers in early breast cancer may represent a new dawn, and use of immunotherapy, especially immune checkpoint inhibitors, probably is the future for the breast cancer but it is not yet ready for prime time.

Circulating PD-L1 (programmed death-ligand 1) and outcomes in a HER2-positive metastatic breast cancer cohort treated with first-line trastuzumab.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1024-1024 ◽  
Author(s):  
Ayesha Ali ◽  
Laura Krecko ◽  
Kim Leitzel ◽  
Suhail M. Ali ◽  
Joseph J. Drabick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
First Line ◽  
Her2 Positive ◽  
Breast Cancer Cohort

1024 Background: Recently the immune checkpoint inhibitors (ICIs) have demonstrated efficacy across a wide variety of cancers, but have been less effective in breast cancer. PD-L1 (B7-H1, CD274) is a ligand produced by many tumor cells and some immune cells, and suppresses the T cell immune response. This allows tumor cells to escape immune detection. PD-L1 is used as a companion tumor tissue IHC biomarker for patient selection for some of the FDA-approved ICIs (pembrolizumab), but not for others (nivolumab, atezolizumab). Circulating PD-L1 has been detected in multiple myeloma, renal, lung, and gastric cancer, but not in breast cancer. Here we correlated serum PD-L1 levels with outcome in a HER2-positive metastatic breast cancer cohort treated with trastuzumab. Methods: Pretreatment serum was obtained from 63 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. A novel ELLA microfluidic channel immunoassay platform (ProteinSimple, San Jose, CA) was employed to quantitate serum PD-L1. Serum PD-L1 levels were analyzed using continuous, quartile, and dichotomous (25%, median, and 75%) cutpoints. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Results: On a continuous basis, patients with higher serum PD-L1 had a significantly reduced PFS (p = 0.045) and overall survival OS (p = 0.004) compared to patients with lower serum PD-L1 levels. Patients with the higher quartiles of serum PD-L1 also trended to have reduced PFS (0.11) and significantly reduced OS (p = 0.015) compared to the lower quartiles of serum PD-L1. Finally, using either the 25th or 75th percentile of serum PD-L1 as dichotomous cutpoint, patients with higher serum PD-L1 had significantly reduced OS (p = 0.04). Conclusions: Higher circulating PD-L1 levels were prognostic for reduced PFS and OS in HER2-positive metastatic breast cancer patients treated with first-line trastuzumab. Circulating PD-L1 deserves further study for prognostic and predictive biomarker utility in larger trials of immune checkpoint inhibitors and other immunotherapies in breast and other cancers. AA, LK contributed equally.

scholarly journals Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1863
Author(s):  
Nan Chen ◽  
Nicole Higashiyama ◽  
Valentina Hoyos
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Large Scale ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Predictive Biomarkers

Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.

Rechallenge of anti-PD-1/PD-L1 antibody showed a good response to metastatic breast cancer: a case report

Immunotherapy ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 189-194
Author(s):  
Yoko Otani ◽  
Kiyoshi Mori ◽  
Nozomi Morikawa ◽  
Makiko Mizutani ◽  
Hiroyuki Yasojima ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Metastasis ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Metastatic Breast ◽  
Initial Response ◽  
High Status ◽  
Best Response ◽  
Multiple Metastases

Rechallenge of immune checkpoint inhibitors has been reported for neoplasms other than breast cancer. Reported here is a case of a 55-year old woman diagnosed as having triple-negative right breast cancer with multiple metastases including lung. Atezolizumab and nab-paclitaxel were administered followed by epirubicin–cyclophosphamide. With subsequent eribulin, the overall best response was progressive disease, and curative surgical resection was performed. Three months after surgery (1.5 years after initial response of lung metastasis), right lung metastasis emerged at a site different from baseline. Based on the microsatellite instability-high status, pembrolizumab was administered and showed a good response. The patient has been treated with pembrolizumab, maintaining partial response, for over 9 months, which suggests the benefit of immune checkpoint inhibitors rechallenge in breast cancer.

scholarly journals Immune landscape of inflammatory breast cancer suggests vulnerability to immune checkpoint inhibitors

2021 ◽  
Vol 10 (1) ◽  
pp. 1929724
Author(s):  
François Bertucci ◽  
Laurys Boudin ◽  
Pascal Finetti ◽  
Christophe Van Berckelaer ◽  
Peter Van Dam ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Inflammatory Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

scholarly journals How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

2021 ◽  
Vol 10 (7) ◽  
pp. 1412
Author(s):  
Michele Ghidini ◽  
Angelica Petrillo ◽  
Andrea Botticelli ◽  
Dario Trapani ◽  
Alessandro Parisi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Clinical Implementation ◽  
T Cell Therapy ◽  
Dismal Prognosis

Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

scholarly journals Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

2021 ◽  
Vol 22 (10) ◽  
pp. 5207
Author(s):  
Chi Yan ◽  
Jinming Yang ◽  
Nabil Saleh ◽  
Sheau-Chiann Chen ◽  
Gregory D. Ayers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mtor Pathway ◽  
Complete Regression ◽  
Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

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