Tumor mutational load in gynecological and breast cancer.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 44-44 ◽  
Author(s):  
Filipa Lynce ◽  
Joanne Xiu ◽  
Elias Obeid ◽  
Antoinette R. Tan ◽  
Zoran Gatalica ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Response ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Molecular Profiling ◽  
Mutational Load ◽  
Wild Type ◽  
Test Standardization ◽  
Infiltrating Lymphocytes

44 Background: Lack of test standardization and conflicting results on PD1 and PD-L1 immunohistochemistry (IHC) assays challenge their use as predictive biomarkers for checkpoint inhibitors. High tumor mutational load (TML) has been linked to therapeutic response with immune checkpoint inhibition in melanoma, lung and colorectal cancer. Herein, we explore association of TML and PD1/PD-L1 expression in gynecological (GC) and breast cancer (BC). As secondary aim we explore the association of TML with BRCA1/2 mutations. Methods: De-identified data from molecular profiling on GC and BC tumors from the CARIS Life Sciences database was analyzed after obtaining IRB approval. TML was defined as the total number of nonsynonymous, somatic mutations per Mb sequenced with a 592-gene panel. PD-1 IHC was tested on Tumor Infiltrating Lymphocytes (TIL) with the cutoff of 1/HPF; PD-L1 expression was measured on tumor cells with the cutoff of 2+, 5%. Biomarker association was tested with ANOVA test (SPSS v23, IBM). Results: As shown in table, cervical (CC) and endometrial cancers (EC) had the highest TML and squamous CC and triple negative BC (TNBC) tumors with highest PD-L1. In EC, MSI-H was associated with higher TML when compared to MSS (20.1 vs. 6.1, p<0.001); 4 POLE-mutated tumors all carried TML (36-678) higher than mean (11.5). TML was not associated with PD1 or PDL1 positivity in any of the diseases. BRCA1/2 mutations were associated with higher mean TML in ovarian cancer (OC) (6.8 vs. 5.4 in wild type, p<0.001) but not in BC (6.3 vs. 6.8 in wild type, p=0.48). Conclusions: In this sample of patients who underwent molecular profiling, there was no association between TML and PD1 or PD-L1 expression. Association between BRCA1/2 tumor mutations and TML in OC is worth exploring. High TML in CC and EC support the development of immunotherapy for these diseases. [Table: see text]

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.

scholarly journals Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3153
Author(s):  
Makito Miyake ◽  
Shunta Hori ◽  
Takuya Owari ◽  
Yuki Oda ◽  
Yoshihiro Tatsumi ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Retroperitoneal Sarcoma ◽  
Prognostic Impact ◽  
Lymphocyte Migration ◽  
Primary Tumors ◽  
Urological Malignancies ◽  
Infiltrating Lymphocytes ◽  
Shed Light

Over the past decade, an “immunotherapy tsunami”, more specifically that involving immune checkpoint inhibitors (ICIs), has overtaken the oncological field. The interaction and cross-talk among tumor cells and several immune cells in the tumor microenvironment are dynamic and complex processes. As immune contexture can vary widely across different types of primary tumors and tumor microenvironments, there is still a significant lack of clinically available definitive biomarkers to predict patient response to ICIs, especially in urogenital malignancies. An increasing body of evidence evaluating urological malignancies has proven that tumor-infiltrating lymphocytes (TILs) are a double-edged sword in cancer. There is an urgent need to shed light on the functional heterogeneity in the tumor-infiltrating immune system and to explore its prognostic impact following surgery and other treatments. Notably, we emphasized the difference in the immunological profile among urothelial carcinomas arising from different primary origins, the bladder, renal pelvis, and ureter. Significant differences in the density of FOXP3-positive TILs, CD204-positive tumor-infiltrating macrophages, PD-L1-positive cells, and colony-stimulating factors were observed. This review discusses two topics: (i) the prognostic impact of TILs and (ii) predictive biomarkers for ICIs, to shed light on lymphocyte migration in four solid tumors, the urothelial carcinoma, renal cell carcinoma, prostate cancer, and retroperitoneal sarcoma.

scholarly journals Immunomodulating Therapies in Breast Cancer—From Prognosis to Clinical Practice

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4883
Author(s):  
Marcus Schmidt ◽  
Anne-Sophie Heimes
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Response To Chemotherapy ◽  
Infiltrating Lymphocytes

The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the “immune checkpoint”. Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as “brakes” on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.

scholarly journals Immunotherapy in Breast Cancer Patients: A Focus on the Use of the Currently Available Biomarkers in Oncology

2021 ◽  
Vol 21 ◽  
Author(s):  
Carmen Criscitiello ◽  
Elena Guerini-Rocco ◽  
Giulia Viale ◽  
Caterina Fumagalli ◽  
Elham Sajjadi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Randomized Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Optimal Timing ◽  
Breast Cancer Patients ◽  
Tumor Mutational Burden ◽  
Clinical Benefits

: Immune checkpoint inhibitors (ICIs) have remarkably modified the way solid tumors are managed, including breast cancer. Unfortunately, only a relatively small number of breast cancer patients significantly respond to these treatments. To maximize the immunotherapy benefit in breast cancer, several efforts are currently being put forward for the identification of i) the best therapeutic strategy (i.e. ICI monotherapy or in association with chemotherapy, radiotherapy, or other drugs); ii) the optimal timing for administration (e.g. early/advanced stage of disease; adjuvant/neoadjuvant setting); iii) the most effective and reliable predictive biomarkers of response (e.g. tumor-infiltrating lymphocytes, programmed death-ligand 1, microsatellite instability associated with mismatch repair deficiency, and tumor mutational burden). This article reviews the impacts and gaps in the characterization of immune-related biomarkers raised by clinical and translational research studies with immunotherapy treatments. Particular emphasis has been put on the documented evidence of significant clinical benefits of ICI in different randomized clinical trials, along with preanalytical and analytical issues in predictive biomarkers pathological assessment.

Effect of CTLA-4 overexpression on response to ipilimumab in melanoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 190-190
Author(s):  
Mary Nesline ◽  
Igor Puzanov ◽  
Marc S. Ernstoff ◽  
Sarabjot Pabla ◽  
Jeffrey M. Conroy ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Therapy Group ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Gene ◽  
Formalin Fixed Paraffin ◽  
Significant Difference ◽  
Formalin Fixed Paraffin Embedded ◽  
Infiltrating Lymphocytes

190 Background: CD8 positive tumor infiltrating lymphocytes (TILS) are highly associated with immune response and prognosis, and are also under investigation as a marker of response to checkpoint inhibitors. Given lack of predictive biomarkers for ipilimumab, growing number of trials for new indications for combination ipilimumab + nivolumab, and evidence to support therapeutic target overexpression as markers of response, we examined the role of CTLA-4 expression and TILS in response to ipilimumab and combination ipilimumab + nivolumab in melanoma. Methods: Formalin-fixed paraffin embedded melanoma samples taken prior to treatment by ipilimumab (n = 36) or combination ipilimumab + nivolumab (n = 10) were evaluated by a comprehensive immune gene expression profile to establish the relationship between CTLA-4 and CD8 and therapeutic response (RECIST v1.1). Results: Increased CTLA-4 expression was moderately associated with increased TILS (r2= .41, p = .004). This was observed in the monotherapy group (r2= .38, p = .02), and was higher in the smaller combination therapy group, though not statistically significant (r2= .59, p = .06). Higher levels of TILS were observed in responders who achieved clinical benefit from either regimen within 6 months (n = 20). No significant difference was observed between responders (M = 57.1, SD = 30.2) and nonresponders (M = 48.6, SD = 32.9); t(44) = -.895, p = .376. Lower levels of CTLA-4 were observed in responders who achieved clinical benefit from either regimen within 6 months. No significant difference was observed between responders (M = 54, SD = 35) and nonresponders (M = 38.7, SD = 26.8); t(44) = 1.70, p = .09. The ratio of TILS to CTLA-4 expression was higher in responders who achieved clinical benefit within 6 months (n = 20).No significant difference was observed between responders (M = 5.2, SD = 14.0) and nonresponders (M = 1.4, SD = 2.7); t(41) = -1.2, p = .212. Conclusions: While not statistically significant, CTLA-4 expression in melanoma patients treated with either ipilimumab or combination ipilimumab + nivolumab was lower in responders compared to nonresponders. This analysis does not support the concept that over-expression of CTLA-4 is a biomarker of response to anti-CTLA-4 therapy.

Abstract 575: PD-L1 positive tumor-infiltrating lymphocytes and mutational load in breast cancer

2017 ◽  
Author(s):  
Marcelo Sobral-Leite ◽  
Koen Van de Vijver ◽  
Magali Michaut ◽  
Hugo M. Horlings ◽  
Tesa M. Severson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Mutational Load ◽  
Infiltrating Lymphocytes

scholarly journals New Insights into the Role of the Immune Microenvironment in Breast Carcinoma

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Luis de la Cruz-Merino ◽  
Antonio Barco-Sánchez ◽  
Fernando Henao Carrasco ◽  
Esteban Nogales Fernández ◽  
Ana Vallejo Benítez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Exciting Field ◽  
Immune Synapse ◽  
New Concepts ◽  
Therapeutic Algorithms ◽  
Metastatic Setting ◽  
Bona Fide ◽  
Infiltrating Lymphocytes

Recently, immune edition has been recognized as a new hallmark of cancer. In this respect, some clinical trials in breast cancer have reported imppressive outcomes related to laboratory immune findings, especially in the neoadjuvant and metastatic setting. Infiltration by tumor infiltrating lymphocytes (TIL) and their subtypes, tumor-associated macrophages (TAM) and myeloid-derived suppressive cells (MDSC) seem bona fide prognostic and even predictive biomarkers, that will eventually be incorporated into diagnostic and therapeutic algorithms of breast cancer. In addition, the complex interaction of costimulatory and coinhibitory molecules on the immune synapse and the different signals that they may exert represent another exciting field to explore. In this review we try to summarize and elucidate these new concepts and knowledge from a translational perspective focusing on breast cancer, paying special attention to those aspects that might have more significance in clinical practice and could be useful to design successful therapeutic strategies in the future.

scholarly journals Integrating Immunotherapy with Chemotherapy: A New Approach to Drug Repurposing

2021 ◽  
Author(s):  
Hina Qayoom ◽  
Umar Mehraj ◽  
Shariqa Aisha ◽  
Shazia Sofi ◽  
Manzoor Ahmad Mir
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Breast Cancer Subtype ◽  
Drug Repurposing ◽  
Tumor Infiltrating Lymphocytes ◽  
Her2 Receptor ◽  
Infiltrating Lymphocytes

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking the three hormonal receptors namely estrogen receptor, progesterone receptor and HER2 receptor, and the only treatment option available for TNBC is chemotherapy. Chemotherapy lacks specificity since it acts on normal healthy cells as well resulting into secondary diseases in TNBC patients. In addition chemotherapy poses recurrence and relapse issues due to the development of chemoresistance among TNBC patients. Immunotherapy remarkably immune checkpoint inhibitors show a great therapeutic potential in TNBC. As TNBC contain an increased TILs (tumor infiltrating lymphocytes) infiltration making it more suitable as a therapeutic target anti-tumor immune strategy. Moreover, evidences have indicated that chemotherapy upregulates the anti-tumor immune response in TNBC. As a result, a combination of immunotherapy with chemotherapy may increase the overall relapse and recurrence free survival of TNBC patients. Therefore, in this chapter we will focus on how the immunotherapy works in TNBC, their effects and consequences. We will further be discussing the clinical studies and the importance of immune checkpoint inhibitors (ICIs) in combination with various therapeutic agents and target. Further, we will explore the processes involved.

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