In recent decades, the increasing interest in the field of immunotherapy has fostered an intense investigation of the breast cancer (BC) immune microenvironment. In this context, tumor-infiltrating ...lymphocytes (TILs) have emerged as a clinically relevant and highly reproducible biomarker capable of affecting BC prognosis and response to treatment. Indeed, the evaluation of TILs on primary tumors proved to be strongly prognostic in triple-negative (TN) BC patients treated with either adjuvant or neoadjuvant chemotherapy, as well as in early TNBC patients not receiving any systemic treatment, thus gaining level-1b evidence in this setting. In addition, a strong relationship between TILs and pathologic complete response after neoadjuvant chemotherapy has been reported in all BC subtypes and the prognostic role of higher TILs in early HER2-positive breast cancer patients has also been demonstrated. The interest in BC immune infiltrates has been further fueled by the introduction of the first immune checkpoint inhibitors in the treatment armamentarium of advanced TNBC in patients with PD-L1-positive status by FDA-approved assays. However, despite these advances, a biomarker capable of reliably and exhaustively predicting immunotherapy benefit in BC is still lacking, highlighting the imperative need to further deepen this issue. Finally, more comprehensive evaluation of immune infiltrates integrating both the quantity and quality of tumor-infiltrating immune cells and incorporation of TILs in composite scores encompassing other clinically or biologically relevant biomarkers, as well as the adoption of software-based and/or machine learning platforms for a more comprehensive characterization of BC immune infiltrates, are emerging as promising strategies potentially capable of optimizing patient selection and stratification in the research field. In the present review, we summarize available evidence and recent updates on immune infiltrates in BC, focusing on current clinical applications, potential clinical implications and major unresolved issues.
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, ...and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifications, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, class-specific toxicity profiles and correctly designing clinical trials to address these different issues.
The aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast ...cancer (TNBC).
Participating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic samples of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS; primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors.
We collected individual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age ( P = .001), larger tumor size ( P = .01), more nodal involvement ( P = .02), and lower histologic grade ( P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio χ
, 48.9 iDFS; P < .001; χ
, 55.8 D-DFS; P < .001; χ
, 48.5 OS; P < .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs ≥ 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%).
This pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org .
Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is ...available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing.
Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate FDR < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI 9-155, p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2- mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival.
This work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations.
In the light of recent advances in the immunotherapy field for breast cancer (BC) treatment, especially in the triple‐negative subtype, the identification of reliable biomarkers capable of improving ...patient selection is paramount, because only a portion of patients seem to derive benefit from this appealing treatment strategy. In this context, the role of programmed cell death ligand 1 (PD‐L1) as a potential prognostic and/or predictive biomarker has been intensively explored, with controversial results. The aim of the present review is to collect available evidence on the biological relevance and clinical utility of PD‐L1 expression in BC, with particular emphasis on technical aspects, prognostic implications, and predictive value of this promising biomarker.
Implications for Practice
In the light of the promising results coming from trials of immune checkpoint inhibitors for breast cancer treatment, the potential predictive and/or prognostic role of programmed cell death ligand 1 (PD‐L1) in breast cancer has gained increasing interest. This review provides clinicians with an overview of the available clinical evidence regarding PD‐L1 as a biomarker in breast cancer, focusing on both data with a possible direct impact on clinic and methodological pitfalls that need to be addressed in order to optimize PD‐L1 implementation as a clinically useful tool for breast cancer management.
摘要
鉴于人们在乳腺癌 (BC)(特别是三阴性亚型)治疗的免疫治疗领域取得的最新进展，确定能够改善患者选择的可靠生物标志物至关重要，因为仅有一部分患者似乎可以从这种具有吸引力的治疗策略中获益。在这种背景下，程序性细胞死亡配体 1 (PD‐L1) 作为一种潜在的预后和/或预测生物标志物的作用已被深入探索，并取得了具有争议性的结果。本报告旨在收集关于BC中的 PD‐L1 表达的生物相关性和临床实用性的有效证据，特别强调了技术因素、预后意义以及这种前景可期的生物标志物的预测价值。
实践意义:鉴于针对乳腺癌治疗的免疫检查点抑制剂的试验结果前景可期，程序性细胞死亡配体 1 (PD‐L1) 在乳腺癌中的潜在预测和/或预后作用已得到人们越来越多的重视。本综述为临床医生提供了关于 PD‐L1 作为乳腺癌生物标志物的现有临床证据的概述，重点关注可能对临床产生直接影响的数据和需要解决的方法学缺陷，从而对在临床上对乳腺癌管理十分有益的工具 PD‐L1 的应用进行优化。
This article presents a comprehensive review of the current evidence related to PD‐L1 testing in breast cancer and its use as a biomarker in prediction of response to immunotherapies.
The characterization of tumor biology and consequently the identification of prognostic and predictive biomarkers represent key issues for the translational research in breast cancer (BC). ...Phosphatase and tensin homolog deleted on chromosome ten (PTEN), the negative regulator of the proto-oncogenic phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, constitutes one of the most intriguing tumor suppressor genes involved in a series of biological processes, such as cell growth and survival, cellular migration and genomic stability. Loss of PTEN activity, due to protein, genetic or epigenetic alterations, was reported in up to almost half of BC cases. Recently, besides the role of PTEN in the pathogenesis of BC, investigated for over 20 years after the PTEN discovery, several retrospective and prospective translational studies, in the early and advanced setting, reported controversial results regarding the association between PTEN functional status and both clinical outcome and response to various BC treatments. This review explores the pre-clinical and clinical role of PTEN in BC with regard to the potential association of PTEN with prognosis and treatment response or resistance, underlying the complexity of the interpretation of available results and suggesting potential future perspectives.
Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the ...post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies.
Growing evidence suggests a clear role of the host immune system in HER2+ breast cancer. In addition, HER2+ breast cancer is generally considered more immunogenic than hormone receptor-positive ...(HR+)/HER2-, and specific molecular HER2+ subgroups (e.g. HER2-enriched disease) are more immunogenic than others (e.g. Luminal A or B). From a clinical perspective, the immune system plays a relevant prognostic role in HER2+ breast cancer and contributes to the therapeutic effects of trastuzumab. However, as more HER2-targeted agents become available, a better understanding of the role played by the immune system in modulating therapy response to different agents will be needed. Furthermore, the recent introduction in oncology of immune checkpoint inhibitors capable of unleashing anti-tumor immune response opens new possibilities for therapeutic combinations in HER2+ breast cancer. Here, we review the current pre-clinical and clinical data on the interplay between the immune system and HER2+ breast cancer, focusing on different HER2-targeted treatments and the biological heterogeneity that exists within HER2+ disease. Finally, we discuss new therapeutic approaches exploiting the immune system to increase activity or revert resistance to HER2-targeted agents.
Young women with germline
mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients ...with
mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline
mutations.
This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline
mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors.
Of 1,252 patients with germline
mutations (
, 811 patients;
, 430 patients;
, 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio HR, 0.87; 95% CI, 0.61 to 1.23;
= .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56;
= .66) were observed between the pregnancy and nonpregnancy cohorts.
Pregnancy after breast cancer in patients with germline
mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with
-mutated breast cancer interested in future fertility.
PDF
