High expression of pdl-1 in patients with triple negative breast cancer with residual tumor burden after neoadjuvant chemotherapy.

Abstract Background Studies on PD-L1 expression in breast cancer have gained importance in recent years, especially in triple-negative breast cancer (TNBC). Our aim was to analyze the differential expression of PD-L1 to explore its correlation with response to neoadjuvant chemotherapy (NACT) and patient survival. Methods PD-L1 expression was evaluated immunohistochemically (Ventana SP263 clone kit) by staining tumor specimen. PD-L1 positivity was defined as membranous staining > 1%, > 5%, > 10%, and > 20% on either tumor cell (TC) and /or immune cell (IC). Results Fifty patients with locally advanced TNBC, who had a partial response to NACT, were included in the study. PD-L1 staining was observed in TCs in 25 patients (50%) and in ICs in 23 patients (46%) when PD-L1 > 1% was considered positive. Patients with PD-L1 positivity on ICs were more likely to respond to chemotherapy as measured by “MD Anderson Cancer Center Residual Cancer Burden Index” (14/22, 63.6% vs. 10/27, 37%, p = 0.064). The 5-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 46.3% and 51.4%, respectively. A high (> 20%) tumoral PD-L1 positivity was associated with a better DFS and DSS. Conclusions Studies in the literature mostly focused on PD-L1 expression in inflammatory cells. However, our results suggest that patients with a high PD-L1 expression on TCs were more likely to have a better outcome. Since patients with residual tumor burden who express PD-L1 on TILs were more likely to respond to NACT, an immune checkpoint inhibitor therapy in addition to NACT would be an important option for TNBC with locally advanced disease.

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Significance of Tumor-Infiltrating Lymphocytes and the Expression of Topoisomerase IIα in the Prediction of the Clinical Outcome of Patients with Triple-Negative Breast Cancer after Taxane-Anthracycline-Based Neoadjuvant Chemotherapy

Chemotherapy ◽

10.1159/000470900 ◽

2017 ◽

Vol 62 (4) ◽

pp. 246-255 ◽

Cited By ~ 4

Author(s):

Nanyan Rao ◽

Jiayin Qiu ◽

Jiannan Wu ◽

Hong Zeng ◽

Fengxi Su ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Independent Predictor ◽

Tumor Infiltrating Lymphocytes ◽

High Expression ◽

Topoisomerase Iiα ◽

Infiltrating Lymphocytes ◽

High Infiltration

Purpose: The aim of this study was to determine factors able to predict chemotherapeutic responses and clinical outcomes in patients with triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). Methods: Fifty-two TNBC patients on taxane-anthracycline-based NAC were included. The expression of Ki67, topoisomerase IIα (TOPOIIα), and p53, as well as the presence of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs were evaluated in biopsy specimens by immunohistochemistry. The expression of Ki67, TOPOIIα, and p53, as well as CD4 and CD8 in TILs was calculated according to the pathological response to NAC, disease-free survival (DFS), and overall survival (OS). Results: Fourteen (26.9%) TNBC patients demonstrated a pathological complete response (pCR). According to univariate analyses, significant factors associated with pCR were high infiltration of CD4+ TILs (p = 0.004), high infiltration of CD8+ TILs (p = 0.010), and high expression of topoisomerase IIα (TOPOIIα) (p = 0.006). CD4+ TILs and TOPOIIα were significantly positively correlated with CD8+ TILs. Multivariate analyses indicated that TOPOIIα was an independent predictor of pCR. Although TNBC patients with high infiltration of CD4+ TILs, CD8+ TILs, or with high expression of TOPOIIα exhibited a significantly good 5-year DFS, only TNBC patients with a high infiltration of CD8+ TILs exhibited significantly positive 5-year OS probabilities. Conclusion: Our study demonstrated that CD4+ TILs and TOPOIIα in pretreated cancer tissues were significantly correlated with CD8+ TILs. CD4+ TILs, CD8+ TILs, and TOPOIIα expression were predictors of pCR and 5-year DFS of TNBC patients who were treated with NAC, and TOPOIIα was an independent predictor of pCR. CD8+ TILs were a key factor in the prediction of good 5-year OS rates of TNBC patients after taxane-anthracycline-based NAC.

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Prognostic and predictive value of circulating tumor DNA during neoadjuvant chemotherapy for triple negative breast cancer

Scientific Reports ◽

10.1038/s41598-020-71236-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Luca Cavallone ◽

Adriana Aguilar-Mahecha ◽

Josiane Lafleur ◽

Susie Brousse ◽

Mohammed Aldamry ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Predictive Value ◽

Triple Negative ◽

Residual Tumor ◽

Complete Response ◽

Circulating Tumor Dna ◽

Droplet Pcr ◽

Tumor Dna

Abstract Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. To evaluate the predictive and prognostic values of circulating tumor DNA (ctDNA) in this setting, we analyzed tumor and serial bloods from 26 TNBC patients collected prior, during, and after NAC. Individual digital droplet PCR assays were developed for 121 variants (average 5/patient) identified from tumor sequencing, enabling ctDNA detection in 96% of patients at baseline. Mutant allele frequency at baseline was associated with clinical characteristics. Levels drastically fell after one cycle of NAC, especially in patients whose tumors would go on to have a pathological complete response (pCR), but then rose significantly before surgery in patients with significant residual tumor at surgery (p = 0.0001). The detection of ctDNA early during treatment and also late at the end of NAC before surgery was strongly predictive of residual tumor at surgery, but its absence was less predictive of pCR, especially when only TP53 variants are considered. ctDNA detection at the end of neoadjuvant chemotherapy indicated significantly worse relapse-free survival (HR = 0.29 (95% CI 0.08–0.98), p = 0.046), and overall survival (HR = 0.27 95% CI 0.075–0.96), p = 0.043). Hence, individualized multi-variant ctDNA testing during and after NAC prior to surgery has prognostic and predictive value in early TNBC patients.

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TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer

BMC Cancer ◽

10.1186/s12885-021-08054-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Neslihan Cabioglu ◽

Semen Onder ◽

Gizem Oner ◽

Hüseyin Karatay ◽

Mustafa Tukenmez ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Immune Checkpoint ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Expression Patterns ◽

Locally Advanced ◽

High Expression ◽

Chemotherapy Response

Abstract Background The expression of immune checkpoint receptors (ICRs) on tumor-infiltrating lymphocytes (TILs) is associated with better response to immunotherapies via immune checkpoint inhibitors. Therefore, we investigated various ICR expressions on TILs in patients with locally advanced triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). Methods Expressions of ICRs were examined immunohistochemically in surgical specimens (n = 61) using monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, and CTLA-4. Positivity was defined as staining > 1% on TILs. Results The median age was 49 (24–76) years. The majority of patients were clinically T3–4 (n = 31, 50.8%) and clinically N1–3 (n = 58, 95.1%) before NAC. Of those, 82% were found to have CTLA-4 positivity, whereas PD1, PDL-1, LAG3, and TIM-3 expressions on TILs were 62.3, 50.9, 26.2, and 68.9%. A high expression of CTLA-4 was found to be associated with a better chemotherapy response (OR = 7.94, 95% CI: 0.9–70.12, p = 0.06), whereas TIM-3 positivity was contrarily associated with a worse chemotherapy response (OR = 0.253, 95% CI: 0.066–0.974, p = 0.047) as measured by the MDACC Residual Cancer Burden Index. At a 47-month follow-up, ypN0 (DFS; HR = 0.31, 95% CI: 0.12–0.83, p = 0.02 and DSS; HR = 0.21, 95% CI: 0.07–0.62, p = 0.005) and CTLA-4 high expression on TILs (DFS; HR = 0.38, 95% CI: 0.17–0.85, p = 0.019 and DSS; HR = 0.34, 95% CI: 0.15–0.78, p = 0.01) were found to be associated with improved survival. Conclusions These findings demonstrate that CTLA-4, PD-1, PDL-1, and TIM-3 were highly expressed in TNBC. Based on these high expression patterns, further studies directed towards combined therapies are warranted in advanced TNBC in future.

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Recurrence biomarkers of triple negative breast cancer treated with neoadjuvant chemotherapy and anti-EGFR antibodies

npj Breast Cancer ◽

10.1038/s41523-021-00334-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Nina Radosevic-Robin ◽

Pier Selenica ◽

Yingjie Zhu ◽

Helen H. Won ◽

Michael F. Berger ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Neoadjuvant Chemotherapy ◽

Mhc Class Ii ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

High Expression ◽

Rapid Progression ◽

Metastatic Recurrence ◽

Nanostring Technology

AbstractTo find metastatic recurrence biomarkers of triple-negative breast cancer (TNBC) treated by neoadjuvant chemotherapy and anti-EGFR antibodies (NAT), we evaluated tumor genomic, transcriptomic, and immune features, using MSK-IMPACT assay, gene arrays, Nanostring technology, and TIL assessment on H&E. Six patients experienced a rapid fatal recurrence (RR) and other 6 had later non-fatal recurrences (LR). Before NAT, RR had low expression of 6 MHC class I and 13 MHC class II genes but were enriched in upregulated genes involved in the cell cycle-related pathways. Their TIL number before NAT in RR was very low (<5%) and did not increase after treatment. In post-NAT residual tumors, RR cases showed high expression of SOX2 and CXCR4. Our results indicate that high expression of cell cycle genes, combined with cold immunological phenotype, may predict strong TNBC resistance to NAT and rapid progression after it. This biomarker combination is worth validation in larger studies.

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Direct comparison of magnetic resonance imaging and pathological shrinkage patterns of triple-negative breast cancer after neoadjuvant chemotherapy

10.21203/rs.3.rs-23891/v1 ◽

2020 ◽

Author(s):

Katsuhiro Yoshikawa ◽

Mitsuaki Ishida ◽

Naoki Kan ◽

Hirotsugu Yanai ◽

Koji Tsuta ◽

...

Keyword(s):

Breast Cancer ◽

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Tumor Size ◽

Triple Negative ◽

Residual Tumor ◽

Predictive Equation ◽

Resonance Imaging

Abstract Background We aimed to investigate the usefulness of magnetic resonance imaging (MRI) and histopathological shrinkage patterns to formulate a predictive equation for estimating residual tumor size after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients.Methods We enrolled 34 TNBC patients who underwent MRI before and after NAC. The MRI and histopathological shrinkage patterns were analyzed and classified into five categories—types I and II (concentric shrinkage without or with surrounding lesions, respectively), type III (shrinkage with residual multinodular lesions), type IV (diffuse contrast enhancement in the entire quadrant), and non-visualization. The residual tumor sizes following MRI and histopathological examination were also compared.Results The most common MRI and histopathological shrinkage pattern was type I (41.2% and 38.2%, respectively), followed by non-visualization (26.5% and 32.4%, respectively); the concordance rate between MRI and histopathological shrinkage patterns was 41.2%. There was a strong correlation between MRI tumor size and pathological tumor size (r = 0.89). Based on these findings, a predictive equation for pathological tumor size was formulated as follows: pathological tumor size \left(mm\right) = 1.1502 \times \left(MRI tumor size \right[mm\left]\right) + 8.4277.Conclusions Our equation may aid accurate preoperative assessment. Further studies are needed to determine its predictive value and applicability.

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Patterns of Relapse Related to High Expression of Ki-67 After Neoadjuvant Chemotherapy in Triple Negative Breast Cancer

Journal of Gynecology and Obstetrics ◽

10.11648/j.jgo.20210905.11 ◽

2021 ◽

Vol 9 (5) ◽

pp. 139

Author(s):

Gines Hernandez-Cortes ◽

Javier Hornedo ◽

Raquel Murillo ◽

Ricardo Sainz De La Cuesta ◽

Lucia Gonzalez-Cortijo

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

High Expression ◽

Ki 67

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Prognostic Influence of Residual Tumor-Infiltrating Lymphocyte Subtype After Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.636716 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jesse Lopes da Silva ◽

Lucas Zanetti de Albuquerque ◽

Fabiana Resende Rodrigues ◽

Guilherme Gomes de Mesquita ◽

Priscila Valverde Fernandes ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Immune Cell ◽

Clinical Stage ◽

Residual Tumor ◽

Tissue Microarrays ◽

Curative Surgery

ObjectiveThis study aimed to examine the prevalence and prognostic role of tumor microenvironment (TME) in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) through immunohistochemical characterization.MethodsThe internal database of the Brazilian National Cancer Institute for women diagnosed with TNBC who underwent NACT and thereafter curative surgery between January 2010 and December 2014 was queried out. Core biopsy specimens and tissue microarrays containing surgical samples of TNBC from 171 and 134 women, respectively, were assessed by immunohistochemistry for CD3, CD4, CD8, CD14, CD56, CD68, CD117, FOXP3, PD-1, PD-L1, and PD-L2. Immune cell profiles were analyzed and correlated with response and survival.ResultsMean age was 50.5 years, and most cases were clinical stage III [143 cases (83.6%)]. According to the multivariate analysis, only Ki67 and clinical stage significantly influenced the pattern of response to systemic treatment (p = 0.019 and p = 0.033, respectively). None of the pre-NACT IHC markers showed a significant association with event-free survival (EFS) or overall survival (OS). As for post-NACT markers, patients with high CD14 had significantly shorter EFS (p = 0.015), while patients with high CD3 (p = 0.025), CD4 (p = 0.025), CD8 (p = 0.030), CD14 (p = 0.015), FOXP3 (p = 0.005), high CD4/FOXP3 (p = 0.034), and CD8/FOXP3 (p = 0.008) showed longer EFS. Only high post-NACT CD4 showed significantly influenced OS (p = 0.038).ConclusionThe present study demonstrated that the post-NACT TIL subtype can be a determining factor in the prognosis of patients with TNBC.

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Adjuvant Capecitabine in Triple Negative Breast Cancer with Residual Tumor after Neoadjuvant Chemotherapy: A Case Series

Annals of Oncology ◽

10.1093/annonc/mdx621.002 ◽

2017 ◽

Vol 28 ◽

pp. ix96

Author(s):

Miyuki Uchiyama ◽

Hiromichi Nakajima ◽

Jun Masuda ◽

Yukinori Ozaki ◽

Chihiro Kondo ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Case Series ◽

Residual Tumor

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Direct comparison of magnetic resonance imaging and pathological shrinkage patterns of triple-negative breast cancer after neoadjuvant chemotherapy

10.21203/rs.3.rs-23891/v2 ◽

2020 ◽

Author(s):

Katsuhiro Yoshikawa ◽

Mitsuaki Ishida ◽

Naoki Kan ◽

Hirotsugu Yanai ◽

Koji Tsuta ◽

...

Keyword(s):

Breast Cancer ◽

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Tumor Size ◽

Triple Negative ◽

Residual Tumor ◽

Predictive Equation ◽

Resonance Imaging

Abstract Background: We aimed to investigate the usefulness of magnetic resonance imaging (MRI) and histopathological shrinkage patterns to formulate a predictive equation for estimating residual tumor size after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients. Methods: We enrolled 34 TNBC patients who underwent MRI before and after NAC. The MRI and histopathological shrinkage patterns were analyzed and classified into five categories—types I and II (concentric shrinkage without or with surrounding lesions, respectively), type III (shrinkage with residual multinodular lesions), type IV (diffuse contrast enhancement in the entire quadrant), and non-visualization. The residual tumor sizes following MRI and histopathological examination were also compared.Results: The most common MRI and histopathological shrinkage pattern was type I (41.2% and 38.2%, respectively), followed by non-visualization (26.5% and 32.4%, respectively); the concordance rate between MRI and histopathological shrinkage patterns was 41.2%. There was a strong correlation between MRI tumor size and pathological tumor size (r = 0.89). Based on these findings, a predictive equation for pathological tumor size was formulated as follows: BConclusions: Our equation may aid accurate preoperative assessment. Further studies are needed to determine its predictive value and applicability.

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