Tumor-Associated Lymphocytes As an Independent Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer

2010 ◽  
Vol 28 (1) ◽  
pp. 105-113 ◽  
Author(s):  
Carsten Denkert ◽  
Sibylle Loibl ◽  
Aurelia Noske ◽  
Marc Roller ◽  
Berit Maria Müller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Validation Cohort ◽  
Independent Predictor ◽  
Pathologic Complete Response ◽  
Marker Genes ◽  
Cancer Tissue ◽  
Chemotherapy Response ◽  
Training Cohort ◽  
Response To Neoadjuvant Chemotherapy

Purpose Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. Methods We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell–related markers CD3D and CXCL9 with pCR. Conclusion The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.

Evaluation of tumor-associated lymphocytes as a predictor of response to neoadjuvant chemotherapy in breast cancer: Results from the GeparDuo and GeparTrio trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11054-11054
Author(s):  
C. Denkert ◽  
S. Loibl ◽  
A. Noske ◽  
B. M. Müller ◽  
R. Kronenwett ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Inflammatory Infiltrate ◽  
Inflammatory Marker ◽  
Strong Predictor ◽  
Complete Response ◽  
Multivariate Regression Analysis ◽  
Marker Genes ◽  
Cancer Tissue ◽  
Chemotherapy Response

11054 Background: Preclinical investigations suggest an involvement of the immune system in chemotherapy response; however, this contribution has not been validated in prospective clinical trials so far. Methods: We investigated the inflammatory infiltrate in a total of 1058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline-taxane-based studies. As a training cohort, we used 218 core biopsies from the GeparDuo study. The results were validated in a completely independent cohort of 840 samples from the GeparTrio study. In addition, molecular parameters of lymphocyte recruitment and activation in breast cancer tissue were evaluated by kinetic PCR. Results: While the overall rate of pathological complete response (pCR) in the GeparDuo cohort was 12.8%, it was significantly increased to 42.7% in the tumors with more than 60% intratumoral or stromal lymphocytes. In a multivariate regression analysis, the percentage of intratumoral lymphocytes (iTu-Ly) was an independent significant parameter for pCR (P = 0.013) in the GeparDuo cohort. In the validation set from the GeparTrio trial, the inflammatory infiltrate was a strong predictor of pCR in univariate (P < 0.0005) and multivariate logistic regression (P < 0.0005). For tumors with 60% iTu-Ly the pCR rate was 40% with an odds ratio (OR) of 8.5 (4.0–18.2) which were similar to those values in hormone receptor negative samples (pCR: 36%; OR: 6.0 [4.0–9.1]). The expression of inflammatory marker genes and chemokines related to B and T infiltration in tumor tissue was significantly linked to the presence of a lymphocytic infiltrate and mRNA expression data showed a significant association of T cell markers with a pCR (P < 0.003). Conclusions: An increased lymphocytic inflammatory infiltrate in breast cancer is a new independent predictor of response to anthracyclin-taxane neoadjuvant chemotherapy and might be helpful to identify patients with benefit from cytotoxic chemotherapy. [Table: see text]

Value of Ki-67 in prediction of response to neoadjuvant chemotherapy in breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e12025-e12025
Author(s):  
Kwanil Kim ◽  
Kyunghee Lee ◽  
Heungkyu Park
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Predictive Factor ◽  
Response Rate ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Chemotherapy Response ◽  
Her2 Positive ◽  
Ki 67 ◽  
Response To Neoadjuvant Chemotherapy

e12025 Background: The expression of the human Ki-67 protein has been described as being associated with cellular proliferative activity. The objective of this study is to assess the potential value of Ki-67 for the prediction of therapeutic response after neoadjuvant chemotherapy in breast cancer. Methods: Sixty-eight patients who underwent anthracyclin based neoadjuvant chemotherapy between 2007 and 2012 were included for this study. The chemotherapy response was evaluated by comparing the pre- and post-neoadjuvant chemotherapy tumor size on radiologic imaging study with the tumor size at pathologic specimens according to RECIST (response evaluation criteria in solid tumors) version 1.1. We analyzed immunohistochemical(ER, PR, HER2, Ki-67, p53) profiles from both pre-neoadjuvant core biopsy and postoperative specimens to find their correlations with chemotherapy response. Results: Ten patients(14.7%) achieved pathologic complete response(pCR), 38 patients(55.9%) had pathologic partial response(pPR) and 20 patients(29.4%) had pathologic stable disease(pSD). The mean Ki-67 value of tumors with pCR was 61.0%, the Ki-67 value of tumors with pPR was 35.9%, and the Ki-67 value of tumors with pSD was 21.0%(p = 0.013). The analysis of Ki-67 values of the patients also showed that 25% of Ki-67 level is a reasonable cut-off value for defining higher Ki-67 level. In subgroup analysis, the higher Ki-67 level was significant factor of the response to neoadjuvant chemotherapy, especially in ER negative patients(p = 0.009) and HER2 negative patients(p = 0.009). In addition, the analaysis of response group showed that ER negative(p = 0.027), HER2 positive(p = 0.048), and higher Ki-67 level(p = 0.002) were predictive indicators of complete response. Conclusions: The higher Ki-67 level of breast cancer tissue may effectively indicate the higher response rate to chemotherapy and also the higher complete response rate. The results of our study suggest that the Ki-67 value before neoadjuvant chemotherapy is a predictive factor for the response to neoadjuvant chemotherapy. Moreover, the Ki-67 is a predictive factor of the pathologic complete response especially in patients with ER negative or HER2 positive.

scholarly journals Relationship Between Obesity and Pathologic Response to Neoadjuvant Chemotherapy Among Women With Operable Breast Cancer

2008 ◽  
Vol 26 (25) ◽  
pp. 4072-4077 ◽  
Author(s):  
Jennifer K. Litton ◽  
Ana M. Gonzalez-Angulo ◽  
Carla L. Warneke ◽  
Aman U. Buzdar ◽  
Shu-Wan Kau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Patients ◽  
Pathologic Complete Response ◽  
Operable Breast Cancer ◽  
Obese Patients ◽  
Breast Cancer Patients ◽  
Significant Difference ◽  
Response To Neoadjuvant Chemotherapy

Purpose To understand the mechanism through which obesity in breast cancer patients is associated with poorer outcome, we evaluated body mass index (BMI) and response to neoadjuvant chemotherapy (NC) in women with operable breast cancer. Patients and Methods From May 1990 to July 2004, 1,169 patients were diagnosed with invasive breast cancer at M. D. Anderson Cancer Center and received NC before surgery. Patients were categorized as obese (BMI ≥ 30 kg/m2), overweight (BMI of 25 to < 30 kg/m2), or normal/underweight (BMI < 25 kg/m2). Logistic regression was used to examine associations between BMI and pathologic complete response (pCR). Breast cancer–specific, progression-free, and overall survival times were examined using the Kaplan-Meier method and Cox proportional hazards regression analysis. All statistical tests were two-sided. Results Median age was 50 years; 30% of patients were obese, 32% were overweight, and 38% were normal or underweight. In multivariate analysis, there was no significant difference in pCR for obese compared with normal weight patients (odds ratio [OR] = 0.78; 95% CI, 0.49 to 1.26). Overweight and the combination of overweight and obese patients were significantly less likely to have a pCR (OR = 0.59; 95% CI, 0.37 to 0.95; and OR = 0.67; 95% CI, 0.45 to 0.99, respectively). Obese patients were more likely to have hormone-negative tumors (P < .01), stage III tumors (P < .01), and worse overall survival (P = .006) at a median follow-up time of 4.1 years. Conclusion Higher BMI was associated with worse pCR to NC. In addition, its association with worse overall survival suggests that greater attention should be focused on this risk factor to optimize the care of breast cancer patients.

Multi-gene prognostic assays and age-related differences in prediction of pathologic complete response to neoadjuvant chemotherapy and survival in breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 591-591
Author(s):  
Kent Hanson ◽  
Kent Hoskins ◽  
Naomi Yu Ko ◽  
Gregory Sampang Calip
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Neoadjuvant Chemotherapy ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Genomic Testing ◽  
Younger Women ◽  
Her2 Breast Cancer ◽  
Response To Neoadjuvant Chemotherapy ◽  
Overall Mortality

591 Background: Multi-gene testing of primary breast tumors in early-stage breast cancer is used to classify the risk of developing distant metastases and predict the benefit of adjuvant chemotherapy. The association between the tumor genomic prognostic score (GPS) and response to neoadjuvant chemotherapy (NACT) and survival is not well characterized. Our objective was to describe the association between GPS and rates of pathologic complete response (PCR) and subsequent overall survival among women with or without PCR. Methods: We utilized the National Cancer Database to perform a hospital-based, retrospective cohort study of breast cancer patients ages 18 years and older. We included women diagnosed with first primary stages I-III hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer who received NACT and surgery between 2010 and 2017. Women were categorized as having low (0-10 or 200), intermediate (11-25 or 300), or high-risk (25-199 or 400) GPS based on OncotypeDX or MammaPrint scores. Multivariable modified Poisson regression models with robust error variance were used to estimate the crude and adjusted relative risk and 95% confidence intervals (CI) for PCR associated with GPS groups. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) and 95% CI for associations between the GPS and overall survival (OS) in women who did and did not have PCR. Results: A cohort of 3,446 women (mean [SD] age, 56.7 [12.0] years; median [interquartile range] follow-up of 47 [31-68] months) who received genomic testing and neoadjuvant chemotherapy were included in our analysis, of which 935 (27%) were low risk, 1,357 (39%) intermediate risk, and 1,154 (34%) high risk GPS. The relative risk of PCR for all women with high GPS was 1.81 (95% CI, 1.47-2.22; p < 0.001) in crude models and 1.49 (95% CI, 1.16-1.92; p = 0.002) after full adjustment compared to low GPS. Across all models, having a high GPS was significantly associated with achieving PCR in younger women ( < 65 years). In women ages ≥65 years, the association between GPS and PCR was not predictive nor statistically significantly. Among women with no response or partial response to NACT, high GPS was associated with a significantly increased risk of overall mortality (HR 2.41; 95% CI, 1.61-3.60; p < 0.001) compared to low GPS. Conversely, in women who did achieve PCR, GPS was not predictive of overall mortality across all age groups. Conclusions: In women with HR+/HER2- breast cancer, high risk GPS was predictive of PCR following NACT, primarily in younger women ( < 65 years). Our findings also indicated GPS was associated with lower OS in high-risk patients who do not achieve PCR and unpredictive of OS in those without PCR. The utility of tumor genomic testing in the neoadjuvant setting needs further investigation.

Chemotherapy-elicited exosomal miR-378a-3p and miR-378d to promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12615-e12615
Author(s):  
Jin Zhang
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Neoadjuvant Chemotherapy ◽  
Pathologic Complete Response ◽  
Chemotherapeutic Agents ◽  
Cell Counting ◽  
Chemotherapy Response ◽  
Mouse Tumor ◽  
Response To Chemotherapy ◽  
Serum Exosomes

e12615 Background: Not all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chemotherapy-resistant phenotype in tumors. However, the role of BC chemo-elicited exosomes in regulating chemoresistance is poorly understood. Methods: Using commercial kits, serum exosomes were extracted from patients before neoadjuvant chemotherapy, after one cycle of chemotherapy and after four cycles of chemotherapy consisting of doxorubicin (DOX) and paclitaxel (PTX). Their miRNAs were sequenced, and the correlation between the sequencing results and chemotherapy effects was further verified by RT-qPCR using patient serum exosomes. Cell Counting Kit-8 (CCK-8) was used to detect chemosensitivity. Stemness was assessed by CD44+/CD24- population analysis and mammosphere formation assays. Chromatin immunoprecipitation (ChIP) experiments were performed to verify the binding of signal transducer and activator of transcription 3 (STAT3) to the promoter of miRNAs. Results: Here, we provide clinical evidence that chemotherapy-elicited exosomal miR-378a-3p and miR-378d are closely related to the chemotherapy response and that exosomes produced by BC cells after stimulation with DOX or PTX deliver miR-378a-3p and miR-378d to neighboring cells to activate WNT and NOTCH stemness pathways and induce drug resistance by targeting Dickkopf 3 (DKK3) and NUMB. In addition, STAT3, which is enhanced by zeste homolog 2 (EZH2), bound to the promoter regions of miR-378a-3p and miR-378d, thereby increasing their expression in exosomes. More importantly, chemotherapeutic agents combined with the EZH2 inhibitor tazemetostat reversed chemotherapy-elicited exosome induced drug resistance in a nude mouse tumor xenograft model. Conclusions: This study revealed a novel mechanism of acquired chemoresistance whereby chemotherapy activates the EZH2/STAT3 axis in BC cells, which then secrete chemotherapy-elicited exosomes enriched in miR-378a-3p and miR-378d. These exosomes are absorbed by chemotherapy-surviving BC cells, leading to activation of WNT and NOTCH stem cell pathways via the targeting of DKK3 and NUMB and subsequently resulting in drug resistance. Therefore, blocking this adaptive mechanism during chemotherapy may reduce the development of chemotherapy resistance and maximize the therapeutic effect.

Association of the ABCB1 C3435T gene polymorphism (SNPs) with the response to neoadjuvant chemotherapy in women with breast cancer in northeastern Brazil

2020 ◽  
Vol 19 (2) ◽  
pp. 305
Author(s):  
Diego de Aragão Bezerra De Aragão Bezerra ◽  
José Juvenal Linhares ◽  
Emmanuelle Coelho Noronha ◽  
Kaio César Simiano Tavares ◽  
André Saraiva Leão Marcelo Antunes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Gene Polymorphism ◽  
Cancer Susceptibility ◽  
Northeastern Brazil ◽  
P Value ◽  
Chemotherapy Response ◽  
Female Population ◽  
C3435t Polymorphism ◽  
Response To Neoadjuvant Chemotherapy

<p><strong>Introduction</strong>: breast cancer (BC) is the most common tumor and the leading cause of cancer-related death among the female population<br />worldwide. Polymorphisms genetics of ABCB1 gene contributed to breast cancer susceptibility and interindividual differences in<br />chemotherapy response. <strong>Objectives</strong>: to evaluate the association between the ABCB1 C3435T gene polymorphism (SNPs) with the<br />response to neoadjuvant chemotherapy in women with breast cancer. <strong>Methodology</strong>: this study included 32 female patients who<br />received neoadjuvant chemotherapy. The polymorphisms were genotyped through real-time allele-specific polymerase chain reaction<br />(PCR). The statistical analysis was performed using the Fisher’s exact test or Pearson’s chi-square test in the Statistical Package for<br />Social Sciences (SPSS) version 20.0 software. <strong>Results</strong>: the genotypes found for the C3435T polymorphism were in Hardy-Weinberg<br />equilibrium and their genotypic distributions were CC= 10 (31.1%), CT= 14 (43.8%), and TT= 08 (25.0%) with χ2: 0.86 and p-value &gt;<br />0.05. Allele frequencies were C = 0.54 and T = 0.46. There were no significant statistical differences between genotypes considering the<br />response to neoadjuvant chemotherapy and immunohistochemistry; the presence of the T allele was associated with worsen axillary<br />status response to neoadjuvant chemotherapy. <strong>Conclusion</strong>: no definite association between the presence of C3435T polymorphism<br />and the response to neoadjuvant chemotherapy was observed. Further studies in Brazil involving larger samples will contribute to<br />validating the results of this study.</p>

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