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Methods: We analyzed TIL CD4 and CD8 subpopulations in BC patients treated with sequential anthracyclines and taxanes NC. A tissue microarray with paired pre- and post- NC biopsies was built, and immunohistochemically stained for CD4 and CD8. Tumor area- adjusted morphometric analysis was performed with Image J software after slide scanning and digitalization (results expressed as TIL count/mm2 ). Statistical analysis was done with SPSS 15.0 software. Results: We included 121 consecutive patients. Clinical stages: 15,7% IIA, 28% IIB, 33,3% IIIA, 6,6% IIIB, 16,5% IIIC. Histology: 93% ductal infiltrating carcinomas. Phenotypic classification by immunohistochemistry (IHC): 50,4% RE+ and/or RP+ and HER2NEU negative; 13,2% RE+ and/or RP+ and HER2NEU positive; 9,9% RE- and RP- and HER2NEU positive; 21,5% RE- and RP- and HER2NEU negative; 5% non-classifiable. Treatment: 80.2% AC x 4 courses followed by docetaxel x 4 courses. Pathological response: complete pathologic response (pCR) rate was 17,4% (primary tumor pCR: 20,7%; axillary pCR: 35,5%). After a median follow up of 52 months neither overall survival (OS) nor disease free survival (DFS) has been reached. Mean pre-chemotherapy CD4 count was 59,98 (± 107,53, SD). We did not found any association with clinical or pathologic tumor characteristic at diagnosis (stage, grade, hormonosensitivity, HER2NEU overexpression or IHC tumor classification). Mean CD4 count was significantly higher in patients achieving pCR than in patients without pCR (112,43 vs 49,91 CD4/mm²; p 0,009). Mean pre-chemotherapy CD8 count was 16,23 (± 56,96, SD) and was higher in grade 3 carcinomas (32,83 vs 22,37; p < 0,03); no other association with tumor characteristics or with pCR was found. Mean variation in CD4 after NC (=postNC -- preNC count) was 47,35 (± 104,49) CD4/mm2 , and it was larger in patients with pCR (102,01 vs 36,85 CD4/mm² ; p < 0,010). An opposite non-significant trend was observed for CD8 variation after NC (pCR: 39,42 vs non-pCR: 20,22, p < 0,14). To integrate the influence of both CD4 and CD8 on response to chemotherapy, the predictive value of pre-treatment ratio between CD4 and CD8 counts (CD4/CD8) was analyzed. We found a highly significant difference for CD4/CD8 between patients with and without pCR to NC (103 vs 17; p 0.002). Multivariate logistic regression analysis demonstrated that only a high pretreatment CD4/CD8 ratio (p < 0,006), hormone sensitivity (p < 0,03) and Her2 overexpression (p < 0.01) independently predicted pCR after NC. No differences in overall or disease-free survival were demonstrated for high vs. low CD4/CD8 pre-NC ratio. Conclusion: A high pretreatment CD4/CD8 ratio independently predicted pathological complete response in patients with invasive breast cancer receiving anthracyclines and taxanes NC. Our results support the contribution of tumor microenvironment immunologic response to chemotherapy effects on breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: The prognostic utility and biological correlates of neutrophil to lymphocyte ratio (NLR), a potential biomarker of the balance between immune response and the inflammatory status, are still uncertain in breast cancer (BC)., Methods: We analysed a cohort of 959 women with early breast cancer, mostly treated with neoadjuvant or adjuvant chemotherapy. Clinical and pathological data, survival, NLR (continuous and categorical) and stromal tumor infiltrating lymphocytes (sTIL) were evaluated., Results: NLR was only weakly associated with Ki67, while no association was found for grade, histology, immunohistochemical subtype or stage. Lymphocyte infiltration of the tumor did not correlate with NLR (Rho: 0.05, p = 0.30). These results were similar in the whole group and across the different BC subtypes, with no differences in triple negative BC. Relapse free interval (RFI), breast cancer specific survival (BCSS) and overall survival (OS) changed according to pre-treatment NLR neither in the univariate nor in the multivariate Cox models (RFI: HR 0.948, p = 0.61; BCSS: HR 0.920, p = 0.57; OS: HR 0.96, p = 0.59)., Conclusion: These results question the utility of NLR as a prognostic biomarker in early breast cancer and suggest the lack of correlation of NLR with tumor microenvironment immune response., (© 2024. The Author(s).)

Background: Up to 30% of breast cancer (BC) patients treated with neoadjuvant chemotherapy (NCT) will relapse. Our objective was to analyze the predictive capacity of several markers associated with immune response and cell proliferation combined with clinical parameters., Methods: This was a single-center, retrospective cohort study of BC patients treated with NCT (2001-2010), in whom pretreatment biomarkers were analyzed: neutrophil-to-lymphocyte ratio (NLR) in peripheral blood, CD3+ tumor-infiltrating lymphocytes (TILs), and gene expression of AURKA, MYBL2 and MKI67 using qRT-PCR., Results: A total of 121 patients were included. Median followup was 12 years. In a univariate analysis, NLR, TILs, AURKA, and MYBL2 showed prognostic value for overall survival. In multivariate analyses, including hormone receptor, HER2 status, and response to NCT, NLR (HR 1.23, 95% CI 1.01-1.75), TILs (HR 0.84, 95% CI 0.73-0.93), AURKA (HR 1.05, 95% CI 1.00-1.11) and MYBL2 (HR 1.19, 95% CI 1.05-1.35) remained as independent predictor variables., Conclusion: Consecutive addition of these biomarkers to a regression model progressively increased its discriminatory capacity for survival. Should independent cohort studies validate these findings, management of early BC patients may well be changed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 García-Torralba, Navarro Manzano, Luengo-Gil, De la Morena Barrio, Chaves Benito, Pérez-Ramos, Álvarez-Abril, Ivars Rubio, García-Garre, Ayala de la Peña and García-Martínez.)

Luminal breast cancer (BC) is associated with less immune activation, and the significance of stromal lymphocytic infiltration (sTIL) is more uncertain than in other BC subtypes. The aim of this study was to investigate the predictive and prognostic value of sTIL in early luminal BC. The study was performed with an observational design in a prospective cohort of 345 patients with predominantly high-risk luminal (hormone receptor positive, HER2 negative) BC and with luminal B features ( n = 286), in which the presence of sTIL was analyzed with validated methods. Median sTIL infiltration was 5% (Q1-Q3 range (IQR), 0-10). We found that sTIL were associated with characteristics of higher biological and clinical aggressiveness (tumor and lymph node proliferation and stage, among others) and that the percentage of sTIL was predictive of pathologic complete response in patients treated with neoadjuvant chemotherapy (OR: 1.05, 95%CI 1.02-1.09, p < 0.001). The inclusion of sTIL (any level of lymphocytic infiltration: sTIL > 0%) in Cox regression multivariable prognostic models was associated with a shorter relapse-free interval (HR: 4.85, 95%CI 1.33-17.65, p = 0.016) and significantly improved its performance. The prognostic impact of sTIL was independent of other clinical and pathological variables and was mainly driven by its relevance in luminal B BC.

While the role of miR-200c in cancer progression has been established, its expression and prognostic role in breast cancer is not completely understood. The predictive role of miR-200c in response to chemotherapy has also been suggested by some studies, but only limited clinical evidence is available. The purpose of this study was to investigate miR-200c-3p in the plasma and primary tumor of BC patients. The study design included two cohorts involving women with locally advanced (LABC) and metastatic breast cancer. Tumor and plasma samples were obtained before and after treatment. We found that miR-200c-3p was significantly higher in the plasma of BC patients compared with the controls. No correlation of age with plasma miR-200c-3p was found for controls or for BC patients. MiR-200c-3p tumor expression was also associated with poor overall survival in LABC patients treated with neoadjuvant chemotherapy, independently of pathological complete response or clinical stage. Our findings suggest that plasmatic miR-200c-3p levels could be useful for BC staging, while the tumor expression of miR-200c-3p might provide further prognostic information beyond residual disease in BC treated with neoadjuvant chemotherapy.

Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2 - ) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017., Patients and Methods: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR + /HER2 - mBC who had progressed on ≥4 treatments for advanced disease were eligible., Results: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia., Conclusions: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET., Competing Interests: Declaration of competing interest L. Manso reports consulting or advisory roles from Roche, AstraZeneca, Novartis, Tesaro, and Pfizer; speaker’s bureau participation from Roche, AstraZeneca, Novartis, Tesaro, and Pfizer; research funding from Tesaro; travel expenses from Roche, Novartis, and Tesaro. M. Oliveira reports receiving speaking and advisory honoraria as from Roche and Seattle Genetics; speaking fees from Novartis; and advisory honoraria from GSK, PUMA Biotechnology and AstraZeneca; and financial support from AstraZeneca, Philips, Genentech, Roche, Seattle Genetics, Zenith Epigenetics, GSK, Immunomedics, Novartis, Boehringer-Ingelheim, and PUMA Biotechnology. M. Ruiz-Borrego reports speaker grants and advisory fees from Pfizer, Eli Lilly and Co., and Novartis. Iñaki Álvarez-Busto reports consultant or advisory roles from Kyowa Kirin and Pharma Mar; speaker honoraria from Angelini, Astra-Zeneca, Bayer, Boehringer Ingelheim, EISAI, Grunenthal pharma, Novartis, Pierre Fabre, Pfizer, and Roche; financial support for attending symposia from Roche; and financial support for educational programs from Bristol-Myers Squibb and Roche. E. Aguirre reports financial support for attending symposiafrom Roche and MSD; financial support for educational programs from Astra Zeneca and MSD; and participation in advisory board from Roche, Pfizer and AstraZeneca. J. E. Alés-Martínez reports speaking honoraria from Roche, MSD and BMS; consulting honoraria from Tesaro and Pfizer; and travel grants from MSD, BMS, and Roche. D. Malón reports participation in advisories, formative activities, and financial support for attending symposia from Pfizer, Roche, Novartis, BMS, MSD, Eisai, and Ipsen. I. Echevarría reports receiving travel grants from Pfizer, Novartis, and Lilly; and speaking honoraria from Novartis. S. Servitja reports receiving speaking honoraria from Roche and Pfizer; advisory board participation with Genomichealth, AstraZeneca, and MSD; and financial support for attending symposia from Roche, Pfizer, and MSD. F. Moreno reports receiving financial support for attending symposia from Pfizer, Roche, Novartis; support from Pfizer as project sponsor; and positions on advisory board or board of directors or other type of management relationships from Roche, Novartis, Pfizer, and MSD. Other authors declare no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The prognostic impact of neutrophil-lymphocyte ratio (NLR) in metastatic breast cancer (MBC) has been previously evaluated in early and metastatic mixed breast cancer cohorts or without considering other relevant prognostic factors. Our aim was to determine whether NLR prognostic and predictive value in MBC was dependent on other clinical variables. We studied a consecutive retrospective cohort of patients with MBC from a single centre, with any type of first line systemic treatment. The association of NLR at diagnosis of metastasis with progression free survival (PFS) and overall survival (OS) was evaluated using Cox univariate and multivariate proportional hazard models. In the full cohort, that included 263 MBC patients, a higher than the median (>2.32) NLR was significantly associated with OS in the univariate analysis (HR 1.36, 95% CI 1.00-1.83), but the association was non-significant (HR 1.12, 95% CI 0.80-1.56) when other clinical covariates (performance status, stage at diagnosis, CNS involvement, visceral disease and visceral crisis) were included in the multivariate analysis. No significant association was observed for PFS. In conclusion, MBC patients with higher baseline NLR had worse overall survival, but the prognostic impact of NLR is likely derived from its association with other relevant clinical prognostic factors.

Purpose: The analysis of breast cancer residual tumors after neoadjuvant chemotherapy (nCT) may be useful for identifying new biomarkers. MicroRNAs are known to be involved in oncogenic pathways and treatment resistance of breast cancer. Our aim was to determine the role of miR-18a, a member of the miR-17-92a cluster, in breast cancer behavior and outcome after nCT., Methods: Pre- and post-nCT tumor miR-18a expression was retrospectively assessed by qRT-PCR in 121 patients treated with nCT and was correlated with survival outcomes and with clinical and pathological characteristics. Breast cancer-derived MCF-7 and MDA-MB-231 cell lines were transfected with miR-18a and anti-miR-18a to evaluate the biological effects of this molecule. In addition, whole-transcriptome expression analysis was performed., Results: High miR-18a expression in post-nCT residual tumors was found to be associated with a significantly worse overall survival [hazard ratio (HR): 2.80, 95% confidence interval (CI): 1.01-7.76] and a strong trend towards a poorer disease-free survival (HR: 2.44, 95% CI: 0.99-5.02) compared to low miR-18a expressing post-nCT residual tumors. Clinical and experimental data were found to be in conformity with the proliferative effects of miR-18a, which showed a significant correlation with Ki67 and MYBL2 expression, both in pre- and post-nCT tumors and in public databases. In vitro analysis of the role of miR-18a in breast cancer-derived cell lines showed that a high expression of miR-18a was associated with a low expression of the estrogen receptor (ER), a decreased sensitivity to tamoxifen and an enrichment in luminal B and endocrine resistance gene expression signatures., Conclusions: From our data we conclude that post-nCT miR-18a expression in breast cancer serves as a negative prognostic marker, especially in luminal tumors. Clinical, in vitro and in silico data support the role of miR-18a in breast cancer cell proliferation and endocrine resistance and suggest its potential utility as a biomarker for additional adjuvant treatment in patients without a pathologic complete response to neoadjuvant therapy.

Purpose: Therapeutic exploitation of angiogenesis in breast cancer has been limited by the lack of reliable biomarkers. Circulating small-sized endothelial microparticles (sEMP) are likely to play a significant role as messengers of angiogenesis. Higher levels of EMP have been observed in cancer patients, but their prognostic value in breast cancer is unknown. Our aim was to determine the value of circulating sEMP as a marker of response to chemotherapy in breast cancer., Methods: We included patients with breast cancer treated with neoadjuvant or first-line chemotherapy. Baseline and post-treatment circulating sEMP (CD144+) were quantified using a flow cytometer approach specifically designed for analysis of small-sized particles (0.1-0.5 μm). Small-sized EMP response was defined as a post-treatment decrease of sEMP larger than the median decrease of sEMP after chemotherapy. Baseline and post-chemotherapy VEGFA levels were determined with ELISA., Results: Forty-four breast cancer patients were included (19 with metastatic and 25 with locally advanced disease). Median levels of sEMP decreased after chemotherapy (P = 0.005). Response to chemotherapy showed a non-significant trend to associate with sEMP response (P = 0.056). A sEMP response was observed in 51% of patients and was associated with better overall survival (HR 0.18; 95% CI 0.04-0.87; P = 0.02) and progression free survival (HR 0.30; 95% CI 0.09-0.99; P = 0.04) in the group of women with metastatic disease. Post-chemotherapy decrease of VEGFA levels was not associated with breast cancer prognosis., Conclusions: Our results did not support sEMP as a marker of response to chemotherapy. However, our exploratory analysis suggests that in patients with metastatic breast cancer, the decrease of sEMP levels after chemotherapy is associated with better overall and disease free survival and might be superior to VEGFA levels as an angiogenesis-related prognostic marker.

The effects of breast cancer conventional chemotherapy on tumor angiogenesis need to be further characterized. Neoadjuvant chemotherapy is an ideal model to evaluate the results of chemotherapy, allowing intra-patient direct comparison of antitumor and antiangiogenic effects. We sought to analyze the effect of neoadjuvant chemotherapy on tumor angiogenesis and its clinical significance in breast cancer. Breast cancer patients (n = 108) treated with neoadjuvant sequential anthracyclines and taxanes were studied. Pre- and post-chemotherapy microvessel density (MVD) and mean vessel size (MVS) were analyzed after CD34 immunohistochemistry and correlated with tumor expression of pro- and antiangiogenic factors (VEGFA, THBS1, HIF1A, CTGF, and PDGFA) by qRT-PCR. Angiogenic measures at diagnosis varied among breast cancer subtypes. Pre-treatment higher MVS was associated with triple-negative subtype and more advanced disease. Higher MVS was correlated with higher VEGFA (p = 0.003), while higher MVD was correlated with lower antiangiogenic factors expression (THBS1, p < 0.0001; CTGF, p = 0.001). Increased angiogenesis at diagnosis (high MVS and glomeruloid microvascular proliferation) and higher VEGFA expression were associated with tumor recurrence (p = 0.048 and 0.009, respectively). Chemotherapy-induced angiogenic response (defined as decreased MVD) was present in 35.2 % of patients. This response correlated with an increase in antiangiogenic factors (THBS1) without changes in VEGFA expression, and it was associated with tumor downstaging, but not with clinical response, pathologic complete response, or prognosis. Global effects of chemotherapy mainly consisted in an increased expression of antiangiogenic factors (THBS1, CTGF), with significant changes neither of tumor VEGFA nor of MVS. Conventionally scheduled neoadjuvant chemotherapy exerts antiangiogenic effects, through an increase in antiangiogenic factors, THBS1 and CTGF, but the expression of VEGFA is maintained after treatment. Better markers of angiogenic response and a better understanding of the cooperation of chemotherapy and antiangiogenic therapy in the neoadjuvant clinical scenario are needed.

Purpose: Although diabetes mellitus (DM) is recognized as a risk factor for chemotherapy-induced neurotoxicity, its true impact on intensity and time course of peripheral neuropathy is still unclear. The goal was to analyze the relevance of preexisting DM to weekly paclitaxel-induced peripheral neuropathy (PIPN)., Methods: We performed a retrospective case-control study (1:2) including a total of 129 patients with breast cancer (43 with DM and 86 controls) treated with single-agent weekly paclitaxel (wP)., Results: Compared with controls, patients with DM treated with wP experienced PIPN more frequently (74.4% vs 58.4%; P=.016) and with higher severity (grade 2-3: 51.2% vs 27.7%; P=.014). A significant delay in PIPN resolution was observed in women with DM (P=.001) and, in a multivariate analysis, DM was the only independent predictor for delayed recovery (hazard ratio [HR], 0.16; 95% CI, 0.05-0.55; P=.003). After 2 years, 68.7% of patients with DM (vs 29.2% of women without DM) still experienced PIPN, which was functionally significant (grade 2-3) in 18.2%., Conclusions: Significantly more dose delays and reductions because of PIPN occurred in patients with DM. Preexisting DM associates with long-lasting significant PIPN in patients treated with wP. Benefits and risks of long-term significant PIPN should be carefully balanced in patients with DM before starting wP chemotherapy., (Copyright © 2015 by the National Comprehensive Cancer Network.)

Introduction: Tumor microenvironment immunity is associated with breast cancer outcome. A high lymphocytic infiltration has been associated with response to neoadjuvant chemotherapy, but the contribution to response and prognosis of immune cell subpopulations profiles in both pre-treated and post-treatment residual tumor is still unclear., Methods: We analyzed pre- and post-treatment tumor-infiltrating immune cells (CD3, CD4, CD8, CD20, CD68, Foxp3) by immunohistochemistry in a series of 121 breast cancer patients homogeneously treated with neoadjuvant chemotherapy. Immune cell profiles were analyzed and correlated with response and survival., Results: We identified three tumor-infiltrating immune cell profiles, which were able to predict pathological complete response (pCR) to neoadjuvant chemotherapy (cluster B: 58%, versus clusters A and C: 7%). A higher infiltration by CD4 lymphocytes was the main factor explaining the occurrence of pCR, and this association was validated in six public genomic datasets. A higher chemotherapy effect on lymphocytic infiltration, including an inversion of CD4/CD8 ratio, was associated with pCR and with better prognosis. Analysis of the immune infiltrate in post-chemotherapy residual tumor identified a profile (cluster Y), mainly characterized by high CD3 and CD68 infiltration, with a worse disease free survival., Conclusions: Breast cancer immune cell subpopulation profiles, determined by immunohistochemistry-based computerized analysis, identify groups of patients characterized by high response (in the pre-treatment setting) and poor prognosis (in the post-treatment setting). Further understanding of the mechanisms underlying the distribution of immune cells and their changes after chemotherapy may contribute to the development of new immune-targeted therapies for breast cancer.

Radiation recall dermatitis is defined as an inflammatory reaction of the skin at the site of previous irradiation. Different drugs have been associated with triggering this phenomenon, and it can also affect other areas and organs where previous radiotherapy has been administered. The time gap between the inflammatory reaction and previous radiation can range from days to several years. We report what we believe to be the first case of Capecitabine-induced Radiation Therapy Oncology Group (RTOG) Grade 4 recall skin toxicity (ulcerating dermatitis), which occurred three years after skin irradiation. Clinicians should be aware of this phenomenon, even when considering patients for whom it has been a long time since previous radiation therapy. This unusual and late drug side effect should be borne in mind in the differential diagnosis and management of advanced-disease patients as it may be confused with local relapse or infectious complication of previously operated areas.

To evaluate the dose-response effect of an adjuvant anthracycline-based non-taxane chemotherapy in early breast cancer patients. This was a retrospective database analysis. Selection criteria included patients treated for early breast cancer from years 1980 to 2000 with an adjuvant anthracycline-based non-taxane chemotherapy. The delivery of chemotherapy was assessed through the number of delayed cycles, the number of delayed days and the relative dose intensity (RDI) administered (>or= 85%, <85%). Seven hundred and ninety-three breast cancer patients were included. The Kaplan-Meier disease-free survival (DFS) was affected by the number of delayed cycles (P<0.0001), the number of delayed days (P<0.0001) and the RDI (P=0.0029). The Kaplan-Meier overall survival (OS) was also affected by the number of delayed cycles (P=0.0008) and days (P=0.0115), as well as the RDI (P=0.0055). The Cox regression models showed that, when the number of nodes affected and the hormonal receptor status were controlled, all the study variables maintained their significance on DFS, but not on OS. The dose-response effect is a crucial factor in the administration of anthracycline-based non-taxane schedules for the adjuvant treatment of early breast cancer. Delays and/or reductions of chemotherapy should be avoided if possible to achieve the maximal benefit.