Deconstructing neutrophil to lymphocyte ratio (NLR) in early breast cancer: lack of prognostic utility and biological correlates across tumor subtypes.

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.

A new prognostic model including immune biomarkers, genomic proliferation tumor markers (AURKA and MYBL2) and clinical-pathological features optimizes prognosis in neoadjuvant breast cancer patients.

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.

Clinical Meaning of Stromal Tumor Infiltrating Lymphocytes (sTIL) in Early Luminal B Breast Cancer.

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.

Neutrophil-lymphocyte ratio in metastatic breast cancer is not an independent predictor of survival, but depends on other variables.

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.

Circulating small-sized endothelial microparticles as predictors of clinical outcome after chemotherapy for breast cancer: an exploratory analysis.

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.

38th Annual San Antonio Breast Cancer Symposium. Resumen de las aportaciones más relevantes / 38th Annual San Antonio Breast Cancer Symposium. Summary of key contributions

Se resumen en este trabajo las comunicaciones más relevantes y con mayor impacto clínico presentadas en el Simposio Internacional de Cáncer de Mama, celebrado en San Antonio en diciembre de 2015. Desde el punto de vista translacional, las principales aportaciones han sido las referidas a la dinámica clonal y a la heterogeneidad tumoral, así como a la posibilidad de estudiar mutaciones emergentes relacionadas con resistencia mediante biopsia líquida y técnicas de secuenciación masiva, como demuestran los datos de los ensayos BELLE-2 y BOLERO-2. Desde el punto de vista clínico, los resultados finales del estudio BCIRG-006 y los intermedios del estudio ExteNET en cáncer de mama HER2 modifican el panorama de la adyuvancia en este grupo de pacientes. Los resultados del estudio ABCSG-18 con denosumab adyuvante en enfermedad luminal apoyan los resultados previos con bifosfonatos. En enfermedad triple negativa, se han aportado datos interesantes acerca de la utilización de carboplatino y nab-paclitaxel en esquemas neoadyuvantes. El estudio CREATE-X con capecitabina adyuvante plantea la posibilidad de mejorar el pronóstico de las pacientes que no alcanzan respuesta completa tras neoadyuvancia, especialmente en el grupo triple negativo. La posibilidad de reducir la intensidad del tratamiento en algunos subgrupos de pacientes, las controversias sobre la irradiación nodal y el manejo quirúrgico de la axila, y los datos iniciales sobre inmunoterapia completan este resumen (AU)

We summarise the most interesting and clinically relevant works presented at the 38th Annual San Antonio Breast Cancer Symposium (December 2015). In the field of translational research, the main contributions were made in clonal dynamics and tumour heterogeneity, as well as in the possibility of studying emerging resistance mutations with liquid biopsy and next-generation sequencing, as shown by data from the BELLE-2 and BOLERO-2 trials. From the clinical point of view, the final analysis of BCIRG-006 trial and the intermediate analysis of the ExteNET trial will probably change the adjuvant treatment of HER2 breast cancer patients. The results of the ABCSG-18 trial with adjuvant denosumab in luminal breast cancer are consistent with previous data from trials of adjuvant bisphosphonate therapy. In triple-negative breast cancer, interesting data were reported supporting the addition of carboplatin and nab-paclitaxel to neoadjuvant chemotherapy regimens. The CREATE-X trial is the first study showing a survival benefit (larger in triple negative disease) of adjuvant chemotherapy with capecitabine in those patients without pathologic complete response after neoadjuvant chemotherapy. Finally, other problems addressed during the meeting were treatment de-escalation in some patient subgroups, the controversies surrounding and integration of nodal irradiation and axillary surgery, and early clinical results with immune therapy (AU)