Beatriz Cirauqui

The Prognostic Value of BRCA1 mRNA Expression Levels Following Neoadjuvant Chemotherapy in Breast Cancer

Background A fraction of sporadic breast cancers has low BRCA1 expression. BRCA1 mutation carriers are more likely to achieve a pathological complete response with DNA-damage-based chemotherapy compared to non-mutation carriers. Furthermore, sporadic ovarian cancer patients with low levels of BRCA1 mRNA have longer survival following platinum-based chemotherapy than patients with high levels of BRCA1 mRNA. Methodology/Principal Findings Tumor biopsies were obtained from 86 breast cancer patients who were candidates for neoadjuvant chemotherapy, treated with four cycles of neoadjuvant fluorouracil, epirubicin and cyclophosphamide. Estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin 5/6 and vimentin were examined by tissue microarray. HER2 were also assessed by chromogenic in situ hybridization, and BRCA1 mRNA was analyzed in a subset of 41 patients for whom sufficient tumor tissue was available by real-time quantitative PCR. Median time to progression was 42 months and overall survival was 55 months. In the multivariate analysis for time to progression and overall survival for 41 patients in whom BRCA1 could be assessed, low levels of BRCA1 mRNA, positive PR and negative lymph node involvement predicted a significantly lower risk of relapse, low levels of BRCA1 mRNA and positive PR were the only variables associated with significantly longer survival. Conclusions/Significance We provide evidence for a major role for BRCA1 mRNA expression as a marker of time to progression and overall survival in sporadic breast cancers treated with anthracycline-based chemotherapy. These findings can be useful for customizing chemotherapy.

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer

BACKGROUND In the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial. PATIENTS AND METHODS We analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). RESULTS A basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 ≤ 50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2- and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 ≤ 50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%. CONCLUSION Basal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis. IMPLICATIONS FOR PRACTICE The use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis.

PIK3CA Mutations and BRCA1 Expression in Breast Cancer: Potential Biomarkers for Chemoresistance

Mutations in PIK3CA and alterations of BRCA1 expression are common in breast cancer and have been correlated with altered sensitivity to taxanes in human cancer cell lines and with outcome of patients. We assessed mutations in the three hotspots of PIK3CA (E542K, E545K and H1047R) and intratumoral BRCA1 mRNA expression by quantitative RT-PCR in 61 breast cancer patients. Mutations of PIK3CA were found in 17 (27.9%) and did not correlate with BRCA1 transcript levels. Correlation with clinical and pathological features identified a significant association of mutations with older patients (P = 0.03). Higher BRCA1 mRNA expression was significantly correlated with advanced disease (P = 0.01) and ERBB2 overexpression (P = 0.02). These findings may help to identify a subgroup of patients who will likely benefit from chemotherapy regimens containing microtubule-disrupting agents.

DNA repair pathways to regulate response to chemoradiotherapy in patients with locally advanced head and neck cancer

Platinum-based chemoradiotherapy (CRT) is a preferred standard of care for locally advanced head and neck cancer (HNC). However, survival benefit is small, with substantial toxicity and biomarkers of CRT resistance that could guide treatment selection and spare morbidity. Increased DNA repair in solid tumors may contribute to cancer cells’ ability to survive in genotoxic stress environments afforded by therapy. We assessed mRNA expression levels of DNA repair-related genes BRCA1, RAP80, 53 binding protein 1 (53BP1), mediator of DNA damage checkpoint 1 (MDC1), and RNF8. We correlated our findings with response and overall survival in 72 head and neck patients treated with weekly carboplatin AUC 2 and radiotherapy. Complete response (CR) to CRT was 50 % in patients with low levels of 53BP1 compared to 6.3 % in patients with high levels (p = 0.0059). Of high BRCA1 mRNA expressors, 41.2 % had CR compared to 29.4 % of low expressors (p = 0.72). For a small group of patients with low 53BP1 and either high BRCA1 or RAP80, CRs were 66.7 and 71.4 %, respectively. A trend for better overall survival (OS) was found for patients with low 53BP1 (15 vs 8 m; p = 0.056). Our findings highlight the potential usefulness of 53BP1 mRNA as a predictive biomarker of response and overall survival in HNC patients treated with chemoradiotherapy. Those with high 53BP1 expression could derive only a meager benefit from treatment. Analysis of BRCA1 and RAP80 could further reinforce the predictive value of 53BP1. Although this was a retrospective study with small sample size, it could inform larger translational studies in HNC.

Detection of disseminated tumor cells in locally advanced breast cancer patients before primary systemic therapy

AIM To assess the prevalence and prognostic power of disseminated tumor cells (DTC) in patients with locally advanced breast cancer (LABC) before primary systemic therapy (PST). MATERIALS AND METHODS LABC patients attending our Breast Unit were studied between 2002 and 2012, all of them being considered for PST. To determine the presence of DTC, posterior iliac crest aspirates were obtained and marrow samples were processed by gradient separation with Ficoll (Lymphoprep(®)) and immunohistochemical staining using the antiCK A45-B/B3 (EPIMET) antibody. Clinicopathologic variables were recorded before and after PST to assess response. Disease-free survival (DFS) and overall survival (OS) were determined after follow-up. The presence of DTC as a predictor of response to PST and as a prognostic tool for OS and DSF was evaluated. RESULTS DTC were observed in 26% of 47 patients included in the study. PST consisted of chemotherapy in 94% and hormone therapy in 6%. Breast-conserving therapy was attained in 33%. Mean follow-up was 68 months. Complete clinical response (CR) after PST was seen in 26%, disease recurrence in 38%, and cancer-related death in 8%; tumor size and negative estrogen receptors were significant predictors of CR and mastectomy was associated with DFS. Persistent axillary disease after PST and previous recurrence were predictive of OS. DTC were detected more often in patients who did not achieve CR and those who presented recurrence. DTC detection was a significant prognostic factor for a worse OS (OR = 7.62; CI95%: 1.46-39.61; p = 0.009) and a decreased survival time (62 versus 82 months, p = 0.004). CONCLUSION Presence of DTC before PST was found in a significant number of patients with LABC. DTC were found to be a significant prognostic factor for cancer-related death. DTC could be a surrogate predictor of response to PST and also of disease recurrence in LABC patients.

Neumonías en pacientes con leucemia linfática crónica. Estudio de 30 episodios

Fundamento Analizar la etiologia, los metodos diagnosticos y la respuesta al tratamiento en 30 episodios de neumonia diagnosticados en 17 pacientes con leucemia linfatica cronica (LLC) entre 1995 y 2000. Pacientes y metodo En cada episodio se registraron los siguientes parametros: edad, sexo, tratamiento de la LLC, profilaxis antiinfecciosa, granulocitopenia, cociente de linfocitos CD4 y CD8, hipogammaglobulinemia, tipo de neumonia (intra o extrahospitalaria), localizacion, insuficiencia respiratoria, necesidad de ventilacion mecanica, tratamiento antimicrobiano y respuesta. Se realizaron hemocultivos, cultivo de esputo, fibrobroncoscopia y deteccion de antigenos en orina (Legionella pneumophila serogrupo 1, galactomanano y Streptococcus pneumoniae). Resultados La edad mediana de la serie fue de 60 anos (limites, 50-86); 12 eran varones. La combinacion de clorambucilo y prednisona fue el tratamiento mas utilizado para la LLC (13 pacientes) seguido de la fludarabina (8 casos). Existia granulocitopenia en 14 episodios, habia hipogammaglobulinemiaen 22 y el cociente de linfocitos CD4 y CD8 fue inferior a uno en 8 de 14 determinaciones. Se establecio la etiologia de las neumonias en 16 episodios (53%). La fibrobroncoscopia fue la prueba con mayorrentabilidad diagnostica (83%), seguida de los hemocultivos (38%). Dos pacientes fueron diagnosticadosen la autopsia de aspergilosis pulmonar. El neumococo fue el germen aislado con mayor frecuencia(5) seguido de Pseudomonas aeruginosa (4), Pneumocystis carinii (2) y Aspergillus fumigatus (2). Delos 2 pacientes con neumocistosis uno habia recibido fludarabina y el otro glucocorticoides de formaprolongada. Diez pacientes (30%) fallecieron a causa de los siguientes germenes: P. aeruginosa (3),P. carinii (2), A. fumigatus (2), Mycobacterium xenopi (1) y germen no identificado (2). Conclusiones En esta serie de pacientes con LLC la tasa global de diagnostico etiologico de las neumonias fue aceptable. El germen mas frecuente fue el neumococo. Las neumonias por microorganismos oportunistas se relacionaron con la administracion de fludarabina o el tratamiento prolongado con glucocorticoides y tuvieron una elevada mortalidad.

Prognostic role of peripheral blood scores in lymphoepithelioma of the nasopharynx (LN).

e17564Background: Neutrophil/lymphocyte (NLR) and lymphocyte/monocyte ratio (LMR) have been described as prognostic factors in cancer. Lymphoepithelioma is a type of poorly differentiated nasophary...