Tumor-infiltrating lymphocytes refine outcomes in triple-negative breast cancer treated with anthracycline-free neoadjuvant chemotherapy.

BACKGROUND: Stromal tumor-infiltrating lymphocytes (sTILs) are associated with pathologic complete response (pCR) and long-term outcomes for triple-negative breast cancer (TNBC) in setting of anthracycline-based chemotherapy. Impact of sTILs on refining outcomes beyond prognostic information provided by pCR in anthracycline-free neoadjuvant chemotherapy (NAC) is not known. PATIENTS & METHODS: This is pooled analysis of two studies where patients with stage I(T>1cm)-III TNBC received carboplatin(AUC 6) plus docetaxel(75mg/m2) (CbD) NAC. sTILs were evaluated centrally on pre-treatment H&E slides using standard criteria. Cox regression analysis was used to examine effect on event-free survival (EFS) and overall survival (OS). RESULTS: Among 474 patients, 44% had node-positive disease. Median sTILs were 5% (range 1%-95%), and 32% of patients had ≥30% sTILs. pCR rate was 51%. On multivariable analysis, T stage (OR=2.08,p=0.007), nodal status (OR=1.64,p=0.035), and sTILs (OR=1.10,p=0.011) were associated with pCR. On multivariate analysis, nodal status (HR=0.46,p=0.008), pCR(HR=0.20,p<0.001), and sTILs(HR=0.95,p=0.049) were associated with OS. At 30% cut-point, sTILs stratified outcomes in stage III disease, 5-year OS 86% vs 57% in ≥30% vs <30% sTILs (HR=0.29,p=0.014), and numeric trend in stage II, 5-year OS 93% vs 89% in ≥30% vs <30% sTILs (HR=0.55,p=0.179). Among stage II-III patients with pCR, EFS was better in those with ≥30% sTILs (HR=0.16,p=0.047). CONCLUSIONS: sTILs density was independent predictor of OS beyond clinicopathologic features and pathologic response in TNBC patients treated with anthracycline-free CbD chemotherapy. Notably, sTILs density stratified outcomes beyond TNM stage and pathologic response. These findings highlight role of sTILs in patient selection/stratification for neo/adjuvant escalation and de-escalation strategies.

Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts.

Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.

Concordance of Genomic Variants in Matched Primary Breast Cancer, Metastatic Tumor, and Circulating Tumor DNA: The MIRROR Study.

PURPOSE: Genetic heterogeneity between primary tumors and their metastatic lesions has been documented in several breast cancer studies. However, the selection of therapy for patients with metastatic breast cancer and the search for biomarkers for targeted therapy are often based on findings from the primary tumor, mainly because of the difficulty of distant metastasis core biopsies. New methods for monitoring genomic changes in metastatic breast cancer are needed (ie, circulating tumor DNA [ctDNA] genomic analysis). The objectives of this study were to assess the concordance of genomic variants between primary and metastatic tumor tissues and the sensitivity of plasma ctDNA analysis to identify variants detected in tumor biopsies. PATIENTS AND METHODS: Next-generation sequencing technology was used to assess the genomic mutation profile of a panel of 54 cancer genes in matched samples of primary tumor, metastatic tumor, and plasma from 40 patients with metastatic breast cancer. RESULTS: Using Ion Torrent technology (ThermoFisher Scientific, Waltham, MA), we identified 110 variants that were common to the primary and metastatic tumors. ctDNA analysis had a sensitivity of 0.972 in detecting variants present in both primary and metastatic tissues. In addition, we identified 13 variants in metastatic tissue and ctDNA not present in primary tumor. CONCLUSION: We identified genomic variants present in metastatic biopsies and plasma ctDNA that were not present in the primary tumor. Deep sequencing of plasma ctDNA detected most DNA variants previously identified in matched primary and metastatic tissues. ctDNA might aid in therapy selection and in the search for biomarkers for drug development in metastatic breast cancer.

Evaluation of Breast Cancer Patients with Genetic Risk in a University Hospital: Before and After the Implementation of a Heredofamilial Cancer Unit.

The identification of patients at risk for breast cancer by genetic testing has proven to reduce breast cancer mortality. In 2010, due to a lack of systematization in hereditary cancer assistance in our center, we implemented a multidisciplinary Heredofamilial Cancer Unit (HFCU). We analyze if the HFCU improved the rates of referrals and preventive management of breast cancer patients with genetic risk. We retrospectively compared family history records, referrals of high-risk patients to genetic counseling, and detection and management of patients with BRCA1/2 mutations in two cohorts of breast cancer patients diagnosed before (first period: 2007-2010) and after the creation of the HFCU (second period: 2010-2013). In the first period, 893 patients were included, and 902 were included in the second. Due to the inability to establish their genetic risk, 142 patients (15.9%) vs. 70 (7.8%) were excluded from analysis (p < 0.001). Among the evaluable patients, 194 (25.8%) vs. 223 (26.8%) fulfilled one or more risk criteria (p = 0.65). Family history documentation in patient's medical records (92.4 vs. 97.8%, p < 0.001) and referral rate (26.3 vs. 52%, p < 0.0001) significantly increased in the second period. Eight BRCA1/2 mutations were detected among patients referred in the first period and 17 among those referred to the HFCU. The rate of preventive surgeries in patients with BRCA mutations significantly increased in the second period (25 vs. 76.5%, p = 0.03). In conclusion, there was a clear improvement in family history records, referrals, and preventive surgeries in breast cancer patients with genetic risk after the implementation of the HFCU.

Enfoques de la reforma de la salud en el Perú de 1998: Ecos de un debate / Approaches to the peruvian health care reform of 1998: about a discussion

La Mesa Redonda organizada por el Departamento de Medicina Preventiva y Salud Pública de la Facultad de Medicina de San Fernando, contó con la participación de connotados representantes del Estado y la sociedad peruanos ligados a la Salud Pública: el Dr. Oscar Bueno del Ministerio de Salud, el Dr. Julio Castro del Colegio Médico del Perú, y el Dr. Francisco Sánchez Moreno de la Academia Peruana de Salud. Ellos debatieron sobre la Reforma de la Salud en el Perú de hoy. Mientras para el representante del Ministerio de Salud la Reforma es una realidad que va transformando al sector y particularmente la antigua estructura sanitaria, de exclusiva responsabilidad estatal; para el representante de la Academia Peruana de Salud, ésta es la segunda reforma puesta en marcha por el mismo gobierno (1990-98) y ambas han fracasado, proponiendo los principios de una auténtica Reforma. Por último, el representante del Colegio Médico igualmente criticó los fundamentos de la Reforma, remarcando su carácter no democrático y centralista. Todos coincidieron en la necesaria participación de la Universidad para una adecuada Reforma de la Salud en el Perú. Finalmente, concuerdan en la necesidad de construir un consenso nacional para la Reforma de la Salud a mediano y largo plazo.

Mortalidad materna: dos estudios en la provincia de LIma / Maternal death: two studies in Lima

Estudia los aspectos cualitativos y cuantitativos del flujo a través de las instancias formales de los datos e información relacionada a muerte materna en la provincia de Lima. Señala que la información sobre mortalidad materna, no refleja la magnitud del problema. Entre las explicaciones de la deficiente información sobre mortalidad materna menciona como las más importantes, el alto porcentaje de omisión en el registro y procesamiento de los datos. Considera que las bajas coberturas en salud y del registro civil hacen de la mortalidad materna una realidad no transparente