The mutational load and a T-cell inflamed tumour phenotype identify ovarian cancer patients rendering tumour-reactive T cells from PD-1+ tumour-infiltrating lymphocytes.

BACKGROUND: Adoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those patients capable of rendering tumour-reactive TILs. We have investigated this in ovarian cancer (OC) patients as candidates for TIL therapy implementation. METHODS: PD-1- and PD-1+ CD8 TILs were isolated from ovarian tumours and expanded cells were tested against autologous tumour cells. Baseline tumour samples were examined using flow cytometry, multiplexed immunofluorescence and Nanostring technology, for gene expression analyses, as well as a next-generation sequencing gene panel, for tumour mutational burden (TMB) calculation. RESULTS: Tumour-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Importantly, a high TIL density in the fresh tumour, the presence of CD137+ cells within the PD-1+CD8+ TIL subset and their location in the tumour epithelium, together with a baseline T-cell-inflamed genetic signature and/or a high TMB, are features that identify patients rendering tumour-reactive TIL products. CONCLUSION: We have demonstrated that PD-1 identifies ovarian tumour-specific CD8 TILs and has uncovered predictive factors that identify OC patients who are likely to render tumour-specific cells from PD-1+ TILs.

37th Annual San Antonio Breast Cancer Symposium. Resumen de las aportaciones translacionales y clínicas más relevantes / 37th Annual San Antonio Breast Cancer Symposium. Summary of the most important translational and clinical contributions

En diciembre de 2014 hemos tenido la oportunidad de ampliar nuestro conocimiento en el Simposio Internacional de Cáncer de Mama, celebrado en San Antonio, resaltando: 1) en el escenario básico, la adquisición de mutaciones durante el proceso de carcinogénesis y metástasis, aumentando la clonalidad y heterogeneidad tumoral, el papel pronóstico de los neoantígenos y los linfocitos infiltrantes en el residuo tumoral tras la neoadyuvancia, así como el mayor conocimiento de alteraciones en el receptor de estrógeno asociadas a hormonorresistencia; 2) en el translacional, el empleo de xenoinjertos derivados de tumores de pacientes en modelos murinos para evitar las resistencias terapéuticas, y los biomarcadores líquidos para descartar enfermedad mínima residual en cáncer de mama precoz; y 3) en clínica los resultados tanto en prevención como en adyuvancia con hormonoterapia, la quimioterapia en triples negativos y las novedades en inmunoterapia (AU)

The 37th San Antonio Breast Cancer Symposium, held in December 2014, provided an opportunity to gain greater knowledge. Notable contributions were the following: 1) in basic research, the acquisition of mutations in carcinogenesis and metastasis, which increase with clonality and heterogeneity; the prognostic role of neoantigens and infiltrating lymphocytes in the residual tumor after neoadjuvant chemotherapy; and an increased knowledge of molecular mutations in the estrogen receptor, which explain hormonal resistance; 2) in the translational arena, the role of patient-derived xenografts to avoid therapeutic resistance; and the role of liquid biomarkers to detect minimal residual disease in early breast cancer; and 3) in the clinical scenario, advances in prevention and hormone therapy, and news on triple-negative tumors and immunotherapy (AU)

Neurological and cytological response as potential early predictors of time-to-progression and overall survival in patients with leptomeningeal carcinomatosis treated with intrathecal liposomal cytarabine: a retrospective cohort study.

Interesting neurological and cytological response rates after intrathecal (i.t) liposomal cytarabine have been observed in patients with leptomeningeal carcinomatosis (LMC) from solid tumors. However, the potential use of those responses as early predictors of time-to-progression (TTP) and overall survival (OS) is unexplored. 27 consecutive patients with LMC treated with 50 mg i.t liposomal cytarabine under compassionate drug use were retrospectively studied. All patients received i.t treatment every 2 weeks during induction and every 4 weeks during maintenance periods. Neurological and cytological responses were assessed before every liposomal cytarabine cycle. Most of the patients were female (17/27) diagnosed with breast cancer (15/27). A complete neurological response was seen among 11 % of the patients; partial response in 22 % of the patients; stable disease in 30 % of the patients and progressive disease in 37 % of them. Cytological assessment was available in 11/27 patients showing a 26 % complete response rate. The median time to neurological and cytological response was 15 days and 14 days, respectively. Patients showing a combined neurological and cytological response showed a significantly longer median TTP (122 vs. 3 days; p = 0.001) and OS (141 vs. 3 days; p = 0.002) compared to those showing both neurological and cytological progression. No grade 4 toxicities were recorded. According to these preliminary results, early neurological and cytological responses may be further studied as early predictors of TTP and OS in patients receiving i.t liposomal cytarabine for LMC.

A novel mutation in BRCA1 linked to breast and ovarian cancer and a genotype-phenotype correlation.

We report a novel BRCA1 germline 4156delAA mutation detected in a 41-year-old woman with breast and ovarian cancer. Genomic DNA was obtained from peripheral blood. Standard polymerase chain reactions and direct sequencing were performed. This mutation originates a premature stop at codon 1354 of BRCA1 protein and has not been documented in any published report to the best of our knowledge. The mutation was not observed in any other family studied. Since this novel mutation was associated with both breast and ovarian cancer, the genotype-phenotype correlation was investigated in a patient base of 30 families.

A novel BRCA2 mutation that segregates with breast and prostate cancer in a Spanish family.

We report a novel germline 5369delATTT mutation in BRCA2 gene, detected in a 45-year-old woman with bilateral breast cancer. This deletion was also detected in her father with prostatic cancer and her sister with breast cancer. The mutation originates a premature stop at codon 1723 of BRCA2 protein and has not been documented in any published report to the best of our knowledge.

Docetaxel administered during pregnancy for inflammatory breast carcinoma.

We report the case of a 35-year-old pregnant woman with inflammatory breast carcinoma initially treated with 5-fluorouracil/doxorubicin/cyclophosphamide beginning her 13th week of pregnancy. There was no noticeable shrinkage of the axillary or breast tumors after 4 cycles, at which point the patient accepted a treatment change to docetaxel. Four cycles of docetaxel at 100 mg/m2 every 21 days were delivered from the 25th week of pregnancy with good tolerance. She exhibited a clinical complete response, determined by clinical examination and imaging tests. Obstetric monitoring with fetal ultrasound showed normal fetal development throughout chemotherapy. After delivery of a healthy child, she underwent surgery, which showed tumor downstaging to pT0 N2, followed by radiation therapy and hormone therapy. This report suggests the safety of docetaxel after the first trimester of pregnancy.