The aim was to identify mutations in serum cell-free DNA (cfDNA) associated with disease progression on tamoxifen treatment in metastatic breast cancer (MBC). Sera available at start of therapy, ...during therapy and at disease progression were selected from 10 estrogen receptor (ER)-positive breast cancer patients. DNA from primary tumor and normal tissue and cfDNA from minute amounts of sera were analyzed by targeted next generation sequencing (NGS) of 45 genes (1,242 exons). At disease progression, stop-gain single nucleotide variants (SNVs) for CREBBP (1 patient) and SMAD4 (1 patient) and non-synonymous SNVs for AKAP9 (1 patient), PIK3CA (2 patients) and TP53 (2 patients) were found. Mutations in CREBBP and SMAD4 have only been occasionally reported in breast cancer. All mutations, except for AKAP9, were also present in the primary tumor but not detected in all blood specimens preceding progression. More sensitive detection by deeper re-sequencing and digital PCR confirmed the occurrence of circulating tumor DNA (ctDNA) and these biomarkers in blood specimens.
PIK3CA is the most frequent somatic mutated oncogene in estrogen receptor (ER) positive breast cancer. We previously observed an association between PIK3CA genotype and aromatase inhibitors (AI) ...treatment outcome. This study now evaluates whether expression of mRNAs and miRs are linked to PIK3CA genotype and are independently related to AI therapy response in order to define potential expressed biomarkers for treatment outcome.
The miR and mRNA expression levels were evaluated for their relationship with the PIK3CA genotype in two breast tumor datasets, i.e. 286 luminal cancers from the TCGA consortium and our set of 84 ER positive primary tumors of metastatic breast cancer patients who received first line AI. BRB Array tools class comparison was performed to define miRs and mRNAs whose expression associate with PIK3CA exon 9 and 20 status. Spearman correlations established miR–mRNA pairs and mRNAs with related expression. Next, a third dataset of 25 breast cancer patients receiving neo-adjuvant letrozole was evaluated, to compare expression levels of identified miRs and mRNAs in biopsies before and after treatment. Finally, to identify potential biomarkers miR and mRNA levels were related with overall survival (OS) and progression free survival (PFS) after first-line AI therapy.
Expression of 3 miRs (miR-449a, miR-205-5p, miR-301a-3p) and 9 mRNAs (CCNO, FAM81B, LRG1, NEK10, PLCL1, PGR, SERPINA3, SORBS2, VTCN1) was related to the PIK3CA status in both datasets. All except miR-301a-3p had an increased expression in tumors with PIK3CA mutations. Validation in a publicly available dataset showed that LRG1, PGR, and SERPINA3 levels were decreased after neo-adjuvant AI-treatment. Six miR–mRNA pairs correlated significantly and stepdown analysis of all 12 factors revealed 3 mRNAs (PLCL1, LRG1, FAM81B) related to PFS. Further analyses showed LRG1 and PLCL1 expression to be unrelated with luminal subtype and to associate with OS and with PFS, the latter independent from traditional predictive factors.
We showed in two datasets of ER positive and luminal breast tumors that the expression of 3 miRs and 9 mRNAs associate with the PIK3CA status. Expression of LRG1 is independent of luminal (A or B) subtype, decreased after neo-adjuvant AI-treatment, and is proposed as potential biomarker for AI therapy outcome.
•Expression of 9 mRNAs and 3 miRs relates to PIK3CA genotype in 2 breast cancer cohorts.•All 9 mRNAs and 2 miRs were upregulated in tumors with PIK3CA mutations.•LRG1 and PLCL1 mRNA levels relate to PIK3CA status irrespective luminal subtype.•LRG1 and PLCL1 mRNA levels associate with aromatase inhibitor therapy outcome.•LRG1 expression is decreased after neo-adjuvant letrozole treatment.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PIK3CA
mutations occur frequently in breast cancer, predominantly in exons 9 and 20. The aim of this retrospective study is to evaluate the
PIK3CA
mutation status for its relationship with prognosis ...and first-line endocrine therapy outcome.
PIK3CA
exon 9 and 20 were evaluated for mutations in 1,352 primary breast cancer specimens by SnaPshot multiplex analyses. The mutation status was studied for their relationship with metastasis-free survival (MFS) in 342 untreated lymph node-negative (LNN) patients and to time to progression (TTP) in estrogen receptor (ER)-positive patients with metastatic disease treated with first-line tamoxifen (
N
= 447) or aromatase inhibitors (AIs;
N
= 84). We detected in 423 patients hotspot mutations for
PIK3CA
(31 %). Mutations in exon 20 were detected in 251 patients (59 %), with H1047L and H1047R mutations in 37 (15 %) and 214 (85 %) cases, respectively. Mutations in
PIK3CA
exon 9 were discovered in 173 patients (41 %), with E542K and E545K mutations in 57 (32 %) and 104 (60 %) cases as most prevalent ones. Evaluation of the untreated LNN patients for prognosis showed no relationship between MFS and
PIK3CA
mutations, neither for exon 9 HR = 1.04 (95 % CI 0.57–1.89),
P
= 0.90 nor for exon 20 HR = 0.98 (95 % CI 0.63–1.54);
P
= 0.94 when compared to wild-type. The
PIK3CA
mutation status was also not associated with treatment outcome after first-line tamoxifen. On the other hand, patients treated with first-line AIs showed a longer TTP when having a
PIK3CA
mutation in exon 9 HR = 0.40 (95 % CI 0.17–0.95);
P
= 0.038 or exon 20 HR = 0.50 (95 % CI 0.27–0.91);
P
= 0.024 compared to wild-types, both significant in uni- and multivariate analysis including traditional predictive factors. All results remained when only HER2-negative patients were evaluated for each cohort.
PIK3CA
mutations in ER-positive tumors were significantly associated with a favorable outcome after first-line AIs, which needs further confirmation in other datasets. Mutations were not associated with prognosis in untreated LNN patients nor predictive outcome after first-line tamoxifen therapy in advanced disease patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
As a conceptual model of disease mechanisms, a disease map integrates available knowledge and is applied for data interpretation, predictions and hypothesis generation. It is possible to model ...disease mechanisms on different levels of granularity and adjust the approach to the goals of a particular project. This rich environment together with requirements for high-quality network reconstruction makes it challenging for new curators and groups to be quickly introduced to the development methods. In this review, we offer a step-by-step guide for developing a disease map within its mainstream pipeline that involves using the CellDesigner tool for creating and editing diagrams and the MINERVA Platform for online visualisation and exploration. We also describe how the Neo4j graph database environment can be used for managing and querying efficiently such a resource. For assessing the interoperability and reproducibility we apply FAIR principles.
Patients with Estrogen Receptor α-positive (ER+) Inflammatory Breast Cancer (IBC) are less responsive to endocrine therapy compared with ER+ non-IBC (nIBC) patients. The study of ER+ IBC samples ...might reveal biomarkers for endocrine resistant breast cancer.
Gene expression profiles of ER+ samples from 201 patients were explored for genes that discriminated between IBC and nIBC. Classifier genes were applied onto clinically annotated expression data from 947 patients with ER+ breast cancer and validated with RT-qPCR for 231 patients treated with first-line tamoxifen. Relationships with metastasis-free survival (MFS) and progression-free survival (PFS) following adjuvant and first-line endocrine treatment, respectively, were investigated using Cox regression analysis.
A metagene of six genes including the genes encoding for 4-aminobutyrate aminotransferase (ABAT) and Stanniocalcin-2 (STC2) were identified to distinguish 22 ER+ IBC from 43 ER+ nIBC patients and remained discriminatory in an independent series of 136 patients. The metagene and two genes were not prognostic in 517 (neo)adjuvant untreated lymph node-negative ER+ nIBC breast cancer patients. Only ABAT was related to outcome in 250 patients treated with adjuvant tamoxifen. Three independent series of in total 411 patients with advanced disease showed increased metagene scores and decreased expression of ABAT and STC2 to be correlated with poor first-line endocrine therapy outcome. The biomarkers remained predictive for first-line tamoxifen treatment outcome in multivariate analysis including traditional factors or published signatures. In an exploratory analysis, ABAT and STC2 protein expression levels had no relation with PFS after first-line tamoxifen.
This study utilized ER+ IBC to identify a metagene including ABAT and STC2 as predictive biomarkers for endocrine therapy resistance.
•ER+ inflammatory breast cancer (IBC) can be used as endocrine therapy resistance model.•Molecular characterization revealed ABAT and STC2 as ER+ IBC discriminatory genes.•ABAT and STC2 are novel biomarkers for tamoxifen resistance in advanced breast cancer.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
While mutations in PIK3CA are most frequently (45%) detected in luminal breast cancer, downstream PI3K/AKT/mTOR pathway activation is predominantly observed in the basal subtype. The aim was to ...identify proteins activated in PIK3CA mutated luminal breast cancer and the clinical relevance of such a protein in breast cancer patients.
Expression levels of 171 signaling pathway (phospho-)proteins established by The Cancer Genome Atlas (TCGA) using reverse phase protein arrays (RPPA) were in silico examined in 361 breast cancers for their relation with PIK3CA status. MAPK1/3 phosphorylation was evaluated with immunohistochemistry on tissue microarrays (TMA) containing 721 primary breast cancer core biopsies to explore the relationship with metastasis-free survival.
In silico analyses revealed increased phosphorylation of MAPK1/3, p38 and YAP, and decreased expression of p70S6K and 4E-BP1 in PIK3CA mutated compared to wild-type luminal breast cancer. Augmented MAPK1/3 phosphorylation was most significant, i.e. in luminal A for both PIK3CA exon 9 and 20 mutations and in luminal B for exon 9 mutations. In 290 adjuvant systemic therapy naïve lymph node negative (LNN) breast cancer patients with luminal cancer, high MAPK phosphorylation in nuclei (HR=0.49; 95% CI, 0.25-0.95; P=.036) and in tumor cells (HR=0.37; 95% CI, 0.18-0.79; P=.010) was related with favorable metastasis-free survival in multivariate analyses including traditional prognostic factors.
Enhanced MAPK1/3 phosphorylation in luminal breast cancer is related to PIK3CA exon-specific mutations and correlated with favorable prognosis especially when located in the nuclei of tumor cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background: Evaluation of cell-free DNA (cfDNA) is a very attractive tool to serve as "liquid biopsy" to define and establish mutational changes in circulating tumor DNA (ctDNA) ...non-invasively during therapy.
Aim: To identify tumor specific mutations in serum cfDNA associated with resistance against tamoxifen in metastatic breast cancer.
Materials & Methods: Ten metastatic ER-positive breast cancer patients treated with first-line tamoxifen of whom blood sera was available at start therapy, during treatment and at disease progression were selected. DNA was isolated from normal (nDNA) and primary tumor (ptDNA) tissue and from sera (cfDNA). DNA was analyzed with next generation sequencing by the ion-PGM system (Life Technologies) for a panel of 45 cancer genes. This panel included the most frequently mutated genes for breast, colon, prostate and ovarian cancer reported in the Catalogue Of Somatic Mutations In Cancer (Cosmic database, Release 67; cancer.sanger.ac.uk/). In total 1242 exons (∼255kb) were sequenced with 200 to 5000x reads depth coverage. The panel analyzed all exons for 39 genes and only hotspot exons for 6 oncogenes. Variant Caller software (Life Technologies; version 4.16) was applied to detect non-synonymous and stop-gain single nucleotide variants (SNVs) within the sequenced DNA. Hotspot mutations detected in PIK3CA exons 9 and 20 were validated with snapshot multiplex assays.
Results: Variant Caller analyses revealed in total 252 SNVs within the 40 DNAs from tumor tissue and/or serum analyzed which were not detected in normal tissue. Of these, 229 SNVs were novel and not yet reported in the Cosmic database. Mutations were detected for 10 genes in both ptDNA and cfDNA, which enabled us to characterize ctDNA in serum of nine out of ten patients. The discovered mutations were already reported in Cosmic for PIK3CA, TP53, and NF1, but not for CDH1, APC, SMAD4, MLL, AKAP, CREBBP and MLL2. The PIK3CA, TP53 and APC mutations were observed in tumor and sera for 2, 3 and 2 patients, respectively. Mutations in the other genes, except MLL, were unique for individual patients. The mutation for MLL was seen in almost all patients at low frequencies (1-5%). The hotspot mutations in PIK3CA were confirmed with snapshot assays in the sequenced samples and in additional sera. In four patients, Cosmic reported mutations in BRCA1, KAT6B, MAP3K1, MLL2, PTCH1 and PTEN occurred in ctDNA at disease progression while they were not found in the primary tumor nor in preceding sera. The mutation frequencies ranged from 3% for BRCA1 and MAP3K1 to 6% for MLL2. Moreover, mutations for MED12 (3%) and MLL3 (4%), not yet reported in Cosmic, were each observed in two sera at disease progression for two additional patients. The remaining SNVs are currently verified for their authenticity and occurrence in ptDNA and/or ctDNA.
Conclusion: Molecular characterization of tumor and serum derived DNA with targeted next generation sequencing enabled us to identify ctDNA in serum and to detect mutations at disease progression that might play a role in resistance to first-line tamoxifen.
Citation Format: Maurice Jansen, Corine Beaufort, Jean Helmijr, Ronald van Marion, Niels Krol, Kim Monkhorst, Marian van Fessem, Ron van Schaik, Marcel Smid, Marion Meijer van Gelder, Maxime Look, Anita Trapman, Diana Ramirez-Ardila, Irene Lurkin, Ellen Zwarthoff, John Martens, John Foekens, Winand Dinjens, Stefan Sleijfer, Els Berns. Targeted molecular characterization of serum derived cell free DNA from metastatic breast cancer patients treated with first-line tamoxifen abstract. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-02-02.
PIK3CA mutations occur frequently in breast cancer, predominantly in exons 9 and 20. The aim of this retrospective study is to evaluate the PIK3CA mutation status for its relationship with prognosis ...and first-line endocrine therapy outcome. PIK3CA exon 9 and 20 were evaluated for mutations in 1,352 primary breast cancer specimens by SnaPshot multiplex analyses. The mutation status was studied for their relationship with metastasis-free survival (MFS) in 342 untreated lymph node-negative (LNN) patients and to time to progression (TTP) in estrogen receptor (ER)-positive patients with metastatic disease treated with first-line tamoxifen (N = 447) or aromatase inhibitors (AIs; N = 84). We detected in 423 patients hotspot mutations for PIK3CA (31 %). Mutations in exon 20 were detected in 251 patients (59 %), with H1047L and H1047R mutations in 37 (15 %) and 214 (85 %) cases, respectively. Mutations in PIK3CA exon 9 were discovered in 173 patients (41 %), with E542K and E545K mutations in 57 (32 %) and 104 (60 %) cases as most prevalent ones. Evaluation of the untreated LNN patients for prognosis showed no relationship between MFS and PIK3CA mutations, neither for exon 9 HR = 1.04 (95 % CI 0.57-1.89), P = 0.90 nor for exon 20 HR = 0.98 (95 % CI 0.63-1.54); P = 0.94 when compared to wild-type. The PIK3CA mutation status was also not associated with treatment outcome after first-line tamoxifen. On the other hand, patients treated with first-line AIs showed a longer TTP when having a PIK3CA mutation in exon 9 HR = 0.40 (95 % CI 0.17-0.95); P = 0.038 or exon 20 HR = 0.50 (95 % CI 0.27-0.91); P = 0.024 compared to wild-types, both significant in uni- and multivariate analysis including traditional predictive factors. All results remained when only HER2-negative patients were evaluated for each cohort. PIK3CA mutations in ER-positive tumors were significantly associated with a favorable outcome after first-line AIs, which needs further confirmation in other datasets. Mutations were not associated with prognosis in untreated LNN patients nor predictive outcome after first-line tamoxifen therapy in advanced disease patients.PUBLICATION ABSTRACT
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Primary central nervous system (CNS) tumors are the second most common cancer in children and adolescents, leading to premature death and disability. Population-based survival estimates aid ...decision-making in cancer control, however data on survival for primary CNS tumors in Latin America is lacking. We describe survival rates for children with primary CNS tumors treated in ten Colombian cities.
We analyzed data from children and adolescents newly diagnosed with cancer between 2012 and 2021, participating in the Childhood Cancer Clinical Outcomes Surveillance System (VIGICANCER) in ten cities in Colombia. VIGICANCER collects information on clinical outcomes from twenty-seven pediatric oncology units and conducts active follow-up every three months. VIGICANCER does not register craniopharyngiomas; we excluded intracranial germ cell tumors for this report. We used the Kaplan-Meier method to estimate the overall survival probability, stratified by sociodemographic variables, topography, WHO grading, receipt of radiation therapy, and type of surgical resection. We analyzed the prognostic capacity of variables using multivariate proportional Cox's regression, stratified by city and year of diagnosis.
During the study period, VIGICANCER included 989 primary CNS tumors in 879 children and 110 adolescents. The cohort median age was 9 years; 53% of patients were males, and 8% were Afro-descendants. Most common tumors were supratentorial astrocytomas (47%), astrocytic tumors (35%), medulloblastomas (20%), ependymomas (11%), and mixed and unspecified gliomas (10%). Five-year overall survival of the entire cohort was 54% (95% CI, 51-58); for supratentorial gliomas, WHO grade I was 77%, II was 62%, III-IV was 27%, respectively, and for medulloblastoma was 61%. The adjusted hazard rate ratio for patients with WHO grade III and IV, for those with subtotal resection, for brainstem location, and for those not receiving radiation therapy was 7.4 (95% CI, 4.7-11.8), 6.4 (95% CI, 4.2-9.8), 2.8 (95% 2.1-3.8), 2.0 (95% CI, 1.3-2.8) and 2.3 (95% CI, 1.7-3.0), respectively.
We found that half of Colombia's children and adolescents with primary CNS tumors survive five years, compared to 70% to 80% in high-income countries. In addition to tumor biology and location, gross total resection was crucial for improved survival in this cohort. Systematic monitoring of survival and its determinants provides empirical data for guiding cancer control policies.
EndoFLIP: una nueva tecnología Hani, Albis; Delgado Villarreal, Andres Fernando; Bejarano, Janeth ...
Revista Colombiana de Gastroenterología,
06/2021, Volume:
36, Issue:
2
Journal Article
Peer reviewed
Open access
Mediante la distensión de un balón con líquido conductor, la sonda de imagen luminal funcional endoluminal (EndoFLIP) evalúa las propiedades biomecánicas como la distensibilidad, volumen, presión e ...inclusive diámetros de regiones esfinterianas como la unión gastroesofágica, píloro y ano. La mayor evidencia en la utilidad clínica de la EndoFLIP está en los trastornos de motilidad esofágica, principalmente para identificar acalasia cuando la manometría esofágica de alta resolución y otras imágenes no logran diagnosticarla e inclusive, mediante el programa de FLIP 2.0, caracteriza la acalasia en subtipos a partir de patrones de motilidad del esófago distal en respuesta a la distensión. Se ha demostrado recientemente que la EndoFLIP tiene un rol diagnóstico, pronóstico o terapéutico en otras patologías como la esofagitis eosinofílica, reflujo gastroesofágico, gastroparesia, durante la fundoplicatura y dilatación esofágica.
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