Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial.

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). Interpretation: In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.

Recurrent genetic variants and prioritization of variants of uncertain clinical significance associated with hereditary breast and ovarian cancer in families from the Region of Murcia.

Objectives: Hereditary breast and ovarian cancer (HBOC) follows an autosomal dominant inheritance pattern of cancer susceptibility genes. The risk of developing this disease is primarily associated with germline mutations in the BRCA1 and BRCA2 genes. The advent of massive genetic sequencing technologies has expanded the mutational spectrum of this hereditary syndrome, thereby increasing the number of variants of uncertain clinical significance (VUS) detected by genetic testing. Methods: A prevalence study of HBOC was performed within 2,928 families from the Region of Murcia, in southeastern Spain. Genetic testing enabled the identification of recurrent pathogenic variants and founder mutations, which were mainly related to the BRCA1 and BRCA2 genes. VUS testing was performed using a prioritization algorithm designed by our working group. Results: Variants c.68_69del, c.212+1G>A, and c.5123C>A were detected in 30 % of BRCA1 carriers, whereas exon 2 deletion concurrent with c.3264dupT, c.3455T>G and c.9117G>A variants were found in 30 % of BRCA2 carriers. A total of 16 VUS (15 %) were prioritized. Conclusions: The genotype-phenotype correlation observed in our study is consistent with the scientific literature. Furthermore, the founder effect of c.1918C>T (BRCA1) and c.8251_8254del (ATM) was verified in the Murcian population, whereas exon 2 deletion (BRCA2) was proven to be a Spanish founder mutation. Our algorithm enabled us to prioritize potentially pathogenic VUS that required further testing to determine their clinical significance and potential role in HBOC.

Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.

BACKGROUND: The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer. METHODS: In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete. FINDINGS: Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction). INTERPRETATION: Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials. FUNDING: F Hoffmann-La Roche.

Identification of ALK-positive patients with advanced NSCLC and real-world clinical experience with crizotinib in Spain (IDEALK study).

OBJECTIVES: To determine the incidence of ALK translocations in patients with advanced/metastatic NSCLC in Spain, to describe the clinical characteristics of these patients, and to evaluate the effectiveness and safety of treatment with crizotinib in a real-world setting. METHODS: This is an observational prospective and retrospective cohort study to determine the incidence of ALK translocations and to analyze the effectiveness and safety of crizotinib in a real-world setting. Patient characteristics, treatment patterns, time to best overall response, duration of treatment, objective response rates (ORR), rates of adverse events (AE), progression free survival (PFS) and overall survival (OS) were evaluated in the ALK study cohort of patients treated with crizotinib (prospective and retrospective). ALK incidence and quality of life (QoL) questionnaires were measured from patients included in the prospective cohort. RESULTS: The incidence of ALK translocations was 5.5 % (31 of 559 patients). Compared with ALK-negative patients, ALK-positive patients were significantly younger, predominantly female, and non-smokers. In the crizotinib effectiveness and safety study, 91 patients (42 prospective, 49 retrospective) with ALK-positive NSCLC (43.9 % in first-line, 56.1 % in second or more lines) were included. The ORR was 59.3 % and the median duration of response was 13.5 months (IQR, 5.3-26.2). The median PFS was 15.8 months (95 % CI, 11.8-22.3) and the median OS was 46.5 months, with 53 patients (58.2 %) still alive at data cut-off date. Frequently reported AEs included elevated transaminases, gastrointestinal disorders, and asthenia. Most patients (76.5 %) reported improved or stable scores for global QoL during treatment. CONCLUSIONS: The observed incidence of ALK translocations in NSCLC patients is aligned with published reports. This analysis of the real-world clinical experience in Spain confirms the therapeutic benefit and safety of crizotinib in advanced/metastatic ALK-positive NSCLC. CLINICALTRIALS: gov: NCT02679170.

Drug cost avoidance analysis of cancer clinical trials in Spain: a study on cost contributors and their impact.

OBJECTIVE: Analyze the cost contributors and their impact on the drug cost avoidance (DCA) resulting from cancer clinical trials over the period of 2015-2020 in a tertiary-level hospital in Spain (HCUVA). METHODS: We performed a cross-sectional, observational, retrospective study of a total of 53 clinical trials with 363 patients enrolled. We calculated the DCA from the price of the best standard of care (i.e.: drugs that the institution would otherwise fund). A linear regression model was used to determine cost contributors and estimate their impact. RESULTS: The total DCA was ~ 4.9 million euros (31 clinical trials; 177 enrollees), representing ~ 30% and ~ 0,05% approximately of the annual pharmaceutical expenditures at the HCUVA and for the Spanish Health System, respectively. Cancer type analysis showed that lung cancer had the highest average DCA by trial, indicating that treatments in these trials were the most expensive. Linear regression analysis showed that the number of patients in a trial did not significantly affect that trial's DCA. Instead, cancer type, phase trials, and intention of treatment were significant cost contributors to DCA. Compared to digestive cancer trials, breast and lung trials were significantly more expensive, (p < 0.05 and p < 0.1, respectively). Phase III trials were more expensive than Phase II (p < 0.01) and adjuvant trials were less expensive than palliative (p < 0.05). CONCLUSION: We studied cost contributors that significantly impacted the estimated DCA from cancer clinical trials. Our work provides the groundwork to explore DCA contributors with potential to enhance public relations material and serve as a negotiating tool for budgeting, thus playing an important role to inform decisions about resource allocation.

Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance.

INTRODUCTION: BRCA1 and BRCA2 are the two main genes causing hereditary breast and ovarian cancer (HBOC). However, thanks to the development of Next Generation Sequencing (NGS), other genes linked to this syndrome (CHEK2, BRIP1, ATM and PALB2 among others) can be analysed. MATERIAL AND METHODS: an analysis by multigene panel testing was performed in 138 index cases (ICs) from HBOC Spanish families with a previous non-informative result for BRCA1/2. The BRCA Hereditary Cancer Master™ Plus kit, including 26 actionable and candidate genes related to HBOC was employed. Once classified, an algorithm was employed to prioritized those variants of unknown significance with a higher risk of having a deleterious effect. Moreover, a mRNA splicing assay was performed for the prioritized VUS c.3402+3A > C in ATM, located at intron 23. RESULTS: A total of 82 variants were found: 70 VUS and 12 pathogenic or probably pathogenic variants. The diagnostic yield in actionable genes non-BRCA was 7.97% of the total tested ICs. Overall, 19 VUS were prioritized, which meant 27% of the 70 total VUS. RNA analysis of the variant 3402+3A > C confirmed a deleterious impact on splicing. DISCUSSION: The implementation of a multigene panel in HBOC studied families improved the diagnostic yield, concordant with results obtained in previous publications. Due to the important number of VUS obtained in NGS, the application of a prioritization algorithm is needed in order to select those variants in which it is necessary to conduct further studies.

Analysis of adolescent oncology cases from 2008 through 2018 in a tertiary-level hospital: an opportunity for improvement.

Purpose: The purpose of this study was to disclose the variability of pathways currently taken in the treatment of adolescent patients from diagnosis to final follow-up with a view to developing a more homogenous system. Patients & methods: A cross-sectional, observational and retrospective study of the cancer diagnosis and assignment to medical care teams in adolescent patients (12-20 years) from January 2008 to December 2018 was conducted. A total of 345 adolescent patients aged between 12 and 20 years, diagnosed with cancer and treated at Hospital Clinico Universitario Virgen de la Arrixaca were included. Results: CNS tumors, followed by leukemia were the most frequent tumors. At the time of diagnosis, the highest incidences of patients were assisted in the pediatrics service adult oncology service (21.7%) and hematology (11%). Conclusion: Our aim is to highlight the need for a better transition for patients from pediatric to adult oncology and hematology services.

Lay abstract This study shows the reality of the care of adolescent cancer patients in a hospital in southern Spain. A cross-sectional, observational and retrospective study of cancer diagnoses and assignment to medical care teams in adolescent patients (12­20 years) from January 2008 to December 2018 was conducted. A total of 345 adolescent patients between 12 and 20 years old who had a cancer diagnosis and were treated at Hospital Clinico Universitario Virgen de la Arrixaca were included. CNS tumors, followed by leukemia were the most frequent. At the time of diagnosis, the patients were most commonly attended by the pediatrics service, which concentrates 46.5% of the study population. There is great variability in the treatment and follow-up of the same tumors. The need for a better transition for patients from pediatric to adult oncology and hematology services is demonstrated.

Immunoscore: a novel prognostic tool. Association with clinical outcome, response to treatment and survival in several malignancies.

The predictive accuracy of the traditional staging system for cancer, the American Joint Committee on Cancer/Union Internationale Centre le Cancer (AJCC/UICC) classification of malignant tumors, is based on disease progression as a tumor cell-autonomous process, regardless the effects of the host immune response. The natural history of a tumor includes different phases of growth, migration and invasion. During these phases, tumor cells interact with their microenvironment and are influenced by signals from stromal, endothelial, inflammatory and immune cells. Indeed, tumors are often infiltrated by defensive cells such as lymphocytes, macrophages or mast cells and it has been shown extensively that lymphocytes may control cancer outcome, as evidenced in several human malignancies. Increasing evidence suggests that cancer progression is strongly influenced by host immune response, which is represented by immune cell infiltrates. The T-lymphocyte-based immunoscore (IS) has proved to be a prognostic factor in human malignancies such as colon, pancreas and lung cancer, hepatocellular carcinoma, melanoma and even brain metastases. Although the IS was initially established to evaluate the prognosis of stage I/II/III colon cancer patients, its association with clinical outcomes and survival has been shown in other malignancies. The aim of this review is to analyze the association of IS with prognosis, survival and response to therapy in different tumor types.

New insights into the performance of multigene panel testing: Two novel nonsense variants in BRIP1 and TP53 in a young woman with breast cancer.

Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the tumour suppressor gene TP53. Here we report the case of a family whose index case was a woman diagnosed with bilateral breast cancer at the age of 18 and who had a non-informative result after BRCA1 and BRCA2 testing. After extending the study through multigene panel testing, two clinically relevant variants in the TP53 and BRIP1 genes, respectively, were found. Afterwards, the patient developed a glioblastoma. Both tumours were consistent with Li-Fraumeni syndrome. Thanks to the possibility of studying different genes related with hereditary breast and ovarian cancer, it was possible to find out the gene variant that caused the early onset cancers in the patient. Furthermore, genetic counselling was provided to the index case and her family.

SIRT1 and Estrogen Signaling Cooperation for Breast Cancer Onset and Progression.

Breast cancer remains a significant female mortality cause. It constitutes a multifactorial disease for which research on environmental factors offers little help in predicting onset or progression. The pursuit for its foundations by analyzing hormonal changes as a motive for disease development, indicates that increased exposure to estrogens associates with increased risk. A prevalent number of breast cancer cases show dependence on the increased activity of the classic nuclear estrogen receptor (ER) for cell proliferation and survival. SIRT1 is a Type III histone deacetylase which is receiving increasing attention due to its ability to perform activities over relevant non-histone proteins and transcription factors. Interestingly, concomitant SIRT1 overexpression is commonly found in ER-positive breast cancer cases. Both proteins had been shown to directly interact, in a process related to altered intracellular signaling and aberrant transcription, then promoting tumor progression. Moreover, SIRT1 activities had been also linked to estrogenic effects through interaction with the G-protein coupled membrane bound estrogen receptor (GPER). This work aims to summarize present knowledge on the interplay between SIRT1 and ER/GPER for breast cancer onset and progression. Lastly, evidences on the ability of SIRT1 to interact with TGFß signaling, a concurrent pathway significantly involved in breast cancer progression, are reported. The potential of this research field for the development of innovative strategies in the assessment of orphan breast cancer subtypes, such as triple negative breast cancer (TNBC), is discussed.

Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain).

RAD51C and RAD51D have been defined as susceptibility genes for hereditary breast and ovarian cancer syndrome in several studies. In the present study, a mutation analysis of these genes was performed on non BRCA1/2 families. RAD51C and RAD51D genes were analyzed in 141 and 77 families, respectively. The analysis included direct sequencing and multiple ligation probe analysis. The RAD51C pathogenic variant c.404G > A was identified in a breast and ovarian cancer family (0.7%), while the RAD51D pathogenic variant c.694C > T was described in an ovarian cancer family (1.3%). Moreover, three unknown clinical significance variants were detected: c.307T > G in RAD51C, and c.413A > G and c.715C > T in RAD51D. No large genomic rearrangements (LGRs) were found. RAD51D carriers suffered from premenopausal ovarian tumors. These results increase our knowledge about the RAD51C and RAD51D mutation spectrum and support the notion that these genes should be included in the gene panel testing performed on patients with hereditary breast and ovarian cancer syndrome.

Sirt1 interaction with active Smad2 modulates transforming growth factor-ß regulated transcription.

BACKGROUND: The simplicity of Transforming Growth Factor ß (TGFß) signaling pathway, linear and non-amplified, hardly sustains its variety of responses. This is often justified by the complex regulation showed by Smad proteins, TGFß signaling intracellular transducers, object of post-translational modifications that modulate TGFß-dependent transcription. Protein acetylation is emerging as a compelling mechanism affecting the activities of significant transcription factors, including p53, FOXO or NF-kB. Smad proteins might be controlled by this mechanism, implying that accessory factors capable of altering Smads-transcriptional complexes acetylation status and hence regulate TGFß responses remain to be identified. Understanding this interaction may help in the assessment of TGFß signaling outcomes, extending from healthy physiology to pathological conditions and cancer. METHODS: A two-hybrid chimera interacting system allowed to identify Sirt1, a NAD+ dependent type III histone deacetylase, as a novel Smad2 interactor. Several well stablished cellular models were applied to characterize this interaction by means of co-immunoprecipitation of tagged proteins and immuno-fluorescence staining. The occurrence of the interaction at Smad2 driven transcriptomic complexes was studied by means of DNA-pull-down and chromatin immunoprecipitation (ChIP), while its effects were assessed by protein over-expression and siRNA applied into a TGFß-dependent reporter gene assay. RESULTS: The interaction was confirmed and observed to be enhanced upon Smad2 acetylation, a known feature of active and nuclear Smad2. However, Sirt1 did not play a major role in Smad2 deacetylation. Anti-Sirt1 ChIP showed increased recovery of promoter regions corresponding to Smad2-driven genes after TGFß-stimulation, while its occurrence at Smad2-dependent transcriptomic complexes on DNA was found to effectively modulate gene expression. CONCLUSIONS: Sirt1 presence on Smad2-driven TGFß-dependent regulatory elements was detected and found to increase after TGFß treatment. Moreover, Sirt1 overexpression resulted in a decrease of the activity of a Smad2-driven TGFß-dependent reporter gene, while Sirt1 interference increased its activity. This would confirm the relevance of the discovered Sirt1-Smad2 interaction for the regulation of TGFß-dependent gene transcription.

Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers.

This is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C > T) and the most frequently detected mutations were c.68_69delAG, c.212 + 1G > A, c.5123C > A, c.211A > G and c.1918C > T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G > A, c.3264dupT and c.3455T > G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212 + 1G > A appeared in an important percentage of breast and ovarian cancer cases, c.5123C > A in bilateral breast cancer and c.9117G > A in bilateral breast cancer and ovarian cancer. With respect to clinical-pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained.

Potential drug-drug interactions in oncological adult inpatients at a Spanish hospital: epidemiology and risk factors.

BACKGROUND: Oncological patients are at high risk for drug-drug interactions (DDIs), which may contribute to therapeutic failure or lead to serious adverse events. OBJECTIVE: To determine the prevalence of potential DDIs in medication lists, to describe the most frequent DDIs and to investigate the possible risk factors associated with them. A prospective cohort study was performed at the Oncology Department of a tertiary hospital over a 12-week period. Twice a week, every inpatient's treatment sheet was collected and screened through two databases: Micromedex™ and Drug Interaction Facts™. All identified potential DDIs with a moderate or higher severity rating were recorded. Multivariate analysis was used to identify risk factors associated with DDIs. RESULT: A total of 1956 DDIs were detected in 699 treatment sheets. The prevalence of treatment sheets with DDIs was 81.0 % and 32.6 % by Micromedex™ and Drug Interaction Facts™, respectively. Central nervous depressant agents and antiemetics were the most commonly involved groups in DDIs. A higher number of non-antineoplastic drugs was related with potential DDIs [adjusted-OR 1.398 and 1.613 by Micromedex™ and Drug Interaction Facts™, respectively]. CONCLUSION The prevalence of potential DDIs was widely variable among databases. The main risk factor associated with DDIs was a higher number of non-antineoplastic medicines.

Novel BRCA1 deleterious mutation (c.1918C>T) in familial breast and ovarian cancer syndrome who share a common ancestry.

Mutations in breast cancer susceptibility (BRCA) genes lead to defects in DNA repair processes resulting in elevated genome instability and predisposing to breast and ovarian cancer. We report a novel mutation (c.1918C>T) in the exon 11 of the BRCA1 gene that consists of a nonsense mutation that causes a stop codon downstream in the 640 position of the protein. The mutation was present in two Spanish unrelated families and was associated with four breast cancer cases, including two bilateral breast cancer (one of them synchronous). The median age/mean age (range) was 48.5/44.25 years (27-53). This finding led us to perform haplotype analysis in all family carriers. Four highly polymorphic microsatellite markers were used (17-3858, 17-3930, D17S855, D17S1326) to establish whether or not all these families had a common ancestor. This analysis showed that all mutation carriers of these families had a common haplotype. None of the noncarriers of the mutation or of the 24 healthy controls showed this haplotype. Therefore, the c.1918C>T mutation carriers from these two families allows us to assert that all analyzed mutation carriers share a common ancestry.

[Immunohistochemical characterisation of breast cancer: towards a new clasification?]. / Características inmunohistoquímicas del cáncer de mama: hacia una nueva clasificación?

BACKGROUND: The aim of this paper is to determine the possible association between five different profiles of immunohistochemical expression related to clinical, histopathological and immunohistochemical known prognostic value variables for breast cancer. MATERIAL AND METHOD: A total of 194 breast carcinoma tumour samples were studied. In this study five groups or immunohistochemical profiles were defined, based on expression of hormone receptors (oestrogen or progesterone) and/or Her2/neu (luminal-type A, luminal-type B, mixed profile, Her2/neu profile and triple-negative-type profile) and we studied whether there are differences between them with regard to clinical, histopathological and immunohistochemical variables that have a known prognostic significance. RESULTS: In the series we found 134 (69%) cases corresponding to a luminal immunophenotype, of which 98 (50.5%) were from the luminal A group and 36 (18.6%) from luminal B. Twenty-nine cases (15.9%) were triple-negative, 18 (9.3%) mixed and 13 (6.7%) Her2/neu type. It is worth noting the relationship between the triple-negative and Her2/neu immunophenotypes and the more poorly differentiated histological forms (62% and 60%, respectively) and between the luminal A group and well-differentiated tumours (p = 0.008). Expression of ki67 was high in the triple-negative group (73.9%) and low in the luminal A group (26.3%; p = 0.001). The expression of p53 was also greater for the Her2/neu (55.5%) and triple-negative (60.8%) groups (p = 0.0005) than for the others. CONCLUSIONS: The subgroups without hormone receptor expression, with Her2/neu overexpression or without (triple-negative group), have characteristics associated with variables of a poorer prognosis. The lack of progesterone receptor expression also seems to be associated with these.

Características inmunohistoquímicas del cáncer de mama: ¿hacia una nueva clasificación? / Immunohistochemical characterisation of breast cancer: towards a new classification?

Introducción. El objetivo de este trabajo es determinarla posible asociación de cinco perfiles diferentes de expresión inmunohistoquímica con variables clínicas, histopatológicas e inmunohistoquímicas de conocido valor pronóstico en el cáncer de mama. Material y método. Se estudiaron 194 muestras de carcinoma ductal infiltrante de mama. Se definieron 5perfiles inmunohistoquímicos basados en la expresión de receptores hormonales (estrogénicos o de progesterona)y/o Her2neu (luminal A, luminal B, mixto,Her2neu y triple negativo) y se estudió si había diferencias entre ellos en relación con variables clínicas, histopatológicas e inmunohistoquímicas de conocido valor pronóstico. Resultados. En la serie se encontraron 134 (69%) casos correspondientes a un inmunofenotipo luminal, de los que 98 (50,5%) fueron del grupo luminal A y 36(18,6%) del luminal B; 29 (15,9%) casos fueron triples negativos, en 18 (9,3%) se daba un tipo mixto y en 13(6,7%), del tipo Her2neu. Destaca la relación entre los inmunofenotipos triple negativos y Her2neu con formas histológicas peor diferenciadas (el 62 y el 60%,respectivamente) y del grupo luminal A con tumores bien diferenciados (p = 0,008). La expresión de ki67fue mayor en el grupo triple negativo (73,9%) y baja en el luminal A (26,3%) (p = 0,001). La expresión de p53también fue mayor para los grupos Her2neu (55,5%) y triple negativo (60,8%) (p = 0,0005) respecto a los otros. Conclusiones. Los subgrupos sin expresión de receptores hormonales, con sobreexpresión de Her2neuo sin ella (triple negativo) presentan características asociadas con variables de peor pronóstico. La pérdida de expresión de receptores a progesterona también parece asociarse con ellas (AU)

Background. The aim of this paper is to determine the possible association between five different profiles of immunohistochemical expression related to clinical, histopathological and immunohistochemical known prognostic value variables for breast cancer. Material and method. A total of 194 breast carcinomatumour samples were studied. In this study five groups or immunohistochemical profiles were defined, based on expression of hormone receptors (oestrogenor progesterone) and/or Her2/neu (luminaltypeA, luminal-type B, mixed profile, Her2/neu profile and triple-negative-type profile) and we studied whether there are differences between them with regard to (..) (AU)

[Primary non-lymphoid thymic neoplasms. A study of 58 cases]. / Neoplasias primarias del timo de estirpe no linfoide. Estudio de 58 casos.

BACKGROUND AND OBJECTIVE: Primary non-lymphoid thymus tumors (PNLTT) are an uncommon though quite varied pathology. Our objective was to identify the clinical, therapeutic and histologic variables with a prognostic value in these neoplasms. PATIENTS AND METHOD: We studied 58 PNLTT cases, corresponding to 52 epithelial neoplams (PTEN), 4 thymolipomas (7%) and 2 neuroendocrine tumors (3%). Commonest clinical manifestations were myasthenia gravis (41%) and dyspnea (21%). Three patients were symptom-free (24%). We used Kaplan-Meier survival curves and Cox regression model. RESULTS: All patients underwent surgery which consisted of thymectomy. Four patients underwent a biopsy procedure alone. Perioperative mortality was 3% (n = 2) and morbidity was 31% (n = 18), mainly because of respiratory and wound problems. 24 patients with PTEN, Masaoka degrees III and IV, and a patient with a lymphoepithelial carcinoma received adjuvant chemotherapy and/or radiotherapy. With a follow-up of 13 + 5 years, 12 PTEN patients and one patient with a neuroendrocrine tumor died as a consequence of the evolution of the disease. Cumulative survival was 80% at 5 years, 71% at 7 years and 63% at 10 years. There are currently two local relapses in two PTEN cases after 9 and 8 years of follow-up, respectively. Main prognostic factors are the histologic type and subtype and the clinical stage (p < 0.001). CONCLUSIONS: In PNLTT early diagnosis is crucial in order to administer a correct treatment before the clinical stage is more advanced. Main prognostic factors are the histologic type and subtype and the clinical stage.