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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.

El síndrome de cáncer de mama y ovario hereditario (SCMOH) presenta un patrón de herencia autosómica dominante en genes de susceptibilidad al cáncer y su riesgo está principalmente vinculado a mutaciones germinales en BRCA1 y BRCA2. Sin embargo, la implementación de paneles genéticos mediante secuenciación masiva en la práctica asistencial, ha ampliado el espectro mutacional de este síndrome hereditario y el número de variantes de significado clínico desconocido (VUS) detectadas en los estudios genéticos.

Despite the fact that thromboembolism is relatively common in oncology patients and that the interrelationship between thrombotic risk and specific mechanisms of tumorigenesis has long been known, many cardinal elements of prevention and treatment remain unresolved. Among the existing knowledge gaps, the need to validate the Ay scale and compare it to the Khorana index, develop, and standardize the use of predictive biomarkers for thrombotic risk, conduct clinical trials in thromboprophylaxis adapted to thrombotic risk, evaluate the efficacy and safety of direct anticoagulants, select patients who can benefit from anticoagulants for antitumor treatment, validate the EPIPHANY study decision tree to choose patients with low-risk pulmonary embolism, and accumulate more practical experience in special situations (rethrombosis, prolonged therapy beyond 6 months, etc.) are especially remarkable. These gray areas surrounding cancer-related thromboembolism explain why it continues to be a relatively common cause of serious events, at times interfering significantly with the development of new tumor-fighting strategies. [ABSTRACT FROM AUTHOR]

Unlabelled: `Background: Predictive models to identify low-risk febrile neutropenia (FN) have been developed with heterogeneous samples, which included stable and unstable patients, solid tumours, acute leukaemia and bone marrow transplantation. These models fail to recognise 5-15% of cases with unexpected complications, and literature specifically addressing apparently stable patients (ASPs) is scarce.Methods: We reviewed 861 episodes of FN in outpatients with solid tumours, including 692 (80%) episodes with apparent clinical stability. We aimed to investigate the prognosis of this latter group and explore the possibility of stratifying it according to the presenting features. A case-control study was performed and the MASCC index was evaluated.Results: The rates of complications and bacteraemia in ASPs were 7.3% and 6.2%, respectively. The MASCC index yielded a low sensitivity to detect complications (36%). Prognostic factors were identified: ECOG performance status ≥2, chronic bronchitis, chronic heart failure, stomatitis NCI grade ≥2, monocytes <200 mm(-3) and stress hyperglycaemia.Conclusion: A very simple assessment is useful to classify the patients with FN according to the risk of complications. A few additional variables may predict the clinical course of the patients. We additionally show that the MASCC index applied to this specific group has a low sensitivity to predict complications. [ABSTRACT FROM AUTHOR]

Methods: We analyzed TIL CD4 and CD8 subpopulations in BC patients treated with sequential anthracyclines and taxanes NC. A tissue microarray with paired pre- and post- NC biopsies was built, and immunohistochemically stained for CD4 and CD8. Tumor area- adjusted morphometric analysis was performed with Image J software after slide scanning and digitalization (results expressed as TIL count/mm2 ). Statistical analysis was done with SPSS 15.0 software. Results: We included 121 consecutive patients. Clinical stages: 15,7% IIA, 28% IIB, 33,3% IIIA, 6,6% IIIB, 16,5% IIIC. Histology: 93% ductal infiltrating carcinomas. Phenotypic classification by immunohistochemistry (IHC): 50,4% RE+ and/or RP+ and HER2NEU negative; 13,2% RE+ and/or RP+ and HER2NEU positive; 9,9% RE- and RP- and HER2NEU positive; 21,5% RE- and RP- and HER2NEU negative; 5% non-classifiable. Treatment: 80.2% AC x 4 courses followed by docetaxel x 4 courses. Pathological response: complete pathologic response (pCR) rate was 17,4% (primary tumor pCR: 20,7%; axillary pCR: 35,5%). After a median follow up of 52 months neither overall survival (OS) nor disease free survival (DFS) has been reached. Mean pre-chemotherapy CD4 count was 59,98 (± 107,53, SD). We did not found any association with clinical or pathologic tumor characteristic at diagnosis (stage, grade, hormonosensitivity, HER2NEU overexpression or IHC tumor classification). Mean CD4 count was significantly higher in patients achieving pCR than in patients without pCR (112,43 vs 49,91 CD4/mm²; p 0,009). Mean pre-chemotherapy CD8 count was 16,23 (± 56,96, SD) and was higher in grade 3 carcinomas (32,83 vs 22,37; p < 0,03); no other association with tumor characteristics or with pCR was found. Mean variation in CD4 after NC (=postNC -- preNC count) was 47,35 (± 104,49) CD4/mm2 , and it was larger in patients with pCR (102,01 vs 36,85 CD4/mm² ; p < 0,010). An opposite non-significant trend was observed for CD8 variation after NC (pCR: 39,42 vs non-pCR: 20,22, p < 0,14). To integrate the influence of both CD4 and CD8 on response to chemotherapy, the predictive value of pre-treatment ratio between CD4 and CD8 counts (CD4/CD8) was analyzed. We found a highly significant difference for CD4/CD8 between patients with and without pCR to NC (103 vs 17; p 0.002). Multivariate logistic regression analysis demonstrated that only a high pretreatment CD4/CD8 ratio (p < 0,006), hormone sensitivity (p < 0,03) and Her2 overexpression (p < 0.01) independently predicted pCR after NC. No differences in overall or disease-free survival were demonstrated for high vs. low CD4/CD8 pre-NC ratio. Conclusion: A high pretreatment CD4/CD8 ratio independently predicted pathological complete response in patients with invasive breast cancer receiving anthracyclines and taxanes NC. Our results support the contribution of tumor microenvironment immunologic response to chemotherapy effects on breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Peripherally inserted central venous catheters (PICC) in the onco-hematological patients may be associated with thrombosis or infections that may have short- to medium-term repercussions., Material and Methods: Single-centre retrospective analysis of a prospectively collected cohort. Primary objective was to establish the PICC-thrombosis and infections incidence. Secondary objectives were to analyze profile of patients suffering from these complications and variables associated with an increased likelihood of developing these events., Results: 549 patients were recruited. 58.5% (n = 321) were oncology patients and 41.5% (n = 228) hematology patients. The incidence of PICC-associated thrombosis was 3.5% (n = 19). Thrombosis was associated with progression of the underlying malignant pathology in 10.6% (n = 2) of cases. No association was found between clinical variables analysed and development of thrombosis. Incidence of PICC-associated infections was 7.65% (n = 42). In the 30 days prior to PICC infection, 57.1% (n = 24) had a febrile syndrome of another focus, 73.8% (n = 11) had been hospitalized, 49.5% (n = 25) had a neutrophil count of 0-500 cells/mm3 and 47.6% (n = 20) had an episode of neutropenic fever. Variables significantly associated with the development of infection were hematological patients, high-flow PICC, 3-lm PICC or PICC insertion because of administration of vesicant therapy., Conclusions: Incidence of PICC-associated thrombosis is low and apparently less prognostically aggressive than other forms of thrombosis associated with cancer, without identify predictive factors. Infection was more prevalent and the identification of risk factors in our series could facilitate its prevention., Competing Interests: Declarations Conflicts of interest The authors of this article have no conflicts of interest in relation to this work., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Purpose: The prognostic utility and biological correlates of neutrophil to lymphocyte ratio (NLR), a potential biomarker of the balance between immune response and the inflammatory status, are still uncertain in breast cancer (BC)., Methods: We analysed a cohort of 959 women with early breast cancer, mostly treated with neoadjuvant or adjuvant chemotherapy. Clinical and pathological data, survival, NLR (continuous and categorical) and stromal tumor infiltrating lymphocytes (sTIL) were evaluated., Results: NLR was only weakly associated with Ki67, while no association was found for grade, histology, immunohistochemical subtype or stage. Lymphocyte infiltration of the tumor did not correlate with NLR (Rho: 0.05, p = 0.30). These results were similar in the whole group and across the different BC subtypes, with no differences in triple negative BC. Relapse free interval (RFI), breast cancer specific survival (BCSS) and overall survival (OS) changed according to pre-treatment NLR neither in the univariate nor in the multivariate Cox models (RFI: HR 0.948, p = 0.61; BCSS: HR 0.920, p = 0.57; OS: HR 0.96, p = 0.59)., Conclusion: These results question the utility of NLR as a prognostic biomarker in early breast cancer and suggest the lack of correlation of NLR with tumor microenvironment immune response., (© 2024. The Author(s).)

Breast cancer is the leading cause of cancer in women in Spain and its annual incidence is rapidly increasing. Thanks to the screening programs in place, nearly 90% of breast cancer cases are detected in early and potentially curable stages, despite the COVID-19 pandemic possibly having impacted these numbers (not yet quantified). In recent years, locoregional and systemic therapies are increasingly being directed by new diagnostic tools that have improved the balance between toxicity and clinical benefit. New therapeutic strategies, such as immunotherapy, targeted drugs, and antibody-drug conjugates have also improved outcomes in some patient subgroups. This clinical practice guideline is based on a systematic review of relevant studies and on the consensus of experts from GEICAM, SOLTI, and SEOM., (© 2023. The Author(s).)

Importance: Biomarkers to guide the use of pertuzumab in the treatment of early-stage ERBB2 (formerly HER2)-positive breast cancer beyond simple ERBB2 status are needed., Objective: To determine if use of the HER2DX genomic assay (Reveal Genomics) in pretreatment baseline tissue samples of patients with ERBB2-positive breast cancer is associated with response to neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab., Design, Setting, and Participants: This is a retrospective diagnostic/prognostic analysis of a multicenter academic observational study in Spain performed during 2018 to 2022 (GOM-HGUGM-2018-05). In addition, a combined analysis with 2 previously reported trials of neoadjuvant cohorts with results from the assay (DAPHNe and I-SPY2) was performed. All patients had stage I to III ERBB2-positive breast cancer, signed informed consent, and had available formalin-fixed paraffin-embedded tumor specimens obtained prior to starting therapy., Exposures: Patients received intravenous trastuzumab, 8 mg/kg, loading dose, followed by 6 mg/kg every 3 weeks in combination with intravenous docetaxel, 75 mg/m2, every 3 weeks and intravenous carboplatin area under the curve of 6 every 3 weeks for 6 cycles, or this regimen plus intravenous pertuzumab, 840 mg, loading dose, followed by an intravenous 420-mg dose every 3 weeks for 6 cycles., Main Outcome and Measures: Association of baseline assay-reported pathologic complete response (pCR) score with pCR in the breast and axilla, as well as association of baseline assay-reported pCR score with response to pertuzumab., Results: The assay was evaluated in 155 patients with ERBB2-positive breast cancer (mean [range] age, 50.3 [26-78] years). Clinical T1 to T2 and node-positive disease was present in 113 (72.9%) and 99 (63.9%) patients, respectively, and 105 (67.7%) tumors were hormone receptor positive. The overall pCR rate was 57.4% (95% CI, 49.2%-65.2%). The proportion of patients in the assay-reported pCR-low, pCR-medium, and pCR-high groups was 53 (34.2%), 54 (34.8%), and 48 (31.0%), respectively. In the multivariable analysis, the assay-reported pCR score (as a continuous variable from 0-100) showed a statistically significant association with pCR (odds ratio [OR] per 10-unit increase, 1.43; 95% CI, 1.22-1.70; P < .001). The pCR rates in the assay-reported pCR-high and pCR-low groups were 75.0% and 28.3%, respectively (OR, 7.85; 95% CI, 2.67-24.91; P < .001). In the combined analysis (n = 282), an increase in pCR rate due to pertuzumab was found in the assay-reported pCR-high tumors (OR, 5.36; 95% CI, 1.89-15.20; P < .001) but not in the assay-reported pCR-low tumors (OR, 0.86; 95% CI, 0.30-2.46; P = .77). A statistically significant interaction between the assay-reported pCR score and the effect of pertuzumab in pCR was observed., Conclusions and Relevance: This diagnostic/prognostic study demonstrated that the genomic assay predicted pCR following neoadjuvant trastuzumab-based chemotherapy with or without pertuzumab. This assay could guide therapeutic decisions regarding the use of neoadjuvant pertuzumab.

Background: Up to 30% of breast cancer (BC) patients treated with neoadjuvant chemotherapy (NCT) will relapse. Our objective was to analyze the predictive capacity of several markers associated with immune response and cell proliferation combined with clinical parameters., Methods: This was a single-center, retrospective cohort study of BC patients treated with NCT (2001-2010), in whom pretreatment biomarkers were analyzed: neutrophil-to-lymphocyte ratio (NLR) in peripheral blood, CD3+ tumor-infiltrating lymphocytes (TILs), and gene expression of AURKA, MYBL2 and MKI67 using qRT-PCR., Results: A total of 121 patients were included. Median followup was 12 years. In a univariate analysis, NLR, TILs, AURKA, and MYBL2 showed prognostic value for overall survival. In multivariate analyses, including hormone receptor, HER2 status, and response to NCT, NLR (HR 1.23, 95% CI 1.01-1.75), TILs (HR 0.84, 95% CI 0.73-0.93), AURKA (HR 1.05, 95% CI 1.00-1.11) and MYBL2 (HR 1.19, 95% CI 1.05-1.35) remained as independent predictor variables., Conclusion: Consecutive addition of these biomarkers to a regression model progressively increased its discriminatory capacity for survival. Should independent cohort studies validate these findings, management of early BC patients may well be changed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 García-Torralba, Navarro Manzano, Luengo-Gil, De la Morena Barrio, Chaves Benito, Pérez-Ramos, Álvarez-Abril, Ivars Rubio, García-Garre, Ayala de la Peña and García-Martínez.)

Luminal breast cancer (BC) is associated with less immune activation, and the significance of stromal lymphocytic infiltration (sTIL) is more uncertain than in other BC subtypes. The aim of this study was to investigate the predictive and prognostic value of sTIL in early luminal BC. The study was performed with an observational design in a prospective cohort of 345 patients with predominantly high-risk luminal (hormone receptor positive, HER2 negative) BC and with luminal B features ( n = 286), in which the presence of sTIL was analyzed with validated methods. Median sTIL infiltration was 5% (Q1-Q3 range (IQR), 0-10). We found that sTIL were associated with characteristics of higher biological and clinical aggressiveness (tumor and lymph node proliferation and stage, among others) and that the percentage of sTIL was predictive of pathologic complete response in patients treated with neoadjuvant chemotherapy (OR: 1.05, 95%CI 1.02-1.09, p < 0.001). The inclusion of sTIL (any level of lymphocytic infiltration: sTIL > 0%) in Cox regression multivariable prognostic models was associated with a shorter relapse-free interval (HR: 4.85, 95%CI 1.33-17.65, p = 0.016) and significantly improved its performance. The prognostic impact of sTIL was independent of other clinical and pathological variables and was mainly driven by its relevance in luminal B BC.

Introduction: Hepsin is a type II transmembrane serine protease and its expression has been linked to greater tumorigenicity and worse prognosis in different tumors. Recently, our group demonstrated that high hepsin levels from primary tumor were associated with a higher risk of metastasis and thrombosis in localized colorectal cancer patients. This study aims to explore the molecular role of hepsin in colorectal cancer. Methods: Hepsin levels in plasma from resected and metastatic colorectal cancer patients were analyzed by ELISA. The effect of hepsin levels on cell migration, invasion, and proliferation, as well as on the activation of crucial cancer signaling pathways, was performed in vitro using colorectal cancer cells. A thrombin generation assay determined the procoagulant function of hepsin from these cells. A virtual screening of a database containing more than 2000 FDA-approved compounds was performed to screen hepsin inhibitors, and selected compounds were tested in vitro for their ability to suppress hepsin effects in colorectal cancer cells. Xenotransplantation assays were done in zebrafish larvae to study the impact of venetoclax on invasion promoted by hepsin. Results: Our results showed higher plasma hepsin levels in metastatic patients, among which, hepsin was higher in those suffering thrombosis. Hepsin overexpression increased colorectal cancer cell invasion, Erk1/2 and STAT3 phosphorylation, and thrombin generation in plasma. In addition, we identified venetoclax as a potent hepsin inhibitor that reduced the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells. Interestingly, pretreatment with Venetoclax of cells overexpressing hepsin reduced their invasiveness in vivo . Discussion: Our results demonstrate that hepsin overexpression correlates with a more aggressive and prothrombotic tumor phenotype. Likewise, they demonstrate the antitumor role of venetoclax as a hepsin inhibitor, laying the groundwork for molecular-targeted therapy for colorectal cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rodenas, Peñas-Martínez, Pardo-Sánchez, Zaragoza-Huesca, Ortega-Sabater, Peña-García, Espín, Ricote, Montenegro, Ayala-De La Peña, Luengo-Gil, Nieto, García-Molina, Vicente, Bernardi, Lozano, Mulero, Pérez-Sánchez, Carmona-Bayonas and Martínez-Martínez.)

Introduction: There is currently no validated score capable of classifying cancer-associated pulmonary embolism (PE) in its full spectrum of severity. This study has validated the EPIPHANY Index, a new tool to predict serious complications in cancer patients with suspected or unsuspected PE., Method: The PERSEO Study prospectively recruited individuals with PE and active cancer or receiving antineoplastic therapy from 22 Spanish hospitals. The estimation of the relative frequency θ of complications based on the EPIPHANY Index categories was made using the Bayesian alternative for the binomial test., Results: A total of 900 patients, who were diagnosed with PE between October 2017 and January 2020, were enrolled. The rate of serious complications at 15 days was 11.8%, 95% highest density interval [HDI], 9.8-14.1%. Of the EPIPHANY low-risk patients, 2.4% (95% HDI, 0.8-4.6%) had serious complications, as did 5.5% (95% HDI, 2.9-8.7%) of the moderate-risk participants and 21.0% (95% HDI, 17.0-24.0%) of those with high-risk episodes. The EPIPHANY Index was associated with overall survival (OS) in patients with different risk levels: median OS was 16.5, 14.4, and 4.4 months for those at low, intermediate, and high risk, respectively. Both the EPIPHANY Index and the Hestia criteria exhibited greater negative predictive value and a lower negative likelihood ratio than the remaining models. The incidence of bleeding at 6 months was 6.2% (95% HDI, 2.9-9.5%) in low/moderate-risk vs 12.7% (95% HDI, 10.1-15.4%) in high-risk (p-value = 0.037) episodes. Of the outpatients, serious complications at 15 days were recorded in 2.1% (95% HDI, 0.7-4.0%) of the cases with EPIPHANY low/intermediate-risk vs 5.3% (95% HDI, 1.7-11.8%) in high-risk cases., Conclusion: We have validated the EPIPHANY Index in patients with incidental or symptomatic cancer-related PE. This model can contribute to standardize decision-making in a scenario lacking quality evidence., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sánchez-Cánovas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

While the role of miR-200c in cancer progression has been established, its expression and prognostic role in breast cancer is not completely understood. The predictive role of miR-200c in response to chemotherapy has also been suggested by some studies, but only limited clinical evidence is available. The purpose of this study was to investigate miR-200c-3p in the plasma and primary tumor of BC patients. The study design included two cohorts involving women with locally advanced (LABC) and metastatic breast cancer. Tumor and plasma samples were obtained before and after treatment. We found that miR-200c-3p was significantly higher in the plasma of BC patients compared with the controls. No correlation of age with plasma miR-200c-3p was found for controls or for BC patients. MiR-200c-3p tumor expression was also associated with poor overall survival in LABC patients treated with neoadjuvant chemotherapy, independently of pathological complete response or clinical stage. Our findings suggest that plasmatic miR-200c-3p levels could be useful for BC staging, while the tumor expression of miR-200c-3p might provide further prognostic information beyond residual disease in BC treated with neoadjuvant chemotherapy.

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., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)