Contribution of Endothelial Dysfunction to Cancer Susceptibility and Progression: A Comprehensive Narrative Review on the Genetic Risk Component.

Venous thromboembolism (VTE) is a challenging clinical obstacle in oncological settings, marked by elevated incidence rates and resulting morbidity and mortality. In the context of cancer-associated thrombosis (CAT), endothelial dysfunction (ED) plays a crucial role in promoting a pro-thrombotic environment as endothelial cells lose their ability to regulate blood flow and coagulation. Moreover, emerging research suggests that this disorder may not only contribute to CAT but also impact tumorigenesis itself. Indeed, a dysfunctional endothelium may promote resistance to therapy and favour tumour progression and dissemination. While extensive research has elucidated the multifaceted mechanisms of ED pathogenesis, the genetic component remains a focal point of investigation. This comprehensive narrative review thus delves into the genetic landscape of ED and its potential ramifications on cancer progression. A thorough examination of genetic variants, specifically polymorphisms, within key genes involved in ED pathogenesis, namely eNOS, EDN1, ACE, AGT, F2, SELP, SELE, VWF, ICAM1, and VCAM1, was conducted. Overall, these polymorphisms seem to play a context-dependent role, exerting both oncogenic and tumour suppressor effects depending on the tumour and other environmental factors. In-depth studies are needed to uncover the mechanisms connecting these DNA variations to the pathogenesis of malignant diseases.

Haemostatic gene variations in cervical cancer-associated venous thrombosis: considerations for clinical strategies.

Venous thromboembolism (VTE) is a life-threatening haemostatic disease frequently diagnosed among the cancer population. The Khorana Score is currently the primal risk assessment model to stratify oncological patients according to their susceptibility to VTE, however, it displays a limited performance. Meanwhile, intensive research on VTE pathophysiology in the general population has uncovered a range of single-nucleotide polymorphisms (SNPs) associated with the condition. Nonetheless, their predictive ability concerning cancer-associated thrombosis (CAT) is controversial. Cervical cancer (CC) patients undergoing chemoradiotherapy often experience VTE, which negatively affects their survival. Thus, aiming for an improvement in thromboprophylaxis, new thrombotic biomarkers, including SNPs, are currently under investigation. In this study, the predictive capability of haemostatic gene SNPs on CC-related VTE and their prognostic value regardless of VTE were explored. Six SNPs in haemostatic genes were evaluated. A total of 401 CC patients undergoing chemoradiotherapy were enrolled in a retrospective cohort study. The implications for the time to VTE occurrence and overall survival (OS) were assessed. CAT considerably impacted the CC patients' OS (log-rank test, P < 0.001). SERPINE1 rs2070682 (T > C) showed a significant association with the risk of CC-related VTE (CC/CT vs. TT, log-rank test, P = 0.002; C allele, Cox model, hazard ratio (HR) = 6.99 and P = 0.009), while F2 rs1799963 (G > A) demonstrated an important prognostic value regardless of VTE (AA/AG vs. GG, log-rank test, P = 0.020; A allele, Cox model, HR = 2.76 and P = 0.026). For the remaining SNPs, no significant associations were detected. The polymorphisms SERPINE1 rs2070682 and F2 rs1799963 could be valuable tools in clinical decision-making, aiding in thromboprophylaxis and CC management, respectively.

Paradigm Shift: A Comprehensive Review of Ovarian Cancer Management in an Era of Advancements.

Ovarian cancer (OC) is the female genital malignancy with the highest lethality. Patients present a poor prognosis mainly due to the late clinical presentation allied with the common acquisition of chemoresistance and a high rate of tumour recurrence. Effective screening, accurate diagnosis, and personalised multidisciplinary treatments are crucial for improving patients' survival and quality of life. This comprehensive narrative review aims to describe the current knowledge on the aetiology, prevention, diagnosis, and treatment of OC, highlighting the latest significant advancements and future directions. Traditionally, OC treatment involves the combination of cytoreductive surgery and platinum-based chemotherapy. Although more therapeutical approaches have been developed, the lack of established predictive biomarkers to guide disease management has led to only marginal improvements in progression-free survival (PFS) while patients face an increasing level of toxicity. Fortunately, because of a better overall understanding of ovarian tumourigenesis and advancements in the disease's (epi)genetic and molecular profiling, a paradigm shift has emerged with the identification of new disease biomarkers and the proposal of targeted therapeutic approaches to postpone disease recurrence and decrease side effects, while increasing patients' survival. Despite this progress, several challenges in disease management, including disease heterogeneity and drug resistance, still need to be overcome.

Cancer-associated thrombosis: What about microRNAs targeting the tissue factor coagulation pathway?

Cancer patients are often diagnosed with venous thromboembolism (VTE), a cardiovascular disease that substantially decreases their quality of life and survival rate. Haemostasis in these patients is deregulated, which is reflected in the common presentation of a blood hypercoagulation state. Despite the inconsistent results, existing evidence suggests that the expression of microRNAs (miRNAs) is deregulated in the context of venous thrombogenesis in the general population. However, few miRNAs are known to be linked to cancer-associated VTE due to the lack of studies with oncological patients. Parallelly, coagulation factor III, also known as tissue factor (TF), tissue factor pathway inhibitor 1 (TFPI1) and tissue factor pathway inhibitor 2 (TFPI2) have been proposed to have a central role in cancer-associated VTE and tumour progression. Yet, contrary to what was expected, the role of miRNAs targeting the TF coagulation pathway (or extrinsic coagulation pathway) is poorly explored in cancer-induced thrombogenesis. In this review, in addition to miRNAs implicated in VTE, TF and TFPI1/2-targeting miRNAs were revised. Future studies should clarify the implications of these non-coding RNAs in tumour coagulome.

Bilateral breast cancer and the influence of body mass index in clinicopathological features and overall survival.

BACKGROUND: Breast cancer (BC) and obesity are two closely associated pathologies with increasing incidence and mortality rates. Bilateral Breast Cancer (BBC) displays a low incidence rate within BC and obesity represents a major risk factor. OBJECTIVE: The aim of this study is to analyzed BBC clinicopathological features distribution and determine the potential influence of obesity in BBC in these same features and overall survival. METHODS: Clinicopathological information was obtained from 42 cases of women with BBC diagnosed in IPO-Porto. To evaluate the frequency distribution of the clinicopathological data, a chi-square goodness of fit test was performed for BBC cases. A chi-square test of independence was applied for BMI stratification. Cox regression was performed for overall survival. Statistical significance was set at p-value < 0.05. RESULTS: Distribution of BBC clinicopathological features was found to be statistically significant in family history (p-value < 0.001), BBC type (p-value < 0.001), stage (p-value = 0.005), differentiation grade (p-value < 0.001), receptor expression (p-value < 0.001) and histological type (p-value = 0.031). In comparison to the statistical expected results, we observed an increased cases of absence of family history and less cases of metachronous BBC. Histological types between tumours of BBC were mostly concordant. All cases presented concordant receptor expression. Analysis stratified by BMI revealed that obese women were diagnosed later, although without statistical significance. All obese women presented poor differentiation grade (n = 6). Overweight patients display a tendency to a better overall survival with lower tumour stages and lower differentiation grades. CONCLUSIONS: Our results reveal the same receptor expression between contralateral tumours. Also, most tumours share the same histological type. When stratified by BMI, we observed a tendency for overweight women to have improved overall survival.

Long Non-Coding RNAs in Venous Thromboembolism: Where Do We Stand?

Venous thromboembolism (VTE), a common condition in Western countries, is a cardiovascular disorder that arises due to haemostatic irregularities, which lead to thrombus generation inside veins. Even with successful treatment, the resulting disease spectrum of complications considerably affects the patient's quality of life, potentially leading to death. Cumulative data indicate that long non-coding RNAs (lncRNAs) may have a role in VTE pathogenesis. However, the clinical usefulness of these RNAs as biomarkers and potential therapeutic targets for VTE management is yet unclear. Thus, this article reviewed the emerging evidence on lncRNAs associated with VTE and with the activity of the coagulation system, which has a central role in disease pathogenesis. Until now, ten lncRNAs have been implicated in VTE pathogenesis, among which MALAT1 is the one with more evidence. Meanwhile, five lncRNAs have been reported to affect the expression of TFPI2, an important anticoagulant protein, but none with a described role in VTE development. More investigation in this field is needed as lncRNAs may help dissect VTE pathways, aiding in disease prediction, prevention and treatment.

Practical lessons learned from real-world implementation of the molecular classification for endometrial carcinoma.

OBJECTIVES: This study aimed to explore the practical organisational aspects and difficulties in the implementation of the molecular classification of endometrial carcinoma (EC), and to demonstrate its potential impact in prognostic risk group classification. METHODS: We conducted a multicentre, retrospective cohort study of 230 patients with EC diagnosed between 2019 and 2022. Sample processing, clinicopathological, treatment and follow-up data were collected. Molecular classification was obtained by p53 and mismatch repair proteins immunohistochemistry, and POLE next-generation sequencing. RESULTS: Implementation was achieved through centralization of molecular analysis. In practice, it was possible to optimise turnaround times of complete integrative reports for hysterectomy specimens to a median time of 18 workdays. If genetic study was started in endometrial biopsies before surgery, 82.0% were available at the time of multidisciplinary tumour board, compared to 8.4% if performed in hysterectomy. ECs were classified as follows: 37.8% no specific molecular profile, 31.7% p53 abnormal, 24.3% mismatch repair deficient, and 6.1% POLE mutant. Integration of these results with traditional clinicopathologic factors led to a change in prognostic risk group in 15 (6.5%) patients, most being initially allocated to high-intermediate (n = 8) and low (n = 5) risk groups. Eight patients changed to a higher risk, and 7 to a lower risk group, whereas 2 remained in the same group. CONCLUSIONS: Centralization of EC molecular classification is a feasible option for countries with limited resources. Optimization of workflows may be achieved by earlier analysis in biopsies and prioritisation of patients whose results imply changes in risk group classification.

Thrombogenesis-associated genetic determinants as predictors of thromboembolism and prognosis in cervical cancer.

Venous thromboembolism (VTE) is a leading cause of death among cancer patients. Khorana score (KS) is the most studied tool to predict cancer-related VTE, however, it exerts poor sensitivity. Several single-nucleotide polymorphisms (SNPs) have been associated with VTE risk in the general population, but whether they are predictors of cancer-related VTE is a matter of discussion. Compared to other solid tumours, little is known about VTE in the setting of cervical cancer (CC) and whether thrombogenesis-related polymorphisms could be valuable biomarkers in patients with this neoplasia. This study aims to analyse the effect of VTE occurrence on the prognosis of CC patients, explore the predictive capability of KS and the impact of thrombogenesis-related polymorphisms on CC-related VTE incidence and patients' prognosis regardless of VTE. A profile of eight SNPs was evaluated. A retrospective hospital-based cohort study was conducted with 400 CC patients under chemoradiotherapy. SNP genotyping was carried on by using TaqMan® Allelic Discrimination methodology. Time to VTE occurrence and overall survival were the two measures of clinical outcome evaluated. The results indicated that VTE occurrence (8.5%) had a significant impact on the patient's survival (log-rank test, P < 0.001). KS showed poor performance (KS ≥ 3, χ2, P = 0.191). PROCR rs10747514 and RGS7 rs2502448 were significantly associated with the risk of CC-related VTE development (P = 0.021 and P = 0.006, respectively) and represented valuable prognostic biomarkers regardless of VTE (P = 0.004 and P = 0.010, respectively). Thus, thrombogenesis-related genetic polymorphisms may constitute valuable biomarkers among CC patients allowing a more personalized clinical intervention.

Does body mass index influence surgical options and overall survival in breast cancer patients?

Obesity is a relevant risk factor in breast cancer (BC), but little is known about the effects of overweight and obesity in surgical outcomes of BC patients. The aim of this study is to analyse surgical options and associated overall survival (OS) in overweight and obese women with BC. In this study, 2143 women diagnosed between 2012 and 2016 at the Portuguese Oncology Institute of Porto (IPO-Porto) were included, and the clinicopathological information was retrieved from the institutional database. Patients were stratified by body mass index (BMI). Statistical analysis included Pearson's chi-squared test with statistical significance set at p < 0.05. Multinomial, binary logistic regression and cox proportional-hazards model were also performed to calculate odd ratios and hazard ratios with 95% confidence intervals for adjusted and non-adjusted models. The results revealed no statistical difference in histological type, topographic localization, tumour stage and receptor status and in the number of surgical interventions. Overweight women have increased probability to be subjected to sentinel node biopsy. Obese and overweight women are more likely to be submitted to conservative surgery and contrariwise, less likely to undergo total mastectomy. Patients submitted to conservative surgery and not submitted to total mastectomy had a favourable OS although without statistical significance. No significant differences were observed in OS when stratified by BMI. Our results revealed significant variations regarding the surgical options in overweight and obese patients, but these were not translated in OS difference. More research is recommended to better address treatment options in overweight and obese BC patients.

Map of thrombogenesis in viral infections and viral-driven tumours.

Viruses are pathogenic agents responsible for approximately 10% of all human cancers and significantly contribute to the global cancer burden. Until now, eight viruses have been associated with the development of a broad range of malignancies, including solid and haematological tumours. Besides triggering and promoting oncogenesis, viral infections often go hand-in-hand with haemostatic changes, representing a potential risk factor for venous thromboembolism (VTE). Conversely, VTE is a cardiovascular condition that is particularly common among oncological patients, with a detrimental impact on patient prognosis. Despite an association between viral infections and coagulopathies, it is unclear whether viral-driven tumours have a different incidence and prognosis pattern of thromboembolism compared to non-viral-induced tumours. Thus, this review aims to analyse the existing evidence concerning the association of viruses and viral tumours with the occurrence of VTE. Except for hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection, which are associated with a high risk of VTE, little evidence exists concerning the thrombogenic potential associated with oncoviruses. As for tumours that can be induced by oncoviruses, four levels of VTE risk are observed, with hepatocellular carcinoma (HCC) and gastric carcinoma (GC) associated with the highest risk and nasopharyngeal carcinoma (NPC) associated with the lowest risk. Unfortunately, the incidence of cancer-related VTE according to tumour aetiology is unknown. Given the negative impact of VTE in oncological patients, research is required to better understand the mechanisms underlying blood hypercoagulability in viral-driven tumours to improve VTE management and prognosis assessment in patients diagnosed with these tumours.

A retrospective study in tumour characteristics and clinical outcomes of overweight and obese women with breast cancer.

INTRODUCTION: Obesity and breast cancer are two major pathologies closely associated with increasing incidence and mortality rates, especially amongst women. The association between both diseases have been thoroughly discussed but much is still to uncover. AIM: The aim of this study is to analyse tumour characteristics and clinical outcomes of overweight and obese women to disclosure potential associations and better understand the impact of obesity in breast cancer. MATERIALS AND METHODS: Clinicopathological information of 2246 women were extracted from the institutional database of comprehensive cancer centre in Portugal diagnosed between 2012 and 2016. Women were stratified according to body mass index as normal, overweight, and obese. Patients' demographic information and tumour features (age, family history, topographic localization, laterality, histological type, and receptor status) were taken as independent variables and overall survival, tumour stage, differentiation grade and bilaterality were considered clinical outcomes. RESULTS: The main results reveal that overweight and obesity are predominantly associated with worse outcomes in breast cancer patients. Obese patients present larger (p-value: 0.002; OR 1.422; 95% CI 1.134-1.783) and more poorly differentiated tumours (p-value: 0.002; OR 1.480; 95% CI 1.154-1.898) and tend to have lower overall survival although without statistical significance (p-value: 0.117; OR 1.309; 95% CI 0.934-1.833). Overweighted women are more likely to have bilateral breast cancer (p-value: 0.017; OR 3.076; 95% CI 1.225-7.722) than obese women. The results also reveal that overweight women present less distant metastasis (p-value: 0.024; OR 0.525; 95%CI 0.299-0.920). Topographic localization and laterality did not achieve statistical significance.

Long Non-Coding RNAs: Bridging Cancer-Associated Thrombosis and Clinical Outcome of Ovarian Cancer Patients.

Ovarian cancer (OC) and venous thromboembolism (VTE) have a close relationship, in which tumour cells surpass the haemostatic system to drive cancer progression. Long non-coding RNAs (lncRNAs) have been implicated in VTE pathogenesis, yet their roles in cancer-associated thrombosis (CAT) and their prognostic value are unexplored. Understanding how these lncRNAs influence venous thrombogenesis and ovarian tumorigenesis may lead to the identification of valuable biomarkers for VTE and OC management. Thus, this study evaluated the impact of five lncRNAs, namely MALAT1, TUG1, NEAT1, XIST and MEG8, on a cohort of 40 OC patients. Patients who developed VTE after OC diagnosis had worse overall survival compared to their counterparts (log-rank test, p = 0.028). Elevated pre-chemotherapy MEG8 levels in peripheral blood cells (PBCs) predicted VTE after OC diagnosis (Mann-Whitney U test, p = 0.037; Χ2 test, p = 0.033). In opposition, its low levels were linked to a higher risk of OC progression (adjusted hazard ratio (aHR) = 3.00; p = 0.039). Furthermore, low pre-chemotherapy NEAT1 levels in PBCs were associated with a higher risk of death (aHR = 6.25; p = 0.008). As for the remaining lncRNAs, no significant association with VTE incidence, OC progression or related mortality was observed. Future investigation with external validation in larger cohorts is needed to dissect the implications of the evaluated lncRNAs in OC patients.

Prognostic Factors and Survival According to Tumor Subtype in Women With Breast Cancer Brain Metastases.

Breast cancer (BC) is the second most cause of central nervous system (CNS) metastases. Studies report that almost one third of patients (pts) with triple-negative, one-third with human epidermal growth factor receptor 2 (HER2)-positive and 15% of those with hormone receptor-positive, HER2-negative metastatic breast cancer will develop brain metastases. It is known that the development of symptomatic brain metastases in women with advanced breast cancer is associated with poor prognosis, irrespective of local and systemic treatments. In the present study, we aim to determine the association between BC subtypes and CNS metastases occurrence and prognosis. Retrospective analysis of 309 BC patients with CNS metastases, confirmed by pathological and/or radiological methods, treated in a Cancer Center between 2003 and 2021, was obtained to identify clinicopathologic factors associated with early onset of brain metastases and survival outcomes. For analysis purposes, 3 BC subtypes were considered according to hormone receptor status and HER-2 expression: ER and/or PR positive, HER-2 positive and triple negative. The median time between diagnosis of BC and detection of CNS metastases was 43 months, and it was significantly shorter in triple negative group (8 months). Twenty-one patients (6,8%) had CNS metastases at BC diagnosis, with CNS being the first site of recurrence in 35,3%, mainly in HER2 positive. Most of the patients had parenchymal metastases (n = 245) and 37 (12%) had leptomeningeal (LM) disease, with predominance in ER and/or PR positive subtype (70,3%). In patients submitted to CNS surgery, the concordance between primary tumor and metastases subtype was higher in triple negative (76,9%) compared to 63,2% in HER-2 positive and 38,9% in ER and/or PR positive group (P < 0.05). After CNS involvement, 25,4% (n = 34) of patients with triple negative disease did not receive any systemic therapy, compared to 30,6% (n = 41) in HER-2 positive and 44% (n = 59) in ER and/or PR positive groups (P = 0.05). Median survival after CNS metastases was 9 months, but significantly longer in HER-2 positive group (16 months) and in patients submitted to surgical resection of CNS metastases, irrespectively of subtype (22 months vs 5 months in other treatment modalities). In multivariate Cox regression analysis, having HER-2 positive tumor was an independent prognostic factor for increasing survival after CNS metastases (HR 0.60, 95% CI: 0.41-0.87, P = 0.007), regardless the therapeutic strategy. Clinical behavior and prognosis of CNS metastases varies according to BC subtype. The association between LM disease and ER and/or PR positive tumors should be explored in upcoming studies. Also, these patients' prognosis depends on the availability of specific treatment options, therefore, innovative and effective therapeutic approaches are needed, in order to improve survival and quality of life of these patients.

Impact of hereditary thrombophilia on cancer-associated thrombosis, tumour susceptibility and progression: A review of existing evidence.

Venous thromboembolism (VTE) is a cardiovascular disorder frequently diagnosed among cancer patients. Aside from being common, VTE severely deteriorates the prognosis of these patients as they face a higher risk of morbidity and mortality, which makes clinical tools able to identify the patients more prompt to thrombogenesis very attractive. Over the years, several genetic polymorphisms have been linked with VTE susceptibility in the general population. However, their clinical usefulness as predictive biomarkers for cancer-related VTE is yet unclear. Furthermore, as a two-way association between cancer and VTE is well-recognized, with haemostatic components fuelling tumour progression, haemostatic gene polymorphisms constitute potential cancer predictive and/or prognostic biomarkers as well. Thus, in this article, we review the existing evidence on the role of these polymorphisms on cancer-related VTE and their impact on cancer onset and progression. Despite the promising findings, the existing studies had inconsistent results most likely due to their limited statistical power and population heterogeneity. Future studies are therefore required to clarify the role of these polymorphisms in setting of malignancy.

Impressive and durable clinical responses obtained with dabrafenib and trametinib in low-grade serous ovarian cancer harbouring a BRAF V600E mutation.

Low-grade serous ovarian cancer (LGSOC) is now considered a different entity from high-grade serous ovarian cancer. The chemoresistance inherent to this type of ovarian cancer narrows the therapeutic options, especially in the recurrent setting. It is thought that the mitogen-activated protein kinase (MAPK) pathway plays a significant role in the pathogenesis of these tumours, and about 2 to 20% of LGSOC harbour a BRAF mutation. Here we present a case report of two patients with a BRAF V600E mutation that achieved sustained clinical responses with combination treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor).

Genetic Polymorphisms as Predictors of Survival in Breast Cancer: Future Lessons in Historical Data.

Introduction Breast cancer is the most common cancer among women worldwide and one of the main causes of death in the female sex. Genetic polymorphisms in the mu-opioid receptor (OPRM1) and catechol-o-methyltransferase (COMT) genes have been shown to increase breast cancer risk. Variants in these genes may carry a prognostic impact in breast cancer. Long follow-up intervals are critical to adequately analyze prognosis in diseases with prolonged survival times and late relapses. Objective To analyze the impact of genetic polymorphisms on the survival of a cohort of breast cancer patients with very long follow-up. Methods This was a retrospective study of patients treated at Portuguese Oncology Institute of Porto (IPO Porto), a Portuguese comprehensive cancer center, with invasive carcinoma of the breast with very long follow-up, with analysis of genetic polymorphisms OPMR1 rs1799971 (AA vs. G allele) and COMT rs4680 (CC vs T allele) on biological samples. Statistical analysis of survival was performed using the Kaplan-Meier method, log-rank test, and Cox regression method. Results A total of 143 patients with invasive breast cancer were included, with a median follow-up of 21.5 years. There was a statistically significant difference in overall survival (OS) at 30 years according to the OPMR1 polymorphism, with lower survival in patients with the AA genotype (p<0.05). The difference in OS according to the COMT polymorphism was also statistically significant, with worse survival in patients with genotype T allele (p<0.05). The genetic variants were not associated with patient age, stage at diagnosis, or tumor grade. Discussion The genetic polymorphisms of OPRM1 and COMT affected the overall survival of breast cancer patients, in concordance with previous research. Further investigation is needed in order to clarify the prognostic impact of these genetic alterations on breast cancer.

The addition of neoadjuvant pertuzumab for the treatment of HER2+ breast cancer: a cost estimate with real-world data.

BACKGROUND: Breast cancer (BC) is largely prevalent worldwide. HER2-positive BC account for roughly 20-25% of all BC cases and has an overall survival lower than other BC. Innovation on BC therapeutics is a constant, but novel therapies have higher costs. Therefore, cost-effectiveness research is essential to provide healthcare decision-makers with solid foundations for a resource allocation. This study aims to estimate the average direct medical costs/patient and cost-effectiveness of adding pertuzumab in neoadjuvant treatment (NeoT) for HER2-positive breast cancer (BC). METHODS: Two retrospective real-world consecutive cohorts of ≥18yo female patients diagnosed with HER2-positive BC treated with NeoT at the Breast Clinic of IPO-Porto were studied. The AC-DH regimen (2012-2015) comprised 8 cycles of neoadjuvant therapy (4 cycles of doxorubicin + cyclosphosphamide followed by 4 cycles ofdocetaxel + trastuzumab), while the AC-DHP regimen (2015-2017) included also pertuzumab as NeoT. NeoT was followed by surgery and adjuvant trastuzumab. Micro-costing technique and a bottom-up approach was used comprising all medical direct costs from the hospital perspective. Unit costs were obtained from government official prices or from IPO-Porto costing system. Costs were adjusted to 2017 and are expressed in euros. Multivariable logistic regression models were used for effectiveness assessment, while generalized linear models with gamma distribution were used for costs. ICER was calculated using the pathological complete response (pCR) as the preferential measure of effectiveness. Sensitivity analysis was also performed. RESULTS: AC-DHP (n = 40) and AC-DH (n = 54) cohorts had heterogenous patient profiles (median age 43y/53y; 67.5%/59.3% positive HR; 60.0%/27.8% operable; 25.0%/24.1% inflammatory, respectively). The AC-DHP average total cost/patient was 56,375€, with pertuzumab accounting for 13,978€ (24.79%) and increasing in 15,982€ the average cost/patient (p < 0.001). Clinical staging and hormone receptors (HR) were significantly associated with pCR. ICER was 1.370€ per percentage point of pCR. CONCLUSIONS: ICER was more favourable in stage III HR negative BC patients compared to other patient profiles. Innovative treatments access is critical to deliver high-quality healthcare, but sustainability must be considered. These results suggest the importance of establishing a cost-effectiveness profile of Pertuzumab in NeoT for HER2-positive BC.

Implications of venous thromboembolism GWAS reported genetic makeup in the clinical outcome of ovarian cancer patients.

Ovarian cancer (OC) represents the most lethal gynaecological neoplasia. Conversely, venous thromboembolism (VTE) and OC are intricately connected, with many haemostatic components favouring OC progression. In light of this bilateral relationship, genome-wide association studies (GWAS) have reported several single-nucleotide polymorphisms (SNPs) associated with VTE risk that could be used as predictors of OC clinical outcome for better therapeutic management strategies. Thus, the present study aimed to analyse the impact of VTE GWAS-identified SNPs on the clinical outcome of 336 epithelial ovarian cancer (EOC) patients. Polymorphism genotyping was performed using the TaqMan® Allelic Discrimination methodology. Carriers with the ZFPM2 rs4734879 G allele presented a significantly higher 5-year OS, 10-year OS and disease-free survival (DFS) compared to AA genotype patients with FIGO I/II stages (P = 0.009, P = 0.001 and P = 0.003, respectively). Regarding SLC19A2 rs2038024 polymorphism, carriers with the CC genotype presented a significantly lower 5-year OS, 10-year OS and DFS compared to A allele carriers in the same FIGO subgroup (P < 0.001, P = 0.004 and P = 0.005, respectively). As for CNTN6 rs6764623 polymorphism, carriers with the CC genotype presented a significantly lower 5-year OS compared to A allele carriers with FIGO I/II stages (P = 0.015). As for OTUD7A rs7164569, F11 rs4253417 and PROCR rs10747514, no significant impact on EOC patients' survival was observed. However, future studies are required to validate these results and uncover the biological mechanisms underlying our results.

Healthcare use and costs in early breast cancer: a patient-level data analysis according to stage and breast cancer subtype.

BACKGROUND: The cost of breast cancer care rises with higher stage at diagnosis; however, there are no real-world data regarding the cost of care according to breast cancer subtypes. This study aimed to estimate direct medical costs for early breast cancer care in the first 3 years after diagnosis according to subtype and stage, using patient-level data. METHODS: Women with newly diagnosed stage I-III breast cancer, admitted in 2012 to a Portuguese cancer centre were prospectively followed within the NEON-BC cohort. The use of health resources was obtained from each patient's clinical and administrative records and costs were computed. Tumours were classified into the classic subtypes (hormone receptor-positive (HR+)/HER2-; HER2-positive (HER2+); triple-negative breast cancer (TNBC)) and surrogate intrinsic subtypes (luminal A-like; luminal B-like; HER2 enriched; basal like). RESULTS: A total of 703 patients were included: 48.9% had stage I, 35.8% stage II and 15.2% stage III breast cancer; 76.4% had HR+/HER2-, 15.9% HER2+ and 7.7% TNBC. Median cost of care was €9215/patient in stage I, €13 019/patient in stage II and €15 011/patient in stage III and €10 540/patient in HR+/HER2-, €11 224/patient in TNBC and €41 513/patient in HER2+ breast cancer. Systemic therapy accounted for 69.2% of the cost of care among patients with HER2+, 12.0% among HR+/HER2- and 7.5% among TNBC patients. Similar differences were observed across surrogate intrinsic subtypes. CONCLUSIONS: The cost of early breast cancer care was mainly driven by the tumour subtype and, to a lesser extent, by stage. The median cost of care was fourfold higher among patients with HER2+ tumours compared with those with HR+/HER2- and TNBC. These data provide information for the economic evaluation of innovative treatments for early breast cancer and highlight the weight that targeted systemic therapy might have in the overall cost of care among patients with early breast cancer.

Tumor Testing for Somatic and Germline BRCA1/BRCA2 Variants in Ovarian Cancer Patients in the Context of Strong Founder Effects.

Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency (HRD) status are considered strong predictors of response to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). The introduction of PARPi in clinical practice for the treatment of patients with advanced ovarian cancer imposed changes in the molecular diagnosis of BRCA1/BRCA2 variants. BRCA1/BRCA2 tumor testing by next-generation sequencing (NGS) can detect simultaneously both somatic and germline variants, allowing the identification of more patients with higher likelihood of benefiting from PARPi. Our main goal was to determine the frequency of somatic and germline BRCA1/BRCA2 variants in a series of non-mucinous OC, and to define the best strategy to be implemented in a routine diagnostic setting for the screening of germline/somatic variants in these genes, including the BRCA2 c.156_157insAlu Portuguese founder variant. We observed a frequency of 19.3% of deleterious variants, 13.3% germline, and 5.9% somatic. A higher prevalence of pathogenic variants was observed in patients diagnosed with high-grade serous ovarian cancer (23.2%). Considering the frequencies of the c.3331_3334del and the c.2037delinsCC BRCA1 variants observed in this study (73% of all BRCA1 pathogenic germline variants identified) and the limitations of NGS to detect the BRCA2 c.156_157insAlu variant, it might be cost-effective to test for these founder variants with a specific test prior to tumor screening of the entire coding regions of BRCA1 and BRCA2 by NGS in patients of Portuguese ancestry.