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Background and Objectives : The new molecular classification of endometrial cancer continuously changes the management of the disease in everyday clinical practice. Recently, FIGO released a new staging system for endometrial cancer, which incorporates molecular substages and subdivides further early-stage disease. The aim of this study was to investigate the differences between the two FIGO staging systems and evaluate the prognostic precision of the new one. Materials and Methods : We retrospectively analyzed the records of patients with endometrial cancer that were fully treated in the 1st Department of Obstetrics & Gynecology, in 2012-2023. Patient characteristics, oncological outcome, and follow-up information were collected. The primary outcomes were the stage shifts and the survival data. Results : Sixty-seven (15.5%) patients had a stage shift and the majority of them concerned early-stage disease and specifically an upshift from 2009 stages IA and IB to 2023 stage IIC. Concerning survival, a better median and 5-year PFS was present in stage II disease, and when comparing the prognostic precision of the two FIGO staging systems no significant difference was present. Conclusions : The new 2023 FIGO staging system better distinguishes early-stage endometrial cancer into its prognostic groups and seems to be as precise as the old 2009 FIGO staging system.

Introduction: Data regarding quality of life (QoL) of oncologic patients experiencing dermatologic immune-related adverse events (dirAEs) and their course after dermatologic intervention are scarce., Objectives: To assess the impact of dirAEs on patients QoL and to investigate the correlation between dermatologic and oncologic indexes used for estimating QoL., Methods: We enrolled oncologic patients with dirAEs managed in two supportive onco-dermatology outpatient clinics in Greece. Patient-reported outcomes included DLQI, EORTC-QLQ-C30 and Numerical Rating Scale for pruritus (pNRS)., Results: Overall, 110 patients were enrolled in the study. Mean (standard deviation) DLQI and pNRS scores were 15.54 (5.44) and 7.25 (2.95), correspondingly, while functional, symptom and summary scores of EORTC-C30 were 79.17 (2.11), 17.66 (3.60) and 80.67 (3.08), respectively. After therapeutic interventions, there was a statistically significant decrease in DLQI scores after first intervention compared to baseline, and second intervention compared to first (mean decrease 4.38 (2.91), P < 0.001 and 5.16 (3.99), P < 0.001, respectively). DLQI showed no correlation with global health status/QoLs (rho 0.01, P = 0.90) of EORTC-C30., Conclusions: DirAEs negatively affect QoL. Dermatologic intervention improves patients QoL, facilitating an unimpaired oncologic treatment. Poor correlation between DLQI and EORTC-QLQ-30 highlights the need for adapted QoL measurement tools in the context of immune checkpoint inhibitors treatment.

BRCA mutation and homologous recombination deficiency (HRD) are the criteria for the administration of PARP inhibitor (PARPi) maintenance therapy. It is known that PARPi efficacy is related to platinum sensitivity and that the latter can be demonstrated from the CA-125 elimination rate constant (KELIM). This study aims to investigate if KELIM can be another tool in the identification of patients that could be benefit from PARPi therapy. Retrospective analysis of patients with high-grade serous advanced ovarian cancer that underwent cytoreduction and was further tested for HRD status. The HRD status was tested either by myChoice HRD CDx assay or by RediScore assay. KELIM score was measured in both neoadjuvant and adjuvant settings with the online tool biomarker-kinetics.org. A total of 39 patients had available data for estimating both HRD status and KELIM score. When assuming KELIM as a binary index test with the value 1 as the cut-off point, the sensitivity was 0.86, 95% CI (0.64-0.97) and the specificity was 0.83, 95% CI (0.59-0.96). On the other hand, when assuming KELIM as a continuous index test, the area under the curve (AUC) was 81% and the optimal threshold, using the Youden index, was identified as 1.03 with a sensitivity of 85.7% and a specificity of 83.3%. KELIM score seems to be a new, cheaper, and faster tool to identify patients that can benefit from PARPi maintenance therapy.

Non-small cell lung cancer, even when diagnosed in early stages, has been linked with poor survival rates and distant recurrence patterns. Novel therapeutic approaches harnessing the immune system have been implemented in early stages, following the designated steps of advanced NSCLC treatment strategies. Immune-checkpoint inhibitor (ICI) regimens as monotherapy, combinational, or alongside chemotherapy have been intensely investigated as adjuvant, neoadjuvant, and, more recently, perioperative therapeutic strategies, representing pivotal milestones in the evolution of early lung cancer management while holding great potential for the future. The subject of current ongoing research is optimizing treatment outcomes for patient subsets with different needs and identifying biomarkers that could be predictive of response while translating the trials' endpoints to survival rates. The aim of this review is to discuss all current treatment options with the pros and cons of each, persistent challenges, and future perspectives on immunotherapy as illuminating the path to a new era for resectable NSCLC.

(1) Background: Neoadjuvant chemotherapy followed by interval debulking surgery is used in the treatment of advanced ovarian cancer. However, no tool can safely predict if complete cytoreduction after 3-4 cycles can be achieved. This study aims to investigate if the KELIM score can be a triage tool in the identification of patients that will be ideal candidates for interval debulking surgery (IDS). (2) Methods: We retrospectively analyzed the records of patients with high-grade serous advanced ovarian cancer that were treated in the 1st Department of Obstetrics-Gynecology, 2012-2022, with neoadjuvant chemotherapy followed by IDS. Patient characteristics, oncological outcome and follow-up information were collected. The primary outcome was the association of the KELIM score with residual disease. (3) Results: 83 patients were categorized into two groups: Group A (51 patients) with favorable (≥1) and Group B (32 patients) with unfavorable (<1) KELIM scores. A statistically significant correlation between KELIM and residual disease ( p < 0.05) exists, showing that patients with a favorable KELIM score can achieve a complete IDS. Furthermore, there was a statistically significant difference in overall survival ( p = 0.017), but no difference was observed in progression-free survival ( p = 0.13); (4) Conclusions: KELIM seems to safely triage patients after neoadjuvant chemotherapy and decide who will benefit from IDS.

Aims: Left ventricular ejection fraction (LVEF) calculation by echocardiography is pivotal in evaluating cancer patients' cardiac function. Artificial intelligence (AI) can facilitate the acquisition of optimal images and automated LVEF (autoEF) calculation. We sought to evaluate the feasibility and accuracy of LVEF calculation by oncology staff using an AI-enabled handheld ultrasound device (HUD)., Methods and Results: We studied 115 patients referred for echocardiographic LVEF estimation. All patients were scanned by a cardiologist using standard echocardiography (SE), and biplane Simpson's LVEF was the reference standard. Hands-on training using the Kosmos HUD was provided to the oncology staff before the study. Each patient was scanned by a cardiologist, a senior oncologist, an oncology resident, and a nurse using the TRIO AI and KOSMOS EF deep learning algorithms to obtain autoEF. The correlation between autoEF and SE-ejection fraction (EF) was excellent for the cardiologist ( r = 0.90), the junior oncologist ( r = 0.82), and the nurse ( r = 0.84), and good for the senior oncologist ( r = 0.79). The Bland-Altman analysis showed a small underestimation by autoEF compared with SE-EF. Detection of impaired LVEF < 50% was feasible with a sensitivity of 95% and specificity of 94% for the cardiologist; sensitivity of 86% and specificity of 93% for the senior oncologist; sensitivity of 95% and specificity of 91% for the junior oncologist; and sensitivity of 94% and specificity of 87% for the nurse., Conclusion: Automated LVEF calculation by oncology staff was feasible using AI-enabled HUD in a selected patient population. Detection of LVEF < 50% was possible with good accuracy. These findings show the potential to expedite the clinical workflow of cancer patients and speed up a referral when necessary., Competing Interests: Conflict of interest: This study was performed with a loan of handheld ultrasound devices and technical support by Echonous Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: As advances in oncology have led to remarkable and steady improvements in the survival rates of patients with cancer and anticancer treatment can cause premature ovarian failure in women, fertility preservation (FP) has become a global public health concern and an integral part of the care for women diagnosed with cancer during reproductive age. However, for various reasons, FP remains underutilized for patients with cancer. There are substantial gaps in our knowledge about women's experiences and perceptions of the issue. This study aims to contribute to bridging that gap., Methods: This prospective qualitative study was conducted from March 2018 to February 2023. A combination of purposive and snowball sampling was used. Data were collected by semistructured interviews with nineteen reproductive-age women who had been recently diagnosed with cancer. Data were classified and analysed with a thematic analysis approach., Results: A variety of distinct themes and subthemes emerged from the analysis of the interview data. The cancer diagnosis emerged as a factor that considerably affects the women's attitudes towards biological parenthood: It can further increase their (strong) previous desire or decrease their previous (weak) desire. Women with a recent cancer diagnosis had not received adequate and multidisciplinary counselling, including clear and sufficient information. However, participants felt satisfied with the information they received because they either received the information they requested or remained in denial about the need to be informed (i.e., because they felt overwhelmed after the cancer diagnosis). Embryo cryopreservation emerged as a less desirable FP option for women with cancer. Participants showed respect for human embryos, not always for religious reasons. Surrogacy emerged as the last resort for most participants. Religious, social or financial factors did play a secondary (if any) role in women's decision-making about FP. Finally, male partners' opinions played a secondary role in most participants' decision-making about FP. If embryo cryopreservation was the selected option, partners would have a say because they were contributing their genetic material., Conclusions: The findings that emerged from the data analysis were partly consistent with prior studies. However, we identified some interesting nuances that are of clinical importance. The results of this study may serve as a starting point for future research., (© 2024. The Author(s).)

Several tumor types have been efficiently treated with PARP inhibitors (PARPis), which are now approved for the treatment of ovarian, breast, prostate, and pancreatic cancers. The BRCA1/2 genes and mutations in many additional genes involved in the HR pathway may be responsible for the HRD phenomenon. The aim of the present study was to investigate the association between genomic loss of heterozygosity (gLOH) and alterations in 513 genes with targeted and immuno-oncology therapies in 406 samples using an NGS assay. In addition, the %gLOHs of 24 samples were calculated using the Affymetrix technology in order to compare the results obtained via the two methodologies. HR variations occurred in 20.93% of the malignancies, while BRCA1/2 gene alterations occurred in 5.17% of the malignancies. The %LOH was highly correlated with alterations in the BRCA1/2 genes, since 76.19% (16/21) of the BRCA1/2 positive tumors had a high %LOH value ( p = 0.007). Moreover, the LOH status was highly correlated with the TP53 and KRAS statuses, but there was no association with the TMB value. Lin's concordance correlation coefficient for the 24 samples simultaneously examined via both assays was 0.87, indicating a nearly perfect agreement. In conclusion, the addition of gLOH analysis could assist in the detection of additional patients eligible for treatment with PARPis.

Lipidomics is a comprehensive study of all lipid components in living cells, serum, plasma, or tissues, with the aim of discovering diagnostic, prognostic, and predictive biomarkers for diseases such as malignant tumors. This systematic review evaluates studies, applying lipidomics to the diagnosis, prognosis, prediction, and differentiation of malignant and benign ovarian tumors. A literature search was performed in PubMed, Science Direct, and SciFinder. Only publications written in English after 2012 were included. Relevant citations were identified from the reference lists of primary included studies and were also included in our list. All studies included referred to the application of lipidomics in serum/plasma samples from human cases of OC, some of which also included tumor tissue samples. In some of the included studies, metabolome analysis was also performed, in which other metabolites were identified in addition to lipids. Qualitative data were assessed, and the risk of bias was determined using the ROBINS-I tool. A total of twenty-nine studies were included, fifteen of which applied non-targeted lipidomics, seven applied targeted lipidomics, and seven were reviews relevant to our objectives. Most studies focused on the potential application of lipidomics in the diagnosis of OC and showed that phospholipids and sphingolipids change most significantly during disease development. In conclusion, this systematic review highlights the potential contribution of lipids as biomarkers in OC management.

Background: Limited data on immune checkpoint inhibitor (ICI)-induced pruritus per se and efficacy of different therapeutic modalities in its management exist., Objective: To study the quantitative and qualitative characteristics of ICI-induced pruritus per se and to assess the efficacy of the therapeutic modalities usually applied., Methods: We retrospectively reviewed the records of 91 patients who were under treatment with ICIs for any kind of neoplasia and developed pruritus during treatment., Results: Twenty out of 91 individuals (22.0%) with ICI-induced pruritus had pruritus as the only symptom, while 71/91 (78.0%) presented with pruritus coexisting with an additional cutaneous toxicity. Pruritus was treated with antihistamines (18/20, 90.0%) and/or topical regimens, as first-line choice. In resistant cases, as a second therapeutic intervention, narrow-band UVB (NBUVB), oral steroids and GABA analogs were added (70.0%). Statistical analysis revealed a significant difference in mean pruritus Numerical Rating Scale (NRS) scores between baseline and sequential visits. Moreover, subgroup analysis revealed a significant reduction in mean NRS scores in those treated with phototherapy., Limitations: Retrospective design, low number of patients and survivorship bias., Conclusion: Pruritus per se was present in a substantial portion of our cohort (22.0%). Our study confirms the efficacy of current treatment strategies and suggests NBUVB as a potential steroid-sparing therapeutic alternative., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Radiation therapy (RT) treatment for head and neck cancer has been associated with dysphagia manifestation leading to worse outcomes and decrease in life quality. In this study, we investigated factors leading to dysphagia and treatment prolongation in patients with primaries arising from oral cavity or oropharynx that were submitted to radiation therapy concurrently with chemotherapy. The records of patients with oral cavity or oropharyngeal cancer that received RT treatment to the primary and bilateral neck lymph nodes concurrently with chemotherapy were retrospectively reviewed. Logistic regression models were used to analyze the potential correlation between explanatory variables and the primary (dysphagia ≥ 2) and secondary (prolongation of total treatment duration ≥ 7 days) outcomes of interest. The Toxicity Criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) were used to evaluate dysphagia. A total of 160 patients were included in the study. Age mean was 63.31 (SD = 8.24). Dysphagia grade ≥ 2 was observed in 76 (47.5%) patients, while 32 (20%) experienced treatment prolongation ≥ 7 days. The logistic regression analysis showed that the volume in the primary site of disease that received dose ≥ 60 Gy (≥118.75 cc, p < 0.001, (OR = 8.43, 95% CI [3.51-20.26]) and mean dose to the pharyngeal constrictor muscles > 40.6 Gy ( p < 0.001, OR = 11.58, 95% CI [4.84-27.71]) were significantly associated with dysphagia grade ≥ 2. Treatment prolongation ≥ 7 days was predicted by higher age ( p = 0.007, OR = 1.079, 95% CI [1.021-1.140]) and development of grade ≥ 2 dysphagia ( p = 0.005, OR = 4.02, 95% CI [1.53-10.53]). In patients with oral cavity or oropharyngeal cancer that receive bilateral neck irradiation concurrently with chemotherapy, constrictors mean dose and the volume in the primary site receiving ≥ 60 Gy should be kept below 40.6 Gy and 118.75 cc, respectively, whenever possible. Elderly patients or those that are considered at high risk for dysphagia manifestation are more likely to experience treatment prolongation ≥ 7 days and they should be closely monitored during treatment course for nutritional support and pain management.

Background: The growing incidence of cancer globally, and the importance of nutrition support for these patients, emphasize the need for the development of nutritional clinical practice guidelines and consensus papers (CPGs) in the field. Numerous relevant CPGs have been published by several organizations worldwide. The aim of this systematic review was to compare the content of the existing CPGs and evaluate the quality of their development using the AGREE-II tool., Methods: A systematic literature search in PubMed, Embase and Web of Science databases was conducted for the identification of relevant CPGs and consensus papers. Eligible CPGs was blindly evaluated by four appraisers according to the Appraisal of Guidelines for Research and Evaluation ΙΙ (AGREE-II) tool., Results: In total 15 CPGs were identified and were evaluated. All but one set of CPGs underlined the importance of nutritional screening and assessment, whereas recommendations on nutritional interventions, supplements, management of complications and nutritional follow-up were also reported by several organizations. AGREE-II results showed that two CPGs were characterized as high, eight as moderate and five as low regarding their quality of development., Conclusions: Variety on recommendations could be observed between CPGs that should be considered when applied into clinical practice. Limitations of the existing CPGs could be the fact that they are non-specific and only a minority of them are focused to specific cancer types. Frequent updates for CPGs and inclusion of more nutritional topics should be considered for some CPGs. Improvement of the quality of the CPGs development should also be pursued in future., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction: Nail toxicity represents one of the most common cutaneous adverse effects of both classic chemotherapeutic agents and new oncologic drugs, including targeted treatments and immunotherapy., Objectives: We aimed to provide a comprehensive literature review of nail toxicities derived from conventional chemotherapeutic agents, targeted therapies (EGFR inhibitors, multikinase inhibitors, BRAF and MEK inhibitors) and immune checkpoint inhibitors (ICIs), including clinical presentation, implicated drugs and approaches for prevention and management., Methods: Retrieved literature from PubMed registry database was reviewed to include all articles published up to May 2021 relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of oncologic treatment-induced nail toxicity. The internet was searched for relevant studies., Results: A wide spectrum of nail toxicities is associated with both, conventional and newer anticancer agents. The frequency of nail involvement, especially with immunotherapy and new targeted agents remains unknown and patients with different cancer types receiving different regimens may develop the same nail disorder, whereas patients with the same type of cancer under the same chemotherapeutic treatment may develop different types of nail alterations. The underlying mechanisms of the varying individual susceptibility and the diverse nail responses to various anticancer treatments need further investigation., Conclusion: Early recognition and treatment of nail toxicities can minimize their impact, allowing better adherence to conventional and newer oncologic treatments. Dermatologists, oncologists and other implicated physicians should be aware of these burdensome adverse effects in order to guide management and prevent impairment of patients' quality of life.

This non-interventional, multicenter, prospective study aimed to evaluate the real-world activity of trabectedin, and its impact on symptom burden and quality of life in patients with advanced soft tissue sarcoma (aSTS) treated in routine clinical settings in Greece. Patients with histologically confirmed aSTS newly initiated on trabectedin were enrolled. The primary endpoint was progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS rate at 3 months, median PFS, objective response rate (ORR), disease control rate (DCR), overall survival (OS), and an assessment of the impact of treatment on health-related quality of life (HRQoL), cancer-related symptom burden and symptom interference with function, as well as all-cause treatment discontinuation rate. A total of 64 eligible patients from 13 Greek centers were evaluated. Patients received a median of three trabectedin cycles per patient (interquartile range [IQR]: 2.0-6.0). Median PFS was 6.6 months with 67.9% and 51.2% of patients free from progression at 3 and 6 months, respectively. ORR was 7.8% and DCR 21.9%. Median OS was 13.1 months. No significant changes from enrolment were noted in HRQoL scores. In total, 30 patients (46.9%) had at least one trabectedin-related adverse drug reaction (ADR) and 9 (14.1%) at least one serious ADR. The treatment discontinuation rate due to toxicity was 9.4%. These results suggest that trabectedin is an active treatment with clinically meaningful benefits in patients with aSTS with no new safety signals.

Thromboprophylaxis, as a preventive measure for cancer-associated thrombosis (CAT), may be beneficial for patients with active cancer and high-risk for thrombosis. The present post hoc analysis include a total of 407 patients enrolled in the Greek Management of Thrombosis study, who received thromboprophylaxis with tinzaparin. The objectives of the present analysis were: i) To obtain sufficient evidence for the administration of prophylaxis in patients with active cancer, irrespective of Khorana risk assessment model score; ii) to identify the selection criteria for both dose and duration of tinzaparin; and iii) to evaluate the efficacy and safety of tinzaparin administered for CAT prophylaxis. The main tumor types for the patients included in the present study were as follows: Lung (25.1%), pancreatic (14.3%), breast (9.1%), stomach (8.4%), colorectal (7.9%) and ovarian (7.6%). Furthermore, metastatic disease was observed in 69.5% of the patients. High thrombotic burden agents (HTBAs) were administered to 66.3% of the patients, and 17.4% received erythropoietin. A total of 43.7% of the patients exhibited a Khorana score <2. The results of the present study demonstrated that both the presence of metastatic disease and the use of HTBAs seemed to influence oncologists' decisions for the use of thromboprophylaxis in patients with active cancer, regardless of Khorana score. Tinzaparin, in dose expressed in the standard notation for heparins, i.e., anti-Xa factor international units (Anti-Xa IU), was administered at an intermediate dose (InterD; 8,000-12,000 Anti-Xa IU; once daily) to 52.4% of patients, while the remaining patients received a prophylactic dose (ProD; ≤4,500 Anti-Xa IU; once daily). The average duration of thromoprophylaxis was 5 months. Furthermore, a total of 14 (3.4%) thrombotic events and 6 (1.5%) minor bleeding events were recorded. A total of four thrombotic events were observed following an InterD treatment of tinzaparin, while 10 thrombotic events were observed following ProD treatment. The present study also demonstrated that an InterD of tinzaparin was administered more frequently to patients with a body mass index >30 kg/m 2 , a history of smoking and a history of metastatic disease, along with administration of erythropoietin. InterD tinzaparin treatment was found to be potentially more efficacious and without safety concerns. The present study is a registered clinical trial (ClinicalTrials.gov code, NCT03292107; registration date, September 25, 2017)., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Christopoulou et al.)

New treatment modalities have been recently introduced in the management of ovarian cancer (OC). Herein, we sought to investigate their implementation in routine clinical practice and examine the real-world management of OC in Greece. EpOCa was a non-interventional, multicenter, retrospective study in patients with advanced epithelial OC. The primary outcome was to estimate the proportions of the different treatment regimens used per line of therapy, while progression-free survival (PFS) and overall survival (OS) were the key secondary endpoints. A total of 154 patients were enrolled in the study, among whom, 40% were tested for BRCA mutations and 30% were found to be positive. Nearly 90% of patients underwent debulking surgery at diagnosis, with few operations being also recorded upon relapse. Platinum-based chemotherapy (CT) was predominantly used in the first line with half of patients also receiving angiogenesis inhibitor (AI), while non-platinum-based CT was preferred in later lines. The median PFS was 18.2 and 8.8 months in the first- and second-line setting, respectively, whereas the median OS was approximately 50 months. Our study adds to the available, but limited, real world data on the management of ovarian cancer providing evidence regarding the applied treatment strategies and outcomes of patients in Greece.

Background: Cancer patients are at high risk for cancer-associated thrombosis (CAT). CAT is the second leading cause of death in these patients but it can be preventable with thromboprophylaxis. Patients and Methods: An observational, prospective, multicenter study aiming to record CAT management in clinical practice was conducted by the Hellenic Society of Medical Oncology (HeSMO). Results: A total of 426 active cancer patients (mean age 65.3 years, mean BMI: 26.1 kg/m 2 ) who received thromboprophylaxis, were included from 18 oncology units. Tumor types were lung 25.1%, pancreas 13.9%, breast 8.7%, stomach 8.5%, ovarian 7.8%, and others 36%, while 69% had metastases. A total of 71% had a Khorana score ≤2 and 61% received High Thrombotic Risk Chemotherapy Agents (HTRCAs, e.g., platinum). For thromboprophylaxis patients received mainly Low Molecular Weight Heparins (LMWHs), on higher than prophylactic doses in 50% of cases. Overall, 16 (3.8%) thrombotic events and 6 (1.4%) bleeding events were recorded. Notably, patients on higher doses of LMWHs compared to patients who received standard prophylactic doses had 70% lower odds to develop thrombotic events (OR: 0.3, 95% CI: 0.10-1.0, p = 0.04). Conclusion: CAT is an important issue in oncology. Along with the Khorana score, factors as metastasis and use of HTRCAs should also be taken into consideration. Thromboprophylaxis for active cancer patients with LMWHs, even on higher doses is safe and efficient.

Background: Cancer-associated thrombosis (CAT), the second leading cause of death in patients with cancer can be treated with low molecular weight heparin (LMWH) according to guidelines., Patients and Methods: A multicenter prospective observational study was carried out to record anti-thrombotic treatment practice, assess thrombosis recurrence and bleeding, and identify potential risk factors. Adult patients from 18 Oncology Departments throughout Greece were followed-up for 12 months., Results: A total of 120 patients with CAT receiving anticoagulant treatment were enrolled (35% incidental); 85% were treated for more than 6 months, 95.8% were treated with tinzaparin and smaller percentages with other agents. Thrombosis recurred in three patients and there was minor bleeding in four patients. Bleeding was associated with high body mass index (>35 kg/m 2 ), trauma history, renal insufficiency and bevacizumab use., Conclusion: Incidental thrombosis contributes significantly to CAT burden. Long-term use of LMWH seems to be effective and safe. Several risk factors associated with bleeding should be considered during anti-coagulation therapy planning., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: PTEN-loss and PIK3CA mutations have been addressed as markers of PI3K activation in breast cancer. We evaluated these markers in early high-risk breast cancer (EBC) focusing on PTEN immunohistochemistry (IHC) issues, particularly in HER2-positive disease., Materials and Methods: We examined PTEN-loss and PIK3CA mutations in 1265 EBC patients treated with adjuvant chemotherapy within two clinical trials. Two different methods for the evaluation of PTEN IHC were used, one upfront binary (loss; no-loss) and the other initially multi-scale allowing for the classification of "grey zone" tumors with low and very low PTEN protein expression., Results: PTEN-loss (33.4% and 22.1%, depending on the IHC method) and PIK3CA mutations (29.6%) were associated with ER/PgR/HER2-negative and ER/PgR-positive disease, respectively. Concordance of the two IHC methods was moderate (Cohen's kappa 0.624). PTEN-loss discrepancy and intra-tumor heterogeneity concerned "grey zone" tumors that were prevalent among HER2-positive cancers. PTEN-loss independently conferred higher risk for relapse and death. Compared to single PIK3CA mutations,single PTEN-loss was independently associated with increased risk for relapse and death. Depending on the evaluation method, in HER2-positive cancer, PTEN-loss was without- or of marginal unfavorable prognostic significance., Conclusion: In EBC, PTEN-loss is an independent predictor of poor outcome. When occurring singly, PTEN-loss and PIK3CA mutations have opposite prognostic impact. In HER2-positive disease, assessment of PTEN-loss by IHC appears unreliable and the marker is without clear prognostic significance., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Despite the large use of nab-paclitaxel as a treatment option in metastatic breast cancer (MBC) across different countries, no definitive data are available in particular clinical situations., Areas Covered: Efficacy, safety and schedule issues concerning available literature on nab-paclitaxel in advanced breast cancer and in specific subgroups of patients have been discussed and voted during an International Expert Meeting. Ten expert specialists in oncology, with extensive clinical experience on Nab-P and publications in the field of MBC have been identified. Six scientific areas of interest have been covered, generating 13 specific Statements for Nab-P, after literature review. For efficacy issues, a summary of research quality was performed adopting the GRADE algorithm for evidence scoring. The panel members were invited to express their opinion on the statements, in case of disagreement all the controversial opinions and the relative motivations have been made public., Expert Opinion: Consensus was reached in 30.8% of the Nab-P statements, mainly those regarding safety issues, whereas ones regarding efficacy and schedule still remain controversial areas, requiring further data originated by the literature.

Background: The prognostic/predictive value of aberrant MYC gene copies and protein expression is not clear in breast cancer., Patients and Methods: Early breast cancer patients were treated with anthracycline-containing chemotherapy within 2 randomized adjuvant trials. MYC gene and centromere-8 status, as well as Myc protein expression were investigated on 1060 paraffin tumors with fluorescence in situ hybridization and immunohistochemistry, respectively., Results: MYC amplification was present in 45% and polysomy-8 in 23% of the tumors. Cytoplasmic staining was observed in 60% and nuclear staining in 26% of the tumors, strongly correlating with each other but not with MYC gene status. MYC gene amplification in the absence of polysomy-8 was associated with adverse disease-free survival (DFS) and overall survival (OS), and remained as an independent unfavorable prognostic factor in multivariate analysis (Wald P = .022 for DFS; P = .032 for OS), whereas patients with MYC amplification and polysomy-8, with polysomy-8 only, and with normal MYC without polysomy-8 performed significantly better compared with those with MYC gene amplification only. Nuclear Myc protein expression benefitted patients treated with paclitaxel (interaction P = .052 for DFS; P = .049 for OS). This interaction remained independently significant in multivariate analysis for OS (overall P = .028)., Conclusion: The effect of MYC gene status on breast cancer patient outcome seems to depend on the underlying chromosomal instability and appears unfavorable for tumors with MYC amplification without polysomy. Nuclear Myc protein expression seems predictive for benefit from adjuvant paclitaxel. These data might aid in the interpretation of relevant findings from large clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival is anticipated., Patients and Methods: Early breast cancer patients, who had been treated with anthracycline-based chemotherapy within two randomized trials, were included in the study. We evaluated, by quantitative reverse transcription-polymerase chain reaction, 819 formalin-fixed paraffin-embedded tumor tissue samples for mRNA expression of RANK, OPG, and RANKL, as well as their ratios, for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival., Results: Median age was 52.7years, whereas 54.2% of the patients were postmenopausal and 78.3% estrogen receptor/progesterone receptor positive. After a median follow-up of 119.9months, 226 patients (27.6%) had died and 291 patients (35.5%) had disease progression. Low mRNA expression of RANKL was associated with postmenopausal status and greater number of positive lymph nodes (P=.002 and P<.001, respectively). In the univariate analysis, low RANKL mRNA expression was found to be an unfavorable factor for DFS [hazard ratio (HR)=1.33, 95% confidence interval (CI) 1.05-1.68, Wald's P=.018] and bone metastasis-free survival (HR=1.67, 95% CI 1.09-2.56, P=.018), although it did not retain its significance in the multivariate analysis., Conclusions: Low RANKL mRNA expression in early breast cancer patients is of prognostic significance for increased risk for relapse and bone metastases and might potentially guide clinical decision-making for the use of anti-RANKL agents in the treatment of early breast cancer patients at high risk for metastatic spread, provided that our findings are validated in independent cohorts., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The shift towards an earlier diagnosis of breast cancer (BC) highlights the need for biomarkers that would identify patients at risk for relapse and metastatic spread and indicate the potential value of additional treatment strategies. Osteopontin (OPN) is a matricellular protein that has been suggested to be a potential biomarker in BC. In the present study, we used archived BC patient samples to assess the clinical utility of OPN., Methods: Formalin-fixed paraffin-embedded tumor tissue samples from 975 patients were collected from two large phase III randomized adjuvant chemotherapy trials (HE10/97 and HE10/00) that included patients with high risk BC. All tissue samples were assessed for ER, PgR, Ki67 and HER2 protein expression. OPN protein and mRNA expression was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, respectively., Results: OPN mRNA expression data were available for 814 patients, whereas OPN protein expression data were available for 546 patients. The majority of patients were ER/PgR-positive (78.3%), HER2-negative (76.5%) and Ki67-positive (55.2%) and had received adjuvant radiation therapy (76.8%) and hormonal therapy (81.1%). OPN mRNA expression was significantly associated with age (60.9% in high OPN tumors vs. 54.1% in low OPN tumors, p = 0.047), ER/PgR-negative status (25.7 vs. 17.2%, p = 0.004) and BC subtypes (p = 0.021). In addition, high OPN mRNA expression was significantly associated with reduced DFS (HR 1.26, 95% CI 1.00-1.59, Wald's p = 0.050) and OS (HR 1.37, 95% CI 1.05-1.78, p = 0.019), while it retained its prognostic significance for both DFS (HR 1.39, 95% CI 1.10-1.77, p = 0.007) and OS (HR 1.54, 95% CI 1.61-2.05, p = 0.003) in the multivariate analysis., Conclusions: We showed that high OPN mRNA expression is associated with decreased DFS and OS in a large cohort of BC patients treated with adjuvant chemotherapy in a clinical trial setting. Our results suggest that OPN may serve as a prognostic factor and a potential target for therapy. Trial registration Australian New Zealand Clinical Trials Registry; HE10/97 ACTRN12611000506998; HE10/00 ACTRN12609001036202.

Background-Aim: Early breast cancer is a heterogeneous disease, and, therefore, prognostic tools have been developed to evaluate the risk for distant recurrence. In the present study, we sought to develop a risk for recurrence score (RRS) based on mRNA expression of three proliferation markers in high-risk early breast cancer patients and evaluate its ability to predict risk for relapse and death. In addition the Adjuvant! Online score (AOS) was also determined for each patient, providing a 10-year estimate of relapse and mortality risk. We then evaluated whether RRS or AOS might possibly improve the prognostic information of the clinical treatment score (CTS), a model derived from clinicopathological variables., Methods: A total of 1,681 patients, enrolled in two prospective phase III trials, were treated with anthracycline-based adjuvant chemotherapy. Sufficient RNA was extracted from 875 samples followed by multiplex quantitative reverse transcription-polymerase chain reaction for assessing RACGAP1, TOP2A and Ki67 mRNA expression. The CTS, slightly modified to fit our cohort, integrated the prognostic information from age, nodal status, tumor size, histological grade and treatment. Patients were also classified to breast cancer subtypes defined by immunohistochemistry. Likelihood ratio (LR) tests and concordance indices were used to estimate the relative increase in the amount of information provided when either RRS or AOS is added to CTS., Results: The optimal RRS, in terms of disease-free survival (DFS) and overall survival (OS), was based on the co-expression of two of the three evaluated genes (RACGAP1 and TOP2A). CTS was prognostic for DFS (p<0.001), while CTS, AOS and RRS were all prognostic for OS (p<0.001, p<0.001 and p = 0.036, respectively). The use of AOS in addition to CTS added prognostic information regarding DFS (LR-Δχ2 8.7, p = 0.003), however the use of RRS in addition to CTS did not. For estimating OS, the use of either AOS or RRS in addition to CTS added significant prognostic information. Specifically, the use of both CTS and AOS had significantly better prognostic value vs. CTS alone (LR-Δχ2 20.8, p<0.001), as well as the use of CTS and RRS vs. CTS alone (LR-Δχ2 4.8, p = 0.028). Additionally, more patients were scored as high-risk by AOS than CTS. According to immunohistochemical subtypes, prognosis was improved in the Luminal A (LR-Δχ2 7.2, p = 0.007) and Luminal B (LR-Δχ2 8.3, p = 0.004) subtypes, in HER2-negative patients (LR-Δχ2 23.4, p<0.001) and in patients with >3 positive nodes (LR-Δχ2 23.9, p<0.001) when AOS was added to CTS., Conclusions: The current study has shown a clear benefit in predicting overall survival of high-risk early breast cancer patients when combining CTS with either AOS or RRS. The combination of CTS and AOS adds significant prognostic information compared to CTS alone for DFS, while the combination of CTS with either AOS or RRS has better prognostic value than CTS alone for OS. These findings could possibly add on the information needed for the best risk prediction strategy in high-risk early breast cancer patients in a rather simple and inexpensive way, especially in Luminal A and B subtypes, HER2-negative patients and those with >3 positive nodes., Competing Interests: Zoi Alexopoulou is employed by Health Data Specialists Ltd. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials. The rest of the authors have declared that no competing interests exist. There are no patents, products in development or marketed products to declare.

Background: Paclitaxel-based regimens are frequently associated with the development of peripheral neuropathy. The autonomous nervous system (ANS) effects, however, of this chemotherapeutic agent remain unexplored., Methods: We investigated a group of 31 female patients with ovarian cancer receiving treatment with paclitaxel and carboplatin, as well as a group of 16 healthy age- and gender-matched healthy volunteers. All study participants completed a questionnaire and were assessed neurophysiologically at three time points (baseline, 3-4 months and 6-8 months following the onset of chemotherapy). The evaluation of the ANS included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (30/15 ratio) and sympathetic skin response (SSR)., Results: At the 3-4 months ANS assessment, 19.2 % of the patients had systolic OH and the same percentage had diastolic OH, but at the 6-8 months evaluation no patient had systolic OH and only 13.8 % had diastolic OH. The values of the 30/15 ratio were significantly reduced at both time points, whereas the SSR was not affected., Conclusions: Combined paclitaxel and carboplatin chemotherapy is associated with significant effects on the parasympathetic heart innervation and occasionally with effects on the adrenergic cardiovascular reaction. The SSR remained unaffected. Physicians should be alert to the possibility of these treatment-emergent side effects, so as to monitor ANS parameters and introduce treatment modifications accordingly. Our findings however, should be validated in larger cohorts.

Background: We investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era., Results: TP53 and PIK3CA mutations were found in 380 (21.5%) and 458 (25.9%) cases, respectively, including 104 (5.9%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5%). TP53 mutations (p < 0.001) and p53 protein positivity (p = 0.001) were more frequent in HER2-positive and triple negative (TNBC) tumors, while PIK3CA mutations were more frequent in Luminal A/B tumors (p < 0.001). TP53 mutation status and p53 protein expression but not PIK3CA mutation status interacted with trastuzumab treatment for disease-free survival; patients with tumors bearing TP53 mutations or immunopositive for p53 protein fared better when treated with trastuzumab, while among patients treated with trastuzumab those with the above characteristics fared best (interaction p = 0.017 for mutations; p = 0.015 for IHC). Upon multivariate analysis the above interactions remained significant in HER2-positive patients; in the entire cohort, TP53 mutations were unfavorable in patients with Luminal A/B (p = 0.003) and TNBC (p = 0.025); p53 immunopositivity was strongly favorable in patients treated with trastuzumab (p = 0.009)., Materials and Methods: TP53 and PIK3CA mutation status was examined in 1766 paraffin tumor DNA samples with informative semiconductor sequencing results. Among these, 1585 cases were also informative for p53 protein status assessed by immunohistochemistry (IHC; 10% positivity cut-off)., Conclusions: TP53 mutations confer unfavorable prognosis in patients with Luminal A/B and TNBC tumors, while p53 immunopositivity may predict for trastuzumab benefit in the adjuvant setting., Competing Interests: None.

Wnt and epidermal growth factor receptor (EGFR) pathway abnormalities and de-stabilization of cell adhesion are all important aspects of the pathogenesis of triple-negative breast cancer (TNBC). Herein we investigated how the expression of related protein markers may affect the outcome of patients bearing TNBC treated in the adjuvant setting. Immunohistochemistry for beta-catenin, Myc (Wnt pathway), E-cadherin, P-cadherin (cell-adhesion), EGFR and cytokeratin 5 (CK5) (identification of basal-like tumors) was carried out in 364 centrally confirmed TNBCs. Survival analysis was performed with Cox-regression models according to dichotomized continuous protein expression data and marker interactions. In 352 evaluable tumors, 81.5% were basal-like TNBC. E-cadherin and P-cadherin were positively associated, with co-expression being present in 68% of tumors. Individual markers did not affect patient outcome. However, a statistically significant interaction was shown such that low expression of beta-catenin in the cell membrane, defined as expression below the median of the H-score distribution, was associated with unfavourable disease-free survival among tumors that expressed EGFR, but not in the absence of EGFR expression (interaction p=0.0085). The interaction persisted after correcting for clinicopathological variables. A considerable number of TNBC co-expresses E-cadherin and P-cadherin, while membranous localization of beta-catenin may predict patient outcome in an EGFR-dependent manner. This novel interaction seems worthy for validating with regards to its biological and clinical relevance., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long-term follow-up of patients WHO had been treated with ESA for CIA in the past may provide useful information. In 2002, we undertook a prospective, randomized phase III trial of prophylactic vs. hemoglobin (Hb)-based (threshold: 11 mg/dl) ESA administration in patients with solid tumors and CIA. ESA administration FOR CIA was permanently suspended in 2007 in view of published data at that time, while patient surveillance continued. Among 630 evaluable patients, 38.6% were male, 50.9% had advanced cancer at diagnosis, 40.6% had Hb levels <12 mg/dl at baseline and 47.9% received ESA prophylactically (1:1 randomization). The major tumor types included colorectal (36.0%), breast (20.6%), non-prostate genitourinary (11.0%) and lung CANCER (8.4%). After a median follow-up of 85.4 months, 358 patients had relapsed and 380 had succumbed to the disease. Patients in the prophylactic ESA group (GROUP A; experimental arm), as compared with those in the Hb-based group (GROUP B; iron supplementation alone), exhibited A significantly more prominent increase in median Hb levels, particularly in the subset of patients with non-metastatic disease (two-sided P<0.01) among patients receiving chemotherapy for advanced cancer, those who received ESAs prophylactically exhibited a lower incidence of CIA (all grades: P=0.014, grades 3-4: P=0.034) and fatigue (all grades: P<0.001, grades 3-4: P=0.055), but a higher rate of a composite outcome encompassing all thrombosis-related events (all grades: P=0.043, grades 3-4: P=0.099). These differences were less prominent in the group of patients who received adjuvant treatment. There were no significant differences in overall mortality and relapse/progression rates between the two groups. therefore, prophylactic, compared with Hb-based, administration of ESAs for CIA in patients with solid tumors, was found to be associated with a significantly lower incidence of anemia and fatigue, but with a marginally higher rate of thrombosis-related adverse events, particularly in patients receiving first-line chemotherapy for advanced cancer.

Background: Tumor infiltrating lymphocytes (TILs) are considered in the prognosis of breast cancer (BC) patients. Here, we investigated the prognostic/predictive effect of TILs in patients treated in the frame of four prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-trastuzumab era., Methods: TILs density was histologically assessed as percentage of stromal area on whole routine sections of 2613 BC (1563 Luminal A/B; 477 Luminal HER2; 246 HER2-enriched; 327 triple negative [TNBC]) and were evaluated as high/low at three cut-offs (c/o; 50% [lymphocytic predominance, LP], 35% and 25%), in separate training and validation sets., Results: High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively. TILs status did not interact with BC subtypes or trastuzumab treatment. LPBC patient outcome was not affected by nodal status, while high TILs were favorable in TNBC with unfavorable nodal status. When adjusted for standard clinicopathological parameters and treatment, high TILs independently predicted for favorable outcome, e.g., disease-free survival with the 35% c/o in the entire cohort (HR = 0.44, 95% CI 0.28-0.69, p < 0.001) and in specific subtypes., Conclusions: High TILs tumors, especially LPBC seem worthy validating as a separate entity of favorable prognosis in breast cancer.

Background: The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer., Methods: Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors., Results: PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified., Conclusions: The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.

Background: The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as a validation analysis of another previously published HeCOG study., Methods: RNA was extracted from 663 formalin-fixed paraffin-embedded (FFPE) tumor tissue samples of high-risk early breast cancer patients enrolled in the randomized HE10/00 trial. Relative mRNA expression of all four HER family members was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR)., Results: In compliance with our previous study, the overall agreement between qRT-PCR and IHC/FISH for HER2 status determination was good (69%). Likewise, the overall concordance between qRT-PCR and IHC for EGFR status was high (81%). In line with our previously reported data, we demonstrated a positive association between HER2 and HER3 mRNA expression. Similarly, mRNA expression of HER3 and HER4 was positively associated with each other and negatively associated with EGFR. Regarding relationships with clinico-pathological parameters, our findings are also in agreement with our previous results. Generally, increased EGFR and HER2 mRNA expression was related to unfavorable, whereas high HER3 and HER4 mRNA expression was associated with favorable clinico-pathological parameters. In univariate analysis, no significant association between EGFR, HER2 and HER3 mRNA expression and overall survival (OS) or disease-free survival (DFS) was demonstrated. However, high EGFR protein expression was associated with significantly shorter OS (log-rank, p = 0.015). In compliance with our previously published data, increased HER4 mRNA expression had a significantly favorable prognostic value in terms of OS (p = 0.044) and DFS (p = 0.047). In multivariate analysis, among all HER receptors, only EGFR protein expression was found to affect OS (Wald's p = 0.028) and DFS (p = 0.015) independently. Concerning the combined expression of all four HER family receptors, the combination of high EGFR, high HER2, low HER3 and low HER4 mRNA expression was associated with a trend for shorter OS (log-rank, p = 0.065) and significantly worse DFS (p = 0.033), compared with all other co-expression profiles., Conclusions: These data indicate that qRT-PCR may represent a valid alternative method for evaluating the expression of HER family members in FFPE breast carcinoma tissue samples., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12609001036202.

To investigate the immunohistochemical expression of p85 in a cohort of trastuzumab-treated HER2-positive and HER2-negative metastatic breast cancer patients. The medical records of all patients with metastatic breast cancer treated with trastuzumab-based regimens between 1998 and 2010 were reviewed and clinical information was obtained. Formalin-fixed paraffin-embedded tumor tissue samples with adequate material were retrospectively collected from 183 patients. Samples were evaluated by immunohistochemistry for p85, estrogen receptors (ER), progesterone receptors (PgR), HER2, Ki67, PTEN and phosphorylated Akt (S473 and T308). HER2 status was studied by fluorescence in situ hybridization, as well. PIK3CA mutational status was also evaluated. Median follow-up for all patients was 72 months. Central re-evaluation for HER2 revealed only 111 HER2-positive cases, with the remaining 72 patients being HER2-negative. Median survival was longer in HER2-positive patients (50.7 months) compared to HER2-negative patients (36.6 months) both treated with trastuzumab, but this difference has not reached significance (p = 0.068). In total, 62% of the patients were found positive for p85, however the p85 protein was not found to be differentially expressed in HER2-positive versus HER2-negative cases. There were no significant associations between protein expression of p85 and any of the markers under study, or with time to progression. Positive p85 protein expression was however associated with poor survival in trastuzumab-treated HER2-positive patients. In our cohort of trastuzumab-treated HER2-positive breast cancer patients, positive p85 protein expression appears to be a prognostic factor of poor survival and, if validated, might have important implications in the treatment of such patients.

Background: Dose-dense sequential chemotherapy including anthracyclines and taxanes has been established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration in a dose-dense regimen have not been defined yet., Methods: From July 2005 to November 2008, 1001 patients (990 eligible) were randomized to receive, every 2 weeks, 3 cycles of epirubicin 110 mg/m2 followed by 3 cycles of paclitaxel 200 mg/m2 followed by 3 cycles of intensified CMF (Arm A; 333 patients), or 3 cycles of epirubicin followed by 3 cycles of CMF, as in Arm A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m2 (Arm B; 331), or 9 weekly cycles of paclitaxel 80 mg/m2 (Arm C; 326). Trastuzumab was administered for one year to HER2-positive patients post-radiation., Results: At a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) rate was 86%, 90% and 88%, for Arms A, B and C, respectively, while the 3-year overall survival (OS) rate was 96% in all arms. No differences were found in DFS or OS between the combined B and C Arms versus Arm A (DFS: HR = 0.81, 95% CI: 0.59-1.11, P = 0.20; OS: HR = 0.84, 95% CI: 0.55-1.30, P = 0.43). Among the 255 patients who received trastuzumab, 189 patients (74%) completed 1 year of treatment uneventfully. In all arms, the most frequently reported severe adverse events were neutropenia (30% vs. 27% vs. 26%) and leucopenia (12% vs. 13% vs. 12%), while febrile neutropenia occurred in fifty-one patients (6% vs. 4% vs. 5%). Patients in Arm A experienced more often severe pain (P = 0.002), neurological complications (P = 0.004) and allergic reactions (P = 0.004), while patients in Arm B suffered more often from severe skin reactions (P = 0.020)., Conclusions: No significant differences in survival between the regimens were found in the present phase III trial. Taxane scheduling influenced the type of severe toxicities. HER2-positive patients demonstrated comparable 3-year DFS and OS rates with those reported in other similar studies., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.

The Androgen Receptor (AR) is a potential prognostic marker and therapeutic target in breast cancer. We evaluated AR protein expression in high-risk breast cancer treated in the adjuvant setting. Tumors were subtyped into luminal (ER+/PgR±/AR±), molecular apocrine (MAC, [ER-/PgR-/AR+]) and hormone receptor negative carcinomas (HR-negative, [ER-/PgR-/AR-]). Subtyping was evaluated with respect to prognosis and to taxane therapy. High histologic grade (p < 0.001) and increased proliferation (p = 0.001) more often appeared in MAC and HR-negative than in luminal tumors. Patients with MAC had outcome comparable to the luminal group, while patients with HR-negative disease had increased risk for relapse and death. MAC outcome was favorable upon taxane-containing treatment; this remained significant upon multivariate analysis for overall survival (HR 0.31, 95%CI 0.13-0.74, interaction p = 0.035) and as a trend for time to relapse (p = 0.15). In conclusion, AR-related subtyping of breast cancer may be prognostic and serve for selecting optimal treatment combinations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)