Search

Neoadjuvant chemotherapy (NACT) for certain breast cancer (BC) subtypes confers significant tumor regression rates and a survival benefit for patients with a complete pathologic response. Clinical and preclinical studies have demonstrated that immune-related factors are responsible for better treatment outcomes, and thus, neoadjuvant immunotherapy (IO) has emerged as a means to further improve patient survival rates. Innate immunological "coldness", however, of specific BC subtypes, especially of the luminal ones, due to their immunosuppressive tumor microenvironment, hinders the efficacy of immune checkpoint inhibitors. Treatment policies aiming to reverse this immunological inertia are, therefore, needed. Moreover, radiotherapy (RT) has been proven to have a significant interplay with the immune system and promote anti-tumor immunity. This "radiovaccination" effect could be exploited in the neoadjuvant setting of BC and significantly enhance the effects of the already established clinical practice. Modern stereotactic irradiation techniques directed to the primary tumor and involved lymph nodes may prove important for the RT-NACT-IO combination. In this review, we provide an overview and critically discuss the biological rationale, clinical experience, and ongoing research underlying the interplay between neoadjuvant chemotherapy, anti-tumor immune response, and the emerging role of RT as a preoperative adjunct with immunological therapeutic implications in BC.

Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have been approved in combination with hormone therapy for the treatment of patients with HR+, HER2-negative advanced or metastatic breast cancer (mBC). Despite their promising activity, approximately 10 % of patients have de novo resistance, while the rest of them will develop acquired resistance after 24-28 months when used as first-line therapy and after a shorter period when used as second-line therapy. Various mechanisms of resistance to CDK4/6 inhibitors have been described, including cell cycle-related mechanisms, such as RB loss, p16 amplification, CDK6 or CDK4 amplification, and cyclin E-CDK2 amplification. Other bypass mechanisms involve the activation of FGFR or PI3K/AKT/mTOR pathways. Identifying the different mechanisms by which resistance to CDK4/6 inhibitors occurs may help to design new treatment strategies to improve patient outcomes. This review presents the currently available knowledge on the mechanisms of resistance to CDK4/6 inhibitors, explores possible treatment strategies that could overcome this therapeutic problem, and summarizes relevant recent clinical trials., Competing Interests: Declaration of competing interest The authors do not have any competing financial interest that could influence, or give the perception of such influence on the behavior or content in a way that could undermine the objectivity, integrity, or perceived value of this manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation., Methods: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m 2 ) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m 2 ) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m 2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m 2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease., Results: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms., Conclusions: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background/aim: This study aimed to provide real-world safety and effectiveness data of everolimus (EVE) plus exemestane (EXE) in estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER + /HER2 - ) advanced breast cancer (aBC)., Patients and Methods: This prospective observational study was conducted by 19 hospital-based oncologists in Greece. Eligible patients were treated with EVE+EXE in the first-line setting; EVE was initiated according to the approved label., Results: Overall, 75 eligible patients (mean age: 66.9 years; visceral metastases: 49.3%; bone-only metastases: 37.3%) were included in the effectiveness analyses. Over a median (interquartile range) of 12.1 months (range=4.2-20.5 months) of EVE treatment, the median progression-free survival was 18.0 months and the overall response rate was 22.7%. Among patients that received ≥1 EVE dose (n=80), the incidence of EVE-related adverse events was 72.5% (serious: 55.0%); stomatitis (22.5%), fatigue (22.5%), pneumonitis (18.8%); and cough (18.8%) were the most common., Conclusion: In the routine care in Greece, EVE demonstrates clinical benefit and a predictable safety profile., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: BRCA1/BRCA2 mutation carriers indefinitely comprise a distinct group of patients with breast cancer (BC), with their tumors displaying specific pathologic characteristics. Although these connections are known, they are not fully elucidated. We therefore sought to investigate the clinicopathologic characteristics and overall survival of Greek patients with BC carrying BRCA1/BRCA2 mutations., Patients and Methods: Greek patients with BC diagnosed between 1999 and 2016, fulfilling the National Comprehensive Cancer Network criteria for genetic testing, were analyzed for BRCA1/BRCA2 mutations by Sanger sequencing or by a 94-gene panel. Medical records and pathology reports were retrospectively reviewed to retrieve patient and tumor baseline characteristics. Potential associations with mutation status were assessed using the Fisher exact, Pearson χ 2 , and Mann-Whitney tests., Results: Of 2096 selected patients with BC, we identified 297 (14.2%) BRCA1 and 88 (4.2%) BRCA2 carriers. The mean age at BC diagnosis was 40 and 42.6 years, respectively (P = .02). Tumor histologic subtypes in BRCA1 and BRCA2 carriers were predominantly ductal (79%) followed by medullary (10%), and ductal (72%) followed by lobular (15%), respectively. A significantly higher percentage of BRCA2 tumors were human epidermal growth factor receptor 2-positive, compared with BRCA1 tumors (21.7% vs. 5.8%; P < .001). Second primary cancer diagnosis was more frequent in BRCA1 compared with BRCA2 mutation carriers (36.2% vs. 10.7%; P < .001), whereas there was no difference in 15-year overall survival (hazard ratio, 0.92; 95% confidence interval, 0.48-1.83; P = .804) between the 2 groups., Conclusions: These data confirm established observations in the pathology of BRCA-related tumors and provide further insight on the association of rare histologic entities with mutations in these genes, which can be clinically beneficial., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Gene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations., Methods: To further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case-control analysis., Results: Herein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p < 0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p < 0.01), respectively., Conclusion: Studying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

PALB2 loss-of-function variants play an important role in breast, pancreatic and possibly, ovarian and gastric cancer susceptibility. Their frequency can be influenced by founder effects, already described in some populations. Herein, we have assessed the possible founder effect of PALB2 c.2257C>T (p.Arg753*) truncating variant among Greek breast cancer patients, while investigating possible correlations with cancer diagnoses. Following a lead deriving from a background study of highly selected Greek breast cancer patients, a total of 2496 breast and 697 ovarian cancer patients were directly genotyped for the PALB2 c.2257C>T truncating variant. Consequently, haplotype analysis was conducted on identified carriers, using seven microsatellite markers. The prevalence of the PALB2 variant was 0.24% (6/2496) and 0.14% (1/697) among breast and ovarian cases, respectively. Family history seems to be an important factor for the variant identification, although not reaching statistical significance. Microsatellite analysis on 12 carriers revealed a common shared haplotype, spanning a chromosomal region of ~1.2 Mb; the variant was possibly introduced in the Greek population ~1600 years ago. The variant confers high breast cancer risk, as illustrated by comparison with publicly available control groups. Genetic testing for PALB2, especially for the Greek founder c.2257C>T truncating variant, should be seriously considered in Greek breast cancer cases, since such findings could assist appropriate clinical management for the patients and their families.

Background: The "EMERGE" study, aimed to capture real-life management patterns and outcomes in metastatic breast cancer (MBC) in Greece, also accounting for hormone (HR) and human epidermal growth factor receptor 2 (HER2) status., Methods: "EMERGE" was a multicenter, retrospective cohort study of adult MBC patients diagnosed between 01-Janaury-2010 and 30-June-2012, either de novo or having progressed from a non-metastatic state. Patient data, including treatment patterns and outcomes, were mainly abstracted through medical chart review., Results: 386 patients were enrolled by 16 hospital-based oncologists between 12-March-2013 and 31-March-2015. The median look-back period was 29.1 months. At MBC diagnosis, 56.1% of the patients were HR + /HER2 - , 16.6% HR + /HER2 + , 14.5% HR - /HER2 - , and 12.8% HR - /HER2 + . In the first line setting, chemotherapy, targeted therapy and endocrine therapy were received by 76.7, 52.4, and 28.3% of the overall population, and by 66.5/36.2/42.0%, 80.4/80.4/28.6%, 88.4/90.7/0.0, and 95.6%/56.5/6.5% of the HR + /HER2 - , HR + /HER2 + , HR - /HER2 + , HR - /HER2 - subpopulations, respectively. In the overall population, the disease progression incidence rate was 0.57 [95% confidence interval (CI): 0.48-0.67] per person-year; median progression-free survival (PFS) was 22.4 (95% CI: 20.4-24.7) and overall survival (OS) was 45.0 (95% CI: 40.9-55.0) months. Median PFS was 24.6 (95% CI: 21.3-27.9) in HR + /HER2 - , 19.7 (95% CI: 12.9-25.9) in HR + /HER2 + , 23.0 (95% CI: 16.6-29.7) in HR - /HER2 + and 18.3 (95% CI: 10.0-24.7) months in HR - /HER2 - subpopulations. A multivariable Cox proportional hazards model, adjusted among other factors for age and duration of diagnosis, HR and HER2 status, demonstrated that in the overall population PFS was better among those receiving first line endocrine therapy (hazard ratio: 0.70; 95%CI: 0.51-0.95; p = 0.024)., Conclusions: "EMERGE" demonstrates differences between HR/HER2 subtypes in clinical outcomes and divergence from evidence-based guideline recommendations for MBC management, especially as it pertains to the HR + /HER2 - patients in which chemotherapy was favored over endocrine therapy in the first line setting., Study Registration: The study has been registered on the electronic Registry of Non-Interventional Studies (RNIS) posted on the website of the Hellenic Association of Pharmaceutical Companies (SFEE): https://www.dilon.sfee.gr/studiesp&#95;d.php?meleti&#95;id=NIS-OGR-XXX-2012/1.

RAD51D gene's protein product is known to be involved in the DNA repair mechanism by homologous recombination. RAD51D germline mutations have been recently associated with ovarian and breast cancer (OC and BC, respectively) predisposition. Our aim was to evaluate the frequency of hereditary RAD51D mutations in Greek patients. To address this, we have screened for RAD51D germline mutations 609 BRCA1- and BRCA2-negative patients diagnosed with OC, unselected for age or family history, and 569 BC patients diagnosed under 55 years and with an additional relative with BC or OC. We identified four pathogenic mutations in four unrelated individuals with family history of BC and/or OC. Three of the RAD51D carriers had developed BC, while the other one was an OC patient, thus accounting for a mutation frequency of 0.16% in the OC cohort and 0.53% in the BC cohort. One of the detected mutations is novel (c.738 + 1G > A), whereas the rest had been detected previously (p.Gln151Ter, p.Arg186Ter, and p.Arg300Ter). It is noteworthy that the 4 carrier families had 13 BC cases and only 4 OC cases. Our data support that RAD51D should be implemented into the comprehensive multigene panel, as mutation carriers may benefit from the administration of PARP inhibitors.

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-Aim: To evaluate the prognostic role of elaborate molecular clusters encompassing cyclin D1, cyclin E1, p21, p27 and p53 in the context of various breast cancer subtypes., Methods: Cyclin E1, cyclin D1, p53, p21 and p27 were evaluated with immunohistochemistry in 1077 formalin-fixed paraffin-embedded tissues from breast cancer patients who had been treated within clinical trials. Jaccard distances were computed for the markers and the resulted matrix was used for conducting unsupervised hierarchical clustering, in order to identify distinct groups correlating with prognosis., Results: Luminal B and triple-negative (TNBC) tumors presented with the highest and lowest levels of cyclin D1 expression, respectively. By contrast, TNBC frequently expressed Cyclin E1, whereas ER-positive tumors did not. Absence of Cyclin D1 predicted for worse OS, while absence of Cyclin E1 for poorer DFS. The expression patterns of all examined proteins yielded 3 distinct clusters; (1) Cyclin D1 and/or E1 positive with moderate p21 expression; (2) Cyclin D1 and/or E1, and p27 positive, p53 protein negative; and, (3) Cyclin D1 or E1 positive, p53 positive, p21 and p27 negative or moderately positive. The 5-year DFS rates for clusters 1, 2 and 3 were 70.0%, 79.1%, 67.4% and OS 88.4%, 90.4%, 78.9%, respectively., Conclusions: It seems that the expression of cell cycle regulators in the absence of p53 protein is associated with favorable prognosis in operable breast cancer.

Background: The retinoblastoma (RB) gene is a tumor-suppressor gene that plays a central role in regulating the cell cycle. Inactivation of this gene is involved in breast cancer., Patients and Methods: A total of 827 patients with breast cancer treated with taxane-based adjuvant chemotherapy were included in the study. Protein expression of RB, phosphorylated RB (pRB), p16, cyclin D1 and p53 was evaluated by immunohistochemistry., Results: Neither of the retinoblastoma markers (RB and pRB) reached statistical significance in terms of their association with disease-free or overall survival. Nevertheless, when clustering analysis was performed, patients with tumors featuring low levels of p16, cyclin D1 and p53 with concomitantly high levels of pRB had reduced risk for relapse (Wald's p=0.015)., Conclusion: The p53-mediated sensitivity of breast cancer cells to chemotherapeutic agents appears to be driven mostly by pRB. Using agents that enhance RB phosphorylation might possibly increase the chemosensitivity of breast cancer cells., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Intensive chemotherapy confers benefit to patients with high-risk early breast cancer (BC). We characterized the feasibility and toxicity profile of anthracycline-containing adjuvant chemotherapy (ACAC) in older women with early BC., Patients and Methods: Available data from women who received ACAC for BC in 3 randomized trials were retrieved. We identified women aged >65 years and we examined differences in tolerability and delivery of chemotherapy, toxicity, and treatment outcome., Results: From a total of 2640 patients, we identified 453 patients (17%) as being >65 years old, 89% of whom had tumors that were node-positive, with 77% who were hormone receptor-positive. At least 90% of the planned doses were delivered in 37% of the elderly, compared with 49% in the younger patients (P < .0001). Grade 3 and 4 hematological toxicity was observed in 32% of elderly patients, compared with 21% of the younger (P < .0001). Febrile neutropenia occurred in 4.5% of the elderly patients, as opposed to 2.0% in the younger patients (P < .002). Elderly patients experienced more frequent Grade 3 and 4 fatigue, mucositis, and sensory neuropathy. Relative dose intensities were significantly lower in elderly patients. Treatment discontinuation was not different in the 2 groups. At a median follow-up of 120 months, competing risks analysis showed a significant benefit in disease-free survival for elderly patients., Conclusion: Elderly BC patients treated with ACAC derive clinical benefit comparable to that in younger patients, mainly at the cost of increased risk of hematological toxicity. This should be taken into account in decision-making and treatment individualization in high-risk BC patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Lapatinib plus capecitabine (lap+cap) is approved as treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), who have progressed on prior trastuzumab in the metastatic setting. We previously reported progression-free survival (PFS), overall survival (OS) and safety results from this open-label, multicentre, phase II study (VITAL; NCT01013740) conducted in women with HER2 positive MBC, to evaluate the efficacy and safety of lap plus vinorelbine (lap+vin), an important chemotherapy option for MBC, compared with lap+cap. In total, 112 patients were randomised 2:1 to treatment with lap+vin (N = 75) or lap+cap (N = 37). Results showed that the median PFS (primary endpoint) and OS (secondary endpoint) post-randomisation were comparable between treatment arms, with no new safety signals detected. Here, we assessed the final OS in this study at 40 months post-randomisation. At the time of final analyses, 24 (32%) patients were ongoing in the lap+vin arm, compared with 14 (38%) patients in the lap+cap arm (92% in both arms had discontinued treatment). Median OS in the lap+vin arm was 23.3 months (95% confidence intervals [CI]: 18.5, 31.1), compared with 20.3 months (95% CI: 16.4, 31.8) in the lap+cap arm. The median follow-up in the lap+vin arm was 18.86 months (95% CI: 10.68, 26.02), compared with 19.38 (95% CI: 25.56) months in the lap+cap arm. Similar rates of death (56-57%) were observed in both arms. The final OS was consistent with the previously reported data and suggest that lap+vin offers an effective treatment option for women with HER2-positive MBC., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Plasmablastic lymphoma (PBL) is a rare entity which is often causally related to infection by the Human Immunodeficiency Virus (HIV). Despite its predilection for oral cavity involvement, multiple cases of extra-oral involvement have been reported in the literature, more often among immunocompetent individuals., Case Report: Herein we present the first case of primary PBL of the breast in an otherwise immunocompetent 36-year-old woman who was successfully treated with consolidation megatherapy and autologous stem cell transplantation., Conclusion: PBL carries a particularly poor prognosis and more intensive treatment is usually warranted. However, no treatment guidelines exist and treatment choices are made based on case reports and small retrospective case series., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: HER2 and TOP2A gene status are assessed for diagnostic and research purposes in breast cancer with fluorescence in situ hybridization (FISH). However, FISH probes do not target only the annotated gene, while chromosome 17 (chr17) is among the most unstable chromosomes in breast cancer. Here we asked whether the status of specifically targeted genes on chr17 might help in refining prognosis of early high-risk breast cancer patients., Methods: Copy numbers (CN) for 14 genes on chr17, 4 of which were within and 10 outside the core HER2 amplicon (HER2- and non-HER2-genes, respectively) were assessed with qPCR in 485 paraffin-embedded tumor tissue samples from breast cancer patients treated with adjuvant chemotherapy in the frame of two randomized phase III trials., Principal Findings: HER2-genes CN strongly correlated to each other (Spearman's rho >0.6) and were concordant with FISH HER2 status (Kappa 0.6697 for ERBB2 CN). TOP2A CN were not concordant with TOP2A FISH status (Kappa 0.1154). CN hierarchical clustering revealed distinct patterns of gains, losses and complex alterations in HER2- and non-HER2-genes associated with IHC4 breast cancer subtypes. Upon multivariate analysis, non-HER2-gene gains independently predicted for shorter disease-free survival (DFS) and overall survival (OS) in patients with triple-negative cancer, as compared to luminal and HER2-positive tumors (interaction p = 0.007 for DFS and p = 0.011 for OS). Similarly, non-HER2-gene gains were associated with worse prognosis in patients who had undergone breast-conserving surgery as compared to modified radical mastectomy (p = 0.004 for both DFS and OS). Non-HER2-gene losses were unfavorable prognosticators in patients with 1-3 metastatic nodes, as compared to those with 4 or more nodes (p = 0.017 for DFS and p = 0.001 for OS)., Conclusions: TOP2A FISH and qPCR may not identify the same pathology on chr17q. Non-HER2 chr17 CN patterns may further predict outcome in breast cancer patients with known favorable and unfavorable prognosis.

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.

Lapatinib is approved in combination with capecitabine for treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who have progressed on prior trastuzumab in the metastatic setting. Vinorelbine is an important chemotherapy option for MBC. We evaluated efficacy and safety of lapatinib plus vinorelbine, compared with lapatinib plus capecitabine, in women with HER2-positive MBC. In this open-label, multicenter, phase II study, eligible patients (N = 112) were randomized 2:1 to lapatinib plus vinorelbine [(N = 75) 1,250 mg orally once daily (QD) continuously plus 20 mg/m(2)/day intravenously] or lapatinib plus capecitabine [(N = 37) 1,250 mg orally QD continuously plus 2,000 mg/m(2)/day orally, 2 doses]. The primary endpoint was progression-free survival (PFS). Other endpoints included overall survival (OS) and safety. Patients progressing within the study were given the option of crossover to the other treatment arm; time to second progression was an exploratory endpoint. Patient demographics, stratification, and prognostic factors were well balanced between treatments. Median PFS in both arms was 6.2 months [95 % confidence interval (CI) 4.2, 8.8 (lapatinib plus vinorelbine); 4.4, 8.3 (lapatinib plus capecitabine)]. Median OS on lapatinib plus vinorelbine was 24.3 months (95 % CI 16.4, NE) and 19.4 months (95 % CI 16.4, 27.2) on lapatinib plus capecitabine. In total, 42 patients opted to cross over; median PFS was 3.2 months (95 % CI 1.7, 5.1) on lapatinib plus vinorelbine and 4.0 months (95 % CI 2.1, 5.8) on lapatinib plus capecitabine. Lapatinib plus vinorelbine offers an effective treatment option for patients with HER2-overexpressing MBC, having displayed comparable efficacy and tolerability rates to lapatinib plus capecitabine.

This case control study aims to investigate the role of MMP-2 -1306C>T polymorphism as a potential risk factor and possible prognostic marker for breast cancer in a South European population. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy controls were recruited. MMP-2 -1306C>T polymorphism was genotyped; multivariate logistic regression as well as Cox regression analysis were performed. MMP-2 -1306C>T status was not associated with breast cancer risk either at the total sample or at the subanalyses on premenopausal and postmenopausal women. At the survival analysis, a trend towards a favorable association between MMP-2 -1306C>T allele and disease-free survival as well as overall survival was observed. Regarding subanalyses on ER-negative and ER-positive cases, the favorable association implicating MMP-2 -1306C>T allele was particularly evident among ER-positive cases; no significant associations emerged among ER-negative cases. MMP-2 -1306C>T polymorphism does not seem to be a risk factor for breast cancer in South European population; however, a trend towards a favorable association with survival has been observed.

Unlabelled: To explore the activity and safety of two schedules of ixabepilone, as first line chemotherapy, in patients with metastatic breast cancer previously treated with adjuvant chemotherapy, a randomized non-comparative phase II study was conducted. From November 2008 until December 2010, 64 patients were treated with either ixabepilone 40 mg/m(2) every 3 weeks (Group A, 32 patients) or ixabepilone 20 mg/m(2) on days 1, 8 and 15 every 4 weeks (Group B, 32 patients). Overall response rate (the primary end point) was 47% in Group A and 50% in Group B. The most frequent severe adverse events were neutropenia (32% vs. 23%), metabolic disturbances (29% vs. 27%) and sensory neuropathy (12% vs. 27%). Two patients in Group A and 3 in Group B developed febrile neutropenia. After a median follow-up of 22.7 months, median progression-free survival (PFS) was 9 months in Group A and 12 months in Group B. Median survival was 26 months in Group A, whereas it was not reached in Group B. Multiple genetic and molecular markers were examined in tumor and peripheral blood DNA, but none of them was associated with ORR or drug toxicity. Favorable prognostic markers included: the T-variants of ABCB1 SNPs c.2677G/A/T, c.1236C/T and c.3435C/T, as well as high MAPT mRNA and Tau protein expression, which were all associated with the ER/PgR-positive phenotype; absence of TopoIIa; and, an interaction between low TUBB3 mRNA expression and Group B. Upon multivariate analysis, tumor ER-positivity was a favorable (p = 0.0092) and TopoIIa an unfavorable (p = 0.002) prognostic factor for PFS; PgR-positivity was favorable (p = 0.028) for survival. In conclusion, ixabepilone had a manageable safety profile in both the 3-weekly and weekly schedules. A number of markers identified in the present trial appear to deserve further evaluation for their prognostic and/or predictive value in larger multi-arm studies., Trial Registration: ClinicalTrials.gov NCT 00790894.

Objective: To evaluate breast cancer characteristics in women aged 25 years and younger., Methods: This was a retrospective, nested, within-cases matched study. The study design was based on a two-phase protocol. In the first phase, stage, grade, histologic subtype, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status were compared between 28 patients (aged 25 years and younger) and 685 older premenopausal women (aged older than 25 years) with breast cancer. The second phase aimed to determine whether young patients exhibited worse prognosis when compared with older premenopausal women., Results: Young patients presented at a more advanced stage (P=.012) and exhibited a higher grade (P=.018). No significant differences were noted regarding histologic subtype, estrogen receptor, and progesterone receptor status. Genetic testing for BRCA1 and BRCA2 mutations was performed in 12 of 28 young patients and mutations were found in 25% of them. Moreover, young women presented poorer overall survival (hazard ratio [HR] 4.30, 95% confidence interval [CI] 1.09-17.03) than their older counterparts, matched by histologic subtype, stage, and grade; a similar pattern was noted regarding relapse-free survival (HR 8.28, 95% CI 2.24-30.60)., Conclusion: Breast cancer diagnosis in women aged 25 years and younger is uncommon; however, these patients present at a more advanced stage, with a higher grade, and exhibit poorer survival.

Aims: Our purpose was to investigate, in breast carcinomas, the prognostic importance of the proteins Wnt1 and glycogen synthasekinase (GSK)-3β, and their associations with classic clinicopathological indices., Methods and Results: Immunohistochemistry was performed on paraffin-embedded tissue specimens from 288 invasive breast carcinomas to detect the expression of the proteins Wnt1, GSK3β, oestrogen receptor (ER), progesterone receptor (PR), erbB2, p53, Ki67, caspase-3 and β-catenin. Both Wnt1 and GSK3β were detected predominantly in the cytoplasm of the invasive tumour cells and the in-situ component, while GSK3β was also detected in the stromal fibroblasts. Wnt1 immunoreactivity in the invasive tumour cells showed an inverse association with histological grade (P = 0.002), Ki67 (P = 0.008) and p53 (P = 0.031), while its relation with ER, erbB2 and caspase-3 was found to be positive (P = 0.007, P = 0.018 and P = 0.03, respectively). Cytoplasmic Wnt1 expression was related to a favourable prognosis within the subgroup of patients with stage II disease (P = 0.032)., Conclusions: Wnt1 expression in the invasive tumour cells seems to promote differentiation and apoptosis, while being related inversely to proliferation. Therefore, this suggests its participation in the primary stages of breast carcinogenesis. The latter is supported further by the immunodetection of Wnt1 in in-situ carcinomas., (© 2013 Blackwell Publishing Ltd.)

Background: The HER2 gene has been established as a valid biological marker for the treatment of breast cancer patients with trastuzumab and probably other agents, such as paclitaxel and anthracyclines. The TOP2A gene has been associated with response to anthracyclines. Limited information exists on the relationship of HER2/TOP2A gene status in the presence of centromere 17 (CEP17) gain with outcome of patients treated with anthracycline-containing adjuvant chemotherapy., Methods: Formalin-fixed paraffin-embedded tumor tissue samples from 1031 patients with high-risk operable breast cancer, enrolled in two consecutive phase III trials, were assessed in a central laboratory by fluorescence in situ hybridization for HER2/TOP2A gene amplification and CEP17 gain (CEP17 probe). Amplification of HER2 and TOP2A were defined as a gene/CEP17 ratio of >2.2 and ≥2.0, respectively, or gene copy number higher than 6. Additionally, HER2, TopoIIa, ER/PgR and Ki67 protein expression was assessed by immunohistochemistry (IHC) and patients were classified according to their IHC phenotype. Treatment consisted of epirubicin-based adjuvant chemotherapy followed by hormonal therapy and radiation, as indicated., Results: HER2 amplification was found in 23.7% of the patients and TOP2A amplification in 10.1%. In total, 41.8% of HER2-amplified tumors demonstrated TOP2A co-amplification. The median (range) of HER2, TOP2A and CEP17 gain was 2.55 (0.70-45.15), 2.20 (0.70-26.15) and 2.00 (0.70-26.55), respectively. Forty percent of the tumors had CEP17 gain (51% of those with HER2 amplification). Adjusting for treatment groups in the Cox model, HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with time to relapse or time to death., Conclusion: HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with outcome in high-risk breast cancer patients treated with anthracycline-based adjuvant chemotherapy., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12611000506998 and ACTRN12609001036202.

The main indication of prophylactic mastectomy pertains to BRCA1 or BRCA2 mutation carriers. Prophylactic mastectomy includes the simple method and the subcutaneous method. Both methods can be followed by breast plastic reconstruction either at the same time or later. This review examines key issues regarding prophylactic mastectomy: the selection of patients, its effectiveness, its limitations, convergence/divergence in existing guidelines, and future perspectives.

Landmark studies have established taxanes in the treatment of patients with breast cancer; however, recommendations regarding their administration during pregnancy are controversial. The present systematic review aims to synthesize all available data that stem exclusively from breast cancer case series to evaluate the efficacy and safety of taxanes during pregnancy. Overall, 16 studies (50 pregnancies) were eligible for the systematic review according to prisma guidelines. The mean age of patients with breast cancer at pregnancy was 34.6 years. The gestational age (GA) at chemotherapy administration varied from 12 to 36 weeks. The mean GA at delivery was 35.9 weeks. The mean weight of babies at delivery was 2380 g. In 76.7% of cases, a completely healthy neonate was born; in the remaining cases, a neonate who was dystrophic and premature, one with mild hydrocephalus, one with signs of bacterial sepsis, one with hyperbilirubinemia, one with apnea of prematurity, respiratory distress syndrome and gastroesophageal reflux, one with meconium-stained fluid, and another neonate with neutropenia and pyloric stenosis were reported. Ninety percent of children were completely healthy, with a median follow-up of 16 months; in the remaining cases, one child with recurrent otitis media, one with immunoglobulin A deficiency and mild constipation, and another child with delayed speech were reported. In conclusion, available data suggest that taxanes may potentially play a promising role in the optimal therapeutic strategy of patients with breast cancer diagnosed during pregnancy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aims:   To study the clinicopathological and prognostic value of cyclin D1 overexpression in patients with breast carcinoma., Methods and Results:   Immunohistochemistry was performed on paraffin-embedded tissue specimens from 290 invasive breast carcinomas to detect the proteins cyclin D1, oestrogen receptor (ER), progesterone receptor (PR), p53, c-erbB2, and topoisomerase IIα (topoIIα). Cyclin D1 staining was quantified using a computerized image analysis method. Cyclin D1 overexpression characterized smaller, ER-positive and PR-positive tumours (P = 0.017, P < 0.0001, and P < 0.0001, respectively), of a lower histological and nuclear grade (P = 0.011 and P < 0.0001, respectively), and with reduced expression of topoIIα (P = 0.001) and p53 (P < 0.001). Cyclin D1 was found to have an independent favourable impact on the overall survival of both the unselected cohort of patients (P = 0.011) and of patients with ER-negative and lymph node-positive tumours (P = 0.034 and P = 0.015, respectively). In triple-negative tumours, cyclin D1 overexpression was found to have independent favourable impacts on both overall and relapse-free survival (P = 0.002 for both)., Conclusions:   This is the first immunohistochemical study to dissociate the advantageous prognostic effect of cyclin D1 overexpression from its association with ER expression, and to provide evidence that cyclin D1 overexpression may be a marker of prolonged survival in patient subgroups with aggressive phenotypes., (© 2012 Blackwell Publishing Ltd.)

This case control study aims to investigate the role of HSP90 Gln488His (C > G), HSP70-2 P1/P2, HIF-1 alpha C1772T and HSPA8 intronic 1541-1542delGT polymorphisms as potential risk factors and/or prognostic markers for breast cancer. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy cases were recruited. The above mentioned polymorphisms were genotyped; multivariate logistic regression was performed. HSP90 GG (His/His) genotype was associated with elevated breast cancer risk. Similarly, the allele dose-response model pointed to increase in breast cancer risk per G allele. HSP70-2 P1/P2, HSPA8 intronic 1541-1542delGT and HIF-1 alpha polymorphisms were not associated with breast cancer risk, as evidenced by the dose-response allele models. The positive association between HSP90 G allele and breast cancer risk seemed to pertain to both premenopausal and postmenopausal women. With respect to survival analysis, none of the aforementioned polymorphisms was associated with either disease-free survival or overall survival. HSP90α Gln488His polymorphism seems to be a risk factor for breast cancer. On the other hand, our study did not point to excess risk conferred by HSPA8 1541-1542delGT, Hsp70-2 P1/P2 and HIF-1α C1772T.

This case-control study aims to investigate the role of HTERT MNS16A polymorphism as a potential risk factors and/or a prognostic marker for breast cancer. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy controls were recruited. HTERT MNS16A polymorphism was genotyped (L: long allele, S: short allele); multivariate logistic regression was performed. No significant association was noted either at the overall analysis (OR = 1.57, 95 % CI 0.84-2.93 for heterozygous LS carriers; OR = 1.02, 95 % CI 0.54-1.95 for homozygous SS carriers) or at the subanalyses in premenopausal and postmenopausal women. With respect to survival analysis, HTERT MNS16A polymorphism was not associated with either disease-free survival or overall survival. HTERT MNS16A polymorphism does not seem to be a risk factor for breast cancer in the Caucasian Greek population. Further, larger studies from other countries and subjects seem to be needed as this novel polymorphism is being examined in depth.

Aims: The rate of EGFR amplification in breast cancer ranges between 0% and 15%. Recent studies have focused on the amplification status of cytosine-adenine (CA) repeats in intron 1 of the gene and correlated it with increased EGFR protein. The aim of this study was to investigate, for the first time, the significance of coding exon 8 amplification of EGFR in invasive breast cancer., Methods and Results: We investigated, by means of real-time polymerase chain reaction (PCR), the amplification status of exon 8 of the EGFR gene in 148 paraffin-embedded tissue sections, 115 with invasive breast carcinoma and 33 controls. Immunohistochemistry was utilized to detect EGFR and human epidermal growth factor receptor 2 (HER2) expression. Univariate and multivariate statistical analyses were performed for the evaluation of our results. EGFR amplification was observed in 7.8% of the patients, and EGFR was immunodetected in 9.6%. EGFR amplification was correlated positively with EGFR expression (P < 0.0001), HER2 expression (P = 0.023), coexpression of EGFR/HER2 (P < 0.0001) and nuclear grade (P = 0.047), and inversely with ER protein expression (P = .047)., Conclusion: It appears that amplification of the coding sequence exon 8 exhibits similar biological behaviour to amplification of the regulatory sequence in intron 1, leading to elevated levels of EGFR protein., (© 2012 Blackwell Publishing Ltd.)

Aims:   STAT-1 is the first member of the family of signal transducers and activators of transcription (STATs). In breast cancer experimental models, an apoptotic and antiproliferative effect has been demonstrated. Our aim was to study the role of phosphorylated STAT-1 (pSTAT-1) in invasive breast carcinoma and its prognostic significance in premenopausal and postmenopausal patients., Methods and Results:   Immunohistochemistry was performed in 165 patients in order to detect the expression of pSTAT-1 and its correlation with oestrogen receptor (ER), progesterone receptor (PR), caspase-3, and pAkt. pSTAT-1 was immunodetected in the cytoplasm of the malignant cells (11.6%). In premenopausal patients, cytoplasmic pSTAT-1 was positively correlated with stage (P = 0.014), ER (P = 0.008), caspase-3 (P = 0.029), and pAkt (P = 0.045). Univariate analysis showed that cytoplasmic pSTAT-1 was associated with poor overall survival (P = 0.042) and the phenotype of pSTAT-1/ER or PR coexpression with shorter disease-free survival (P = 0.012). In contrast, in postmenopausal patients, no association with clinicopathological parameters and survival was observed, except for the relationship of pSTAT-1/ER or PR coexpression with longer disease-free survival (P = 0.034)., Conclusions:   This is the first study examining the role of pSTAT-1 in premenopausal and postmenopausal women with invasive breast cancer. Our results suggest that pSTAT-1 is related to tumour progression in premenopausal patients through the advanced stage and worse survival., (© 2012 Blackwell Publishing Ltd.)

To explore the impact of dose intensity (DI) in the adjuvant setting of breast cancer, a randomized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, methotrexate and fluorouracil (CMF)in high-risk breast cancer patients. From Oct 2000 to June 2005, 1,121 node-positive patients were randomized to dose-dense sequential epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, NJ) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of "intensified" combination chemotherapy with CMF. By protocol design total cumulative dose and duration of treatment were identical in both groups. Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm. Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments. Disease-free survival (DFS) was the primary endpoint. At a median follow-up of 76 months, 253 patients (23%) had documented disease relapse (123 vs. 130 in groups A and B, respectively) and 208 deaths (101, group A and 107, group B) had been observed. The 5-year DFS rate of 74 and 74% and OS rate of 86 and 85% were observed for group A and group B, respectively. No differences were found in DFS or OS between the two treatment groups (P = 0.78 and P = 0.45 for DFS and OS, respectively). Safety analysis results showing that both regimens were well tolerated and safe have been previously published (Fountzilas et al. Ann Oncol 2008). No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs. No additional safety issues were raised with long-term follow-up.

Background: Randomized studies have shown that bevacizumab combined with taxane-based regimens increases response rates and prolongs progression-free survival (PFS) of patients with metastatic breast cancer (MBC). However predictive or prognostic biological markers that identify the appropriate target population, thus improving the cost-effectiveness ratio of this treatment, are still needed., Patients and Methods: Retrospectively, 124 patients with MBC treated either with paclitaxel 90 mg/m² weekly x12 plus bevacizumab 10 μg/kg every 2 weeks or 15 μg/kg every 3 weeks (85 patients) or paclitaxel 175 mg/m² plus bevacizumab 15 μg/kg every 3 weeks for 6 cycles (36 patients) were identified. Additionally, the prognostic significance of a panel of key biological markers was evaluated centrally by immunohistochemistry (IHC) in 88 evaluable patients., Results: More than two thirds of the patients completed chemotherapy, as planned. The response rate was almost identical (55.3% vs. 55.6%) in the patients treated with weekly or 3-weekly paclitaxel, respectively. After a median follow-up time of 23 months, the median PFS of the study population was 13 months, while median survival had not yet been reached. Common severe adverse events were neutropenia (33%), neuropathy (18.6%) and metabolic disturbances (17.6%). The incidence of hypertension of all grades was 28.1%. High expression of vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3) was associated with clinical response, while high expression of VEGFR1 was associated with poor survival., Conclusion: The safety and activity of the combination of bevacizumab with paclitaxel given either weekly or 3-weekly in patients with MBC is confirmed.

Background: Elevated Hsp90 expression has been documented in breast ductal carcinomas, whereas decreased Hsp90 expression has been reported in precursor lobular lesions. This study aims to assess Hsp90 expression in infiltrative lobular carcinomas of the breast., Methods: Tissue specimens were taken from 32 patients with infiltrative lobular carcinoma. Immunohistochemical assessment of Hsp90 was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. Concerning Hsp90 assessment: i) the percentage of positive cells and ii) the intensity were separately analyzed. Subsequently, the Allred score was adopted and calculated. The intensity was treated as an ordinal variable-score (0: negative, low: 1, moderate: 2, high: 3). Statistical analysis followed., Results: All infiltrative lobular carcinoma foci mainly presented with a positive cytoplasmic immunoreaction for Hsp90. Compared to the adjacent normal ducts and lobules, infiltrative lobular carcinoma exhibited a statistically significant decrease in Hsp90 expression, both in terms of Hsp90 positive cells (%) and Allred score (74.2 +/- 11.2 vs. 59.1 +/- 14.2 p = 0.0001; 7.00 +/- 0.95 vs. 6.22 +/- 1.01, p = 0.007, Wilcoxon matched-pairs signed-ranks test). Concerning the intensity of Hsp90 immunostaining only a marginal decrease was noted (2.16 +/- 0.68 vs. 1.84 +/- 0.63, p = 0.087, Wilcoxon matched-pairs signed-ranks test)., Conclusion: ILC lesions seem to exhibit decreased Hsp90 expression, a finding contrary to what might have been expected, given that high Hsp90 expression is a trait of invasive ductal carcinomas.

Background: Hsp90 (heat shock protein90) is a chaperone protein essential for preserving and regulating the function of various cellular proteins. Elevated Hsp90 expression seems to be a trait of breast cancer and may be an integral part of the coping mechanisms that cancer cells exhibit vis-à-vis stress. This manuscript tries to examine the immunohistochemical expression of Hsp90 all along the continuum of breast ductal lesions encompassing ductal hyperplasia without atypia (DHWithoutA), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC)., Methods: Tissue specimens were taken from 30 patients with DHWithoutA, 31 patients with ADH, 51 with DCIS and 51 with IDC. Immunohistochemical assessment of Hsp90 was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. Concerning Hsp90 assessment the percentage of positive cells and the intensity were separately analyzed. Subsequently, the Allred score was calculated. Post hoc analysis on the correlations between Hsp90 Allred score and possible predictors (grade, nodal status, tumor size, ER Allred score, PR Allred score, c-erbB-2 status and triple negative status) was conducted in IDC., Results: Hsp90 exhibited mainly cytoplasmic immunoreactivity. Hsp90 Allred score exhibited an increasing trend along the continuum of breast ductal lesions (Spearman's rho = 0.169, p = 0.031). Compared to the adjacent normal ducts and lobules, no statistically significant differences were noted in DHwithoutA, ADH and DCIS. Hsp90 expression (intensity, positive cells, Allred score) was higher in IDC, compared to the adjacent normal tissue. Higher Hsp90 expression was observed in grade 2/3 IDCs (borderline association) and tumors of larger size. At the univariable analysis, higher Hsp90 expression was associated with higher ER Allred score, PR Allred score and c-erbB-2 positivity in IDC. Triple-negative IDCs exhibited significantly lower Hsp90 expression. The multivariable logistic regression model revealed that between the three markers, solely ER Allred score and c-erbB-2 positivity were independently associated with higher Hsp90 expression in IDC., Conclusion: The above point to significant variability in Hsp90 expression with significant implications upon the effectiveness and limitations of anti-Hsp90 drugs.

Aims: Loss of phosphatase and tensin homologue (PTEN) leads to activation of several kinases, including mammalian target of rapamycin (mTOR), which promotes cell cycle progression. The aim was to study the expression of PTEN and phosphorylated (p)-mTOR in familial and sporadic invasive breast carcinomas and their relation to clinicopathological features, molecular indices (Wnt1) and patients' survival., Methods and Results: PTEN and p-mTOR were detected immunohistochemically in 215 sections of invasive breast carcinomas (112 with a familial history of breast cancer). Image analysis was used and univariate and multivariate analyses employed for statistical evaluation of results. PTEN was detected in the nucleus (73.5%) and p-mTOR in the cytoplasm (44.2%) of cancer cells. Loss of PTEN protein was more frequently detected in women with a familial history of breast cancer (72%) (P < 0.0001), while its expression was negatively correlated with Wnt1, in total (P = 0.049). p-mTOR showed a positive association with lymph node status (P = 0.010) and was found to have a negative impact on patients' overall survival (P = 0.016)., Conclusions: Loss of PTEN protein expression appears to occur more frequently in women with a family history of breast cancer, whereas activation of mTOR protein seems to be related to a more aggressive phenotype.

In this study, we examined whether vacuum-assisted breast biopsy (VABB) specimens provide an accurate immunohistochemical assessment of estrogen receptors (ER), progesterone receptors (PR), c-erbB-2, and p53 proteins. Thirty-seven consecutive cases with a VABB diagnosis of ductal carcinoma in situ (DCIS) were included. The immunohistochemical expression of ER and PR, c-erbB-2, and p-53 was assessed in VABB and in surgical specimens with pathological concordance. The "clinically relevant concordance rate" (CRCR) was calculated. The CRCRs were 77.8%, 77.8%, and 89% for ER, PR, and c-erbB-2, respectively. Concerning both ER and PR, the clinically relevant expression was higher in VABB specimens. A difference in borderline significance arose concerning c-erbB-2 expression, pointing to more intense expression in the surgical specimens. The p53 percentage did not differ between the two groups. VABB specimens provide an accurate immunohistochemical assessment of molecular markers. However, bioptical-surgical discrepancies persisted even in this context of a larger quantity of tissue removed., (Copyright 2009 Elsevier GmbH. All rights reserved.)

Background: Burkitt's lymphoma (BL) in pregnancy presenting with breast involvement is a rare clinical entity, and only 13 cases have been reported so far., Case Report: We describe the case of a 28-year-old postpartum woman who presented with markedly enlarged breasts caused by BL. She was treated with 8 cycles of the CALGB 10002 regimen, as well as with irradiation to both breasts. After achieving a complete objective response, the patient received consolidation with high dose BEAM followed by autologous stem cell transplantation. 20 months after the initial diagnosis, our patient remains alive and relapse-free. Data extracted from the published case reports include information regarding demographic details, type of treatment, sites of disease, and survival. The clinical outcome of the reviewed cases was very unfavorable., Conclusions: BL affecting breasts during pregnancy or lactation is a rare entity that requires a prompt diagnosis and an aggressive therapeutic approach., (Copyright © 2010 S. Karger AG, Basel.)

This study evaluates the effect of palpability upon breast self-examination (BSE) and adherence to annual mammogram after benign breast biopsy (BBB). Seven hundred and fifty-two women with palpable (WP, n = 359) or nonpalpable (WNP, n = 393) lesions were evaluated 2 years before and after BBB. BSE was considered adequate when it was performed at least once per month, and inadequate when it was performed with a frequency of less than once per month. Prebiopsy/postbiopsy adherence was characterized as inadequate when at least one session of mammographic examination was lost within the 2-prebiopsy/postbiopsy (including the last visit) years, respectively. The prebiopsy frequency of adequate BSE was higher in WP [49 (176 of 359) vs. 38.9% (153 of 393) for WNP; Pearson's chi2 (1) = 7.77, P = 0.005]. However, the opposite happened regarding the prebiopsy adherence to mammogram, as the frequency of adequate adherence was 64.1% (252 of 393) in WNP, but only 46.0% (165 of 359) in WP. After BBB, adherence to mammogram significantly increased in both groups, reaching 76.1% (299 of 393) for WNP and 65.2% (234 of 359) for WP. However, BSE increased significantly only in WNP. Regarding the WP group, the postBBB BSE did not exhibit any significant change. Noticeably, the aforementioned increase in BSE among WNP resulted in the disappearance of the initial WP-WNP discrepancy regarding BSE; the postBBB BSE did not differ between WP and WNP. However, concerning adherence to mammogram, the superiority of WNP versus WP persisted (76.1 vs. 65.2%, respectively). In conclusion WP and WNP may perceive BBB differently, as reflected upon the differentially modified patterns.

Objective: A randomized phase II trial was conducted to test whether the addition of gemcitabine to weekly docetaxel could improve the objective response rate and survival outcomes as second-line chemotherapy in patients with metastatic breast cancer who have failed a paclitaxel-containing regimen., Methods: Patients were randomized to receive either weekly docetaxel 40 mg/m(2) (group A, n = 34) or the combination of weekly docetaxel 35 mg/m(2) with gemcitabine 600 mg/m(2) (group B, n = 41). Three consecutive weekly infusions followed by a 1-week rest period represented 1 chemotherapy cycle., Results: The objective response rate was 18% and 27.5% in group A and B, respectively (p = 0.413). No statistically significant differences were demonstrated in terms of median overall survival and time to disease progression. The rate and grade 3 and 4 neutropenia were higher in group B (23 vs. 3%)., Conclusions: The weekly administration of docetaxel and gemcitabine did not result in superior clinical outcomes over weekly docetaxel., (Copyright 2009 S. Karger AG, Basel.)

Background: Giant cell arteritis (GCA) of the breast is one of the less recognized variants of this vasculitis and may represent an isolated finding or a manifestation of a more widespread disease., Case Report: We present the case of a 74-year-old woman with malaise and a 14-day persistent fever, reaching 38 degrees C. There was a bilateral, painless and mobile axillary lymphadenopathy and a slight tenderness over the medial and lateral upper quadrants of her left breast, as well as an independent palpable tender mass in the upper outer quadrant of the same breast measuring 2 cm in its greatest diameter. Constitutional symptoms, anemia and an elevated erythrocyte sedimentation rate suggestive of polymyalgia rheumatica were also present. An invasive ductal carcinoma of the breast with coincidental pathologic findings of GCA in the same biopsy specimen was revealed. In this case, arteritis was limited to the breast and presented with diffuse breast tenderness. No other artery was involved by GCA. All arteritis-related symptoms disappeared after the removal of the tumor., Conclusions: There is a relationship between cancer, particularly breast cancer, and GCA of the same organ, but the real nature of this association still remains unknown., (Copyright 2008 S. Karger AG, Basel.)

Background: Heat shock protein 90 (Hsp90) overexpression has been implicated in breast carcinogenesis, with putative prognostic and therapeutic implications. The purpose of this study is to evaluate the immunohistochemical expression of Hsp90 and to examine whether Hsp90 expression is associated with estrogen receptor alpha (ER-alpha) and beta (ER-beta) immunostaining in lobular neoplasia (LN) of the breast., Methods: Tissue specimens were taken from 44 patients with LN. Immunohistochemical assessment of Hsp90, ER-alpha and ER-beta was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. As far as Hsp90 evaluation is concerned: i) the percentage of positive cells, and ii) the intensity was separately analyzed. Additionally, the Allred score was adopted and calculated. Accordingly, Allred score was separately evaluated for ER-alpha and ER-beta. The intensity was treated as an ordinal variable-score (0: negative, low: 1, moderate: 2, high: 3). Statistical analysis followed., Results: Hsp90 immunoreactivity was mainly cytoplasmic in both the epithelial cells of normal breast (ducts and lobules) and LN. Some epithelial cells of LN also showed nuclear staining, but all the LN foci mainly disclosed a positive cytoplasmic immunoreaction for Hsp90. In addition, rare intralobular inflammatory cells showed a slight immunoreaction. The percentage of Hsp90 positive cells in the LN areas was equal to 67.1 +/- 12.2%, whereas the respective percentage in the normal adjacent breast tissue was 69.1 +/- 11.6%; the difference was not statistically significant. The intensity score of Hsp90 staining was 1.82 +/- 0.72 in LN foci, while in the normal adjacent tissue the intensity score was 2.14 +/- 0.64. This difference was statistically significant (p = 0.029, Wilcoxon matched-pairs signed-ranks test). The Hsp90 Allred score was 6.46 +/- 1.14 in the LN foci, significantly lower than in the normal adjacent tissue (6.91 +/- 0.92, p = 0.049, Wilcoxon matched-pairs signed-ranks test). Within the LN foci, the Hsp90 Allred score was neither associated with ER-alpha, nor with ER-beta percentage., Conclusion: Hsp90 was lower in LN foci both at the level of intensity and Allred score, a finding contrary to what might have been expected, given that high Hsp90 expression is detected in invasive breast carcinomas. Hsp90 deregulation does not seem to be a major event in LN pathogenesis.

Primary Objective: Granulocyte-colony stimulating factor (G-CSF) is used for the mobilization of bone marrow and endothelial progenitor cells, though G-CSF-induced inflammation may cause endothelial dysfunction. We examined the effects of G-CSF on endothelium, C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha) and anti-inflammatory cytokines namely interleukin 10 (IL-10)., Research Design: We studied 60 women with breast cancer, who were randomized to either subcutaneous G-CSF (5 microg/kg), o.d. for 5 days after adjuvant chemotherapy (n = 40) or placebo (n = 20)., Experimental Interventions: We measured flow-mediated dilatation (FMD%) of the brachial artery by ultrasonography, CRP, TNF-alpha, IL-10 and the ratio TNF-alpha/ IL-10 blood levels before, 2-h and 5-days after the G-CSF or placebo treatment., Main Outcomes and Results: There was a greater increase of FMD, IL-10 and reduction of TNF-alpha/ IL-10, 2 h and 5 days after the G-CSF treatment compared to placebo. Although, CRP and TNF-alpha were higher, TNF-alpha/IL-10 was lower at the end of G-CSF treatment compared to placebo. Improvement of FMD was related to changes of IL-10 and TNF-alpha/IL-10., Conclusions: Treatment with G-CSF improves endothelial function in vivo, possibly by shifting the balance between the pro- and anti-inflammatory cytokines.

Randomized phase III trials have demonstrated that the addition of paclitaxel is effective in the adjuvant treatment of breast cancer. Forty-five patients with high-risk resected breast cancer entered this study. They were treated with three cycles of epirubicin every 2 weeks, followed by three cycles of intensified CMF, every 2 weeks, followed 3 weeks later by nine weekly cycles of paclitaxel (E-CMF-T). Forty patients (89%) received all cycles of chemotherapy and dose intensity was sufficiently maintained for all drugs. Toxicity was generally mild to moderate. Two cases of febrile neutropenia were reported. The E-CMF-T regimen is feasible and well tolerated.

Currently, randomized phase III trials have demonstrated that docetaxel is an effective strategy in the adjuvant treatment of breast cancer. However, previous attempts to incorporate docetaxel with an anthracycline in a dose-dense regimen have been unsuccessful. Therefore, new schedules containing both drugs should be explored. Forty-four patients with high-risk operable breast cancer entered this feasibility study. They were treated with three cycles of epirubicin 110 mg/m2 every 2 wk with G-CSF followed by three cycles of "intensified" CMF (840 mg/m2 cyclophosphamide; 57 mg/m2 methotrexate; 840 mg/m2 fluorouracil) every 2 wk with G-CSF followed 3 wk later by nine weekly cycles of 35 mg/m2 docetaxel (E-CMF-doc). Totally, 39 patients (89%) received all cycles of chemotherapy. The vast majority (92%) of cycles were administered at full dose. Therefore, dose intensity was sufficiently maintained for all drugs. Toxicity was generally mild to moderate. Most frequently recorded side effects apart from alopecia were neutropenia (54%) and nausea/vomiting (89%). Infection developed in nine patients. Two cases of febrile neutropenia were reported. The E-CMF-doc regimen, as used in this study, is feasible and well tolerated. Its impact on survival should be evaluated in phase III trials.

Paclitaxel (Taxol) and carboplatin are an effective combination regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the first epidermal growth factor receptor tyrosine kinase inhibitor to be approved for cancer treatment. This multicenter phase II trial treated 68 patients with advanced breast cancer with paclitaxel (175 mg/m(2) over 3 h) and 3-weekly carboplatin (area under the curve of 6) for six cycles, and 250 mg/day gefitinib orally. Median age was 57 (range 35-77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2 (2.9%), 82.4% of patients had visceral metastases and 63.2% had received adjuvant chemotherapy. Forty-eight (70.6%) patients completed six cycles of chemotherapy and 20 (29.4%) patients discontinued treatment (seven [10.3%] due to disease progression, seven [10.3%] due to toxicity, five [7.4%] withdrew consent and one [1.5%] died after the first cycle). Sixty-three (92.7%) patients were evaluable for response; nine (13.2%) had complete responses, 30 (44.1%) had partial responses, 21 (30.9%) had stable disease and three (4.4%) had disease progression. Grade 3/4 adverse events in > or =5% of patients except of alopecia, included neutropenia (17.7%), anemia (10.3%), diarrhea (7.4%), thrombocytopenia (5.9%) and peripheral neuropathy (5.9%). Of those tumor biopsies available for immunohistochemical analysis (n=60), 5.0% were positive and 35.0% negative for expression of all HER-family receptors. Comparable numbers of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and 42.7%, respectively), with the majority (72.1%) negative for cytoplasmic p27(kipl). The observed efficacy data in this study were similar to those reported for the combination of paclitaxel and carboplatin alone.