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0000-0002-3665-9056
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Publisher: Anticancer Research USA Inc.
Date: 30-07-2018
DOI: 10.21873/ANTICANRES.12795
Abstract: The combination of platinum with 5-fluorouracil has scarcely been studied in metastatic breast cancer. As this combination does not lead to significant hepatic metabolism, in some clinical situations it may prove useful, especially in cases with liver dysfunction and an urgent clinical need for rapid tumor shrinkage. A retrospective study was conducted to evaluate the efficacy and safety of the combination of cisplatin and 5-fluorouracil in patients with metastatic breast cancer with significant alterations of biochemistry. A total of 109 patients with metastatic breast cancer and liver dysfunction were treated time-to-progression, overall survival and trends in liver function were evaluated. The median time-to-progression was 3.4 months, and median overall survival was 7.8 months. About 50% of patients obtained a complete, partial or stable biochemical response and 24 patients were subsequently able to receive additional therapies. Our results show that this therapeutic doublet represents a clinically effective, safe and well-tolerated treatment option for patients with metastatic breast cancer and liver dysfunction.
Publisher: Impact Journals, LLC
Date: 25-09-2018
Publisher: Elsevier BV
Date: 10-2018
Publisher: Springer Science and Business Media LLC
Date: 24-03-2021
DOI: 10.1186/S13058-021-01415-W
Abstract: Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation. Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood s les were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. S les with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR. All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 ( n = 26) had a worse PFS than those with 0 CTCs ( n = 16) ( p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, ( p = 0.004). Finally, patients with ≥ 5 CTCs at T2 ( n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF ( p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels. CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied s le size.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Elsevier BV
Date: 11-2019
Publisher: Springer Science and Business Media LLC
Date: 29-08-2019
DOI: 10.1038/S41523-019-0123-9
Abstract: Despite recent refinements to the 21-gene g score, allowing a better identification of patients who may derive no benefit from the addition of adjuvant chemotherapy to that of endocrine therapy, patients with early breast cancer still stand to be over-treated in the setting of clinical and/or genomic uncertainty or discordance. Here we describe and demonstrate a potential approach of further refining the OncotypeDX risk score by metabolomic analysis of serum. In a clinical dataset ( N = 87), the risk of recurrence was further sub-stratified by metabolomic signature, with an effective splitting of each Oncotype risk classification. A total of seven recurrences were recorded, with metabolomic analysis accurately predicting six of these. Contrastingly, the genomic risk score of the seven recurrences ranged across all three Oncotype classifications (one recurrence occurred in the “low”-risk group, three in the “intermediate” group and three in the “high”-risk group).
Publisher: Elsevier BV
Date: 04-2019
Publisher: Elsevier BV
Date: 06-2016
Publisher: Springer Science and Business Media LLC
Date: 26-05-2015
Publisher: MDPI AG
Date: 02-06-2021
Abstract: Adjuvant treatment for patients with early stage colorectal cancer (eCRC) is currently based on suboptimal risk stratification, especially for elderly patients. Metabolomics may improve the identification of patients with residual micrometastases after surgery. In this retrospective study, we hypothesized that metabolomic fingerprinting could improve risk stratification in patients with eCRC. Serum s les obtained after surgery from 94 elderly patients with eCRC (65 relapse free and 29 relapsed, after 5-years median follow up), and from 75 elderly patients with metastatic colorectal cancer (mCRC) obtained before a new line of chemotherapy, were retrospectively analyzed via proton nuclear magnetic resonance spectroscopy. The prognostic role of metabolomics in patients with eCRC was assessed using Kaplan–Meier curves. PCA-CA-kNN could discriminate the metabolomic fingerprint of patients with relapse-free eCRC and mCRC (70.0% accuracy using NOESY spectra). This model was used to classify the s les of patients with relapsed eCRC: 69% of eCRC patients with relapse were predicted as metastatic. The metabolomic classification was strongly associated with prognosis (p-value 0.0005, HR 3.64), independently of tumor stage. In conclusion, metabolomics could be an innovative tool to refine risk stratification in elderly patients with eCRC. Based on these results, a prospective trial aimed at improving risk stratification by metabolomic fingerprinting (LIBIMET) is ongoing.
Publisher: Elsevier BV
Date: 09-2013
Abstract: Breast cancer in young women is typically characterised by aggressive disease, and treatment with adjuvant chemotherapy is generally recommended. Chemotherapy has conferred significant improvements in disease-free and overall survival for young women with breast cancer however, with improved cure rates, long-term adverse effects of cytotoxic treatment, such as premature ovarian failure (POF) and infertility, have become increasingly important. A potential fertility preservation strategy is administration of gonadotropin-releasing hormone agonists (GnRHas) during adjuvant chemotherapy. This review analyses and summarises the current evidence for use of GnRHa in preserving ovarian function in young breast cancer patients. Twelve trials, both non-randomised and randomised, have now been conducted assessing GnRHas in fertility preservation in young breast cancer patients, with conflicting results. Limitations of the current data include the use of poorly sensitive end points for fertility preservation, variable age of enrolled patients and limited pregnancy data. The utility of GnRHa as a fertility preservation strategy remains uncertain, and use outside of a clinical trial generally not recommended. Further research into this under-recognised issue is vital.
Publisher: MDPI AG
Date: 28-11-2019
Abstract: Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene ESR1 have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and are infrequent in untreated ER-positive breast cancers. In vitro studies show that these mutations confer ligand-independent activity, resistance to estrogen deprivation, and relative resistance to tamoxifen and fulvestrant. Post-hoc retrospective and prospective analyses of ESR1 mutations in patients with MBC have consistently found that these mutations are markers of poor prognosis and predict resistance to aromatase inhibitors (AIs). These results warrant further investigation and prospective validation in dedicated studies. Moreover, studies are ongoing to clarify the activity of novel drugs in the context of metastatic endocrine resistant luminal breast cancer harboring ESR1 mutations. In this review, we summarize the pre-clinical and clinical findings defining the characteristics of ESR1 mutant breast cancer, and highlight the potential clinical developments in this field.
Publisher: Springer Science and Business Media LLC
Date: 10-04-2019
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.BREAST.2013.07.002
Abstract: The Oxford Overview process has provided us with extremely high-powered meta-analyses assessing the role of adjuvant chemotherapy in early breast cancer. From the most recent publication, the proportional benefits from chemotherapy are relatively equivalent across all patient subgroups, a finding contradictory to our growing understanding of the role of tumour biology in dictating chemosensitivity. Several factors, including heterogeneity of patient groups and chemotherapy regimens, lack of data on underlying tumour biological subtypes, and confounding effect of chemotherapy-induced ovarian suppression in premenopausal women with hormone receptor positive breast cancer, impact on the applicability and clinical utility of the Overview in current and future oncological practice. With these considerations, the Overview has become less clinically relevant as a tool for guiding adjuvant chemotherapy treatment decisions, and a new direction is required.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2020
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2012
Abstract: Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.
Publisher: Elsevier BV
Date: 12-2012
Abstract: The 2012 IMPAKT task force investigated the medical usefulness of current methods for the classification of breast cancer into the 'intrinsic' molecular subtypes (luminal A, luminal B, basal-like and HER2). A panel of breast cancer and/or gene expression profiling experts evaluated the analytical validity, clinical validity and clinical utility of two approaches for molecular subtyping of breast cancer: the prediction analysis of microarray (PAM)50 assay and an immuno-histochemical (IHC) surrogate panel including oestrogen receptor (ER), HER2 and Ki67. The panel found the currently available evidence on the analytical validity and clinical utility of Ki67 based on a 14% cut-off and PAM50 to be inadequate. The majority of the working group members found the available evidence on the analytical validity, clinical validity and clinical utility of ER/HER2 to be convincing. The panel concluded that breast cancer classification into molecular subtypes based on the IHC assessment of ER, HER2 and Ki67 with a 14% cut-off and on the PAM50 test does not provide sufficiently robust information to modify systemic treatment decisions, and recommended the use IHC for ER and HER2 for the identification of clinically relevant subtypes of breast cancers. Methods for breast cancer classification into molecular subtypes should, however, be incorporated into clinical trial design.
Publisher: Elsevier BV
Date: 2018
Publisher: Elsevier BV
Date: 07-2008
Abstract: The role of chemotherapy in addition to combined endocrine therapy for premenopausal women with endocrine-responsive early breast cancer remains an open question, yet trials designed to answer it have repeatedly failed to adequately accrue. The International Breast Cancer Study Group initiated two concurrent trials in this population: in Premenopausal Endocrine Responsive Chemotherapy (PERCHE), chemotherapy use is determined by randomization and in Tamoxifen and Exemestane Trial (TEXT) by physician choice. PERCHE closed with inadequate accrual TEXT accrued rapidly. From 2003 to 2006, 1317 patients (890 with baseline data) were randomly assigned to receive ovarian function suppression (OFS) plus tamoxifen or OFS plus exemestane for 5 years in TEXT. We explore patient-related factors according to whether or not chemotherapy was given using descriptive statistics and classification and regression trees. Adjuvant chemotherapy was chosen for 64% of patients. Lymph node status was the predominant determinant of chemotherapy use (88% of node positive treated versus 46% of node negative). Geography, patient age, tumor size and grade were also determinants, but degree of receptor positivity and human epidermal growth factor receptor 2 status were not. The perceived estimation of increased risk of relapse is the primary determinant for using chemotherapy despite uncertainties regarding the degree of benefit it offers when added to combined endocrine therapy in this population.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2018
DOI: 10.1007/S10549-018-4766-2
Abstract: HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients. We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR. Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively Fisher's exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER-)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group. Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.
Publisher: SAGE Publications
Date: 2018
Abstract: Until recently, the mainstay of treatment in the majority of hormone receptor (HR)-positive, human epidermal growth factor 2 receptor (HER2)-negative advanced breast cancer (ABC) has consisted of single-agent endocrine therapy (ET). However, as understanding of endocrine resistance has grown, newer targeted agents have come to the fore. Inhibition of cyclin-dependent kinase complexes 4 and 6 (CDK4/6) combined with ET has shown significant activity in HR+ HER2− ABC, with impressive results in terms of progression-free survival (PFS) when compared with ET alone. This review summarizes the seminal findings pertaining to CDK4/6 inhibition in this population, specifically focusing on abemaciclib, contrasted with palbociclib and ribociclib. Potential directions for future studies are discussed, as a way of addressing outstanding issues such as establishing optimal treatment sequencing and agent combinations, appropriate patient selection to derive maximal benefits, predictive biomarkers and the employment of CDK4/6 inhibition beyond the ABC setting.
Publisher: American Association for Cancer Research (AACR)
Date: 28-06-2021
DOI: 10.1158/2159-8290.CD-20-1647
Abstract: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic s les from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients. This article is highlighted in the In This Issue feature, p. 2659
Publisher: Elsevier BV
Date: 05-2013
Abstract: Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF) (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.EJCA.2019.04.002
Abstract: Thymidine kinase 1 (TK1) plays a critical role in DNA synthesis and cell proliferation. Recent studies have shown potential for serum TK1 activity (sTKa) as a prognostic marker and indicator of early response to endocrine therapy in advanced breast cancer. The aim of this study is to assess the correlation between sTKa and patient outcome. The Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) was a double-blind, double-dummy, randomised trial of fulvestrant versus exemestane after progression on non-steroidal aromatase inhibitor therapy, in postmenopausal women with advanced breast cancer. Retrospective analyses of serum archived from EFECT were conducted. sTKa was assessed using the DiviTum® assay on s les collected at baseline, after three and six months of endocrine therapy, and at disease progression. The median time to progression (mTTP) for patients with low baseline sTKa levels was 5.03 months (95% confidence interval [CI]: 3.91-5.89) versus 2.57 months (95% CI: 2.04-3.52) in patients with high sTKa baseline levels (P < 0.0001). On treatment, patients whose sTKa increased from baseline had a significantly shorter mTTP (3.39 months, 95% CI: 2.14-4.11) than those without an sTKa increase (5.39 months, 95% CI: 4.01-6.68) (P = 0.0045). Similar results were observed in the separate EFECT treatment arms. After adjusting for major prognostic factors, sTKa remained an independent marker. sTKa is a potential circulating prognostic marker in patients with advanced breast cancer treated with endocrine therapy. It may also represent a tool for upfront identification of endocrine therapy resistance and early positive response to therapy. Independent validation of these results is warranted.
Publisher: Frontiers Media SA
Date: 23-07-2019
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.BREAST.2013.04.019
Abstract: Although dose-dense chemotherapy may reduce breast cancer recurrence and death, phase II studies show that dose-dense docetaxel is poorly tolerated following administration of dose-dense anthracycline-based chemotherapy mainly because of cutaneous toxicity. This pilot study was designed to explore feasibility and safety of dose-dense docetaxel after conventional anthracycline-based therapy. Treatment consisted of sequential administration of 4 cycles of 3-weekly epirubicin (90 mg/m(2)) plus cyclophosphamide (600 mg/m(2)), followed by 4 cycles of bi-weekly docetaxel with pelfilgrastim on day 2 of each docetaxel cycle. Two docetaxel dose levels were planned: 75 mg/m(2) (D75) and 100 mg/m(2) (D100). Patients could only be assigned to the higher docetaxel dose if no early treatment discontinuations due to toxicity were seen, and a median relative dose intensity of docetaxel >90% among the first 5 evaluable patients was achieved. Fifty three patients received 4 cycles of epirubicin/cyclophosphamide (EC). Six patients withdrew from study before commencing docetaxel: four for toxicity, and two who declined further study participation. Eight patients, 2 in the first dose level and 6 in the second dose level, stopped treatment for toxicity after the first cycle of docetaxel and before densification. Therefore these events were not considered early treatment discontinuations. No patients required dose interruption after the second docetaxel administration. Overall 5 patients in the first dose level and 34 patients in the second dose level received 4 cycles of accelerated (dose-dense) docetaxel. No grade 3 or grade 4 toxicities occurred at the first dose level. No grade 4 toxicities occurred at the second dose level, while grade 3 toxicities occurring in >2 patients were myalgia and bone pain (5 and 8 patients respectively, 13% and 20%) and skin-nail toxicity (7 patients, 21%). No dose-reductions or significant treatment delays were required, translating to median relative dose intensity of 100% for docetaxel 75 mg/m(2), and 99% for 100 mg/m(2). Administration of docetaxel 100 mg/m(2) bi-weekly after conventional EC is feasible in selected early breast cancer patients. Lack of prior exposure to dose-dense anthracycline, as well as the use of stringent criteria implemented in the treatment protocol, might explain the improved safety profile and high treatment compliance observed in this study.
Publisher: Elsevier BV
Date: 11-2015
Publisher: Elsevier BV
Date: 02-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540798.V1
Abstract: Supplementary file with the listing of the liver genes excluded from transcriptomic analyses.
Publisher: SAGE Publications
Date: 2018
Abstract: The current therapeutic landscape of luminal human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC) is fundamentally evolving, particularly in the advent of molecularly targeted therapies, such as inhibitors of mammalian target of rapamycin and cyclin-dependent kinase 4/6 (CDK4/6). In the context of CDK4/6 inhibitors, landmark clinical trials for palbociclib (PALOMA-1, PALOMA-2, PALOMA-3), ribociclib (MONALEESA-2, MONALEESA-3, MONALEESA-7) and abemaciclib (MONARCH-1, MONARCH-2, MONARCH-3) have provided solid data regarding progression-free survival and overall response rate, justifying the introduction of this class of drugs into our therapeutic armoury. However, several clinical questions remain open. One of the most relevant issues faced in practice is that of the optimum sequencing of CDK4/6 inhibitors, particularly given the wide range of therapeutic options open to clinicians treating luminal mBC. In this brief commentary, we would like to focus on the best sequence for CDK4/6 inhibitors and their place in this growing, complex scenario.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.EJCA.2015.03.018
Abstract: Breast International Group (BIG) 2-98 is a randomised phase III trial that tested the effect of adding docetaxel, either in sequence to or in combination with anthracycline-based adjuvant chemotherapy, in women with node-positive breast cancer (BC). Here, we present the 10-year final trial safety and efficacy analyses. We also report an exploratory analysis on the predictive value of Ki67 for docetaxel efficacy, in the BIG 2-98 and using a pooled analysis of three other randomised trials. 2887 patients were randomly assigned in a 2×2 trial design to one of four treatments. The primary objective was to evaluate the overall efficacy of docetaxel on disease free survival (DFS). Secondary objectives included comparisons of sequential docetaxel versus sequential control arm, safety and overall survival (OS). Ki67 expression was centrally evaluated by immunohistochemistry. After a median follow-up of 10.1years, the addition of docetaxel did not significantly improve DFS or OS (hazard ratio (HR)=0.91, 95% confidence interval (CI)=0.81-1.04 P=0.16 and HR=0.88, 95% CI=0.76-1.03 P=0.11, respectively). Sequential docetaxel did not improve DFS compared to the sequential control arm (HR=0.86, 95% CI=0.72-1.03 P=0.10). In oestrogen receptor (ER)-positive tumours with Ki67⩾14%, the addition of docetaxel resulted in 5.4% improvement in 10-year OS (P=0.03, test for interaction=0.1). In a multivariate model, there was a trend for improved DFS and OS in ER-positive patients with high Ki67 and treated with docetaxel (HR=0.79, 95% CI=0.63-1.01 P=0.05 and HR=0.76, 95% CI=0.57-1.01 P=0.06, respectively). A pooled analysis of four randomised trials showed a benefit of taxanes in highly proliferative ER-positive disease but not in low proliferating tumours (interaction test P=0.01). The DFS benefit previously demonstrated with sequential docetaxel is no longer observed at 10years. However, an exploratory analysis suggested a benefit of docetaxel in patients with highly proliferative ER-positive BC.
Publisher: Wiley
Date: 10-08-2014
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.CLBC.2019.05.019
Abstract: The landscape of therapeutic options for the treatment of hormone receptor (HR)-positive (HR
Publisher: Spandidos Publications
Date: 27-11-2017
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2017
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540795
Abstract: File with the supplementary material & methods, supplementary tables and supplementary figure.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2009
DOI: 10.1007/S10549-009-0512-0
Abstract: Obesity has been shown to be an indicator of poor prognosis for patients with primary breast cancer (BC) regardless of the use of adjuvant systemic therapy. This is a retrospective analysis of 2,887 node-positive BC patients enrolled in the BIG 02-98 adjuvant study, a randomised phase III trial whose primary objective was to evaluate disease-free survival (DFS) by adding docetaxel to doxorubicin-based chemotherapy. In the current analysis, the effect of body mass index (BMI) on DFS and overall survival (OS) was assessed. BMI was obtained before the first cycle of chemotherapy. Obesity was defined as a BMI >or= 30 kg/m2. In total, 547 (19%) patients were obese at baseline, while 2,340 (81%) patients were non-obese. Estimated 5-year OS was 87.5% for non-obese and 82.9% for obese patients (HR 1.34 P = 0.013). Estimated 5-years DFS was 75.9% for nonobese and 70.0% for obese patients (HR 1.20 P = 0.041). Ina multivariate model, obesity remained an independent prognostic factor for OS and DFS. In this study,obesity was associated with poorer outcome in node-positive BC patients. Given the increasing prevalence of obesity worldwide, more research on improving the treatment of obese BC patients is needed.
Publisher: Oxford University Press (OUP)
Date: 20-02-2018
DOI: 10.1093/JNCI/DJX268
Publisher: Springer International Publishing
Date: 2016
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540798
Abstract: Supplementary file with the listing of the liver genes excluded from transcriptomic analyses.
Publisher: Wiley
Date: 09-12-2014
Publisher: Springer Science and Business Media LLC
Date: 05-03-2015
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.C.6549478.V1
Abstract: Abstract AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for i GATA1 /i and i MEN1 /i somatic mutations. Metastases were enriched in i ESR1, PTEN, CDH1, PIK3CA /i , and i RB1 /i mutations i MDM4 /i and i MYC /i lifications and i ARID1A /i deletions. An increase in clonality was observed in driver genes such as i ERBB2 /i and i RB1 /i . Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with i TP53 /i and/or i PIK3CA /i mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR sup + /sup /HER2 sup − /sup cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. Significance: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic s les from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-11-11-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2659 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22540795.V1
Abstract: File with the supplementary material & methods, supplementary tables and supplementary figure.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.CTRV.2018.04.012
Abstract: Breast cancer (BC) is a heterogeneous disease which has been characterised and stratified by many platforms such as clinicopathological risk factors, genomic assays, computer generated models, and various "-omic" technologies. Genomic, proteomic and transcriptomic analysis in breast cancer research is well established, and metabolomics, which can be considered a downstream manifestation of the former disciplines, is of growing interest. The past decade has seen significant progress made within the field of clinical metabolomic BC research, with several groups demonstrating results with significant promise in the setting of BC screening and biological characterisation, as well as future potential for prognostic metabolomic biomarkers.
Publisher: Elsevier BV
Date: 04-2018
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-03-2016
Abstract: We examined the prognostic and predictive value of serum human epidermal growth factor 2 (HER2) extracellular domain (sHER2) in patients with advanced breast cancer treated with lapatinib using data from three randomized trials. We analyzed sHER2 and tissue HER2 (tHER2) data from 1,902 patients (84%) who were randomly assigned to receive lapatinib or control in the trials EGF30001, EGF30008, and EGF100151. Cox regression analyses were performed to correlate both biomarkers with progression-free survival (PFS) and overall survival (OS). Median sHER2 levels were 25.1 and 10.1 ng/mL in tHER2- lified (tHER-positive) and non lified (tHER-negative) populations, respectively (r = 0.42 for sHER2-tHER2 correlation). Lapatinib had significant PFS benefit over control (hazard ratio [HR], 0.855 P = .004), but not OS (HR, 0.941 P = .33). Lapatinib PFS benefit is independently predicted by higher sHER2 values (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.009 v nonlapatinib-containing therapies, 1.044 P interaction .001) and by positive tHER2 (HR [lapatinib v nonlapatinib]: tHER2 positive, 0.638 v tHER2 negative, 0.940 P interaction = .001). Within the tHER2-positive subpopulation (n = 515), higher sHER2 values still independently predicted lapatinib PFS benefit (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.017 v nonlapatinib-containing therapies, 1.041 P interaction = .008). In control arms (n = 936), higher sHER2 was associated with worse prognosis in multivariable analyses (PFS HR per 10 ng/mL: PFS, 1.024 P .001 and OS, 1.018 P .001). Higher sHER2 predicts greater PFS benefit with lapatinib independent of tHER2 status. High sHER2 is also independently prognostic for worse survival in patients who received nonlapatinib-containing therapies. The predictive role of sHER2 for other anti-HER2 agents requires further research.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.CTRV.2019.01.007
Abstract: Patients with luminal early breast cancer are at risk of relapse, even after five years of adjuvant endocrine therapy. To date, no biomarkers have been clinically validated to identify those patients at risk of late recurrence, who might benefit from extended adjuvant endocrine therapy. In recent decades, multiple clinical trials have tested the role of extending adjuvant endocrine therapies in patients with luminal disease. However, the data currently at our disposal are conflicting. This article reviews all the major trials concerning extended adjuvant endocrine regimens, and formulates some general conclusions and hypotheses of future study.
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.BREAST.2012.03.003
Abstract: The 1st international Consensus Conference for Advanced Breast Cancer (ABC 1) took place on November 2011, in Lisbon. Consensus guidelines for the management of this disease were developed. This manuscript summarizes these international consensus guidelines.
Publisher: American Association for Cancer Research (AACR)
Date: 05-2020
DOI: 10.1158/1078-0432.CCR-19-3271
Abstract: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC. Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor–positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the “To Reverse ENDocrine Resistance” (TREnd) trial (n = 46). Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n = 8) showing an increase—correlating with a worse outcome than those with decreased/stable TKa (n = 33 mPFS 3.0 vs 9.0 months P = 0.002). At T2, mTKa was 251 Du/L patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months P = 0.05). TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2012
DOI: 10.1186/BCR3179
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2013
Abstract: Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT) however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT—in this case, anthracycline-only CT—in selected BC subtypes. We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC s les from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. There was no significant prognostic association in the global nor estrogen receptor (ER) –positive/human epidermal growth factor receptor 2 (HER2) –negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042 OS, P = .018). In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.CTRV.2013.05.003
Abstract: In the setting of breast cancer relapse, treatment decisions are typically made by utilizing HER2, estrogen, and progesterone receptor expression status of the primary breast cancer. Recently, concern regarding receptor discordance has led to recommendations for rebiopsy for all cases of metastatic disease. However, whether this is an appropriate recommendation is uncertain, particularly as the clinical implications for HER2 discordance are unknown. We performed a literature review to identify studies assessing HER2 discordance between primary and metastatic breast cancer. These studies were then reviewed for data relating to (1) impact of clinical factors on discordance rates, (2) prognostic impact of discordance, or (3) clinical outcomes from treatment alteration due to receptor discordance. Results were analyzed qualitatively. From 60 HER2 discordance studies identified, 24 contained information of interest for this review. No clear factor promoting HER2 discordance was identified. Loss of HER2 seemed to result in worse post-relapse survival and overall survival, although these data were often confounded by lack of treatment in the setting of receptor loss. Conversely, HER2 discordance was not associated with shorter DFS. In idual patients with receptor gain appear to have benefited from addition of targeted treatment, although data are limited to case reports. Evidence of HER2 discordance leading to alterations in patient outcomes is limited, highlighting the need for further research in this area. Furthermore, lack of alteration in patient outcomes suggests that a more pragmatic approach to the decision to rebiopsy may be appropriate.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.BREAST.2017.06.021
Abstract: Luminal breast cancers demonstrate significant molecular and clinical heterogeneity, despite the commonality of shared expression of the estrogen receptor (ER). To date, no clinical trial has prospectively investigated the optimal chemotherapy regime according to luminal type, highlighting a paucity of data furthermore required to guide treatment decisions. Current methods of predicting advantage from adjuvant chemotherapy lack refinement and can over-estimate the risk of relapse, inevitably leading to a proportion of patients being unnecessarily exposed to chemotherapy. This paper will explore the evidence behind modalities which may add further value to existing known clinicopathological and molecular profiling techniques in predicting clinical benefit from chemotherapy. Adjuvant chemotherapy regime choice in the context of early luminal breast cancer types will be discussed, and areas for further research and debate identified.
Publisher: Hindawi Limited
Date: 16-07-2019
DOI: 10.1111/TBJ.13437
Abstract: Overall survival (OS), disease-free survival (DFS), and distant recurrence-free interval (DRFI) were evaluated from 169 patients diagnosed with early triple negative breast cancer. Overall, 5 and 10 years OS, DFS, and DRFI were 77% and 65% 60% and 46% and 74% and 73%, respectively. Forty-seven patients did not receive chemotherapy. A separate analysis was performed excluding those patients. In this subgroup, 5- and 10-year OS, DFS, and DRFI were 86% and 77% 68% and 54%, 77% both at 5 and 10 years. Prognosis is better than previously described adjuvant chemotherapy should be offered to fit elderly patients if clinically warranted.
Publisher: Massachusetts Medical Society
Date: 13-07-2017
Publisher: Oxford University Press (OUP)
Date: 08-01-2008
DOI: 10.1093/JNCI/DJM287
Abstract: Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel. Patients with lymph node-positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]) 2) concurrent control (four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2, followed by three cycles of CMF) 3) sequential docetaxel (three cycles of doxorubicin at 75 mg/m2, followed by three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF) 4) concurrent docetaxel (four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, followed by three cycles of CMF). The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided. Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients in control arms had a 5-year DFS of 73% (95% confidence interval [CI] = 70% to 75%). Docetaxel treatment resulted in an improvement in DFS of borderline statistical significance compared with control treatment (HR = 0.86, 95% CI = 0.74 to 1.00 P = .05). However, DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm (HR = 0.83, 95% CI = 0.69 to 1.00) and in the sequential control arm (HR = 0.79, 95% CI = 0.64 to 0.98). Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherapy.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-04-2020
DOI: 10.1200/JCO.18.01967
Abstract: The Tamoxifen and Exemestane Trial (TEXT)/Suppression of Ovarian Function Trial (SOFT) showed superior outcomes for premenopausal women with hormone receptor (HR)–positive breast cancer treated with adjuvant exemestane plus ovarian function suppression (OFS) or tamoxifen plus OFS versus tamoxifen alone. We previously reported the magnitude of absolute improvements in freedom from any recurrence across a continuous, composite measure of recurrence risk to tailor decision making. With longer follow-up, we now focus on distant recurrence. The TEXT/SOFT HR-positive/human epidermal growth factor receptor 2 (HER2)–negative analysis population included 4,891 women stratified by predetermined chemotherapy use. Kaplan-Meier estimates of 8-year freedom from distant recurrence were analyzed using subpopulation treatment effect pattern plot (STEPP) methodology across subpopulations defined by the continuous composite measure of recurrence risk. For each patient, the composite risk value was obtained from a Cox model that incorporated age nodal status tumor size grade and estrogen receptor, progesterone receptor, and Ki-67 labeling index expression levels. The overall rate of 8-year freedom from distant recurrence was 91.1% and ranged from approximately 100% to 63% across lowest to highest composite risks. TEXT patients who received chemotherapy had an average absolute improvement with exemestane plus OFS versus tamoxifen plus OFS of 5.1%, and STEPP analysis showed improvements from less than 1% to more than 15% from lowest to highest composite risks. SOFT patients who remained premenopausal after chemotherapy had an average 5.2% absolute improvement with exemestane plus OFS versus tamoxifen and reached 10% across composite risks for tamoxifen plus OFS versus tamoxifen, the maximum improvement was approximately 3.5%. Women who did not receive chemotherapy had a more than 97% rate of 8-year freedom from distant recurrence, and improvements with exemestane plus OFS ranged from 1% to 4%. Premenopausal women with HR-positive/HER2-negative breast cancer and high recurrence risk, as defined by clinicopathologic characteristics, may experience a 10% to 15% absolute improvement in 8-year freedom from distant recurrence with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone. The potential benefit of escalating endocrine therapy versus tamoxifen alone is minimal for those at low recurrence risk.
Publisher: Impact Journals, LLC
Date: 13-09-2016
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.IJROBP.2018.01.105
Abstract: To analyze the impact of postmastectomy radiation therapy (PMRT) for patients with T1-T2 tumors and 1 to 3 positive lymph nodes enrolled on the Breast International Group (BIG) 02-98 trial. The BIG 02-98 trial randomized patients to receive adjuvant anthracycline with or without taxane chemotherapy. Delivery of PMRT was nonrandomized and performed according to institutional preferences. The present analysis was performed on participants with T1-T2 breast cancer and 1 to 3 positive lymph nodes who had undergone mastectomy and axillary nodal dissection. The primary objective of the present study was to examine the effect of PMRT on risk of locoregional recurrence (LRR), breast cancer-specific survival, and overall survival. We identified 684 patients who met the inclusion criteria and were included in the analysis, of whom 337 (49%) had received PMRT. At 10 years, LRR risk was 2.5% in the PMRT group and 6.5% in the no-PMRT group (hazard ratio 0.29, 95% confidence interval 0.12-0.73 P = .005). Lower LRR after PMRT was noted for patients randomized to receive adjuvant chemotherapy with no taxane (10-year LRR: 3.4% vs 9.1% P = .02). No significant differences in breast cancer-specific survival (84.3% vs 83.9%) or overall survival (81.7% vs 78.3%) were observed according to receipt of PMRT. Our analysis of the BIG 02-98 trial shows excellent outcomes in women with T1-T2 tumors and 1 to 3 positive lymph nodes found in axillary dissection. Although PMRT improved LRR in this cohort, the number of events remained low at 10 years. In all groups, 10-year rates of LRR were relatively low compared with historical studies. As such, the use of PMRT in women with 1 to 3 positive nodes should be tailored to in idual patient risks.
Publisher: SAGE Publications
Date: 2019
Abstract: Chemotherapy added to anti-HER2 agents (H) is the treatment of choice in patients with HER2+ early breast cancer. However, HER2+ tumours are clinically and biologically heterogeneous, and treatment response varies significantly by hormone receptor (HR) status and molecular subtype. Predictive biomarkers are needed in this context. This study assessed whether an RB-1 loss of function gene signature (RBsig) is predictive of response to neoadjuvant chemotherapy in combination with trastuzumab, lapatinib or both, within the NeoALTTO trial. We collected RNA-sequencing data from pretreatment biopsies derived from the NeoALTTO trial. RBsig expression was computed retrospectively and correlated with pathological complete response (pCR) using receiver-operating characteristic (ROC) curves. The RBsig was dichotomised as High/Low in correspondence to the 25th percentile. Reported p values resulted from Fisher’s exact test. Of 455 NeoALTTO patients, 244 were eligible for this substudy (HR+ n = 129 HR− n = 115). Overall, pCR rate was significantly higher in patients with RBsig High tumours than those with RBsig Low (35% versus 18% respectively p = 0.01). The area under the ROC curve (AUC) was 0.60 (95% CI 0.52–0.67). A remarkably low pCR rate of 11% was seen in HR+/RBsig Low patients versus 28% in HR+/RBsig High. These results indicate RBsig may add valuable information to HER2 and HR expression, which may in turn inform treatment choices. HR+/HER2+/RBsig Low breast cancers exhibited the poorest pathological response following chemotherapy plus H. Accordingly, in such patients, endocrine therapy in combination with H and, possibly, a CDK4/6 inhibitor, may potentially prove to be a more effective treatment.
Publisher: MDPI AG
Date: 25-03-2014
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.BREAST.2014.03.012
Abstract: Given recent data on genetic heterogeneity within and in idual's tumor, we investigated if there were differences in the prognostic and predictive abilities of BCL2 and TP53 protein expression in primary breast cancer (TU) and corresponding axillary lymph-nodes (LN). We used patient s les from the adjuvant Belgian three-arm study which randomized between anthracycline containing regimens and traditional CMF. The endpoints analyzed were overall survival (OS), event-free survival (EFS) and interactions between chemotherapy regimens. At a median follow-up of 15.6 years, BCL2 and TP53 (in both TU and LN) were significantly associated with OS but only in the first 5 years. Likewise, BCL2 and TP53 (in both TU and LN) were associated with EFS in the first 2 years after randomization, with no association after 2 years. BCL2 and TP53 remained statistically significant after adjustment for the standard clinical-pathological characteristics in regard to OS and EFS in the respective first years after randomization, (p value < 0.001 for both markers). Furthermore, an interaction was found between high BCL2 expression in the TU (but not in LN) and benefit to CMF over anthracycline-based chemotherapy (interaction p value EFS: 0.042 OS = 0.01). No interaction was found for TP53 expression neither in TU nor in LN. We conclude that BCL2 and TP53 were predictive biomarkers for better and worse survival respectively, but only in the first two to five years after diagnosis. BCL2 expression in the TU but not in the LN was predictive of increased benefit to CMF vs anthracycline-based chemotherapy.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.CTRV.2012.12.001
Abstract: Triple negative breast cancers, which are defined by lack of expression of estrogen, progesterone, or HER2 receptors, represent approximately 15% of all breast cancers, although they account for a much higher proportional of breast cancer mortality. This is due both to their innate aggressive biological characteristics, but also to lack of effective therapies. Conventional chemotherapy is currently the only treatment option, thus there is a critical need to find new and effective targeted therapies in this disease. While investigation of agents such as poly (ADP-ribose) polymerase (PARP) inhibitors and EGFR inhibitors continues, results from recent clinical trials indicate that these therapies are not as active in sporadic triple negative breast cancers as initially hoped. It is important therefore to consider other emerging therapeutic agents. Mutation in p53 is found in the vast majority of triple negative breast cancers, and as such is a target of particular interest. Within this review, several agents with potential activity against aberrant p53 signaling have been considered, as a novel approach to finding an effective targeted therapy for this aggressive breast cancer subtype.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2021
DOI: 10.1038/S41523-021-00277-X
Abstract: Heparanase promotes tumor growth in breast tumors. We now evaluated heparanase protein and gene-expression status and investigated its impact on disease-free survival in order to gain better insight into the role of heparanase in ER-positive (ER+) breast cancer prognosis and to clarify its role in cell survival following chemotherapy. Using pooled analysis of gene-expression data, we found that heparanase was associated with a worse prognosis in estrogen receptor-positive (ER+) tumors (log-rank p 10 −10 ) and predictive to chemotherapy resistance (interaction p = 0.0001) but not hormonal therapy (Interaction p = 0.62). These results were confirmed by analysis of data from a phase III, prospective randomized trial which showed that heparanase protein expression is associated with increased risk of recurrence in ER+ breast tumors (log-rank p = 0.004). In vitro experiments showed that heparanase promoted tumor progression and increased cell viability via epithelial–mesenchymal transition, stemness, and anti-apoptosis pathways in luminal breast cancer. Taken together, our results demonstrated that heparanase is associated with worse outcomes and increased cell viability in ER+ BC.
Location: Italy
Location: Italy
No related grants have been discovered for Angelo Di Leo.