Microarray studies identified a subgroup of molecular apocrine tumors (estrogen receptor ER negative/androgen receptor AR positive) that express luminal genes including FOXA1. FOXA1 may direct AR to ...sites normally occupied by ER in luminal tumors, inducing an estrogen-like gene program that stimulated proliferation.
Expression of AR and FOXA1 was evaluated by immunohistochemistry in 592 patients with nonmetastatic triple-negative breast cancer (TNBC).
Coexpression of AR and FOXA1 was found in 15.2% of patients. These tumors were more frequently lobular, found in older patients and exhibited a lower nuclear grade and a greater degree of node involvement. They less often exhibited lymphocytic infiltrate, pushing margins, syncytial architecture, central fibrosis or necrosis.
TNBC with coexpression of AR and FOXA1 seems to behave like luminal tumors with a morphological profile distinct from other TNBC. These biomarkers could be useful to identify a subgroup of TNBC and could have future therapeutic implications.
Background.
Hand–foot syndrome (HFS) is a common reaction to certain chemotherapies and new targeted therapies, impairing patient quality of life (QoL). However, there is currently no specific tool ...to measure QoL in patients with HFS.
Objective.
The objective was to develop and validate a HFS‐specific QoL questionnaire (HFS‐14).
Patients and Methods.
From a list of 31 items identified from a literature review and patient interview notes, item reduction and pilot testing by cognitive debriefing resulted in a final 14‐item questionnaire with excellent internal reliability. Clinical validity was assessed in 43 patients with HFS by comparing the HFS‐14 score according to HFS clinical grade based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE), version 3.0, and by measuring its correlation with the Dermatology Life Quality Index (DLQI), Skindex‐16, and short‐form 12 health‐related questionnaires and pain measurement.
Results.
The mean HFS‐14 score was significantly higher in patients with clinical grade 2 and grade 3 HFS than in those with grade 1 HFS. The higher the HFS‐14 score, the greater the QoL impairment. The HFS‐14 score was highly correlated with the DLQI and Skindex‐16 scores. In the population of patients with severe grade 3 NCI‐CTCAE HFS, the HFS‐14 score was significantly higher in patients having both hands and feet severely involved than in those with severe involvement of one limb (hands or feet) with the other one less severely affected.
Conclusions.
This scale specifically developed for patients with HFS is a valid and valuable tool for measuring HFS‐related QoL impairment.
摘要
背景. 手‐足综合征（HFS）是一种对某些化疗和新型靶向治疗的常见反应，损害患者的生活质量（QoL）。然而，目前尚无专门衡量HFS患者QoL的工具。
目的. 本研究旨在开发并验证一种HFS特异性问卷（HFS‐14）。
患者和方法. 从文献综述和患者访视记录中，确认一份包含31个条目的清单，通过认知汇报，对条目进行缩减和预初测试，形成包含14个条目的最终问卷，具有卓越的内部信度。临床效度的评估是根据国立癌症研究院不良事件常用术语标准（NCI‐CTCAE） 3.0版，通过比较43例HFS患者的HFS‐14评分，衡量其与皮肤病生活质量指数（DLQI）、Skindex‐16和简式12项健康相关问卷及疼痛指标的相关性。
结果. 临床2级和3级HFS患者的HFS‐14均分显著高于1级HFS患者。HFS‐14评分越高，代表QoL损害越严重。HFS‐14评分与DLQI和Skindex‐16评分高度相关。严重NCI‐CTCAE 3级HFS患者人群中，手和足均严重受累患者的HFS‐14评分显著高于单一肢体（手或足）严重受累而另一肢体受累较轻的患者。
结论. 本量表专为HFS患者开发，是衡量HFS相关QoL损害的有效度、有价值的工具。
A hand–foot syndrome–specific quality of life questionnaire (HFS‐14) for patients treated with chemotherapy and targeted therapy was developed and validated.
Eribulin is approved for advanced breast cancers refractory to anthracyclines and taxanes. Efficacy according to sensitivity to previous therapies has been poorly explored.
Safety data were collected ...prospectively and we retrospectively collected efficacy data from the five French centres that participated in the Eribulin E7389-G000-398 expanded access program. Our main objectiveswere exploration of safety and analysis of eribulin efficacy (progression-free survival PFS and overall survival OS) according to sensitivity to the last microtubule-inhibiting agent administered.
Median eribulin treatment duration was 3.3 months for the 250 patients included in this prospective single-arm study. Two hundreds and thirty-nine patients (95.6%) experienced an adverse event (AE) related to treatment including 129 (51.6%) with grade ≥ 3 AEs. The most frequently observed toxicities were cytopenias (59.6% of included patients), gastrointestinal disorders (59.2%), and asthenia (56.4%). The most frequent grade 3-4 AE was neutropenia (37.2% with 4.8% febrile neutropenia). Median PFS and OS were 4.6 and 11.8 months, respectively. Patients classified as responders to the last microtubule-inhibiting therapy had a longer OS (hazard ratio HR, 0.69; 95% confidence interval CI, 0.51 to 0.94; p=0.017), and tended to display a better PFS (HR, 0.78; 95% CI, 0.58 to 1.04; p=0.086). OS improvement was still significant in multivariate analysis (adjusted HR, 0.53; 95% CI, 0.35 to 0.79; p=0.002).
This work based on a prospective study suggests that identification of patients likely to be more sensitive to eribulin could be based on their previous response to microtubules inhibitors.
Purpose
The identification of biomarkers of hormonal therapy (HT) failure would allow tailored monitoring in metastatic breast cancer (mBC) patients.
PIK3CA
gene mutation is one of the most frequent ...events in mBC and is associated with HT resistance. We evaluated the early prognostic value of cell-free DNA (cfDNA)
PIK3CA
detection in first-line HT-treated mBC patients.
Methods
Between June 2012 and January 2014, 39 patients were prospectively included in a dedicated clinical trial (NCT01612871). Blood sampling was performed before (M0) and 4 weeks (M1), 3 months (M3) and 6 months (M6) after HT initiation, and at tumor progression. Patients were followed until progression or until the end of the study (2 years). Mutation detection was performed using droplet-based digital PCR (ddPCR). Progression-free survival (PFS) was used as primary endpoint.
Results
Median age at inclusion was 63 years (range 40–86). Most patients (34/39) received an aromatase inhibitor and presented a non-measurable disease (71.8%).
PIK3CA
mutations were reported in 10 (27.8%) and 5 (14.3%) cases at M0 and M1, respectively. The persistence of a detectable circulating mutation at M1 was highly correlated with a worse progression-free survival (PFS), rate at 1 year: 40% versus 76.7%;
p
= 0.0053).
Conclusions
Four-week persistence of cfDNA
PIK3CA
mutation appears highly correlated with PFS.
Trial registration
NCT01612871, registered on June 6th, 2012;
https://clinicaltrials.gov/ct2/show/NCT01612871
.
Abstract Background Survival of patients with metastatic breast cancer (MBC) suffering from brain metastasis (BM) is limited and this event is usually fatal. In 2010, the Graesslin's nomogram was ...published in order to predict subsequent BM in patients with breast cancer (BC) with extra-cerebral metastatic disease. This model aims to select a patient population at high risk for BM and thus will facilitate the design of prevention strategies and/or the impact of early treatment of BM in prospective clinical studies. Patients and methods Nomogram external validation was retrospectively applied to patients with BC and later BM between January 2005 and December 2012, treated in our institution. Moreover, risk factors of BM appearance were studied by Fine and Gray's competing risk analysis. Results Among 492 patients with MBC, 116 developed subsequent BM. Seventy of them were included for the nomogram validation. The discrimination is good (area under curve = 0.695 95% confidence interval, 0.61–0.77). Risk factors of BM appearance are: human epidermal growth factor receptor 2 (HER2) overexpression/amplification, triple-negative BC and number of extra-cerebral metastatic sites (>1). With a competing risk model, we highlight the nomogram interest for HER2+ tumour subgroup exclusively. Conclusion Graesslin's nomogram external validation demonstrates exportability and reproducibility. Importantly, the competing risk model analysis provides additional information for the design of prospective trials concerning the early diagnosis of BM and/or preventive treatment on high risk patients with extra-cerebral metastatic BC.
The poly(adenosine diphosphate-ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 ( BRCA1/2).
We conducted a ...randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician's choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review.
Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval CI, 0.41 to 0.71; P<0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P=0.11 57% of projected events). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P<0.001). Hematologic grade 3-4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively. Patient-reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status-quality-of-life and breast symptoms scales were observed.
Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib. (Funded by Medivation Pfizer; EMBRACA ClinicalTrials.gov number, NCT01945775 .).
Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency ...screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine.
Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3'UTR and 5'UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement.
Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3-4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p<0.001) but not with grade 4 toxicity. Considering additional deleterious coding variants D342G, S492L, R592W and F100L increased the sensitivity to 26.7% for grade 3-4 toxicity (PPV 72.7%, RR 7.6, p<0.001), and was significantly associated with grade 4 toxicity (sensitivity 60%, PPV 27.3%, RR 31.4, p = 0.001), suggesting the clinical relevance of extended targeted DPYD genotyping. As compared to extended genotype, combining genotyping (7 variants) and phenotyping (U>16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR.
Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3-4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V.
Abstract The treatment of metastatic breast cancer (MBC) is essentially palliative and should be based on hormone therapy or optimized chemotherapy designed to delay disease progression and maximize ...survival with good quality of life. Novel chemotherapeutic agents introduced in the 1990s include the taxanes (notably docetaxel), which are among the most potent of current anticancer drugs. Current research is also focusing on molecular targeted agents including those against the HER family of transmembrane receptors and vascular endothelial growth factor. Optimal effects are obtained when these compounds are used in combination with chemotherapy, as shown in preclinical models and more recently in clinical trials. Results of a large randomized trial have demonstrated a significant survival advantage for trastuzumab plus docetaxel compared with docetaxel monotherapy. Docetaxel plus bevacizumab combinations have recently been shown to significantly improve progression-free survival and objective response rate compared with docetaxel monotherapy. Overall, docetaxel in combination with novel targeted agents in MBC appears to be highly active in patients with MBC, and such combinations represent promising treatment regimens for clinical investigation.
The natural history of breast diseases has changed overtime and successive therapeutic strategies have been adapted accordingly. Recently, biological findings on geno- and phenotypic characteristics ...of tumor cells offer new basis for the development of treatments that target homogenous and various subtypes of breast cancer. Unfortunately, traditional clinical research tools are not in phase with rapid changes in both biological knowledge of the disease and new targeted agents. New methodological approaches are urgently needed to validate such changes and improvements in prognosis.
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