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Previous epidemiologic studies investigating central venous catheter ( CVC)-related venous thromboembolism ( CRT) were conducted in heterogenous cancer populations and data in breast cancer ( BC) remain limited. To investigate the Doppler ultrasound ( DUS)- CRT incidence, risk factors and outcomes in BC, we designed a prospective, multicenter cohort of nonmetastatic invasive BC patients undergoing insertion of a CVC for chemotherapy. All patients underwent double-blind DUS before, 7, 30, and 90 days after CVC insertion and a 6 months clinical follow-up. Symptomatic DUS- CRT were treated by anticoagulants. D-Dimers, thrombin generation, and platelet-derived microparticles were measured before and 2 days after CVC placement. In DUS- CRT patients, a nested case-control study analyzed the role of thrombophilia. Among 524 patients, the DUS- CRT (14 symptomatic, 46 asymptomatic) cumulative probability was 9.6% at 3 months and 11.5% at 6 months (overall incidence rate: 2.18/100 patient-months). Ten/14 symptomatic DUS- CRT were detected on double-blind DUS before the clinical symptoms, and 3/14 had a simultaneous pulmonary embolism. No clinical thrombotic event subsequently occurred in untreated asymptomatic DUS- CRT. Age >50 years ( OR, 1.80; 95% CI, 1.01-3.22), BMI >30 kg/m² ( OR, 2.64; 95% CI, 1.46-4.76) and comorbidities ( OR, 2.05; 95% CI, 1.18-3.56) were associated with DUS- CRT. No biomarkers was found to predict DUS- CRT. In multivariate analysis, BMI >30 kg/m² ( OR, 2.66; 95% CI, 1.46-4.84) and lobular carcinoma histology ( OR, 2.56; 95% CI, 1.32-4.96) remained the only significant DUS- CRT risk factors. Thrombophilia did not account for DUS- CRT. Only clinical parameters identified high risk DUS- CRT patients who may be considered for thromboprophylaxis. [ABSTRACT FROM AUTHOR]

Objectives Since mammographic screening programmes, the proportion of DCIS has dramatically increased. Adjuvant radiotherapy (RT) after local excision (LE) has become a solid option for DCIS since 4 randomised trials have proven a decrease in local relapse (LR), though failing to prove a benefit on mortality rate. DCIS is a heterogeneous disease and it is unclear whether all patients uniformly benefit from radiotherapy. We report a descriptive analysis including all types of treatment. Materials and methods Our retrospective cohort describes 608 women treated for DCIS in our centre between 1983 and 2013. Mastectomy was recommended before 1992, or for multifocal or >3 cm DCIS. LE alone was an option for DCIS ≤10 mm, with low or intermediate grade, and clear margins (≥2 mm). LE + RT was recommended for all other cases. Results The median follow-up time was 6.7 years. Treatment consisted in mastectomy for 252 women, LE + RT for 269 and LE for 86. The major prognosis factor for LR rate was the type of treatment: LE + RT or LE was associated with a higher LR-rate than those treated by mastectomy (HR respectively 2.06; 95%CI 1.33–3.19; p = 0.001 and 2.12; 95%CI 1.20–3.65; p = 0.007). In our selected population, women treated by LE + RT versus LE showed no significant differences in LR (HR 0.97; 95%CI 0.61–1.7; p = 0.91). The overall survival rate was 99.7% after ten years, with no differences between the treatment groups. Conclusion Although retrospective, our monocentric study suggests that LE alone could be an option for DCIS with good prognosis factors. Confirmation by larger randomised studies is needed. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the accuracy of the apparent diffusion coefficient (ADC) provided by diffusion-weighted imaging (DWI) in predicting the response to neoadjuvant chemotherapy (NACT) at baseline in patients according to their breast tumour phenotypes. Materials & methods: This retrospective study was approved by our institutional review board. One hundred eighteen consecutive women with locally advanced breast cancer who had undergone NACT followed by breast surgery were included. DWI was performed at 1.5 T less than 2 weeks before NACT. We studied the correlation between pretreatment ADC and response in pathology after surgery according to immunohistochemical features and intrinsic subtypes (luminal A, luminal B, HER2-enriched, and triple-negative tumours). Results: After surgery, the pathologist recognized 24 complete responders (CRps) and 94 non-complete responders (NCRps). No difference was identified between the pretreatment ADCs of the CRp and NCRp patients. There were differences in pretreatment ADCs among the luminal A (1.001 ± 0.143 × 10 mm/s), luminal B (0.983 ± 0.150 × 10 mm/s), HER2-enriched (1.132 ± 0.216 × 10 mm/s), and triple-negative (1.168 ± 0.245 × 10 mm/s; P = 0.0003) tumour subtypes. In triple-negative tumours, the pretreatment ADC was higher in NCRp (1.060 ± 0.143 × 10 mm/s) than in CRp patients (1.227 ± 0.271 × 10 mm/s; P = 0.047). Conclusion: Pretreatment ADC can predict the response of breast cancer to NACT if tumour subtypes are considered. Key Points • Apparent diffusion coefficient helps clinicians to assess patients with breast cancer. • Pretreatment ADC is related to tumour grade and hormone receptor status. • Pretreatment ADC is lower in luminal A and B than in triple-negative tumours. • Pretreatment ADC is higher in complete than in non-complete responders to neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

BACKGROUND The objective of this prospective study was to evaluate the ability of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) to predict chemosensitivity in patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS Sixty-four consecutive patients underwent 18F-FDG PET/CT scanning at baseline and after the second course of neoadjuvant chemotherapy (NAC). The evolution (Δ) between the 2 scans of image parameters (maximum standardized uptake value [SUVmax], SUVmean, metabolic tumor volume, and total lesion glycolysis [TLG]) was measured. Correlations between early changes in PET-derived parameters and pathologic response observed in surgical specimens after the completion of 8 courses of NAC were estimated with Mann-Whitney U tests. Response prediction on the basis of clinical data, histologic type, or molecular markers also was assessed (Fisher exact test). Receiver operating characteristic (ROC) analysis was used to compare the area under the curve (AUC) of each parameter. RESULTS The best prediction of chemosensitivity was obtained with ΔTLG (−49% ± 31% in nonresponders vs −73% ± 25% in responders; P < .0001). Among the biologic parameters, only negative progesterone receptor status (57% responders vs 31% nonresponders; P = .04) and luminal B subtype (63% responders vs 22% nonresponders; P = .02) were predictive of a pathologic response. ROC analysis resulted in an AUC of 0.81, 0.73, 0.71, and 0.63 for ΔTLG, ΔSUVmax, luminal subtype, and progesterone receptor status, respectively. CONCLUSIONS When patients responded to NAC, the majority of ER-positive/HER2 negative tumors exhibited partial tumor shrinkage; and the PET parameters that combined volume and activity measurements, such as TLG, offered better accuracy for early prediction than the SUVmax. Negative progesterone receptor status and luminal B subtype had weaker predictive power than PET-derived parameters. Cancer 2013;119:1960-1968. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

• Functional polymorphisms on the VEGF-A gene, known to be linked to cancer risk or to VEGF-A plasma concentrations, have been identified. So far, limited knowledge has been published on the relationships between toxicity/efficacy of bevacizumab-based therapy and VEGF-A polymorphisms (tumoral DNA). We therefore prospectively tested the impact of these five gene polymorphisms (blood DNA) on the pharmacodynamics of bevacizumab-based treatment administered in metastatic breast cancer patients. • Present data obtained from a prospective study suggest a role for VEGF-A 936C > T polymorphism as a potential predictor of time to progression in breast cancer patients receiving bevacizumab-containing therapy. Also, the VEGF-A−634G > C polymorphism was linked to bevacizumab-related toxicity. To test prospectively the impact of VEGF-A gene polymorphisms on the pharmacodynamics of bevacizumab-chemotherapy in breast cancer patients. As part of the single-arm MO19391 trial, 137 women with locally recurrent or metastatic breast cancer receiving first-line bevacizumab-containing therapy were analysed. Patients received bevacizumab associated (76%) or not (24%) with taxane-based chemotherapy. Clinical evaluation included clinical response, time to progression (TTP) and a toxicity score corresponding to the sum of each maximum observed toxicity grade (hypertension, haemorrhage, arterial and venous thrombo-embolism). Functional VEGF-A polymorphisms at position −2578 C > A, −1498 T > C, −1154 G > A, −634 G > C and 936 C > T were analysed by PCR-RFLP (blood DNA). Overall response rate (complete response (CR) + partial response (PR)) was 61%. Median TTP was 11 months. None of the VEGF-A polymorphisms was significantly linked to clinical response. Analysis of the 936C > T polymorphism revealed that the 96 patients homozygous for the 936C allele exhibited a marked tendency for a shorter TTP (median 9.7 months) than the 32 patients bearing the 936T allele (median 11.5 months, P= 0.022) of which 30 were CT and two were homozygous TT. Other polymorphisms did not influence TTP. VEGF-A−634 G > C was significantly related to the toxicity score with 39%, 49% and 81% of patients with score >1 in GG, GC and CC patients, respectively ( P= 0.01). The role for VEGF-A 936C > T polymorphism as a potential marker of TTP in breast cancer patients receiving bevacizumab-containing therapy concords with the known impact of VEGF-A 936C > T polymorphism on VEGF-A expression. [ABSTRACT FROM AUTHOR]

The author reflects on the use of neoadjuvant chemotherapy (NAC) in breast cancer patients with 18F-Fludeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT). He says that NAC increases breast-conserving surgery (BCS) performance and an excellent setting in documenting tumour response after chemotherapy. He mentions that consensual definition of histological response is needed and that early prediction of response allows change of therapy in case of inefficacy.

Background: The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer.Methods: In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1-21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719).Findings: Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5-14·1) in the ipatasertib group and 10·2 months (6·0-13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8-9·0) with ipatasertib versus 4·9 months (3·6-5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37-0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6-9·1) with ipatasertib versus 3·7 months (1·9-7·3) with placebo (stratified HR 0·59, 95% CI 0·26-1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group.Interpretation: Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer.Funding: F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

Purpose Breast conserving treatment, consisting of lumpectomy followed by whole-breast irradiation, is considered the standard of care in early-stage breast cancer. Randomized studies have reported that delivering boost doses to tumor bed improves local control rates, particularly in young women. This study sought to evaluate local control and cosmetic results of delivering boost doses using a high-dose-rate (HDR) brachytherapy (HDRBT) in breast cancer conservative treatment. Methods We included 621 T1–T2, N0–N1 breast cancer patients who underwent lumpectomy, external irradiation (44 Gy over 5 weeks), and a boost dose of two fractions of 5 Gy to the tumor bed by means of HDR iridium brachytherapy. Implantation was performed during the lumpectomy or 2–3 weeks after external irradiation. Population characteristics were as follows: pTis = 11.6%; pT1 = 63.4%; pT2 = 25.0%; median tumor size = 1.5 cm; histology: ductal carcinoma in situ (DCIS): 72 (11.6%); infiltrative ductal carcinoma (IDC): 471 (75.8%); other: 78 (12.6%). For IDCs, the surgical margins were positive in 38 cases (6.2%) and an extensive intraductal component was present in 254 cases. Results With a median follow-up of 10.3 years, 47 local relapses were observed (10-year local relapse rate: 7.4%). Small-volume implantation (V100 < 45 cc) and ductal carcinoma in situ histology both significantly correlated with local relapse. The 10-year overall survival was 91%. Cosmetic results were evaluated in 264 patients, proving excellent in 58 (22%), good in 153 (58%), fair in 40 (15%), and poor in 13 (5%). Conclusions Small implant volume and ductal carcinoma in situ histology significantly correlated with local relapse following HDR brachytherapy dose boost in breast cancer conservative treatment. Modern image-guided breast brachytherapy techniques using surgical clips as a guide may decrease potential treatment targeting errors, consequently improving local control without increasing toxicity. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced HER2-positive breast cancer frequently develop CNS metastases. The metastases that progress after brain radiotherapy and HER2-targeted systemic therapy are a difficult therapeutic challenge. We aimed to assess the efficacy and safety of afatinib, an irreversible blocker of the ErbB protein family, alone or combined with vinorelbine, compared with treatment of the investigator's choice in women with HER2-positive breast cancer with progressive brain metastases during or after treatment with trastuzumab, lapatinib, or both.Methods: We did this randomised, open-label, multicentre, phase 2 trial in 40 hospitals in Canada, Finland, France, Germany, Italy, Spain, South Korea, and the USA. Women older than 18 years with histologically confirmed HER2-overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) during or after treatment with trastuzumab, lapatinib, or both, were eligible. We randomly assigned patients (1:1:1) centrally to afatinib 40 mg orally once per day, afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m(2) once per week, or investigator's choice of treatment in cycles of 3 weeks until disease progression, patient withdrawal, or unacceptable toxicity. Treatment assignment was not masked for clinicians or patients, but the trial team was masked until database lock to reduce bias. The primary endpoint, assessed in the intention-to-treat population, was patient benefit at 12 weeks, defined by an absence of CNS or extra-CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose. Safety was assessed in all patients who received at least one dose of a study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01441596.Findings: Between Dec 22, 2011, and Feb 12, 2013, we screened 132 patients, of whom 121 were eligible and randomly assigned to treatment: 40 to afatinib alone, 38 to afatinib plus vinorelbine, and 43 to investigator's choice. All patients discontinued study treatment before the data collection cutoff on Oct 16, 2014. Patient benefit was achieved in 12 (30·0%; 95% CI 16·6-46·5) patients given afatinib alone (difference vs investigator's choice: -11·9% [95% CI -32·9 to 9·7], p=0·37), 13 (34·2%; 19·6-51·4) given afatinib plus vinorelbine (difference vs investigator's choice: -7·6% [-28·9 to 14·2], p=0·63), and 18 (41·9%; 27·0-57·9) given investigator's choice. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (seven [18%] of 40 patients in the afatinib only group vs nine [24%] of 37 patients in the afatinib plus vinorelbine group vs two [5%] of 42 patients in the investigator's choice group) and neutropenia (none vs 14 [38%] vs four [10%]).Interpretation: Patient benefit with afatinib-containing treatments was not different from that in patients given investigator's choice of treatments; however, adverse events were frequent and afatinib-containing treatments seemed to be less well tolerated. No further development of afatinib for HER2-positive breast cancer is currently planned.Funding: Boehringer Ingelheim. [ABSTRACT FROM AUTHOR]

Purpose Male breast cancer (BC) is a rare disease, with patterns different from those found in women. Most tumors are detected at more advanced stages than in women. The aim of this study was to analyze the performance of [18F]fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) in staging, restaging, and therapy response assessment. Methods We performed a systematic analysis in the database of Saint-Louis Hospital to identify male patients with BC referred for PET/CT. 18 F-FDG-PET/CT findings considered suspicious for malignancy were compared to biopsy results, further work-up and/or patient follow-up of at least 6 months. Performances of 18 F-FDG-PET/CT were compared to that of conventional imaging (CI) using the McNemar test. The impact of PET/CT on management was evaluated. Results During 6 consecutive years, among 12,692 18 F-FDG-PET/CT oncology studies, 30 were performed in 15 men with BC: 7 examinations for initial staging, 11 for restaging, and 12 for response assessment. Tumors profile was ER+ and one had HER2 overexpression. PET/CT sensitivity, specificity, positive predictive value, negative predictive value and accuracy to detect distant metastases were 100%, 67%, 86%, 100% and 89%, respectively. PET/CT was more informative than CI in 40% of studies ( p = 0.03; 95% confidence interval: 3.26 – 40%). Findings from 18 F-FDG-PET/CT led to modification in the planned treatment in 13/30 cases (43%). Conclusion Although all the tumors were ER+, primary lesions and metastases were diagnosed with high sensitivity. 18 F-FDG-PET/CT seems to be a powerful imaging method to perform staging, restaging and treatment response assessment in male patients with BC. [ABSTRACT FROM AUTHOR]

Summary: Background: Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer. Methods: We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30–90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901. Findings: 1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1–51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6–94·9) in the 12-month group and 91·1% (89·7–92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05–1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001). Interpretation: After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care. Funding: French National Cancer Institute. [ABSTRACT FROM AUTHOR]