Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study.
; ; et al
in Annals of oncology : official journal of the European Society for Medical Oncology / ESMO (2014)
BACKGROUND: Neoadjuvant trials conducted using a double HER2-blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological ... [more ▼]
BACKGROUND: Neoadjuvant trials conducted using a double HER2-blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. PATIENTS AND METHODS: Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1:1:1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab+lapatinib at the same dose. The primary endpoint was pCR rate defined as ypT0/is. Secondary endpoints included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies. RESULTS: From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 evaluable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib+trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%). Frequency (%) of the most common grade 3-4 toxicities in the lapatinib /trastuzumab/lapatinib+trastuzumab arms were: febrile neutropenia 23/15/10, diarrhea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8. CONCLUSIONS: This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity. This study is registered with ClinicalTrials.gov, number NCT00450892. [less ▲]Detailed reference viewed: 10 (0 ULg)
A new era of improving progression-free survival with dual blockade in postmenopausal HR, HER2 advanced breast cancer.
Jerusalem, Guy ; ; et al
in Cancer treatment reviews (2014)
Disease progression despite existing endocrine therapies remains a major challenge to the effective management of hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2 ... [more ▼]
Disease progression despite existing endocrine therapies remains a major challenge to the effective management of hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), advanced breast cancer. Recent advances in elucidating the molecular mechanisms of disease progression have identified the existence of adaptive "cross-talk" between the estrogen receptor (ER) and various growth factor receptor and intracellular signaling pathways, allowing breast cancer cells to escape the inhibitory effects of endocrine therapy. These findings provide the clinical rationale for enhancing or extending endocrine sensitivity by combining endocrine therapy with a targeted agent against a compensatory pathway. In BOLERO-2, adding the mTOR inhibitor everolimus to endocrine therapy significantly improved progression-free survival (PFS) in patients with HR+ advanced breast cancer previously treated with nonsteroidal aromatase inhibitor therapy. Notably, PFS benefits were comparable in subgroup analyses of first- and later-line settings. These results contrast with those of the large first-line HORIZON study, wherein adding the mTOR inhibitor temsirolimus to endocrine therapy did not improve PFS. Therefore, it is unclear whether a targeted agent should only be combined with endocrine therapy to restore endocrine sensitivity or whether it may also prevent or delay resistance in hormone-sensitive advanced breast cancer. Numerous additional targeted agents are currently being evaluated in combination with endocrine therapies, including PI3K, cyclin-dependent kinase 4/6, SRC, and histone deacetylase inhibitors. Appropriate patient selection based on prior treatment history will become increasingly important in maximizing the incremental benefit derived from these new agents combined with existing endocrine therapies in HR+ advanced breast cancer. [less ▲]Detailed reference viewed: 16 (1 ULg)
Self-hypnosis, yoga or CBT group to face breast cancer: feasibility study and first results in Belgium
Bragard, Isabelle ; Etienne, Anne-Marie ; Faymonville, Marie-Elisabeth et al
in Psycho-oncology (2014), 23 (suppl 3)Detailed reference viewed: 48 (11 ULg)
Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes.
Jerusalem, Guy ; RORIVE, Andrée ; COLLIGNON, Joëlle
in Breast Cancer (2014), 6
Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, and other targeted agents ... [more ▼]
Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, and other targeted agents. Recently, everolimus, a mammalian target of rapamycin (mTOR) inhibitor, combined with exemestane, an aromatase inhibitor, has been approved in Europe and the USA for patients suffering from estrogen receptor-positive, HER2-negative advanced breast cancer previously treated by a nonsteroidal aromatase inhibitor, based on the results of BOLERO-2 (Breast cancer trials of OraL EveROlimus). This study showed a statistically significant and clinically meaningful improvement in median progression-free survival. Results concerning the impact on overall survival are expected in the near future. This clinically oriented review focuses on the use of mTOR inhibitors in breast cancer. Results reported with first-generation mTOR inhibitors (ridaforolimus, temsirolimus, everolimus) are discussed. The current and potential role of mTOR inhibitors is reported according to breast cancer subtype (estrogen receptor-positive HER2-negative, triple-negative, and HER2-positive ER-positive/negative disease). Everolimus is currently being evaluated in the adjuvant setting in high-risk estrogen receptor-positive, HER2-negative early breast cancer. Continuing mTOR inhibition or alternatively administering other drugs targeting the phosphatidylinositol-3-kinase/protein kinase B-mTOR pathway after progression on treatments including an mTOR inhibitor is under evaluation. Potential biomarkers to select patients showing a more pronounced benefit are reviewed, but we are not currently using these biomarkers in routine practice. Subgroup analysis of BOLERO 2 has shown that the benefit is consistent in all subgroups and that it is impossible to select patients not benefiting from addition of everolimus to exemestane. Side effects and impact on quality of life are other important issues discussed in this review. Second-generation mTOR inhibitors and dual mTOR-phosphatidylinositol-3-kinase inhibitors are currently being evaluated in clinical trials. [less ▲]Detailed reference viewed: 26 (4 ULg)
European inter-institutional impact study of MammaPrint.
; ; et al
in Breast (Edinburgh, Scotland) (2014), 23(4), 423-8
AIM: To measure the impact of MammaPrint on adjuvant treatment decisions and to analyze the agreement in treatment decisions between hospitals from 4 European countries for the same patient cohort ... [more ▼]
AIM: To measure the impact of MammaPrint on adjuvant treatment decisions and to analyze the agreement in treatment decisions between hospitals from 4 European countries for the same patient cohort. METHODS: Breast cancer patients were prospectively enrolled and MammaPrint was assessed. Patients' clinical data without and then with MammaPrint results were sent to the different multidisciplinary teams and treatment advice was provided for each patient. RESULTS: Using MammaPrint, chemotherapy treatment advice for ER+/HER2- breast cancer patients was changed in 37% of patients by the Dutch, 24% by the Belgian, 28% by the Italian and 35% by the Spanish teams. MammaPrint increased the inter-institutional agreement in treatment advice (chemotherapy or no chemotherapy) from 51% to 75%. CONCLUSION: The results of this study indicate that MammaPrint impacts adjuvant chemotherapy recommendation. MammaPrint can decrease inter-institutional and inter-country variability in adjuvant treatment advice for breast cancer patients. [less ▲]Detailed reference viewed: 18 (1 ULg)
Le médicament du mois : Everolimus (Afinitor) dans le traitement du cancer du sein métastatique
JERUSALEM, Guy ; RORIVE, Andrée ; COLLIGNON, Joëlle
in Revue Médicale de Liège (2014), 69(9), 510-517Detailed reference viewed: 5 (1 ULg)
Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
; ; et al
in European heart journal cardiovascular Imaging (2014), 15(10), 1063-93Detailed reference viewed: 8 (2 ULg)
L'âgisme et ses conséquences cliniques en oncogériatrie: état des lieux et pistes d'interventions
Schroyen, Sarah ; Adam, Stéphane ; Jerusalem, Guy et al
in Revue Médicale de Liège (2014), 69(5-6), 395-401Detailed reference viewed: 47 (10 ULg)
Final Overall Survival: Fulvestrant 500 mg vs 250 mg in the Randomized CONFIRM Trial.
; Jerusalem, Guy ; et al
in Journal of the National Cancer Institute (2014), 106(1), 337
BACKGROUND: At the time of the initial analysis of overall survival (OS) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) randomized, double-blind, phase III trial ... [more ▼]
BACKGROUND: At the time of the initial analysis of overall survival (OS) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) randomized, double-blind, phase III trial, approximately 50% of patients had died. A final analysis of OS was subsequently planned for when 75% of patients had died. METHODS: Patients were randomly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0, 14, and 28 and every 28 (+/-3) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo injections only), and 28 and every 28 (+/-3) days thereafter. OS was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) and best response to subsequent therapy were also reported. All statistical tests were two-sided. RESULTS: In total, 736 women (median age = 61.0 years) were randomly assigned to fulvestrant 500mg (n = 362) or 250mg (n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median OS was 26.4 months for fulvestrant 500mg and 22.3 months for 250mg (hazard ratio = 0.81; 95% confidence interval = 0.69-0.96; nominal P = .02). There were no clinically important differences in SAE profiles between the treatment groups; no clustering of SAEs could be detected in either treatment group. Type of first subsequent therapy and objective responses to first subsequent therapy were well balanced between the two treatment groups. CONCLUSIONS: In patients with locally advanced or metastatic estrogen receptor-positive breast cancer, fulvestrant 500mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250mg. Fulvestrant 500mg was well tolerated, and no new safety concerns were identified. [less ▲]Detailed reference viewed: 37 (4 ULg)
Phase Ib study of Buparlisib plus Trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on Trastuzumab-based therapy.
; ; Jerusalem, Guy et al
in Clinical cancer research : an official journal of the American Association for Cancer Research (2014), 20(7), 1935-45
PURPOSE: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2(+)) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose ... [more ▼]
PURPOSE: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2(+)) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2(+) advanced/metastatic breast cancer resistant to trastuzumab-based therapy. EXPERIMENTAL DESIGN: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2(+) breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. RESULTS: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (>/=6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways. CONCLUSIONS: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935-45. (c)2014 AACR. [less ▲]Detailed reference viewed: 30 (2 ULg)
LE DÉFI DU CONTRÔLE LOCAL DANS LE CANCER PULMONAIRE NON A PETITES CELLULES, LOCALEMENT AVANCE, NON OPERABLE
BARTHELEMY, Nicole ; LENNERTS, Evelyne ; MEYNS, Mia et al
in Revue Médicale de Liège (2014), 69(Supp 1), 75-80
Le cancer broncho-pulmonaire non à petites cellules (CBNPC) est fréquent. Pour près d’un patient sur cinq, au moment du diagnostic, la maladie est déjà localement avancée et inopérable. A ce stade, le ... [more ▼]
Le cancer broncho-pulmonaire non à petites cellules (CBNPC) est fréquent. Pour près d’un patient sur cinq, au moment du diagnostic, la maladie est déjà localement avancée et inopérable. A ce stade, le pronostic de cette affection est mauvais, caractérisé, entre autres, par un taux élevé de réci - dive locale, malgré la chimiothérapie et la radiothérapie. Le but de cette revue est de décrire l’hétérogénéité de ce groupe de patients, de clarifier les modalités de traitement combinant la chimiothérapie et la radiothérapie et de préciser l’intérêt des techniques modernes de radiothérapie pour améliorer le contrôle local [less ▲]Detailed reference viewed: 64 (10 ULg)
Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial.
; ; et al
in The lancet oncology (2014)
BACKGROUND: Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We aimed to ... [more ▼]
BACKGROUND: Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We aimed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient screening and randomisation system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m2) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was progression-free survival (PFS) by local assessment in the intention-to-treat population. We report the final analysis for PFS; overall survival follow-up is still in progress. This trial is registered with ClinicalTrials.gov, number NCT01007942. FINDINGS: Between Oct 26, 2009, and May 23, 2012, 569 patients were randomly assigned to everolimus (n=284) or placebo (n=285). Median follow-up at the time of analysis was 20.2 months (IQR 15.0-27.1). Median PFS was 7.00 months (95% CI 6.74-8.18) with everolimus and 5.78 months (5.49-6.90) with placebo (hazard ratio 0.78 [95% CI 0.65-0.95]; p=0.0067). The most common grade 3-4 adverse events were neutropenia (204 [73%] of 280 patients in the everolimus group vs 175 [62%] of 282 patients in the placebo group), leucopenia (106 [38%] vs 82 [29%]), anaemia (53 [19%] vs 17 [6%]), febrile neutropenia (44 [16%] vs ten [4%]), stomatitis (37 [13%] vs four [1%]), and fatigue (34 [12%] vs 11 [4%]). Serious adverse events were reported in 117 (42%) patients in the everolimus group and 55 (20%) in the placebo group; two on-treatment deaths due to adverse events occurred in each group. INTERPRETATION: The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population. FUNDING: Novartis Pharmaceuticals Corporation. [less ▲]Detailed reference viewed: 33 (4 ULg)
A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease.
; ; et al
in Breast cancer research and treatment (2014)
Radium-223 dichloride (radium-223) mimics calcium and emits high-energy, short-range alpha-particles resulting in an antitumor effect on bone metastases. This open-label, phase IIa nonrandomized study ... [more ▼]
Radium-223 dichloride (radium-223) mimics calcium and emits high-energy, short-range alpha-particles resulting in an antitumor effect on bone metastases. This open-label, phase IIa nonrandomized study investigated safety and short-term efficacy of radium-223 in breast cancer patients with bone-dominant disease. Twenty-three advanced breast cancer patients with progressive bone-dominant disease, and no longer candidates for further endocrine therapy, were to receive radium-223 (50 kBq/kg IV) every 4 weeks for 4 cycles. The coprimary end points were change in urinary N-telopeptide of type 1 (uNTX-1) and serum bone alkaline phosphatase (bALP) after 16 weeks of treatment. Exploratory end points included sequential 18F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) to assess metabolic changes in osteoblastic bone metastases. Safety data were collected for all patients. Radium-223 significantly reduced uNTX-1 and bALP from baseline to end of treatment. Median uNTX-1 change was -10.1 nmol bone collagen equivalents/mmol creatinine (-32.8 %; P = 0.0124); median bALP change was -16.7 ng/mL (-42.0 %; P = 0.0045). Twenty of twenty-three patients had FDG PET/CT identifying 155 hypermetabolic osteoblastic bone lesions at baseline: 50 lesions showed metabolic decrease (>/=25 % reduction of maximum standardized uptake value from baseline) after 2 radium-223 injections [32.3 % metabolic response rate (mRR) at week 9], persisting after the treatment period (41.5 % mRR at week 17). Radium-223 was safe and well tolerated. Radium-223 targets areas of increased bone metabolism and shows biological activity in advanced breast cancer patients with bone-dominant disease. [less ▲]Detailed reference viewed: 36 (3 ULg)
Disease management patterns for postmenopausal women in Europe with hormone-receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer.
; ; et al
in Current medical research and opinion (2014)
Abstract Background: International guidelines for hormone-receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (BC) recommend sequential lines of ... [more ▼]
Abstract Background: International guidelines for hormone-receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (BC) recommend sequential lines of hormonal therapy (HT), and only recommend chemotherapy for patients with extensive visceral involvement or rapidly progressive disease. This study evaluated actual physician-reported treatments for advanced BC in Europe. Methods: We conducted a retrospective chart review of 355 postmenopausal women with HR+, HER2- advanced BC who progressed on >/=1 line of HT (adjuvant or advanced) and completed >/=1 line of chemotherapy (advanced). Treatment choice was evaluated for each line of therapy. Results: Of 355 patients, 111 (31%) received first-line chemotherapy, whereas 218 (61%) and 26 (7%) switched from HT to chemotherapy in second and third line, respectively. More patients receiving first-line HT had bone metastases (73% vs 27% chemotherapy). Patients treated with first-line chemotherapy had more brain (12% vs 3% HT) or extensive liver (13% vs 6% HT) metastases. Subgroup analysis of 188 patients who received first-line HT and had de novo advanced BC or relapsed/recurrent disease more than 1 year after adjuvant therapy found that the majority (89%; n = 167) of these patients switched to chemotherapy in second line. However, among these 167 patients, 27% had no significant changes in metastases between first and second line. Among the 73% of patients who had significant changes in metastases, 20% had no brain metastases or extensive visceral disease. Conclusions: Our study suggests that the guideline-recommended use of multiple HT lines is open to interpretation and that optimal treatment for European postmenopausal women with HR+, HER2- advanced BC who responded to HT may not be achieved. [less ▲]Detailed reference viewed: 33 (6 ULg)
Safety analysis of BOLERO-3 : a phase III trial of daily Everolimus vs placebo, both with weekly Trastuzumab and Vinorelbine in Trastuzumab-resistant, advanced breast cancer
JERUSALEM, Guy ; ; et al
Poster (2013, December 12)Detailed reference viewed: 16 (3 ULg)
A miRNA expression based diagnostic tool for breast cancer using random forests
Wenric, Stéphane ; Freres, Pierre ; Josse, Claire et al
Poster (2013, December 09)
We developed a novel diagnostic tool for breast cancer using circulating miRNA expression levels as features of a supervised machine learning problem. We showed very good results on an independent ... [more ▼]
We developed a novel diagnostic tool for breast cancer using circulating miRNA expression levels as features of a supervised machine learning problem. We showed very good results on an independent validation cohort. [less ▲]Detailed reference viewed: 17 (5 ULg)
The SNAP trial : schedules of nab-Paclitaxel in metastatic breast cancer. International breast cancer study group (ICGSG 42-12) and breast international group (BIG 2-12)
; JERUSALEM, Guy ;
Poster (2013, December)Detailed reference viewed: 33 (1 ULg)
BOLERO-3 : Everolimus plus Trastuzumab and Vinorelbine in asian patients with HER2-positive metastatic breast cancer
; ; et al
Poster (2013, December)Detailed reference viewed: 18 (5 ULg)
BOLERO-3 : Quality-of-life maintained in patients with HER-2 positive metastatic breast cancer treated with Everolimus plus Trastuzumab plus Vinorelbine
; ; JERUSALEM, Guy et al
Poster (2013, December)Detailed reference viewed: 21 (2 ULg)