Publications by authors named "Martine J Piccart"

72 Publications

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

N Engl J Med 2021 04;384(16):1529-1541

From the Division of Medical Oncology, Massachusetts General Hospital Cancer Center (A. Bardia), and the Department of Medical Oncology, Dana-Farber Cancer Institute (S.M.T.) - both in Boston; the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles (S.A.H.); the Medical Oncology Department and the Department of Drug Development and Innovation, Institut Curie, Paris (D.L.), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse (F.D.), and the Department of Medical Oncology, Centre Eugène Marquis, Rennes (V.D.) - all in France; the Department of General Medical Oncology and Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven (K.P.), and the Clinical Trials Conduct Unit (P.A.), Institut Jules Bordet-Université Libre de Bruxelles (M.J.P.), Brussels - all in Belgium; the Medical Oncology Department and Breast Cancer Group, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (M.O.), and the International Breast Cancer Center, Quiron Group (J.C.) - all in Barcelona; Magee-Womens Hospital and the Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (A. Brufsky); Ohio State University Wexner Medical Center, Columbus (S.D.S.); Columbia University Irving Medical Center (K.K.) and Memorial Sloan Kettering Cancer Center (T.T.) - both in New York; Northside Hospital, Atlanta (A.B.Z.); Florida Cancer Specialists, Tampa (R.W.); Georgetown Lombardi Comprehensive Cancer Center, Washington, DC (F.L.); Rocky Mountain Cancer Centers, Greenwood Village, CO (S.D.); Baylor University Medical Center and Texas Oncology, Dallas (J.O.); Segal Cancer Centre, Jewish General Hospital, Montreal (C.F.); Barts Cancer Institute, Queen Mary University of London, London (P.S.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (L.A.C.); Gianni Bonadonna Foundation, Milan (L.G.); the Department of Medicine and Research, Hämatologisch-Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus, Frankfurt, Germany (S.L.); Immunomedics, Morris Plains, NJ (D.M.G., Q.H., M.S.O., L.M.I.); and the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.).

Background: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker.

Methods: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases.

Results: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment.

Conclusions: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).
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http://dx.doi.org/10.1056/NEJMoa2028485DOI Listing
April 2021

Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: analysis from the ALTTO (BIG 2-06) trial.

ESMO Open 2020 11;5(6):e000979

Medical Oncology Department, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B.), Brussels, Belgium.

Background: In HER2-positive breast cancer, time elapsed between completion of (neo)adjuvant trastuzumab and diagnosis of metastatic disease ('trastuzumab-free interval', TFI) is crucial to choose the optimal first-line treatment. Nevertheless, there is no clear evidence to support its possible prognostic role.

Methods: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, patients with HER2-positive early breast cancer were randomised to 1 year of either trastuzumab alone, lapatinib alone, their sequence or their combination. This exploratory analysis included only patients in the trastuzumab alone or trastuzumab plus lapatinib arms who developed a distant disease-free survival (DDFS) event. Overall survival (OS) was defined as time between date of DDFS event and death; age at diagnosis, tumour size and hormone receptor status were the variables included in the multivariate models.

Results: Out of 8381 patients included in ALTTO, 404 patients in the trastuzumab alone and trastuzumab plus lapatinib arms developed a DDFS event, of which 201 occurred 12 months (group A) and 203 >12 months (group B) after completion of adjuvant trastuzumab. No significant difference in location of first DDFS event was observed (p=0.073); a numerically higher number of patients in group A than in group B developed brain metastasis (26% vs 15%). Choice of first-line therapy differed between the two groups (p=0.022): in group A, more patients received lapatinib (25% vs 11%) and less pertuzumab (8% vs 17%). Median OS was 29.3 and 18.4 months in groups B and A, respectively (adjusted HR 0.69; 95% CI 0.54-0.89; p=0.004). The longer OS for patients in group B was observed across the analysed subgroups without interaction according to hormone receptor status (p=0.814) nor type of administered adjuvant anti-HER2 treatment (p=0.233).

Conclusions: TFI has prognostic value in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab-based therapy. TFI is a valid tool to better individualise clinical recommendations and to design future first-line treatment trials for metastatic patients.
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http://dx.doi.org/10.1136/esmoopen-2020-000979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643526PMC
November 2020

Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.

J Clin Oncol 2020 12 14;38(34):4120-4129. Epub 2020 Oct 14.

Dana Farber Cancer Institute, Department of Medical Oncology, Boston, MA.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.
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http://dx.doi.org/10.1200/JCO.20.01382DOI Listing
December 2020

Application of the ESMO-Magnitude of Clinical Benefit Scale (V.1.1) to the field of early breast cancer therapies.

ESMO Open 2020 09;5(5):e000743

Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal.

Click here to listen to the Podcast BACKGROUND: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated value scale for solid tumour anticancer treatments. Form 1 of the ESMO-MCBS, used to grade therapies with curative intent including adjuvant therapies, has only been evaluated for a limited number of studies. This is the first large-scale field testing in early breast cancer to assess the applicability of the scale to this data set and the reasonableness of derived scores and to identify any shortcomings to be addressed in future modifications of the scale.

Method: Representative key studies and meta-analyses of the major modalities of adjuvant systemic therapy of breast cancer were identified for each of the major clinical scenarios (HER2-positive, HER2-negative, endocrine-responsive) and were graded with form 1 of the ESMO-MCBS. These generated scores were reviewed by a panel of experts for reasonableness. Shortcomings and issues related to the application of the scale and interpretation of results were identified and critically evaluated.

Results: Sixty-five studies were eligible for evaluation: 59 individual studies and 6 meta-analyses. These studies incorporated 101 therapeutic comparisons, 61 of which were scorable. Review of the generated scores indicated that, with few exceptions, they generally reflected contemporary standards of practice. Six shortcomings were identified related to grading based on disease-free survival (DFS), lack of information regarding acute and long-term toxicity and an inability to grade single-arm de-escalation scales.

Conclusions: Form 1 of the ESMO-MCBS is a robust tool for the evaluation of the magnitude of benefit studies in early breast cancer. The scale can be further improved by addressing issues related to grading based on DFS, annotating grades with information regarding acute and long-term toxicity and developing an approach to grade single-arm de-escalation studies.
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http://dx.doi.org/10.1136/esmoopen-2020-000743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476474PMC
September 2020

Cost-effectiveness analysis of the 70-gene signature compared with clinical assessment in breast cancer based on a randomised controlled trial.

Eur J Cancer 2020 09 11;137:193-203. Epub 2020 Aug 11.

Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands; Health Technology and Services Research Department, Technical Medical Centre, University of Twente, P.O. Box 217, 7500 AE, Enschede, the Netherlands.

Background: The clinical utility of the 70-gene signature (MammaPrint®) to guide chemotherapy use in T1-3N0-1M0 breast cancer was demonstrated in the Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) study. One thousand four ninety seven of 3356 (46.2%) enrolled patients with high clinical risk (in accordance with the modified Adjuvant! Online clinical-pathological assessment) had a low-risk 70-gene signature. Using patient-level data from the MINDACT trial, the cost-effectiveness of using the 70-gene signature to guide adjuvant chemotherapy selection for clinical high risk, estrogen receptor positive (ER+), human epidermal growth factor 2 negative (HER2-) patients was analysed.

Patients And Methods: A hybrid decision tree-Markov model simulated treatment strategies in accordance with the 70-gene signature with clinical assessment versus clinical assessment alone, over a 10-year time horizon. Primary outcomes were quality-adjusted life years (QALYs), country-specific costs and incremental cost-effectiveness ratios (ICERs) for six countries: Belgium, France, Germany, Netherlands, UK and the US.

Results: Treatment strategies guided by the 70-gene signature result in more QALYs compared with clinical assessment alone. Costs of the 70-gene signature strategy were lower in five of six countries. This led to dominance of the 70-gene signature in Belgium, France, Germany, Netherlands and the US and to a cost-effective situation in the UK (ICER £22,910/QALY). Annual national cost savings were €4.2M (Belgium), €24.7M (France), €45.1M (Germany), €12.7M (Netherlands) and $244M (US). UK budget increase was £8.4M.

Conclusion: Using the 70-gene signature to safely guide chemotherapy de-escalation in clinical high risk patients with ER+/HER2- tumours is cost-effective compared with using clinical assessment alone. Long-term follow-up and outcomes from the MINDACT trial are necessary to address uncertainties in model inputs.
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http://dx.doi.org/10.1016/j.ejca.2020.07.002DOI Listing
September 2020

Tumor-Infiltrating Lymphocytes and Prognosis: A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast Cancers.

J Clin Oncol 2019 03 16;37(7):559-569. Epub 2019 Jan 16.

2 Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Purpose: The aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast cancer (TNBC).

Methods: Participating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic samples of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS; primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors.

Results: We collected individual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age ( P = .001), larger tumor size ( P = .01), more nodal involvement ( P = .02), and lower histologic grade ( P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio χ, 48.9 iDFS; P < .001; χ, 55.8 D-DFS; P < .001; χ, 48.5 OS; P < .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs ≥ 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%).

Conclusion: This pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org .
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http://dx.doi.org/10.1200/JCO.18.01010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010425PMC
March 2019

Risk factors for the development of brain metastases in patients with HER2-positive breast cancer.

ESMO Open 2018 24;3(6):e000440. Epub 2018 Oct 24.

Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium.

Background: Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) frequently experience brain metastases (BM). We aimed to define risk factors for the development of BM in patients with HER2+ BC and to report on their outcome.

Methods: This is a retrospective analysis of patients diagnosed with HER2+ BC between January 2000 and December 2014 at Institut Jules Bordet, Belgium. Statistical analyses were conducted with SAS V.9.4 using Kaplan-Meier method and Cox regression analyses.

Results: A total of 483 patients were included of whom 108 (22.4%) developed metastases and 52 (10.8%) BM. Among 96 metastatic patients without BM at diagnosis, 40 (41.7%) developed BM in the course of their disease. In multivariate analysis, risk factors for the development of BM were age ≤40 years (HR 2.10, 95 % CI 1.02 to 4.36), tumour size >2 cm (HR 4.94, 95% CI 1.69 to 14.47), nodal involvement (HR 3.48, 95% CI 1.47 to 8.25), absence or late start (≥6 months after initial diagnosis) of adjuvant anti-HER2 treatment (HR 3.79, 95% CI 1.52 to 9.43 or HR 2.65, 95% CI 1.03 to 6.82) and the development of lung metastases as first site of relapse (HR 6.97, 95% CI 3.41 to 14.24). Twenty-two patients with HER2+ BC and BM sent to our institute for further treatment were included in the outcome analysis. Asymptomatic patients at the time of BM diagnosis showed a better overall survival than symptomatic patients (HR 0.49, 95% CI 0.25 to 0.94).

Conclusion: A considerable number of patients with metastatic HER2+ BC will develop BM. Screening of patients with risk factors for BM might lead to early detection and better outcome. However, randomised controlled trials examining the use of MRI as a screening method for BM in patients with metastatic BC are warranted before such an approach can be recommended.
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http://dx.doi.org/10.1136/esmoopen-2018-000440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212674PMC
October 2018

Neoadjuvant treatment: the future of patients with breast cancer.

ESMO Open 2018 17;3(4):e000371. Epub 2018 May 17.

Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium.

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http://dx.doi.org/10.1136/esmoopen-2018-000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976132PMC
May 2018

RE: Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration.

J Natl Cancer Inst 2018 10;110(10):1142-1143

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1093/jnci/djy029DOI Listing
October 2018

p-STAT3 in luminal breast cancer: Integrated RNA-protein pooled analysis and results from the BIG 2-98 phase III trial.

Int J Oncol 2018 Feb 27;52(2):424-432. Epub 2017 Nov 27.

Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium.

In the present study, in order to investigate the role of signal transducer and activator of transcription 3 (STAT3) in estrogen receptor (ER)-positive breast cancer prognosis, we evaluated the phosphorylated STAT3 (p-STAT3) status and investigated its effect on the outcome in a pooled analysis and in a large prospective adjuvant trial. By using the TCGA repository, we developed gene signatures that reflected the level of p-STAT3. Using pooled analysis of the expression data from luminal breast cancer patients, we assessed the effects of the p-STAT3 expression signature on prognosis. We further validated the p-STAT3 prognostic effect using immunohistochemistry (IHC) and immunofluorescence staining of p-STAT3 tissue microarrays from a large randomised prospective trial. Our analysis demonstrated that p-STAT3 expression was elevated in luminal A-type breast cancer (Kruskal-Wallis test, P<10e-10) and was significantly associated with a good prognosis (log-rank, P<10e-10). Notably, the p-STAT3 expression signature identified patients with a good prognosis irrespective of the luminal subtype (log-rank: luminal A, P=0.026; luminal B, P=0.006). p-STAT3 staining by IHC in the stroma or tumour was detected in 174 out of 610 ER-positive samples (28.5%) from the BIG 2-98 randomised trial. With a median follow-up of 10.1 years, p-STAT3 was associated with a reduced risk of recurrence in ER-positive/HER2-negative breast cancer (Cox univariate HR, 0.66; 95% CI, 0.44-0.98; P=0.04). On the whole, our data indicate that p-STAT3 is associated with an improved outcome in ER-positive breast cancer.
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http://dx.doi.org/10.3892/ijo.2017.4212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903891PMC
February 2018

Detailed statistical assessment of the characteristics of the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) threshold rules.

ESMO Open 2017 9;2(4):e000216. Epub 2017 Oct 9.

Department of Medical Oncology, Cancer Pain and Palliative Medicine Service, Shaare Zedek Medical Center, Jerusalem, Israel.

Background: The European Society for Medical Oncology (ESMO) has developed the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), a tool to assess the magnitude of clinical benefit from new cancer therapies. Grading is guided by a dual rule comparing the relative benefit (RB) and the absolute benefit (AB) achieved by the therapy to prespecified threshold values. The ESMO-MCBS v1.0 dual rule evaluates the RB of an experimental treatment based on the lower limit of the 95%CI (LL95%CI) for the hazard ratio (HR) along with an AB threshold. This dual rule addresses two goals: inclusiveness: not unfairly penalising experimental treatments from trials designed with adequate power targeting clinically meaningful relative benefit; and discernment: penalising trials designed to detect a small inconsequential benefit.

Methods: Based on 50 000 simulations of plausible trial scenarios, the sensitivity and specificity of the LL95%CI rule and the ESMO-MCBS dual rule, the robustness of their characteristics for reasonable power and range of targeted and true HRs, are examined. The per cent acceptance of maximal preliminary grade is compared with other dual rules based on point estimate (PE) thresholds for RB.

Results: For particularly small or particularly large studies, the observed benefit needs to be relatively big for the ESMO-MCBS dual rule to be satisfied and the maximal grade awarded. Compared with approaches that evaluate RB using the PE thresholds, simulations demonstrate that the MCBS approach better exhibits the desired behaviour achieving the goals of both inclusiveness and discernment.

Conclusions: RB assessment using the LL95%CI for HR rather than a PE threshold has two advantages: it diminishes the probability of excluding big benefit positive studies from achieving due credit and, when combined with the AB assessment, it increases the probability of downgrading a trial with a statistically significant but clinically insignificant observed benefit.
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http://dx.doi.org/10.1136/esmoopen-2017-000216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640101PMC
October 2017

Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE).

Eur J Cancer 2017 11 17;85:133-145. Epub 2017 Sep 17.

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Australian New Zealand Breast Cancer Trials Group (ANZBCTG), Newcastle, Australia. Electronic address:

Aim: The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer.

Methods: NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15.

Results: Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA. Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup (P = 0.03).

Conclusions: Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors.

Trial Registration Identifier: NCT01816594.
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http://dx.doi.org/10.1016/j.ejca.2017.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640494PMC
November 2017

Regional Nodal Irradiation After Breast Conserving Surgery for Early HER2-Positive Breast Cancer: Results of a Subanalysis From the ALTTO Trial.

J Natl Cancer Inst 2017 08;109(8)

Breast Data Center, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

Background: Two randomized trials recently demonstrated that regional nodal irradiation (RNI) could reduce the risk of recurrence in early breast cancer; however, these trials were conducted in the pretrastuzumab era. Whether these results are applicable to human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients treated with anti-HER2-targeted therapy is unknown.

Methods: This retrospective analysis was performed on patients with node-positive breast cancer who were enrolled in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization phase III adjuvant trial and subjected to BCS. The primary objective of the present study was to examine the effect of RNI on disease-free survival (DFS). A multivariable cox regression analysis adjusted for number of positive lymph nodes, tumor size, grade, age, hormone receptors status, presence of macrometastatis, treatment arm, and chemotherapy timing was carried out to investigate the relationship between RNI and DFS.

Results: One thousand six hundred sixty-four HER2-positive breast cancer patients were included, of whom 878 (52.8%) had received RNI to the axillary, supraclavicular, and/or internal mammary lymph nodes. Patients in the RNI group had higher nodal burden and more frequently had tumors larger than 2 cm. At a median follow-up of 4.5 years, DFS was 84.3% in the RNI group and 88.3% in the non-RNI group. No differences in regional recurrence (0.9 % vs 0.6 %) or in overall survival (93.6% vs 95.3%) were observed between the two groups. After adjustment in multivariable analysis, there was no statistically significant association between RNI and DFS (hazard ratio = 0.96, 95% confidence interval = 0.71 to 1.29).

Conclusions: Our analysis did not demonstrate a DFS benefit of RNI in HER2-positive, node-positive patients treated with adjuvant HER2-targeted therapy. The benefit of RNI in HER2-positive breast cancer needs further testing within randomized clinical trials.
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http://dx.doi.org/10.1093/jnci/djw331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279283PMC
August 2017

Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial.

JAMA Oncol 2016 Aug;2(8):1040-7

Avera Cancer Institute, Department of Molecular and Experimental Medicine, Sioux Falls, South Dakota.

Importance: A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown.

Objective: To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial.

Design, Setting, And Participants: The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy. This is a secondary analysis of the HERA study. Local ER immunohistochemical (IHC) analyses, HER2 fluorescence in situ hybridization (FISH) ratio, and copy number results were available for 3037 patients (59.6%) randomized to observation and trastuzumab (1 or 2 years) (cohort 1). Transcript levels of ESR1 and HER2 genes were available for 615 patients (12.1%) (cohort 2).

Interventions: Patients were randomized to receive either no trastuzumab or 1 year vs 2 years of trastuzumab. Endocrine therapy was given to patients with hormone receptor-positive disease as per local guidelines.

Main Outcomes And Measures: Disease-free survival (DFS) and overall survival (OS) were the primary and secondary end points in the intent-to-treat population (ITT). Analyses adjusting for crossover (censored and inverse probability weighted [IPW]) were also performed. Interactions among treatment, ER status, and HER2 amplification using predefined cutoffs were assessed in Cox proportional hazards regression models.

Results: Median follow-up time was 8 years. Levels of FISH and HER2 copy numbers were significantly higher in ER-negative patients (P < .001). In cohort 1, for DFS and OS, a significant treatment effect was found for all ER, IHC, and FISH levels, except for the ER-positive/HER2 low FISH ratio (≥2 to <5) group (DFS: 3-way ITT Pvalue for interaction = .07; censored = .02; IPW = .03; OS ITT Pvalue for interaction = .007; censored = .04; IPW = .03). In cohort 2, consistent with cohort 1, a significant predictive effect of the ESR1 gene for both end points was also observed (DFS Pvalue for interaction = .06; OS = .02), indicating that breast cancers with higher ESR1 levels also derive less benefit from trastuzumab.

Conclusions And Relevance: Patients with HER2-positive breast cancers that are ER-positive by IHC analyses with low FISH ratio (≥2 to <5), or with higher ESR1 levels derive significantly less benefit from adjuvant trastuzumab after chemotherapy. These data may explain heterogeneity in response to anti-HER2 agents in HER2-positive, ER-positive breast cancers as some may be more luminal-like than HER2 driven.

Trial Registration: clinicaltrials.gov Identifier: NCT00045032.
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http://dx.doi.org/10.1001/jamaoncol.2016.0339DOI Listing
August 2016

Breast cancer in 2015: Academic research sheds light on issues that matter to patients.

Nat Rev Clin Oncol 2016 Feb 20;13(2):67-8. Epub 2016 Jan 20.

Department of Hematology and Oncology, Hôpital du Sacré-Cœur de Montréal/Université de Montréal, 5400 Boulevard Gouin, Montreal, Quebec H4J 1C5, Canada.

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http://dx.doi.org/10.1038/nrclinonc.2015.236DOI Listing
February 2016

Iterative and prolonged remission in metastatic breast cancer using pegylated irinotecan: a case report.

J Med Case Rep 2015 Feb 12;9. Epub 2015 Feb 12.

Department of Medical Oncology, Jules Bordet Institute, Université Libre de Bruxelles, Boulevard de Waterloo 125, B-1000, Brussels, Belgium.

Introduction: Pegylated irinotecan NKTR-102 is a topoisomerase I inhibitor-polymer conjugate. This new formulation of irinotecan has been evaluated in a phase II clinical trial and is showing remarkable activity. To the best of our knowledge, this is the first case report of an impressive iterative response to pegylated irinotecan NKTR-102 in metastatic breast cancer.

Case Presentation: We report the case of a 49-year-old Caucasian woman diagnosed with metastatic luminal A breast cancer with initial bone followed by liver and bone marrow metastases, treated with three lines of hormonal therapy, targeted therapy and six lines of chemotherapy. She showed no major response to conventional treatment, whereas, the tumor shrinkage under pegylated irinotecan NKTR-102 was impressive, durable and iterative.

Conclusions: Reintroduction of an active drug is a valid approach as illustrated by our case. The results of the current phase III trials of pegylated irinotecan NKTR-102 are eagerly awaited.
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http://dx.doi.org/10.1186/1752-1947-9-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429498PMC
February 2015

Words matter: distinguishing "personalized medicine" and "biologically personalized therapeutics".

J Natl Cancer Inst 2014 Dec 7;106(12). Epub 2014 Oct 7.

Cancer Pain and Palliative Medicine Service, Department of Medical Oncology, Shaare Zedek Medical Center, Jerusalem, Israel (NIC); Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (EGEdV); Kellog School of Management and Northwestern University Medical School, Chicago, IL (LE); Sussex Health Outcomes Research & Education in Cancer (SHORE-C),Brighton & Sussex Medical School, University of Sussex, Falmer, UK (LF); Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia (PAF); Department of Oncology, Shaare Zedek Medical Center, and Hebrew University-School of Medicine, Jerusalem, Israel (AG); Université Libre de Bruxelles, Jules Bordet Institute, Brussels, Belgium (MJP); Department of Otolaryngology and Oncology, Johns Hopkins University, Baltimore, MD (DS); Oncotest/Verify, Teva Pharmaceutical Industries, Petach Tikva, Israel (LS-G); Melabev Community Elders Care Research Department, Jerusalem, Israel (CT).

"Personalized medicine" has become a generic term referring to techniques that evaluate either the host or the disease to enhance the likelihood of beneficial patient outcomes from treatment interventions. There is, however, much more to personalization of care than just identifying the biotherapeutic strategy with the highest likelihood of benefit. In its new meaning, "personalized medicine" could overshadow the individually tailored, whole-person care that is at the bedrock of what people need and want when they are ill. Since names and definitional terms set the scope of the discourse, they have the power to define what personalized medicine includes or does not include, thus influencing the scope of the professional purview regarding the delivery of personalized care. Taxonomic accuracy is important in understanding the differences between therapeutic interventions that are distinguishable in their aims, indications, scope, benefits, and risks. In order to restore the due emphasis to the patient and his or her needs, we assert that it is necessary, albeit belated, to deconflate the contemporary term "personalized medicine" by taxonomizing this therapeutic strategy more accurately as "biologically personalized therapeutics" (BPT). The scope of truly personalized medicine and its relationship to biologically personalized therapeutics is described, emphasizing that the best of care must give due recognition and emphasis to both BPT and truly personalized medicine.
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http://dx.doi.org/10.1093/jnci/dju321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568994PMC
December 2014

Why your preferred targeted drugs may become unaffordable.

Cancer Res 2013 Oct 23;73(19):5849-51. Epub 2013 Sep 23.

Author's Affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

Trastuzumab, a monoclonal antibody directed at the HER2 receptor, is one of the most impressive targeted drugs developed in the last two decades. Indeed, when given in conjunction with chemotherapy, it improves the survival of women with HER2 positive breast cancer, both in advanced and in early disease. Its optimal duration, however, is poorly defined in both settings with a significant economic impact in the adjuvant setting where the drug is arbitrarily given for 1 year. This article reviews current attempts at shortening this treatment duration, emphasizing the likelihood of inconclusive results and, therefore, the need to investigate this important variable as part of the initial pivotal trials and with the support of public health systems. Failure to do so has major consequences on treatment affordability. Ongoing adjuvant trials of dual HER2 blockade, using trastuzumab in combination with a second anti-HER2 agent, and trials of the antibody-drug conjugate T-DM1 (trastuzumab-emtansine) have to all be designed with 12 months of targeted therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-1486DOI Listing
October 2013

Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer.

J Natl Cancer Inst 2013 Jul 5;105(13):960-7. Epub 2013 Jun 5.

Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

Background: Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset.

Methods: The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab. Seven hundred five of 1010 tumors had sufficient DNA for genotyping of 70 somatic hotspot mutations in 20 genes using mass spectrometry. Distant disease-free survival (DDFS), overall survival (OS), and interactions with trastuzumab were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided.

Results: Median follow-up was 62 months. Of 705 tumors, 687 were successfully genotyped. PIK3CA mutations (exons 1, 2, 4, 9, 13, 18, and 20) were present in 25.3% (174 of 687) and TP53 mutations in 10.2% (70 of 687). Few other mutations were found: three ERBB2 and single cases of KRAS, ALK, STK11/LKB1, and AKT2. PIK3CA mutations were associated with estrogen receptor positivity (P < .001) and the luminal-A phenotype (P = .04) but were not statistically significantly associated with prognosis (DDFS: hazard ratio [HR] = 0.88, 95% confidence [CI] = 0.58 to 1.34, P = .56; OS: HR = 0.603, 95% CI = .32 to 1.13, P = .11), although a statistically significant nonproportional prognostic effect was observed for DDFS (P = .002). PIK3CA mutations were not statistically significantly associated with trastuzumab benefit (P(interaction): DDFS P = .14; OS P = .24).

Conclusions: In this dataset, targeted genotyping revealed only two alterations at a frequency greater than 10%, with other mutations observed infrequently. PIK3CA mutations were associated with a better outcome, however this effect disappeared after 3 years. There were no statistically significant associations with trastuzumab benefit.
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http://dx.doi.org/10.1093/jnci/djt121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699437PMC
July 2013

Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.

J Clin Oncol 2013 Mar 22;31(7):860-7. Epub 2013 Jan 22.

Breast Cancer Translational Research Laboratory (BCTL) J.C. Heuson, Institut Jules Bordet, Blvd de Waterloo, 125, 1000 Brussels, Belgium.

Purpose: 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.

Patients And Methods: We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples 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.

Results: 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).

Conclusion: 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.
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http://dx.doi.org/10.1200/JCO.2011.41.0902DOI Listing
March 2013

PIK3CA genotype and a PIK3CA mutation-related gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer.

PLoS One 2013 2;8(1):e53292. Epub 2013 Jan 2.

Breast Cancer Translational Research Laboratory, Jules Bordet Institute, Brussels, Belgium.

The phosphatidylinositol 3' kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer support mTOR activation is a major means of estrogen-independent tumor growth. Hence the means to identify a responsive breast cancer population that would most benefit from these compounds in the adjuvant or earlier stage setting is of high interest. Here we study PIK3CA genotype as well as a previously reported PI3K/mTOR-pathway gene signature (PIK3CA-GS) and their ability to estimate the level of PI3K pathway activation in two clinical trials of newly diagnosed ER-positive breast cancer patients- a total of 81 patients- one of which was randomized between letrozole and placebo vs letrozole and everolimus. The main objectives were to correlate the baseline PIK3CA genotype and GS with the relative change from baseline to day 15 in Ki67 (which has been shown to be prognostic in breast cancer) and phosphorylated S6 (S240) immunohistochemistry (a substrate of mTOR). In the randomized dataset, the PIK3CA-GS could identify those patients with the largest relative decreases in Ki67 to letrozole/everolimus (R = -0.43, p = 0.008) compared with letrozole/placebo (R = 0.07, p = 0.58; interaction test p = 0.02). In a second dataset of pre-surgical everolimus alone, the PIK3CA-GS was not significantly correlated with relative change in Ki67 (R = -0.11, p = 0.37) but with relative change in phosphorlyated S6 (S240) (R = -0.46, p = 0.028). PIK3CA genotype was not significantly associated with any endpoint in either datasets. Our results suggest that the PIK3CA-GS has potential to identify those ER-positive BCs who may benefit from the addition of everolimus to letrozole. Further evaluation of the PIK3CA-GS as a predictive biomarker is warranted as it may facilitate better selection of responsive patient populations for mTOR inhibition in combination with letrozole.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053292PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534682PMC
August 2013

Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study.

J Clin Oncol 2013 Jan 19;31(1):73-9. Epub 2012 Nov 19.

Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

Purpose: We questioned the impact of pregnancy on disease-free survival (DFS) in women with history of breast cancer (BC) according to estrogen receptor (ER) status.

Patients And Methods: A multicenter, retrospective cohort study in which patients who became pregnant any time after BC were matched (1:3) to patients with BC with similar ER, nodal status, adjuvant therapy, age, and year of diagnosis. To adjust for guaranteed time bias, each nonpregnant patient had to have a disease-free interval at least equal to the time elapsing between BC diagnosis and date of conception of the matched pregnant one. The primary objective was DFS in patients with ER-positive BC. DFS in the ER-negative cohort, whole population, and overall survival (OS) were secondary objectives. Subgroup analyses included DFS according to pregnancy outcome and BC-pregnancy interval. With a two-sided α = 5% and β = 20%, 645 ER-positive patients were required to detect a hazard ratio (HR) = 0.65.

Results: A total of 333 pregnant patients and 874 matched nonpregnant patients were analyzed, of whom 686 patients had an ER-positive disease. No difference in DFS was observed between pregnant and nonpregnant patients in the ER-positive (HR = 0.91; 95% CI, 0.67 to 1.24, P = .55) or the ER-negative (HR = 0.75; 95% CI, 0.51 to 1.08, P = .12) cohorts. However, the pregnant group had better OS (HR = 0.72; 95% CI, 0.54 to 0.97, P = .03), with no interaction according to ER status (P = .11). Pregnancy outcome and BC-pregnancy interval did not seem to impact the risk of relapse.

Conclusion: Pregnancy after ER-positive BC does not seem to reduce the risk of BC recurrence.
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http://dx.doi.org/10.1200/JCO.2012.44.2285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530692PMC
January 2013

Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling.

Clin Cancer Res 2012 Mar 18;18(5):1341-51. Epub 2012 Jan 18.

Breast Cancer Translational Research Laboratory (BCTL) J.C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

Purpose: Breast cancer in young women is associated with poor prognosis. We aimed to define the role of gene expression signatures in predicting prognosis in young women and to understand biological differences according to age.

Experimental Design: Patients were assigned to molecular subtypes [estrogen receptor (ER)(+)/HER2(-); HER2(+), ER(-)/HER2(-))] using a three-gene classifier. We evaluated whether previously published proliferation, stroma, and immune-related gene signatures added prognostic information to Adjuvant! online and tested their interaction with age in a Cox model for relapse-free survival (RFS). Furthermore, we evaluated the association between candidate age-related genes or gene sets with age in an adjusted linear regression model.

Results: A total of 3,522 patients (20 data sets) were eligible. Patients aged 40 years or less had a higher proportion of ER(-)/HER2(-) tumors (P < 0.0001) and were associated with poorer RFS after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR = 1.34, 95% CI = 1.10-1.63, P = 0.004). The proliferation gene signatures showed no significant interaction with age in ER(+)/HER2(-) tumors after adjustment for Adjuvant! online. Further analyses suggested that breast cancer in the young is enriched with processes related to immature mammary epithelial cells (luminal progenitors, mammary stem, c-kit, RANKL) and growth factor signaling in two independent cohorts (n = 1,188 and 2,334).

Conclusions: Proliferation-related prognostic gene signatures can aid treatment decision-making for young women. However, breast cancer arising at a young age seems to be biologically distinct beyond subtype distribution. Separate therapeutic approaches such as targeting RANKL or mammary stem cells could therefore be needed.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-2599DOI Listing
March 2012

A dickens tale of the treatment of advanced breast cancer: the past, the present, and the future.

Am Soc Clin Oncol Educ Book 2012 :28-38

From the Indiana University Simon Cancer Center, Indianapolis, IN; Breast Unit, Champalimaud Cancer Center, Lisbon, Portugal; Dana-Farber Cancer Institute, Boston, MA; Institut Jules Bordet, Université Libre de Bruxelles, Belgium.

Metastatic breast cancer (MBC), a usually incurable disease, continues to vex physicians and patients. Recent decades have seen great improvements in the treatment of MBC, based on the availability of novel targeted therapeutics and more standard chemotherapeutic agents. This article describes the goals of therapy for MBC, the progress made against MBC in recent decades, the current standard of care, and the ongoing efforts of basic and translational researchers to transfer the fruits of modern scientific discovery to patients in the clinic.
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http://dx.doi.org/10.14694/EdBook_AM.2012.32.306DOI Listing
April 2016

Low residual proliferation after short-term letrozole therapy is an early predictive marker of response in high proliferative ER-positive breast cancer.

Endocr Relat Cancer 2011 Dec 14;18(6):721-30. Epub 2011 Nov 14.

Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital, University of Toronto, Ontario, Canada.

The gene expression grade index (GGI) is a 97-gene algorithm that measures proliferation and divides intermediate histological grade tumors into two distinct groups. We investigated the association between early changes in GGI and clinical response to neoadjuvant letrozole and compared this to Ki67 values. The paired gene expression data at the beginning and after 10-14 days of neoadjuvant letrozole treatment were available for 52 post-menopausal patients with estrogen receptor (ER)-positive breast cancer. Baseline values and changes in GGI, Ki67, and RNA expression modules representing oncogenic signaling pathways were compared to sonographic tumor volume changes after 3 months of treatment in the subsets of patients defined by high and low baseline GGI. The clinical response was observed in 80% genomic low-grade (24/30) and 59% genomic high-grade (13/22) tumors (P=0.10). Low residual proliferation after 10-14 days of neoadjuvant letrozole therapy, measured by either GGI or Ki67, was associated with sonographic response in genomic high-grade (GGI, P=0.003; Ki67, P=0.017) but not genomic low-grade (GGI, P=0.25; Ki67, P=1.0) tumors. The analysis of expression modules suggested that sonographic response to letrozole in genomic high-grade tumors was associated with an early reduction in IGF1 signaling (unadjusted P=0.018). The major conclusion of this study is that the early assessment of proliferation after short-term endocrine therapy may be useful to evaluate endocrine responsiveness, particularly in genomic high-grade ER-positive breast cancer.
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http://dx.doi.org/10.1530/ERC-11-0180DOI Listing
December 2011

HER2-overexpressing breast cancer: time for the cure with less chemotherapy?

Curr Opin Oncol 2011 Nov;23(6):547-58

Breast Cancer Translational Research Laboratory, Institut Jules Bordet, L'Université Libre de Bruxelles, Brussels, Belgium.

Purpose Of Review: There have been recent new developments in the treatment of breast cancer that over-expresses HER2 (ERRB2/HER2 positive) and the mechanistic understanding of trastuzumab response. We review these findings and reflect on how they may influence the next generation of clinical trials in this breast cancer subtype.

Recent Findings: Two recent trials in the neoadjuvant setting report that treatment with dual anti-HER2 agents was superior, in terms of rates of pathological complete response, to trastuzumab alone. Recent data also highlight that HER2 positive disease is biologically different according to estrogen receptor status and for long lasting clinical remissions, anti-HER2 therapy also seems to require an effective adaptive immune response.

Summary: We are currently in a very exciting era for therapeutic approaches in HER2 positive disease. Recent data suggest that intensive chemotherapy regimens may not be required for some women if we can determine the most potent combinations of signal inhibitors. We also propose that different clinical trials may need to be designed for HER2 positive breast cancer according to estrogen receptor status and consider incorporating immunotherapeutic approaches.
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http://dx.doi.org/10.1097/CCO.0b013e32834bd4c9DOI Listing
November 2011

HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data.

Lancet Oncol 2011 Nov 12;12(12):1134-42. Epub 2011 Sep 12.

Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.

Background: Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer.

Methods: We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts (HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours).

Findings: We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A. For EFS, HRs were 0·89 (95% CI 0·79-1·01) for HER2 non-amplified patients and 0·71 (0·58-0·86) for HER2-amplified patients (p(interaction)=0·0485); for overall survival, HRs were 0·91 (95% CI 0·79-1·05) for HER2 non-amplified patients and 0·73 (0·59-0·89) for HER2-amplified patients (p(interaction)=0·0718). In analysis of TOP2A status, HRs for EFS were 0·88 (0·78-1·00) for normal, 0·63 (0·46-0·87) for deleted, and 0·62 (0·43-0·90) for amplified (p(interaction)=0·0513); HRs for overall survival were 0·89 (0·78-1·03) for normal, 0·68 (0·49-0·95) for deleted, and 0·67 (0·46-0·98) for amplified (p(interaction)=0·1608). When patients with TOP2A-deleted and TOP2A-amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0·64 (0·50-0·81) for altered and 0·88 (0·78-1·00) for normal (p(interaction)=0·0183); HRs for overall survival were 0·67 (0·52-0·86) for altered and 0·89 (0·78-1·03) for normal (p(interaction)=0·0455).

Interpretation: Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumours.

Funding: Associazione Italiana Ricerca Cancro, Academy of Finland, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Scottish Breast Cancer Trials Group, NCIC Clinical Trials Group, Canadian Cancer Society Research Institute, Danish Council for Strategic Research, Pharmacia-Upjohn (now Pfizer), and Abbott Laboratories.
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http://dx.doi.org/10.1016/S1470-2045(11)70231-5DOI Listing
November 2011

Neoadjuvant anthracycline and trastuzumab for breast cancer: is concurrent treatment safe?

Lancet Oncol 2011 Mar 25;12(3):209-11. Epub 2011 Feb 25.

Department of Medical Oncology, Institut Jules Bordet, Universite Libre de Bruxelles, 1000 Brussels, Belgium.

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http://dx.doi.org/10.1016/S1470-2045(11)70013-4DOI Listing
March 2011

Motherhood after breast cancer: searching for la dolce vita.

Expert Rev Anticancer Ther 2011 Feb;11(2):287-98

Department of Medical Oncology, Jules Bordet Institute, Boulevard de Waterloo 121, 1000 Brussels, Belgium.

Advances in the field of adjuvant therapy in breast cancer have led to significant improvements in breast cancer survival. This has resulted in a progressive decline in breast cancer-related mortality, such that in 2010 there were estimated to be 400,000 breast cancer survivors under the age of 40 in the USA. Hence, enquiry into the feasibility of fertility preservation, subsequent pregnancy and breastfeeding is increasingly encountered. Fertility counseling remains suboptimal in breast cancer clinics, and there is a wide perception that pregnancy could worsen the prognosis of young breast cancer survivors, despite the lack of evidence supporting this notion. In addition, fertility preservation by means of embryo or oocyte cryopreservation requires ovarian stimulation, which is associated with a significant rise in estradiol levels and might delay initiation of therapy. All these factors, and others, have influenced the quality of fertility counseling offered to young breast cancer patients. In this article, we will critically analyze the available clinical and biological evidence on the safety and feasibility of pregnancy and breastfeeding following breast cancer. In addition, we will discuss the different fertility-preservation techniques available for these patients.
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http://dx.doi.org/10.1586/era.10.208DOI Listing
February 2011