Publications by authors named "Marc Spielmann"

42 Publications

UCBG 2-08: 5-year efficacy results from the UNICANCER-PACS08 randomised phase III trial of adjuvant treatment with FEC100 and then either docetaxel or ixabepilone in patients with early-stage, poor prognosis breast cancer.

Eur J Cancer 2018 11 26;103:184-194. Epub 2018 Sep 26.

Institut Claudius Regaud, IUCT Oncopole, Toulouse, France.

Purpose: UNICANCER-PACS08 compared adjuvant FEC (5-FU; epirubicin; cyclophosphamide) then docetaxel to FEC then ixabepilone in poor prognosis early breast cancer (BC). We evaluated whether replacing docetaxel with ixabepilone would increase 5-year disease-free survival (DFS).

Patients And Methods: Triple-negative breast cancer (TNBC) or oestrogen receptor (ER)+/progesterone receptor (PR)-/HER2- BC patients were randomised to receive standard FEC (3 cycles) followed by 3 cycles of either docetaxel (100 mg/m) or ixabepilone (40 mg/m). Radiotherapy was mandatory after conservative surgery; ER+ patients received endocrine therapy.

Results: Seven hundred sixty-two patients were enrolled between October 2007 and September 2010. Baseline characteristics were balanced between arms. Median follow-up was 66.7 months. Median DFS was not reached; 5-year DFS rate was 76% with docetaxel and 79% with ixabepilone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.58-1.10; p = 0.175). Median overall survival (OS) was not reached; 5-year OS rate was 86% versus 84% (HR = 0.97; 95% CI = 0.66-1.42; p = 0.897). TNBC patients treated with ixabepilone had a 23% lower risk of relapse compared to docetaxel (HR for DFS = 0.77; 95% CI = 0.53-1.11; p = 0.168). DFS was longer with ixabepilone than docetaxel in patients with grade II-III lymphocytic infiltration (HR = 0.55; 95% CI = 0.29-1.05; p = 0.063). All patients experienced ≥1 adverse events (AEs): 75% reported grade III-IV AEs and two (<1%) had grade V AEs (both with neutropenia and infection receiving ixabepilone).

Conclusion: After adjuvant FEC, ixabepilone was comparable to docetaxel for treating poor prognosis early BC patients. The benefit of ixabepilone in subgroups (patients with TNBC and grade II-III lymphocytic infiltration) requires further evaluation.
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http://dx.doi.org/10.1016/j.ejca.2018.06.025DOI Listing
November 2018

Individualized Prediction of Menses Recovery After Chemotherapy for Early-stage Breast Cancer: A Nomogram Developed From UNICANCER PACS04 and PACS05 Trials.

Clin Breast Cancer 2019 02 23;19(1):63-70. Epub 2018 Aug 23.

Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.

Background: The likelihood of menses recovery varies greatly in premenopausal patients receiving adjuvant chemotherapy for breast cancer. Quantifying this probability for each patient could better inform the chemotherapy discussion and individualize fertility counseling. We performed a pooled analysis of the PACS04 and PACS05 adjuvant randomized trials to develop a nomogram to estimate the probability of menses recovery at 3, 6, and 18 months after the end of adjuvant chemotherapy.

Patients And Methods: Women who were premenopausal and aged ≤ 50 years at randomization in the PACS04 and PACS05 trials were included in the present analysis. The primary endpoint was the probability of menses recovery within 18 months of chemotherapy completion. Multivariable Cox proportional hazards regression was used to estimate the association of each variable with the likelihood of menses resumption. A nomogram was developed to predict menses recovery at different intervals.

Results: The factors associated with menses recovery were assessed for 1210 patients. At a median follow-up of 90 months (range, 3-189 months), 342 of 1210 patients (28.2%) had recovered menses. The probability of menses recovery at 18 months was 25.5% (range, 23.0%-27.9%). After backward elimination, age, final body mass index, type of chemotherapy, and hormone therapy were selected to build the nomogram to predict the probability of menstrual resumption at 3, 6, and 18 months after chemotherapy.

Conclusion: An accurate and individualized prediction of menses recovery is feasible for premenopausal patients eligible for adjuvant chemotherapy for early-stage breast cancer. Our nomogram will be externally validated in a large prospective cohort.
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http://dx.doi.org/10.1016/j.clbc.2018.08.005DOI Listing
February 2019

Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations.

Eur J Hum Genet 2018 12 8;26(12):1732-1742. Epub 2018 Aug 8.

Université de Montpellier, Montpellier, France.

In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients' representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the "actionability" of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.
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http://dx.doi.org/10.1038/s41431-018-0224-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244405PMC
December 2018

[Perception of pT1a,b pN0 breast tumor prognosis by the French oncology community: Results of the EURISTIC national survey].

Bull Cancer 2016 Feb 2;103(2):154-63. Epub 2015 Dec 2.

Institut Curie, department of pathology, 26, rue d'Ulm, 75248 Paris cedex 05, France.

The prognosis of infracentimetric breast cancers (BC) is heterogeneous. The EURISTIC survey describes how French oncology specialists perceive the prognosis of pT1a,b pN0 BCs. A self-administered questionnaire has been sent to over 2000 French BC specialists. Six hundred and sixty-three physicians responded. Fifty-eight percent do not consider tumor size as a key prognostic criterion. They consider that the cutoff for poor prognosis is 22mm, 10mm and 7mm for hormone receptors (HRs)+, HER2+ and triple-negative (TN) tumors respectively. Eighty-three percent of respondents consider that a HR+ pT1a,b tumor has a good prognosis (21% and 8% for HER2+ and TN respectively). Factors perceived as most detrimental are: HER2 overexpression (29% of respondents); HR- (20%); high grade (20%); TN status (14%); high KI67 (5%); presence of lymphovascular invasion (3%); young age (2%) and high mitotic index (1%). For French specialists, immunohistochemical characteristics, in particular hormone and HER2 status, are strong prognostic factors in BCs below 1cm.
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http://dx.doi.org/10.1016/j.bulcan.2015.10.007DOI Listing
February 2016

Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer.

Autophagy 2015 ;11(10):1878-90

f Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus ; Villejuif , France.

In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.
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http://dx.doi.org/10.1080/15548627.2015.1082022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824597PMC
September 2016

Coexpression of androgen receptor and FOXA1 in nonmetastatic triple-negative breast cancer: ancillary study from PACS08 trial.

Future Oncol 2015 ;11(16):2283-97

Department of Pathology, Institut Claudius Régaud, 20/24 rue du Pont Saint Pierre, 31300 Toulouse, France.

Aim: Microarray studies identified a subgroup of molecular apocrine tumors (estrogen receptor [ER] negative/androgen receptor [AR] positive) that express luminal genes including FOXA1. FOXA1 may direct AR to sites normally occupied by ER in luminal tumors, inducing an estrogen-like gene program that stimulated proliferation.

Materials & Methods: Expression of AR and FOXA1 was evaluated by immunohistochemistry in 592 patients with nonmetastatic triple-negative breast cancer (TNBC).

Results: Coexpression of AR and FOXA1 was found in 15.2% of patients. These tumors were more frequently lobular, found in older patients and exhibited a lower nuclear grade and a greater degree of node involvement. They less often exhibited lymphocytic infiltrate, pushing margins, syncytial architecture, central fibrosis or necrosis.

Conclusion: TNBC with coexpression of AR and FOXA1 seems to behave like luminal tumors with a morphological profile distinct from other TNBC. These biomarkers could be useful to identify a subgroup of TNBC and could have future therapeutic implications.
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http://dx.doi.org/10.2217/fon.15.102DOI Listing
May 2016

Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer and Tumors ≤ 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials.

J Clin Oncol 2015 Aug 22;33(24):2600-8. Epub 2015 Jun 22.

Ciara C. O'Sullivan and Jo Anne Zujewski, National Cancer Institute, Bethesda, MD; Ian Bradbury, Christine Campbell, and Eileen Holmes, Frontier Science, Inverness-shire, Scotland; Marc Spielmann and Suzette Delaloge, Institut de Cancérologie Gustave Roussy, Villejuif, France; Edith A. Perez, Mayo Clinic, Jacksonville, FL; Heikki Joensuu, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Joseph P. Costantino and Priya Rastogi, University of Pittsburgh, Pittsburgh, PA; Dimitrios Zardavas, Breast International Group; Karla V. Ballman, Mayo Clinic, Rochester, MN; Evandro de Azambuja and Martine Piccart-Gebhart, Institut Jules Bordet and L'Université Libre de Bruxelles, Brussels, Belgium; and Richard D. Gelber, Harvard Medical School, Harvard T.H. Chan School of Public Health, Dana-Farber Cancer Institute, and Frontier Science and Technology Research Foundation, Boston, MA.

Purpose: We compared efficacy of trastuzumab versus no trastuzumab in patients with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) -positive breast cancer treated in randomized trials.

Methods: A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) -positive and HR-negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status.

Results: Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with zero or one positive lymph nodes, results were 12.7% versus 19.4% (P = .005) for DFS and 5.3% versus 7.4% (P = .12) for OS, respectively. For 1,957 patients with HR-negative disease, 8-year cumulative incidence rates were 24.0% versus 33.4% (P < .001) for DFS and 12.4% versus 21.2% (P < .001) for OS, respectively; for 1,040 HR-negative patients with zero or one positive lymph nodes, results were 20.4% versus 26.3% (P = .05) for DFS and 8.2% versus 12.2% (P = .084) for OS, respectively.

Conclusion: Women with HER2-positive tumors ≤ 2 cm in the randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastuzumab. Trastuzumab-treated patients with HR-positive disease and ≤ one positive lymph node may be candidates for trials assessing less aggressive treatment approaches.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534523PMC
http://dx.doi.org/10.1200/JCO.2015.60.8620DOI Listing
August 2015

Relations between arthralgia and fear of recurrence: results of a cross-sectional study of breast cancer patients treated with adjuvant aromatase inhibitors therapy.

Support Care Cancer 2015 Dec 17;23(12):3581-8. Epub 2015 Apr 17.

Psycho-Oncology Unit, Institut Gustave Roussy, Villejuif, France.

Purpose: The aim of this study was to explore associations between arthralgia and fear of recurrence in breast cancer patients treated by aromatase inhibitors (AI).

Method: We sent a set of questionnaires to 100 patients examining their pain characteristics, anxiety (STAI), depression (BDI-SF), quality of life (SF-36), fear of recurrence (FCRI), and representations of AI treatment (ad hoc questionnaire). Nonparametric tests were used to investigate between-group comparisons (arthralgia vs. nonarthralgia) in these domains as well as the associations between arthralgia and fear of recurrence.

Results: Of the 77 patients who returned the questionnaires (response rate = 77%), 60 (78%) reported arthralgia. The mean score of fear of recurrence exceeded the pathological threshold in the arthralgia group and was significantly higher than that in the nonarthralgia group (14.8 vs. 10.7, p < 0.01). Significant associations were observed between fear of recurrence and pain intensity (r = 0.274, p < 0.05) and pain relief (r = -0.409, p < 0.05). More than 80% of the total sample declared that they were well informed about the aim of AI, their side effects, and the risk of developing arthralgia. Fear of recurrence did not appear to be associated with representations of AI.

Conclusion: The study revealed a close relationship between pain intensity and fear of recurrence. In particular, it showed that effective pain management was accompanied by a reduced fear of recurrence. Information, although essential, appeared insufficient to overcome patients' concerns about pain. Therefore, the implement of a systematic screening for arthralgia and the improvement of analgesic treatment are essential issues. New strategies for pharmacological and nonpharmacological treatment must be developed.
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http://dx.doi.org/10.1007/s00520-015-2722-9DOI Listing
December 2015

Effect of obesity on disease-free and overall survival in node-positive breast cancer patients in a large French population: a pooled analysis of two randomised trials.

Eur J Cancer 2014 Feb 4;50(3):506-16. Epub 2013 Dec 4.

Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France; Institut National de la Santé et de la Recherche Médicale (INSERM), CRI-866 Faculty of Medicine, Dijon, France; University of Burgundy, Dijon, France. Electronic address:

Background: To examine the association between baseline body mass index (BMI), and disease-free survival (DFS) and overall survival (OS) in a large French early-stage breast cancer population included in the UNICANCER Programme d'Action Concerté Sein-01 (PACS01) and PACS04 phase III randomised trials.

Methods: After a median follow-up of 5.9years, this report analyses 4996 patients with node-positive breast cancer, and randomly assigned to adjuvant anthracycline-based chemotherapy combined or not with taxanes. Univariate analyses were used to study the effects of well known prognostic factors and BMI on DFS and OS. BMI was obtained at baseline, before chemotherapy initiation, and obesity was defined as a BMI⩾30kg/m(2). Cox proportional hazards regression models were secondly used to assess the influence of BMI after adjusting for other factors. Exhaustive analysis of the dose intensity delivered was also studied for comparison between obese and non-obese patients.

Results: Obese patients initially present with more advanced disease at diagnosis compared to non-obese patients. By univariate analysis, obesity was moderately associated with poorer DFS (hazard ratio (HR)=1.18 [1.01-1.39] P=0.04), but mostly with poorer OS (HR=1.38 [1.13-1.69] P=0.002). Delivered dose intensity of anthracyclines and taxanes was not significantly different between obese and non-obese patients. After adjustment for disease characteristics, BMI had no influence either on DFS or OS.

Conclusion: This report suggests that in a French population, obesity has no impact on breast cancer prognosis when modern adjuvant chemotherapy, at the appropriate dose intensity, is delivered.
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http://dx.doi.org/10.1016/j.ejca.2013.11.013DOI Listing
February 2014

Prognostic factors of young women (≤ 35 years) with node positive breast cancer: possible influence on post-therapeutic follow-up.

Bull Cancer 2013 Jul-Aug;100(7-8):22-9

Institut Claudius-Regaud, 20-24 rue du Pont-Saint-Pierre, 31052 Toulouse, France.

Purpose: Although young age at diagnosis is an independent prognostic factor of poor survival; no specific recommendation are provided concerning the timing and modalities of follow-up for this population. These patients are followed similarly to older women during post-therapeutic surveillance. The objective of this study is to examine patterns of recurrence in a large series of positive lymph node breast cancer women aged 35 years or below and treated within adjuvant chemotherapy trials.

Methods: Data of 200 patients (≤ 35 years) included in three UNICANCER adjuvant trials for node positive breast cancer were used. Competing risks methodology was used to identify prognostic factors associated with time to first failure according to type of event.

Results: After a median follow-up of 52.4 months, 84 pts had disease related events (17 loco-regional, five contralateral, and 62 distant metastasis). Variables associated with an increased rate of first event were the number of involved lymph nodes and the type of surgery. In univariate analysis, prognostic factors associated with high potential curative recurrence were number of positive lymph nodes and vascular invasion. Only number of positive lymph node remained significant in multivariate analysis. Concerning distant metastasis, only the number of lymph node involved was associated to an increased risk of metastasis.

Conclusion: Using the number of positive nodes as important prognostic factors, it should be possible to identify patients at a higher risk of locoregional relapse or contralateral breast cancer, in order to propose more individualized follow-up.
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http://dx.doi.org/10.1684/bdc.2013.1791DOI Listing
September 2013

Correlation of HER2, FCGR2A, and FCGR3A gene polymorphisms with trastuzumab related cardiac toxicity and efficacy in a subgroup of patients from UNICANCER-PACS 04 trial.

Breast Cancer Res Treat 2013 Jun 19;139(3):789-800. Epub 2013 Jun 19.

ICM, Montpellier, France.

The purpose of this study was to investigate, in the context of a prospective node-positive-breast cancer trial HER2 containing-regimen (UNICANCER-PACS 04 trial), the predictive value of HER2, FCGRIIA, and FCGRIIIA gene polymorphisms for cardiac toxicity and efficacy of trastuzumab. We analyzed HER2-I655V, FCGR2A-H131R, and FCGR3A-V158F single nucleotide polymorphisms in patients in adjuvant setting treated by six courses of either fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2) and cyclophosphamide 500 mg/m(2), or epirubicin 75 mg/m(2) and docetaxel 75 mg/m(2) every 3 weeks then randomly assigned, in case of HER2 overexpressing tumor, to either trastuzumab for 1 year or nothing. Left ventricular ejection fraction and clinical examination were monitored in each patient, seven times throughout the study to detect congestive heart failure or asymptomatic subclinical cardiac toxicity. All genotypes were analyzed in relation to cardiac toxicity, EFS, and OS. One hundred and thirty-two HER2-positive breast cancer patients were analyzed. The HER2-I655V genotype was significantly associated with cardiac toxicity (p = 0.025). The FCGR2A-131 H/H genotype was significantly correlated with a shorter EFS (p = 0.027). The FCGR3A-158 V/V genotype was not correlated with EFS nor OS. These results might be useful in making a treatment choice of HER2 blockers in adjuvant setting by with an increase in efficacy and decrease in toxicity.
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http://dx.doi.org/10.1007/s10549-013-2587-xDOI Listing
June 2013

Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel versus carboplatin/docetaxel in initial treatment of metastatic Her-2-negative breast cancer.

Breast Cancer (Dove Med Press) 2013 17;5:37-42. Epub 2013 Jun 17.

Department of Clinical Oncology, Monufia University, Monufia, Egypt.

Purpose: In view of the previous reports demonstrating the positive outcome of bevacizumab in metastatic breast cancer, we aimed at comparing the role of bevacizumab-based metronomic combination with taxane (paclitaxel) versus a different taxane (docetaxel)-based regimen in addition to carboplatin as initial treatment for metastatic Her-2-negative breast cancer.

Patients And Methods: This is a randomized Phase III study comparing the progression-free survival (PFS) and safety in Her-2-negative female patients with initial diagnosis of metastatic breast cancer with World Health Organization performance status of 0-II. Forty-one patients were randomized from September 2008 to July 2009 to receive either; (1) bevacizumab 5 mg/kg day 1 and day 15, carboplatin area under the curve (AUC)-2 day 1, day 8, and day 15, and paclitaxel 60 mg/m(2) day 1, day 8, and day 15 (arm-I); or (2) carboplatin AUC-5 day 1, docetaxel 75 mg/m(2) day 1 (arm-II). The Kaplan-Meier method was used for estimating survival; log-rank test for comparing survival curves. The primary end point was PFS, and secondary end points were overall survival (OS) and safety.

Results: PFS was 10 months in arm I versus 10.2 months in arm II (P = 0.9). The OS rate was similar in both arms: 37.6 months for arm I versus 37.4 months for arm II (P = 0.92). The toxicity revealed higher incidence of hypertension and proteinuria in arm I; however, with higher incidence of grade III-IV neutropenia and neutropenic fever in arm II. No treatment-related mortality was recorded.

Conclusion: Bevacizumab/carboplatin/paclitaxel and carboplatin/docetaxel show comparable PFS and OS with different toxicity profiles.
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http://dx.doi.org/10.2147/BCTT.S44728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929329PMC
March 2014

Failure event types and prognostic factors after node-positive breast cancer in patients treated by adjuvant chemotherapy: impact on follow-up.

Bull Cancer 2012 Jun;99(6):E64-74

Institut Claudius-Regaud, 20-24, rue du Pont-Saint-Pierre, 31052 Toulouse, France.

Purpose: The role of post-therapeutic follow-up for breast cancer patients (pts) is open to debate. The aim of this study was to identify prognostic factors associated with the type of first event.

Methods: Data of 2,820 pts included in three adjuvant trials for node-positive breast cancer were used. Competing risk methodology was used to identify prognostic factors associated with time to first failure according to type of event.

Results: After a median follow-up of 53 months, 732 pts had disease-related events (114 locoregional, 58 contralateral, and 560 distant metastasis). The prognostic factors associated with high locoregional recurrence were young age, number of positive lymph nodes and grade III. In multivariate analysis, the type of first event influenced post-relapse survival. Nottingham Prognostic Index identified three groups of pts at different risk of relapse.

Conclusion: Early relapse is rare in the first year after surgery and is associated with more aggressive disease. Using the Nottingham Prognostic Index, it is possible to identify pts at lower risks of relapse for whom it seems reasonable to limit the frequency of routine follow-up during the first years. For pts at higher risk of locoregional recurrence, regular follow-up should be maintained in order to detect potential curative events.
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http://dx.doi.org/10.1684/bdc.2012.1592DOI Listing
June 2012

Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial.

Oncologist 2012 18;17(7):900-9. Epub 2012 May 18.

Centre Georges-François Leclerc, Dijon, France.

Purpose: The initial report from the Programme Action Concertée Sein (PACS) PACS01 trial demonstrated a benefit at 5 years for disease-free survival (DFS) and overall survival (OS) rates with the sequential administration of docetaxel after FEC100 (fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2)) for patients with node-positive, operable breast cancer. We evaluate here the impact of this regimen at 8 years.

Patients And Methods: Between June 1997 and March 2000, a total of 1,999 patients (age <65) with localized, resectable, non-pretreated, unilateral breast cancer were randomly assigned to receive either standard FEC100 for 6 cycles or 3 cycles of FEC100 followed by 3 cycles of 100 mg/m(2) docetaxel (FEC-D), both given every 21 days. Radiotherapy was mandatory after conservative surgery and tamoxifen was given for 5 years to hormone receptor (HR)-positive patients. Five-year DFS was the trial's main endpoint. Updated 8-year survival data are presented.

Results: With a median follow-up of 92.8 months, 639 patients experienced at least one event. A total number of 383 deaths were registered. Eight-year DFS rates were 65.8% with FEC alone and 70.2% with FEC-D. OS rates at 8 years were 78% with FEC alone and 83.2% with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 15% reduction in the relative risk of relapse and a 25% reduction in the relative risk of death in favor of FEC-D. Significant relative risk reductions were observed in the HR-positive, HER2-positive, and Ki67 ≥20% subpopulations.

Conclusion: Benefits for DFS and OS rates with the sequential FEC-D regimen are fully confirmed at 8 years.
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http://dx.doi.org/10.1634/theoncologist.2011-0442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399644PMC
February 2013

Phase II trial of 3D-conformal accelerated partial breast irradiation: lessons learned from patients and physicians' evaluation.

Radiother Oncol 2012 May 20;103(2):193-8. Epub 2012 Apr 20.

Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France.

Introduction: The present study prospectively reported both physicians' and patients' assessment for toxicities, cosmetic assessment and patients' satisfaction after 3D-conformal accelerated partial breast irradiation (APBI).

Materials And Methods: From October 2007 to September 2009, 30 early breast cancer patients were enrolled in a 3D-conformal APBI Phase II trial (40 Gy/10 fractions/5 days). Treatment related toxicities and cosmetic results were assessed by both patients and physicians at each visit (at 1, 2, 6 months, and then every 6 months). Patient satisfaction was also scored.

Results: After a median follow-up of 27.7 months, all patients were satisfied with APBI treatment, regardless of cosmetic results or late adverse events. Good/excellent cosmetic results were noticed by 80% of patients versus 92% of cases by radiation oncologists. Breast pain was systematically underestimated by physicians (8-20% vs. 16.6-26.2%; Kappa coefficient KC=0.16-0.44). Grade 1 and 2 fibrosis and/or breast retraction occurred in 7-12% of patients and were overestimated by patients (KC=0.14-0.27).

Conclusions: Present results have shown discrepancies between patient and physician assessments. In addition to the assessment of efficacy and toxicity after 3D-conformal APBI, patients' cosmetic results consideration and satisfaction should be also evaluated.
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http://dx.doi.org/10.1016/j.radonc.2012.03.019DOI Listing
May 2012

Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review.

Breast Cancer Res Treat 2012 Apr 3;132(3):895-915. Epub 2011 Nov 3.

INSERM, Centre d'Investigations Cliniques-9501, CHU Nancy & Nancy-Université, 54511 Vandoeuvre-les-Nancy, France.

Clinicians can use biomarkers to guide therapeutic decisions in estrogen receptor positive (ER+) breast cancer. One such biomarker is cellular proliferation as evaluated by Ki-67. This biomarker has been extensively studied and is easily assayed by histopathologists but it is not currently accepted as a standard. This review focuses on its prognostic and predictive value, and on methodological considerations for its measurement and the cut-points used for treatment decision. Data describing study design, patients' characteristics, methods used and results were extracted from papers published between January 1990 and July 2010. In addition, the studies were assessed using the REMARK tool. Ki-67 is an independent prognostic factor for disease-free survival (HR 1.05-1.72) in multivariate analyses studies using samples from randomized clinical trials with secondary central analysis of the biomarker. The level of evidence (LOE) was judged to be I-B with the recently revised definition of Simon. However, standardization of the techniques and scoring methods are needed for the integration of this biomarker in everyday practice. Ki-67 was not found to be predictive for long-term follow-up after chemotherapy. Nevertheless, high KI-67 was found to be associated with immediate pathological complete response in the neoadjuvant setting, with an LOE of II-B. The REMARK score improved over time (with a range of 6-13/20 vs. 10-18/20, before and after 2005, respectively). KI-67 could be considered as a prognostic biomarker for therapeutic decision. It is assessed with a simple assay that could be standardized. However, international guidelines are needed for routine clinical use.
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http://dx.doi.org/10.1007/s10549-011-1837-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3332349PMC
April 2012

Diagnosis and management of anaemia and iron deficiency in patients with haematological malignancies or solid tumours in France in 2009-2010: the AnemOnHe study.

Eur J Cancer 2012 Jan 31;48(1):101-7. Epub 2011 Oct 31.

Medical Oncology Department, Institut Gustave Roussy, Villejuif, France.

Objective: To describe the management of anaemia in 2009-2010 in France in patients with haematological malignancies (HM) or solid tumours (ST).

Methods: Retrospective observational study in 57 centres, enrolling adult patients with HM or ST treated for an episode of anaemia (duration of the episode ≥ 3 months occurring in the last 12 months).

Results: 220 patients with ST (breast, 18%; lung, 18%) and 56 with HM (lymphoma, 60%) were included (median age, 68 years; female, 53%). Mean haemoglobin level at anaemia diagnosis was 9.3 ± 1.4 g/dL (<8 g/dL for 16%) and 9.8 ± 1.1g/dL (<8 g/dL for 6%) in HM and ST patients, respectively. At least one parameter of iron deficiency (ferritin, transferrin saturation) was assessed in 26% of HM and 19% of ST patients. Treatment of anaemia included erythropoiesis-stimulating agents (ESA) for 98% of HM and 89% of ST patients. Iron was prescribed to 14% (oral, 12%; intravenous, 2%) of HM patients and to 42% (oral, 17%; intravenous, 25%) of ST patients. The rates of blood transfusions were high: 70% in HM and 46% in ST patients; transfusions alone or administrated with ESA were more frequent in patients with Hb <8 g/dL.

Conclusion: Although recent guidelines recommend evaluating iron deficiency and correcting anaemia by using intravenous iron, our study in cancer patients evidenced that ESA and blood transfusions are still frequently used as the treatment of anaemia in cancer patients. Iron deficiency is insufficiently assessed (only one patient among five) and as a consequence iron deficiency is most likely insufficiently treated.
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http://dx.doi.org/10.1016/j.ejca.2011.09.011DOI Listing
January 2012

[Node negative breast cancer. Beyond international consensus: a pragmatic approach].

Bull Cancer 2011 Jul;98(7):807-25

Centre Jean-Perrin, service de pathologie, 58, rue Montalembert BP 392, 63011 Clermont-Ferrand, France.

Apart from therapeutic advances related to new treatments, our practices in the management of early breast cancer have been modified by to key organizational settings (1) mass screening, substantially altering the presentation and epidemiology of breast cancer and (2) the development of guidelines to ensure that any patient management is in agreement with the demonstrated impact in the adjuvant treatment. In daily practice, the impact of screening and guidelines recommendations has put us now in a paradoxical situation: while the majority of non-metastatic breast cancers treated in the hexagon are node negative, most of the results of clinical studies on chemotherapy and targeted therapies today arise from populations predominantly node positive. Therefore, it seemed legitimate to convene a working group around a reflection on the directions of adjuvant chemotherapy in a growing node negative population in order to better respond to the questions of the field oncologists, trying to address the discrepancies between different existing guidelines.
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http://dx.doi.org/10.1684/bdc.2011.1395DOI Listing
July 2011

Exclusive alternating chemotherapy and radiotherapy in nonmetastatic inflammatory breast cancer: 20 years of follow-up.

Int J Radiat Oncol Biol Phys 2012 Feb 27;82(2):690-5. Epub 2011 Jan 27.

Department of Radiation Oncology, Breast Unit, Institut Gustave Roussy, Villejuif, France.

Background: Locoregional treatment of inflammatory breast cancer (IBC) is crucial because local relapses may be highly symptomatic and are commonly associated with distant metastasis. With a median follow-up of 20 years, we report here the long-term results of a monocentric clinical trial combining primary chemotherapy (CT) with a schedule of anthracycline-based CT and an alternating split-course of radiotherapy (RT*CT) without mastectomy.

Methods And Materials: From September 1983 to December 1989, 124 women with nonmetastatic IBC (T4d M0) were treated with three cycles of primary AVCMF chemotherapy (anthracycline, vincristine, cyclophosphamide, methotrexate, and 5-fluorouracil) and then an alternating RT*CT schedule followed by three cycles of FAC. Hormonal therapy was systematically administered: ovarian irradiation (12 Gy in four fractions) or tamoxifen 20 mg daily.

Results: Local control was achieved in 82% of patients. The 10- and 20-year local relapse rates were 26% and 33%, respectively, but only 10% of locally controlled cases were not associated with concurrent distant metastasis. The 10- and 20-year overall survival rates were 39% and 19%, respectively. Severe fibrosis occurred in 54% of patients, grade 3 brachial plexus neuropathy in 4%, grade 2 pneumonitis in 9%. Grade 1, 2 and 3 cardiac toxicity was observed in 3.8%, 3.8% and 1.2% of cases respectively.

Conclusions: This combined regimen allowed good long-term local control without surgery. Survival rates were similar to those obtained with conventional regimens (primary chemotherapy, total mastectomy, and adjuvant radiotherapy). Since IBC continues to be an entity with a dismal prognosis, this approach, safely combining preoperative or postoperative radiation therapy and systemic treatments, should be reassessed when suitable targeted agents are available.
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http://dx.doi.org/10.1016/j.ijrobp.2010.11.040DOI Listing
February 2012

Feasibility of metronomic oral cyclophosphamide plus prednisolone in elderly patients with inoperable or metastatic soft tissue sarcoma.

Eur J Cancer 2011 Mar 19;47(4):515-9. Epub 2011 Jan 19.

Sarcoma Unit, Herault Ward, Department of Medicine, Institut Gustave Roussy, Université Paris 11, 39 Rue Camille Desmoulins, Villejuif, France.

Background: The number of elderly people with soft tissue sarcoma (STS) is increasing. A sizeable population of elderly patients with STS is unfit for conventional doxorubicin- or ifosfamide-based chemotherapy. We assessed the feasibility of metronomic oral cyclophosphamide (CPM) in this population.

Patients And Methods: Patients aged 65 years or older with unresectable STS received CPM 100mg twice daily plus prednisolone 20mg daily, the first week of a 2-week cycle in the outpatient setting. Main evaluation criterion was safety. Secondary evaluation criteria were objective response rate and progression-free survival.

Results: Twenty-six patients (median age: 72, range 66-88) received a total of 330 cycles (median per patient: 10, range 2-41) as first (n=19) or second-line chemotherapy (n=7). The most frequent histological subtypes were poorly differentiated sarcoma (n=8), leiomyosarcoma and liposarcoma (n = 5 each) and angiosarcoma (n=3). Grade ≥3 lymphopenia was observed in 81% of pts but no opportunist infection occurred. Grade 3 anaemia and thrombocytopenia occurred in 2 pts (8%) each. No other grade 3-4 toxicity was seen. The response rate was 26.9% (95%CI: 9.9-44.0) and the disease control rate (responses and stable disease >12 weeks) was 69.2% (95%CI: 51.5-87.0). One complete (hepatic epithelioid haemangio-endothelioma) and 6 partial responses (including 5pts with radiation-induced sarcomas) were seen. Progression-free survival ranged from 0 to 20.6 months (median: 6.8 months) and was significantly longer in patients with radiation-induced sarcomas (median: 7.8 versus 5.2 months, p=0.02).

Conclusion: Metronomic CPM showed good safety results for this frail population, with promising activity in patients with radiation-induced sarcoma. Toxicity profile was favourable, allowing prolonged home staying and rare treatment discontinuations. A larger prospective study is warranted to confirm these encouraging results in elderly with STS.
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http://dx.doi.org/10.1016/j.ejca.2010.11.025DOI Listing
March 2011

Efficacy of trastuzumab in routine clinical practice and after progression for metastatic breast cancer patients: the observational Hermine study.

Oncologist 2010 29;15(8):799-809. Epub 2010 Jul 29.

Institut Paoli-Calmettes, Oncologie Médicale, 232 Boulevard de St Marguerite, 13273 Marseille Cedex 9, France.

Background: The Hermine study observed the use of trastuzumab for metastatic breast cancer (MBC) in routine practice, including patients who received trastuzumab treatment beyond progression (TBP).

Patients And Methods: The study observed 623 patients for > or = 2 years. Treatment was given according to oncologists' normal clinical practices. Endpoints included duration of treatment, efficacy, and cardiac safety. The TBP subanalysis compared overall survival (OS) in 177 patients who received first-line trastuzumab and either continued trastuzumab for > or = 30 days following progression or stopped at or before progression.

Results: The median treatment duration was 13.3 months. In the first-, second-, and third-line or beyond treatment groups, the median time to progression (TTP) were 10.3 months, 9.0 months, and 6.3 months, and the median OS times were 30.3 months, 27.1 months, and 23.2 months, respectively. Heart failure was observed in 2.6% of patients, although no cardiac-associated deaths occurred. In the TBP subanalysis, the median OS duration from treatment initiation and time of disease progression were longer in patients who continued receiving trastuzumab TBP (>27.8 months and 21.3 months, respectively) than in those who stopped (16.8 months and 4.6 months, respectively). However, the groups were not completely comparable, because patients who continued trastuzumab TBP had better prognoses at treatment initiation. The median TTP was longer in patients who continued trastuzumab TBP (10.2 months) than in those who stopped (7.1 months).

Conclusion: The Hermine findings confirm that the pivotal trials of first-line trastuzumab treatment in MBC patients are applicable in clinical practice. The subanalysis suggests that trastuzumab TBP offers a survival benefit to MBC patients treated with first-line trastuzumab.
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http://dx.doi.org/10.1634/theoncologist.2009-0029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228018PMC
December 2010

A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients.

Breast Cancer Res Treat 2010 Jul 18;122(2):429-37. Epub 2010 May 18.

Institut Curie, 26 rue d'Ulm, 75005, Paris, France.

To assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m(2))-cyclophosphamide (750 mg/m(2)) for four cycles followed by docetaxel (100 mg/m(2)) for four cycles]. HER2-negative patients (N = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5-8 or no additional treatment, while HER2-positive patients confirmed by FISH (N = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier's classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming's design used in this trial.
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http://dx.doi.org/10.1007/s10549-010-0939-3DOI Listing
July 2010

3D-conformal accelerated partial breast irradiation treatment planning: the value of surgical clips in the delineation of the lumpectomy cavity.

Radiat Oncol 2009 Dec 31;4:70. Epub 2009 Dec 31.

Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France.

Background: Accurate localisation of the lumpectomy cavity (LC) volume is one of the most critical points in 3D-conformal Partial breast irradiation (3D-APBI) treatment planning because the irradiated volume is restricted to a small breast volume. Here, we studied the role of the placement of surgical clips at the 4 cardinal points of the lumpectomy cavity in target delineation.

Methods: Forty CT-based 3D-APBI plans were retrieved on which a total of 4 radiation oncologists, two trainee and two experienced physicians, outlined the lumpectomy cavity. The inter-observer variability of LC contouring was assessed when the CTV was defined as the delineation that encompassed both surgical clips and remodelled breast tissue.

Results: The conformity index of tumour bed delineation was significantly improved by the placement of surgical clips within the LC (median at 0.65). Furthermore, a better conformity index of LC was observed according to the experience of the physicians (median CI = 0.55 for trainee physicians vs 0.65 for experienced physicians).

Conclusions: The placement of surgical clips improved the accuracy of lumpectomy cavity delineation in 3D-APBI. However, a learning curve is needed to improve the conformity index of the lumpectomy cavity.
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http://dx.doi.org/10.1186/1748-717X-4-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808304PMC
December 2009

CXCR4 expression in early breast cancer and risk of distant recurrence.

Oncologist 2009 Dec 25;14(12):1182-8. Epub 2009 Nov 25.

Breast Medical Oncology Unit, Department of Radiation Therapy, Department of Pathology and Translational Research Unit (UPRES EA03535), Institut Gustave Roussy, University of Paris XI, Villejuif, France.

Background: Chemokine receptor 4 (CXCR4) has been demonstrated to have a critical role in the early metastatic process. The aim of this study was to evaluate the prognostic value of CXCR4 expression in primary breast tumors and describe correlations with the occurrence of metastasis in organs expressing the CXCR4 ligand stromal cell-derived factor 1 (i.e., liver, lung, brain, and bone).

Patients And Methods: CXCR4 expression in primary breast tumors was evaluated by immunohistochemistry in 823 patients included in two prospective clinical trials. CXCR4 expression was considered positive when >1% of tumor cells were stained. The prognostic value of CXCR4 expression was assessed by a Cox regression model adjusted for clinical characteristics. We assessed the association of CXCR4 expression with the rate of distant metastasis to specific organ sites.

Results: CXCR4 was expressed in 92 of 794 primary tumors (12%). CXCR4 expression was not associated with clinical characteristics. CXCR4 was not prognostic for overall survival and showed a nonsignificant trend toward a higher risk for distant metastasis. CXCR4(+) tumors showed a significantly higher risk for bone metastasis. The 10-year incidences of bone metastases were 23% (13.6%-32.6%) and 12% (9.7%-15%) in CXCR4(+) and CXCR4(-) tumors, respectively.

Conclusion: This study suggests that expression of CXCR4 in primary breast tumors is associated with a higher likelihood of developing bone metastases. This finding could open new avenues for the development of novel adjuvant strategies, including bone-targeting agents.
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http://dx.doi.org/10.1634/theoncologist.2009-0161DOI Listing
December 2009

Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial.

J Clin Oncol 2009 Dec 16;27(36):6129-34. Epub 2009 Nov 16.

Institut Gustave Roussy, Département de Médecine, 39, rue Camille Desmoulins, 94908 Villejuif, France.

Purpose: To evaluate the efficacy of trastuzumab in patients with node-positive breast cancer treated with surgery, adjuvant chemotherapy, radiotherapy, and hormone therapy if applicable.

Patients And Methods: Three thousand ten patients with operable node-positive breast cancer were randomly assigned to receive adjuvant anthracycline-based chemotherapy with or without docetaxel. Patients who presented human epidermal growth factor receptor 2 (HER2) -overexpressing tumors were secondary randomly assigned to either a sequential regimen of trastuzumab (6 mg/kg every 3 weeks) for 1 year or observation. The primary end point was disease-free survival (DFS).

Results: Overall 528 patients were randomly assigned between trastuzumab (n = 260) and observation (n = 268) arm. Of the 234 patients (90%) who received at least one administration of trastuzumab, 196 (84%) received at least 6 months of treatment, and 41 (18%) discontinued treatment due to cardiac events (any grade). At the date of analysis (October 2007), 129 DFS events were recorded. Random assignment to the trastuzumab arm was associated with a nonsignificant 14% reduction in the risk of relapse (hazard ratio, 0.86; 95% CI, 0.61 to 1.22; P = .41, log-rank stratified on pathologic node involvement). Three-year DFS rates were 78% (95% CI, 72.3 to 82.5) and 81% (95% CI, 75.3 to 85.4) in the observation and trastuzumab arms, respectively.

Conclusion: After a 47-month median follow-up, 1 year of trastuzumab given sequentially after adjuvant chemotherapy was not associated with a statistically significant decrease in the risk of relapse.
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http://dx.doi.org/10.1200/JCO.2009.23.0946DOI Listing
December 2009

Prognostic role of pregnancy occurring before or after treatment of early breast cancer patients aged <35 years: a GET(N)A Working Group analysis.

Cancer 2009 Nov;115(22):5155-65

Department of Medical Oncology, Centre Azuréen de Cancérologie, Mougins, France.

Background: Usual practices recommend waiting at least 2 years between diagnosis of early breast cancer (EBC) and pregnancy. Few data highlighted a harmful effect of an early pregnancy for low-risk patients. The authors analyzed retrospectively data from women younger than 35 years who became pregnant before or after treatment of EBC.

Methods: Between 1990 and 1999, 908 consecutive EBC patients were analyzed. The primary endpoint was to compare overall survival (OS) between pregnant and nonpregnant patients. The secondary endpoint was to establish a score index laying down the risk of distant recurrence.

Results: Within the year before the diagnosis, 105 (11.6%) patients became pregnant and 118 (13%) were pregnant after treatment. In a multivariate model, a pregnancy before the diagnosis was not predictive of death but of local relapse. A pregnancy subsequent to breast cancer therapy resulted in a 77% decrease of death (P < .001). In good-prognosis score index patients, the annual risk of relapse remained low. In patients having the higher score, recurrences occurred mainly during the first years after the treatment. Beyond 80 months, the annual risk of relapse seemed to be similar to those of lower-risk subgroups.

Conclusions: In women aged younger than 35 years, a pregnancy occurring before or after the diagnosis of breast cancer was not an independent prognostic factor of death. In the subset of patients having a high risk of relapse, it may be preferable to postpone a pregnancy beyond 5 years after the breast cancer therapy.
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http://dx.doi.org/10.1002/cncr.24608DOI Listing
November 2009

Exonic expression profiling of breast cancer and benign lesions: a retrospective analysis.

Lancet Oncol 2009 Apr 25;10(4):381-90. Epub 2009 Feb 25.

Breast Cancer Unit, Department of Medical Oncology, Institut Gustave Roussy France, Villejuif, France.

Background: Gene-expression arrays have generated molecular predictors of relapse and drug sensitivity in breast cancer. We aimed to identify exons differently expressed in malignant and benign breast lesions and to generate a molecular classifier for breast-cancer diagnosis.

Methods: 165 breast samples were obtained by fine-needle aspiration. Complementary DNA was hybridised on splice array. A nearest centroid prediction rule was developed to classify lesions as malignant or benign on a training set, and its performance was assessed on an independent validation set. A two-way ANOVA model identified probe sets with differential expression in malignant and benign lesions while adjusting for scan dates.

Findings: 120 breast cancers and 45 benign lesions were included in the study. A molecular classifier for breast-cancer diagnosis with 1228 probe sets was generated from the training set (n=94). This signature accurately classified all samples (100% accuracy, 95% CI 96-100%). In the validation set (n=71), the molecular predictor accurately classified 68 of 71 tumours (96%, 88-99%). When the 165 samples were taken into account, 37 858 exon probe sets (5.4%) and 3733 genes (7.0%) were differently expressed in malignant and benign lesions (threshold: adjusted p<0.05). Genes involved in spliceosome assembly were significantly overexpressed in malignant disease (permutation p=0.002). In the same population of 165 samples, 956 exon probe sets presented both higher intensity and higher splice index in breast cancer than in benign lesions, although located on unchanged genes.

Interpretation: Many exons are differently expressed by breast cancer and benign lesions, and alternative transcripts contribute to the molecular characteristics of breast malignancy. Development of molecular classifiers for breast-cancer diagnosis with fine-needle aspiration should be possible.
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http://dx.doi.org/10.1016/S1470-2045(09)70024-5DOI Listing
April 2009

Physiopathology and management of osteonecrosis of the jaws related to bisphosphonate therapy for malignant bone lesions. A French expert panel analysis.

Crit Rev Oncol Hematol 2009 Jul 12;71(1):12-21. Epub 2008 Dec 12.

Department of Medical Oncology, Centre René Huguenin, 35 rue Daily, 92210 Saint-Cloud, France.

Bisphosphonates (BP) are the current standard of care for preventing malignant skeletal related-events. Recent reports have documented the relationship between osteonecrosis of the jaws (ONJ) and the use of BPs. Based on the opinion of experts, the purpose of our analysis was to summarize current knowledge, to propose therapeutic options, and to define areas of research. Identified risk factors were long-lasting exposure to BPs, intravenous nitrogen-containing BPs, and poor dental status. Three major hypotheses could explain the genesis of ONJ: excess of bone turnover inhibition, antiangiogenic effect, and local infection. Before the onset of therapy, the dental status must be controlled, and followed during treatment. Dental procedures could worsen the risk of ONJ, and indications must be well evaluated. When an ONJ occurs, the management should be adapted according to its extent. Thereby, a customization of BP therapy should be applied taking into account the aggressiveness of the underlying disease.
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http://dx.doi.org/10.1016/j.critrevonc.2008.10.009DOI Listing
July 2009

[The use of deodorants/antiperspirants does not constitute a risk factor for breast cancer].

Bull Cancer 2008 Sep;95(9):871-80

Centre Antoine-Lacassagne, Nice, France.

Based on the observation of a high incidence of breast cancer in the upper outer quadrant adjacent to the usual area of application of deodorants and/or antiperspirants, several scientific teams have advanced the hypothesis of a possible link between antiperspirants and breast cancer. The possibility of the involvement of parabens and aluminium salts, traditional components of a number of cosmetic products, has been advanced by the same teams. In order to ascertain whether this hypothesis could or could not be confirmed, a group of clinical experts in oncology was set up to search and analyse the literature data relating to the problem raised with the aim of answering three predefined questions: 1) does it exist experimental or biological arguments supporting a potential link between the use of deodorants/antiperspirants and breast cancer? 2) Does the use of deodorants/antiperspirants have any effect on the increase in the risk of breast cancer? 3) Could a causal relationship between the use of deodorants/antiperspirants and breast cancer be accepted? The scientific data were searched systematically in the PubMed database (http://www.ncbi.nlm.nih.gov/sites/entrez) using standardised search equations. Fifty-nine studies resulting from the literature search were reviewed and nineteen articles with various methodologies were selected for in-depth analysis. In view of the fact that parabens are generally not present in deodorants/antiperspirants, the reflection group's search related purely to the question of aluminium salts. Among these nineteen articles, many are methodologically unsound, do not answer to the questions posed or deal with the question of parabens and were therefore discarded by the reflection group. The expert group's conclusion coincides with those of the French, European and American health authorities. After analysis of the available literature on the subject, no scientific evidence to support the hypothesis was identified and no validated hypothesis appears likely to open the way to interesting avenues of research.
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http://dx.doi.org/10.1684/bdc.2008.0679DOI Listing
September 2008