Publications by authors named "Herve Bonnefoi"

67 Publications

Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up.

J Clin Oncol 2021 Feb 4:JCO2001204. Epub 2021 Feb 4.

Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.

Purpose: APHINITY, at 45 months median follow-up, showed that pertuzumab added to adjuvant trastuzumab and chemotherapy significantly improved invasive disease-free survival (IDFS) (hazard ratio 0.81 [95% CI, 0.66 to 1.00], = .045) for patients with early human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), specifically those with node-positive or hormone receptor (HR)-negative disease. We now report the preplanned second interim overall survival (OS) and descriptive updated IDFS analysis with 74 months median follow-up.

Methods: After surgery and central HER2-positive confirmation, 4,805 patients with node-positive or high-risk node-negative BC were randomly assigned (1:1) to either 1-year pertuzumab or placebo added to standard adjuvant chemotherapy and 1-year trastuzumab.

Results: This interim OS analysis comparing pertuzumab versus placebo did not reach the = .0012 level required for statistical significance ( = .17, hazard ratio 0.85). Six-year OS were 95% versus 94% with 125 deaths (5.2%) versus 147 (6.1%), respectively. IDFS analysis based on 508 events (intent-to-treat population) showed a hazard ratio of 0.76 (95% CI, 0.64 to 0.91) and 6-year IDFS of 91% and 88% for pertuzumab and placebo groups, respectively. The node-positive cohort continues to derive clear IDFS benefit from pertuzumab (hazard ratio 0.72 [95% CI, 0.59 to 0.87]), 6-year IDFS being 88% and 83%, respectively. Benefit was not seen in the node-negative cohort. In a subset analysis, IDFS benefit from pertuzumab showed a hazard ratio of 0.73 (95% CI, 0.59 to 0.92) for HR-positive disease and a hazard ratio of 0.83 (95% CI, 0.63 to 1.10) for HR-negative disease. Primary cardiac events remain < 1% in both the treatment groups. No new safety signals were seen.

Conclusion: This analysis confirms the IDFS benefit from adding pertuzumab to standard adjuvant therapy for patients with node-positive HER2-positive early BC. Longer follow-up is needed to fully assess OS benefit.
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http://dx.doi.org/10.1200/JCO.20.01204DOI Listing
February 2021

Clinical behavior of recurrent hormone receptor-positive breast cancer by adjuvant endocrine therapy within the Breast International Group 1-98 clinical trial.

Cancer 2021 Mar 8;127(5):700-708. Epub 2020 Dec 8.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Endocrine therapy resistance is a major cause of distant recurrence (DR) in hormone receptor-positive breast cancer. This study evaluated differences in survival after DR in patients treated with different adjuvant endocrine therapy regimens in the Breast International Group (BIG) 1-98 trial.

Methods: BIG 1-98 compared 5 years of adjuvant treatment among 4 arms: tamoxifen (T), letrozole (L), tamoxifen followed by letrozole (TL), and letrozole followed by tamoxifen (LT). After a median follow-up of 8.1 years, 911 of 8010 patients (T, 302; L, 285; TL, 170; and LT, 154) had DR as the site of first recurrence. Univariate and multivariate Cox analyses were performed to determine features associated with post-DR survival.

Results: The median follow-up time after DR was 59 months (interquartile range, 29-88 months). Among all patients with DR, 38.1% were 65 years old or older at enrollment, 61.9% had tumors larger than 2 cm, and 69.7% were node positive. Neoadjuvant or adjuvant chemotherapy was administered to 35.6% of the patients. There was no difference in post-DR survival by treatment arm (median survival, 20.8 months for T, 17.9 months for L, 17.3 months for TL, and 20.8 months for LT; P = .21). In multivariate analysis, older patients (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.15-1.59) and patients with tumors larger than 2 cm (HR, 1.19; 95% CI, 1.00-1.41), 4 or more positive nodes (HR, 1.31; 95% CI, 1.05-1.64), progesterone receptor (PR)-negative tumors (HR, 1.25; 95% CI, 1.02-1.52), or shorter disease-free survival (DFS) had significantly worse post-DR survival.

Conclusions: Treatment with adjuvant T, L, or their sequences was not associated with differences in survival after DR. Significant differences in survival were observed by age, primary tumor size, nodal and PR status, and DFS, and this suggests that traditional baseline high-risk features remain prognostic in the metastatic setting.
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http://dx.doi.org/10.1002/cncr.33318DOI Listing
March 2021

Cumulative incidence of cardiovascular events under tamoxifen and letrozole alone and in sequence: a report from the BIG 1-98 trial.

Breast Cancer Res Treat 2021 Feb 7;185(3):697-707. Epub 2020 Nov 7.

Division of Biostatistics, IBCSG Statistical Center, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.

Background: Compared to tamoxifen, adjuvant treatment with aromatase inhibitors improves disease outcomes of postmenopausal women with hormone receptor-positive early breast cancer. In the international, randomized, double-blind BIG 1-98 trial, 8010 women were randomized to receive tamoxifen, letrozole, or sequential use of the agents for 5 years. With a focus on switching between agents, we investigated cardiovascular events over the entire 5-year treatment period.

Methods: Of the 6182 patients enrolled, 6144 started trial treatment and were included in this analysis. Adverse events occurring during study treatment until 30 days after cessation were considered. Eight cardiovascular event types were defined. Cumulative incidence of events were estimated using the Kaplan-Meier method, without consideration for competing events. Multivariable Cox models estimated hazard ratios (HR) with 95% confidence intervals (CI) for pairwise comparisons of treatment arms.

Results: While on study treatment, 6.5% of patients (n = 397) had any cardiac events reported; for 2.4%, the event was grades 3-5, of which 11 (0.2%) were grade 5. Letrozole monotherapy was associated with higher risk of grade 1-5 ischemic heart disease (HR = 1.81; 95% CI, 1.06-3.08) compared with tamoxifen monotherapy. Patients assigned sequential tamoxifen →letrozole (HR = 1.59; 95% CI, 0.92-2.74) or sequential letrozole → tamoxifen (HR = 1.20; 95% CI, 0.68-2.14) showed a lesser degree of risk elevation. Patients assigned to tamoxifen-containing regimens had significantly higher risk of grade 1-5 thromboembolic events (tamoxifen monotherapy HR = 2.10; 95% CI, 1.42-3.12; tamoxifen → letrozole HR = 1.96; 95% CI, 1.32-2.92; letrozole → tamoxifen HR = 1.56; 95% CI 1.03-2.35) as compared with patients assigned letrozole alone.

Conclusion: When initiating or switching between adjuvant endocrine treatments in postmenopausal patients, age and medical history, with special attention to prior cardiovascular events, should be balanced with expected benefit of the treatment.
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http://dx.doi.org/10.1007/s10549-020-05981-zDOI Listing
February 2021

Patient-reported outcomes from KATHERINE: A phase 3 study of adjuvant trastuzumab emtansine versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for human epidermal growth factor receptor 2-positive breast cancer.

Cancer 2020 Jul 14;126(13):3132-3139. Epub 2020 Apr 14.

NSABP Foundation and Houston Methodist Cancer Center, Houston, Texas.

Background: The phase 3 KATHERINE trial demonstrated significantly improved invasive disease-free survival with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy.

Methods: Patients who received taxane- and trastuzumab-containing neoadjuvant therapy (with/without anthracyclines) and had residual invasive disease (breast and/or axillary nodes) at surgery were randomly assigned to 14 cycles of adjuvant T-DM1 (3.6 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg intravenously every 3 weeks). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and breast cancer module (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6- and 12-month follow-up visits.

Results: Of patients who were randomly assigned to T-DM1 (n = 743) and trastuzumab (n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 postbaseline assessments. No clinically meaningful changes (≥10 points) from baseline in mean QLQ-C30 and QLQ-BR23 scores occurred in either arm. More patients receiving T-DM1 reported clinically meaningful deterioration at any assessment point in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 60%), nausea/vomiting (39% vs 30%), and systemic therapy side effects (49% vs 36%). These differences were no longer apparent at the 6-month follow-up assessment, except for role functioning (23% vs 16%).

Conclusion: These data suggest that health-related quality of life was generally maintained in both study arms over the course of treatment.
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http://dx.doi.org/10.1002/cncr.32873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317721PMC
July 2020

Predictive factors of 5-year relapse-free survival in HR+/HER2- breast cancer patients treated with neoadjuvant endocrine therapy: pooled analysis of two phase 2 trials.

Br J Cancer 2020 03 31;122(6):759-765. Epub 2020 Jan 31.

Institut Bergonié, Bordeaux, France.

Background: Few data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET).

Methods: This is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies.

Results: In total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9-88) and 92.7% (95% CI: 88.2-95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3-4; p = 0.0001), Ki-67 at surgery (≤10% vs >10%; p = 0.0093), pathological tumour size (pT1-2 vs pT3-4; p = 0.0012) and node status (pN negative vs positive; p = 0.007), adjuvant chemotherapy (p = 0.0167) and PEPI score (PEPI group I + II vs III; p = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS (p = 0.0069, hazard ratio = 3.33 (95% CI: 1.39-7.98)).

Conclusions: Postmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.
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http://dx.doi.org/10.1038/s41416-020-0733-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078275PMC
March 2020

Residual cancer burden index and tumor-infiltrating lymphocyte subtypes in triple-negative breast cancer after neoadjuvant chemotherapy.

Breast Cancer Res Treat 2020 Jan 16;179(1):11-23. Epub 2019 Sep 16.

Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, 229 Cours de l'Argonne CS61283-33076, 33000, Bordeaux, Cedex, France.

Purpose: There is a need to refine the prognosis of triple-negative breast cancer (TNBC) patients after neoadjuvant chemotherapy (NAC) and to study the influence of the tumor microenvironment. We evaluated the prognostic value of pathological and immune markers in TNBC with residual disease (RD) after NAC.

Methods: In a series of 186 TNBC patients treated by NAC, we assessed the prognostic value of the Residual Cancer Burden (RCB) index. In 109 patients with RD, we studied the impact of clinicopathological features and tumor immune response in the residual tumor on overall survival (OS) and distant recurrence-free interval (DRFI).

Results: In the whole group, the OS and DRFI, at 3 years, were statistically different between the different classes of RCB (P = 0.0004 and P < 0.0001, respectively). In univariate analysis of the RD group, low RCB index and high ratios of stromal tumor-infiltrating lymphocytes (TILs), CD3 + TILs, CD4 + TILs, CD8 + TILs, and IDO1-positive cells were significant favorable prognostic factors for DRFI at 3 years. In the final multivariate model, CD4 + TILs and RCB index showed a statistically independent prognostic significance for DRFI [Hazard Ratio (HR) 2.88 (95%CI 1.34-6.17), P = 0.007 and HR 12.04 (95%CI 2.78-52.23, P < 0.0001), respectively]. The CD4 + TIL levels influenced survival in the different RCB classes with a significant effect observed in RCB-II and RCB-III classes (P = 0.05 and P = 0.05, respectively).

Conclusions: These results suggest that the combination of pathological (RCB index) and tumor micro-environmental features (CD4 + TILs) help refining the prognosis of TNBC patients with RD following NAC.
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http://dx.doi.org/10.1007/s10549-019-05437-zDOI Listing
January 2020

Iniparib administered weekly or twice-weekly in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: a phase II randomized open-label study with pharmacokinetics.

Breast Cancer Res Treat 2019 Sep 6;177(2):383-393. Epub 2019 Jun 6.

Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Purpose: Metastatic triple-negative breast cancer (TNBC) is a phenotypic breast cancer subgroup with a very poor prognosis, despite standard treatments. Combined twice-weekly iniparib and gemcitabine/carboplatin (GC+tw-iniparib) showed benefit over gemcitabine/carboplatin in a randomized phase II trial, and a phase III was initiated comparing these regimens. The present phase II study was initiated to compare GC+tw-iniparib with a more practical once-weekly schedule (GC+w-iniparib) in TNBC.

Methods: Metastatic TNBC patients were randomized to receive iniparib weekly (11.2 mg/kg on days 1 and 8) or twice-weekly (5.6 mg/kg on days 1, 4, 8, and 11) with gemcitabine (1000 mg/m) and carboplatin (area under the curve 2 on days 1 and 8), every 3 weeks. The primary endpoint was the overall response rate (ORR). Pharmacokinetics of iniparib and its two metabolites were analyzed.

Results: A total of 163 patients were randomized, 82 GC+w-iniparib and 81 GC+tw-iniparib. Demographic and baseline characteristics were well balanced. ORR was 34.1% (95% CI 23.9-44.4%) vs. 29.6% (95% CI 19.7-39.6%) and median progression-free survival was 5.5 months (95% CI 4.2-5.7) vs. 4.3 months (95% CI 3.0-5.8) for GC+w-iniparib and GC+tw-iniparib, respectively. Safety was similar across treatment arms in terms of event severity and type. Iniparib plasma concentrations and exposure were two-fold higher with w-iniparib compared to tw-iniparib. Iniparib and its metabolites were cleared rapidly with a terminal half-life of < 1 h, without accumulation.

Conclusions: Despite a doubled maximum concentration with weekly iniparib, no detectable differences in safety or efficacy were observed between the weekly and twice-weekly administration schedules in this population.

Trial Registration: ClinicalTrial.gov Identifier NCT01045304.
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http://dx.doi.org/10.1007/s10549-019-05305-wDOI Listing
September 2019

Genomic characterization of metastatic breast cancers.

Nature 2019 05 22;569(7757):560-564. Epub 2019 May 22.

Université Paris Sud, Orsay, France.

Metastasis is the main cause of death for patients with breast cancer. Many studies have characterized the genomic landscape of breast cancer during its early stages. However, there is evidence that genomic alterations are acquired during the evolution of cancers from their early to late stages, and that the genomic landscape of early cancers is not representative of that of lethal cancers. Here we investigated the landscape of somatic alterations in 617 metastatic breast cancers. Nine driver genes (TP53, ESR1, GATA3, KMT2C, NCOR1, AKT1, NF1, RIC8A and RB1) were more frequently mutated in metastatic breast cancers that expressed hormone receptors (oestrogen and/or progesterone receptors; HR) but did not have high levels of HER2 (HER2; n = 381), when compared to early breast cancers from The Cancer Genome Atlas. In addition, 18 amplicons were more frequently observed in HR/HER2 metastatic breast cancers. These cancers showed an increase in mutational signatures S2, S3, S10, S13 and S17. Among the gene alterations that were enriched in HR/HER2 metastatic breast cancers, mutations in TP53, RB1 and NF1, together with S10, S13 and S17, were associated with poor outcome. Metastatic triple-negative breast cancers showed an increase in the frequency of somatic biallelic loss-of-function mutations in genes related to homologous recombination DNA repair, compared to early triple-negative breast cancers (7% versus 2%). Finally, metastatic breast cancers showed an increase in mutational burden and clonal diversity compared to early breast cancers. Thus, the genomic landscape of metastatic breast cancer is enriched in clinically relevant genomic alterations and is more complex than that of early breast cancer. The identification of genomic alterations associated with poor outcome will allow earlier and better selection of patients who require the use of treatments that are still in clinical trials. The genetic complexity observed in advanced breast cancer suggests that such treatments should be introduced as early as possible in the disease course.
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http://dx.doi.org/10.1038/s41586-019-1056-zDOI Listing
May 2019

Molecular apocrine tumours in EORTC 10994/BIG 1-00 phase III study: pathological response after neoadjuvant chemotherapy and clinical outcomes.

Br J Cancer 2019 04 22;120(9):913-921. Epub 2019 Mar 22.

Anglo-Celtic Cooperative Oncology Group (ACCOG), Edinburgh, United Kingdom.

Background: We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen (ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers.

Methods: Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and "other". The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes.

Results: IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4-43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2-68.6). Patients with MA and TN basal-like tumours have lower survival outcomes.

Conclusions: Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.
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http://dx.doi.org/10.1038/s41416-019-0420-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734658PMC
April 2019

Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial.

Lancet Oncol 2019 03 11;20(3):371-382. Epub 2019 Feb 11.

Institut Gustave Roussy, Université Paris Sud, INSERM U981, Villejuif, France.

Background: HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer.

Methods: We did this single-arm, multicentre, phase 1b-2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed.

Findings: Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6-18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9-12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7-29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3-5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3-5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2.

Interpretation: Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients.

Funding: Merck, International Breast Cancer Study Group.
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http://dx.doi.org/10.1016/S1470-2045(18)30812-XDOI Listing
March 2019

Category "viewpoints and debates" Is trastuzumab as a single agent obsolete in early breast cancer? Yes.

Breast 2019 Feb 20;43:146-148. Epub 2018 Oct 20.

Department of Medical Oncology, Institut Bergonié Unicancer, Univ. Bordeaux, INSERM U1218, INSERM CIC1401, Bordeaux, France.

In 2005, two adjuvant trials revolutionised breast cancer treatment demonstrating a 50% reduction in relapses when trastuzumab was added to adjuvant chemotherapy. In order to improve further on these results three large phase III trials were conducted. ALTTO trial evaluated lapatinib. This trial was negative and lapatinib was quite toxic. ExteNET trial evaluated neratinib in patients who already had completed adjuvant treatment with trastuzumab. Neratinib reduced the risk of relapse by 27% and the drug is FDA approved. However 40% of patients experienced grade 3 diarrhoea and this toxicity profile will be an issue in daily practice. APHINITY trial evaluated a combination of pertuzumab and trastuzumab. Pertuzumab reduced the risk of relapse by 19% with a good toxicity profile. However the absolute invasive disease-free survival (IDFS) benefit at 4 years was only 1.7%. Despite this modest absolute benefit we believe that pertuzumab should be added to trastuzumab at least in two indications: first, in patients with node positive breast cancer, in whom the absolute IDFS benefit is 3.2% and qualify for a high clinical benefit based on ESMO magnitude of clinical benefit scale; second, in patients suitable for neoadjuvant chemotherapy. In this group, the absolute IDFS benefit could be estimated as high as 7% (starting pertuzumab in the neoadjuvant setting and following it in the adjuvant setting up to a total of 18 injections). Our arguments are developed in this viewpoint. Pertuzumab is approved in these two indications by FDA and EMA.
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http://dx.doi.org/10.1016/j.breast.2018.10.008DOI Listing
February 2019

Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial.

J Clin Oncol 2019 01 26;37(2):105-114. Epub 2018 Nov 26.

2 Dana-Farber Cancer Institute, Boston, MA.

Purpose: Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years.

Patients And Methods: BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported.

Results: Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up.

Conclusion: Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.
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http://dx.doi.org/10.1200/JCO.18.00440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325353PMC
January 2019

Enhancing Abiraterone Acetate Efficacy in Androgen Receptor-positive Triple-negative Breast Cancer: Chk1 as a Potential Target.

Clin Cancer Res 2019 01 23;25(2):856-867. Epub 2018 Oct 23.

Institut National de la Santé et de la Recherche Médicale (INSERM) UNIT U1218, Institut Bergonié, Bordeaux, France.

Purpose: Our aim was to identify predictive factors of abiraterone acetate efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial. We defined abiraterone acetate response as either complete or partial response, or stable disease at 6 months. We sequenced 91 general and breast cancer-associated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a NanoString platform and performed IHC using tissue microarrays. We assessed abiraterone acetate and Chk1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown and .

Results: Classic IHC apocrine markers including AR, FOXA1, GGT1, and GCDFP15, from patients' tumors allowed identifying abiraterone acetate-responders and nonresponders. All responders had clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression, in nonresponders, of , a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. On the basis of cell line experiments, abiraterone acetate and Chk1 inhibitor combination showed at least additive effect on cell viability, cell cycle, apoptosis, and accumulation of DNA damages. , orthotopic xenograft experiments confirmed the efficacy of this combination therapy.

Conclusions: This study suggests that apocrine features can be helpful in the identification of abiraterone acetate-responders. We identified Chk1 as a putative drug target in AR-positive TNBCs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1469DOI Listing
January 2019

Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer.

N Engl J Med 2018 Jul 4;379(2):122-137. Epub 2018 Jun 4.

From the Peter MacCallum Cancer Centre, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC, and Breast Cancer Trials Australia and New Zealand, University of Newcastle, Newcastle, NSW (P.A.F.), and the University of Sydney, Sydney (A.S.C.) - all in Australia; the Institute of Oncology of Southern Switzerland, Ospedale San Giovanni, Bellinzona (O.P.), Breast Cancer St. Gallen, St. Gallen (T.R.), and the International Breast Cancer Study Group Coordinating Center (R.M., M.R.-P., B.R., A.S.C.), University Hospital Inselspital (M.R.-P.), Bern - all in Switzerland; the University of Chicago Medical Center, Chicago (G.F.F.); the University of Calgary, Calgary, AB, Canada (B.A.W.); the Division of Medical Senology, European Institute of Oncology (M.C.), and the European Institute of Oncology and International Breast Cancer Study Group (A.G.), Milan, Ospedale Papa Giovanni XXIII, Bergamo (C.T.), Azienda Socio Sanitaria Territoriale Sette Laghi-Ospedale di Circolo and Fondazione Macchi, Varese (G.P.), Medical Oncology and Cancer Prevention, IRCCS, National Cancer Institute, Aviano (F.P., S.S.), the Department of Medicine, School of Medical Oncology, University of Udine, Udine (F.P.), Salvatore Maugeri Foundation, Pavia (L.P.), and the Hospital of Prato-Azienda Unità Sanitaria Locale Toscana Centro, Prato (A.D.L.) - all in Italy; the National Institute of Oncology, Budapest, Hungary (I.L.); Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru (H.L.G.); University Hospital 12 de Octubre, Madrid (E.C.), Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona (M.B.), and Instituto Valenciano de Oncologia, Valencia (M.A.C.) - all in Spain; the Susan F. Smith Center for Women's Cancers (H.J.B., E.P.W.) and the International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology (R.D.G., M.M.R.), Dana-Farber Cancer Institute, Harvard Medical School, the Harvard T.H. Chan School of Public Health, and Frontier Science and Technology Research Foundation (R.D.G.) - all in Boston; Institut Bergonié Comprehensive Cancer Center, Université de Bordeaux, Bordeaux, France (H.R.B., M.D.); the Angeles Clinic and Research Institute, Santa Monica, CA (S.M.); Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond (C.E.G.); Mayo Clinic, Rochester, MN (M.P.G., J.N.I.); Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore (V.S.); Fred Hutchinson Cancer Research Center, University of Washington, Seattle (N.E.D.); Weston Park Hospital, Sheffield, United Kingdom (R.C.); and the Department of Obstetrics and Gynecology, University Medical Center, Regensburg, Germany (S.B.).

Background: In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials.

Methods: Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy.

Results: In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group.

Conclusions: Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).
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http://dx.doi.org/10.1056/NEJMoa1803164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193457PMC
July 2018

Do patients whose tumor achieved a pathological response relapse at specific sites? A substudy of the EORTC 10994/BIG-1-00 trial.

Breast Cancer Res Treat 2018 Jun 12;169(3):497-505. Epub 2018 Feb 12.

Department of Medical Oncology, Institut Bergonié Unicancer, Université de Bordeaux, INSERM U1218, INSERM CIC1401, 229 Cours de l'Argonne, 33000, Bordeaux, France.

Purpose: To determine the sites of first distant relapse in patients with or without pCR following neoadjuvant chemotherapy in breast cancer patients enrolled in the EORTC 10994/BIG-1-00 trial.

Methods: We included patients enrolled in the EORTC 10994/BIG-1-00 trial who received at least one chemotherapy cycle before surgery and who had been diagnosed with a distant relapse. pCR was defined as no evidence of residual invasive cancer in the primary tumor and axillary lymph nodes with or without residual ductal carcinoma in situ. Site of first distant relapse was categorized as 'soft tissue,' 'visceral,' 'skeletal,' 'central nervous system (CNS),' and 'other.' The association between relapse site and achievement of pCR was assessed using multivariate logistic regression models for molecular subtypes classification and preceding locoregional recurrence.

Results: The study included 383 (21%) eligible patients out of the 1856 randomized, of whom 28 (7%) had achieved pCR. Median follow-up was 5.4 years. Achievement of pCR was associated with a trend towards a decreased presentation of skeletal metastases [21% (pCR) vs. 50% (non-pCR), OR 0.32, adjusted p value = 0.071] and an increase in the proportion of patients with CNS metastases as first distant relapse site (21% vs. 9%, OR 2.39, adjusted p value = 0.183). Patients with pCR were more likely to present with only one relapse location category when compared to non-pCR (86% vs. 69%).

Conclusion: Patients that achieved a pCR appeared less likely to present with skeletal metastases and more frequently presented with CNS metastases as first site of distant relapse, even after adjustment for molecular subtypes.
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http://dx.doi.org/10.1007/s10549-018-4698-xDOI Listing
June 2018

Assessment of the prognostic role of a 94-single nucleotide polymorphisms risk score in early breast cancer in the SIGNAL/PHARE prospective cohort: no correlation with clinico-pathological characteristics and outcomes.

Breast Cancer Res 2017 Aug 22;19(1):98. Epub 2017 Aug 22.

Centre de Recherche en Cancérologie de Lyon, INSERM U1052 - Centre Léon Bérard, 28 rue Laennec, 69373, Lyon, France.

Background: Genome-wide association studies (GWAS) have to date identified 94 genetic variants (single nucleotide polymorphisms (SNPs)) associated with risk of developing breast cancer. A score based on the combined effect of the 94 risk alleles can be calculated to measure the global risk of breast cancer. We aimed to test the hypothesis that the 94-SNP-based risk score is associated with clinico-pathological characteristics, breast cancer subtypes and outcomes in early breast cancer.

Methods: A 94-SNP risk score was calculated in 8703 patients in the PHARE and SIGNAL prospective case cohorts. This score is the total number of inherited risk alleles based on 94 selected SNPs. Clinical data and outcomes were prospectively registered. Genotyping was obtained from a GWAS.

Results: The median 94-SNP risk score in 8703 patients with early breast cancer was 77.5 (range: 58.1-97.6). The risk score was not associated with usual prognostic and predictive factors (age; tumor, node, metastasis (TNM) status; Scarff-Bloom-Richardson grade; inflammatory features; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 (HER2) status) and did not correlate with breast cancer subtypes. The 94-SNP risk score did not predict outcomes represented by overall survival or disease-free survival.

Conclusions: In a prospective case cohort of 8703 patients, a risk score based on 94 SNPs was not associated with breast cancer characteristics, cancer subtypes, or patients' outcomes. If we hypothesize that prognosis and subtypes of breast cancer are determined by constitutional genetic factors, our results suggest that a score based on breast cancer risk-associated SNPs is not associated with prognosis.

Trial Registration: PHARE cohort: NCT00381901 , Sept. 26, 2006 - SIGNAL cohort: INCa RECF1098, Jan. 28, 2009.
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http://dx.doi.org/10.1186/s13058-017-0888-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568360PMC
August 2017

Constitutional variants are not associated with HER2-positive breast cancer: results from the SIGNAL/PHARE clinical cohort.

NPJ Breast Cancer 2017 23;3. Epub 2017 Feb 23.

Centre de Recherche en Cancérologie de Lyon, INSERM U1052-Centre Léon Bérard, 28 rue Laennec, Lyon, 69373 France.

Human epidermal growth factor receptor 2-positive breast cancer is a subtype of interest regarding its outcome and the impressive impact of human epidermal growth factor receptor 2 targeted therapy. Constitutional variants may be involved in the aetiology of human epidermal growth factor receptor 2-positive breast cancer, and we propose a case-case study to test the hypothesis that single nucleotide polymorphisms may be associated with human epidermal growth factor receptor 2 status. A Genome-Wide Association Study was used in a cohort of 9836 patients from the SIGNAL/PHARE study (NCT00381901-RECF1098). The main goal was to identify variants specifically related to human epidermal growth factor receptor 2-positive breast cancer. A two-staged genotyping strategy was carried out to cover as large a proportion of the genome as possible. All subjects were genotyped using the Illumina HumanCore Exome chip set. Principal Components Analysis and -means were then used to characterize the ancestry of the participants. A random sample of subjects from the main "European" cluster was genotyped with the Omni5 chip set. These data were then used to impute missing genotypes from the remaining subjects genotyped only using the HumanCore Exome array. From the 9836 patients, a total of 8703 cases including 3230 patients with human epidermal growth factor receptor 2-positive breast cancer were analyzed. Despite having 80% power to detect an odds ratio of 1.23 in this population, no variant achieved genome-wide significance for association with the occurrence of human epidermal growth factor receptor 2-positive breast cancer vs. any other subtype of breast tumour. Our study was unable to identify constitutional polymorphisms that are strongly associated with human epidermal growth factor receptor 2-positive status among breast cancer patients.
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http://dx.doi.org/10.1038/s41523-017-0005-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445615PMC
February 2017

Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort.

Eur J Cancer 2017 08 16;81:151-160. Epub 2017 Jun 16.

Oncologie Sénologie, ICM Institut Régional du Cancer, 34298 Montpellier Cedex, France.

Aim: Adjuvant clinical trials in early human epidermal growth factor receptor 2 (HER2)-positive breast cancer have assessed either sequential or concomitant incorporation of trastuzumab with chemotherapy; only the North Central Cancer Treatment Group (NCCTG)-N9831 trial prospectively compared both modalities. In routine trastuzumab has been incorporated into a concurrent regimen with taxane chemotherapy instead of sequential modality on the basis of a positive risk-benefit ratio. This present study assessed sequential versus concomitant administration of adjuvant trastuzumab.

Methods: A population combining patients from Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) a randomised phase III clinical trial (NCT00381901) and SIGNAL (RECF1098) a prospective study specifically designed for Genome-wide Association Studies (GWAS) analyses was studied. In this cohort with 58 months of median follow-up, the comparison in the HER2-positive group of adjuvant trastuzumab and chemotherapy modalities was based on a propensity score methodology. Treatment modalities were based on physician's choice and comparisons adjustment were made by a propensity score methodology. Overall Survival (OS) and Disease-Free Survival (DFS) were estimated using the Kaplan-Meier method, and comparisons between groups were based on the log rank test.

Results: The SIGNAL/PHARE cohort included 11,728 breast cancer cases treated in adjuvant setting; some 5502 of them with HER2-positive tumour: 34.5% (1897/5502) were treated by sequential and 65.5% (3605/5502) by concomitant modality of administration for taxane-chemotherapy and trastuzumab. The adjusted comparison found similar OS (HR = 1.01; 95% CI: 0.86-1.19) and similar DFS (HR = 1.08; 95% CI: 0.96-1.21).

Conclusion: These results suggest that the sequential administration of trastuzumab given after the completion of adjuvant chemotherapy might be as valid as the concomitant administration of trastuzumab and taxane chemotherapy in the adjuvant setting.
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http://dx.doi.org/10.1016/j.ejca.2017.05.020DOI Listing
August 2017

Factors predictive of locoregional recurrence following neoadjuvant chemotherapy in patients with large operable or locally advanced breast cancer: An analysis of the EORTC 10994/BIG 1-00 study.

Eur J Cancer 2017 07 18;79:226-234. Epub 2017 May 18.

Department of Medical Oncology, Institut Bergonié Unicancer, Univ. Bordeaux, INSERM U1218, INSERM CIC1401 Bordeaux, France. Electronic address:

Purpose: Identification of clinicopathological factors predicting for a locoregional recurrence (LRR) after neoadjuvant chemotherapy (NAC) could help to decide on the optimal locoregional radiotherapy. The objective of this trial is to identify those factors in the context of a phase III trial (European Organisation for Research and Treatment of Cancer 10994).

Methods: Patients received NAC followed by surgery with or without radiotherapy. Radiotherapy was administered according to pre-specified guidelines. Patients with hormone receptor positive tumours received adjuvant hormonal therapy. A proportion of patients with human epidermal growth factor receptor 2 (HER2) positive cancer received adjuvant trastuzumab. The predictive factors for LRR were identified by multivariate analysis with time to LRR as first event as the primary end-point.

Results: The median follow-up was 4.4 years. In 1553 eligible patients, there were 76 LRRs with a 5-year cumulative incidence of 4.9% (95% confidence interval, CI [3.76-6.04]). In multivariate analysis, breast cancer subtype was a significant predictor of LRR (p < 0.0001): hazard ratio (HR) 6.44 (95% CI [2.83-14.69]) for triple negative, 6.26 (95% CI [2.81-13.93]) for HER2+ without trastuzumab (T) and 3.37 (95% CI [1.10-10.34]) for HER2+ with T cancers, all compared to luminal A patients. Lack of pathological response was also associated with significantly higher LRR risk in case of ≥4 pathologically positive nodes, HR 2.43 (95% CI [1.34-4.40], p < 0.0001).

Conclusion: Breast cancer subtype and lack of pathological response are predictive factors for high LRR after NAC.
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http://dx.doi.org/10.1016/j.ejca.2017.04.012DOI Listing
July 2017

Expression of Gastrin-Releasing Peptide Receptor in Breast Cancer and Its Association with Pathologic, Biologic, and Clinical Parameters: A Study of 1,432 Primary Tumors.

J Nucl Med 2017 09 9;58(9):1401-1407. Epub 2017 Mar 9.

Nuclear Medicine Department, University Hospital of Bordeaux, F-33076 Bordeaux, France.

A growing body of evidence suggests that gastrin-releasing peptide receptor (GRPR) might be a valuable target in breast cancer. To understand which patients can be potential candidates for GRPR-based imaging or targeted therapy, we screened invasive breast cancers by immunohistochemistry for the presence and intensity of GRPR expression. We explored a tissue microarray of 1,432 primary breast tumors from patients who underwent surgery between 2000 and 2005 at Institut Bergonié, without prior neoadjuvant treatment. We studied associations between GRPR expression and clinical, pathologic, and biologic parameters. The association between GRPR expression and distant metastasis-free interval was also examined. GRPR overexpression was found in 75.8% of the 1,432 tumors and was most strongly associated with estrogen receptor (ER) positivity (GRPR was high in 83.2% of ER-positive and 12% of ER-negative tumors; < 0.00001). When molecular subtypes of breast cancer were considered, GRPR was overexpressed in 86.2% of luminal A-like tumors, 70.5% of luminal B-like human epidermal growth factor receptor 2 (HER2)-negative tumors, 82.8% of luminal B-like HER2-positive tumors, 21.3% of HER2-enriched tumors, and 7.8% of triple-negative tumors. Importantly, when breast tumors overexpressed GRPR, high GRPR expression was also found in metastatic lymph nodes in 94.6% of cases. Primary tumors with high GRPR expression were associated with lower risk of distant metastases at follow-up in univariate analysis (Log-rank = 0.0084) but not in multivariate analysis. Hence, the prognostic impact of GRPR was lost when examined within specific molecular subtypes. Because GRPR is overexpressed in a high percentage of ER-positive tumors, GRPR targeting offers wide perspectives for imaging and treatment in patients with ER-positive breast cancer, using recently developed radiolabeled GRPR ligands.
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http://dx.doi.org/10.2967/jnumed.116.188011DOI Listing
September 2017

Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR, HER2 breast cancer that had progressed during or after prior endocrine therapy.

Breast Cancer Res 2017 02 10;19(1):18. Epub 2017 Feb 10.

Institut Gustave Roussy, Villejuif, France.

Background: Overexpression of fibroblast growth factor receptor 1 (FGFR1), found in ≤8% of hormone receptor-positive (HR), human epidermal growth factor receptor 2-negative (HER2) breast cancer cases, is correlated with decreased overall survival and resistance to endocrine therapy (ET). Dovitinib, a potent FGFR inhibitor, has demonstrated antitumor activity in heavily pretreated patients with FGFR pathway-amplified breast cancer.

Methods: In this randomized, placebo-controlled phase II trial, we evaluated whether the addition of dovitinib to fulvestrant would improve outcomes in postmenopausal patients with HR, HER2 advanced breast cancer that had progressed during or after prior ET. Patients were stratified by FGF pathway amplification and presence of visceral disease, and they were randomized 1:1 to receive fulvestrant plus dovitinib or placebo. The primary endpoint was progression-free survival (PFS).

Results: From 15 May 2012 to 26 November 2014, 97 patients from 36 centers were enrolled. The frequency of FGF pathway amplification was lower than anticipated, and the study was terminated early owing to slow accrual of patients with FGF pathway amplification. The median PFS (95% CI) was 5.5 (3.8-14.0) months vs 5.5 (3.5-10.7) months in the dovitinib vs placebo arms, respectively (HR, 0.68; did not meet predefined efficacy criteria). For the FGF pathway-amplified subgroup (n = 31), the median PFS (95% CI) was 10.9 (3.5-16.5) months vs 5.5 (3.5-16.4) months in the dovitinib vs placebo arms, respectively (HR, 0.64; met the predefined superiority criteria). Frequently reported adverse events in the dovitinib (diarrhea, nausea, vomiting, asthenia, and headache) and placebo (diarrhea, fatigue, nausea, and asthenia) arms were mostly low grade.

Conclusions: The safety profile of dovitinib plus fulvestrant was consistent with the known safety profile of single-agent dovitinib. Dovitinib in combination with fulvestrant showed promising clinical activity in the FGF pathway-amplified subgroup. However, the data reported herein should be interpreted with caution, given that fewer PFS events occurred in the FGF pathway-amplified patients than was expected and that an effect of dovitinib regardless of FGR pathway amplification status cannot be excluded, because the population was smaller than expected.

Trial Registration: ClinicalTrials.gov identifier: NCT01528345 . Registered 31 January 2012.
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http://dx.doi.org/10.1186/s13058-017-0807-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301372PMC
February 2017

Correlation between severe infection and breast cancer metastases in the EORTC 10994/BIG 1-00 trial: Investigating innate immunity as a tumour suppressor in breast cancer.

Eur J Cancer 2017 02 24;72:95-102. Epub 2016 Dec 24.

Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia. Electronic address:

Background: Breast cancer cells which express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced metastatic potential. Infections can induce interferon signalling and may activate an anti-tumour immune response. We investigated whether 'severe infection' can be a clinical surrogate of this phenomenon and/or the presence of high levels of the IRF7 signature at diagnosis before neo-adjuvant chemotherapy (NACT) is associated with a reduced distant relapse risk, specifically in bones.

Methods: Clinical data of the European Organisation for Research and Treatment of Cancer 10994/BIG 1-00 phase III trial which randomised 1856 patients treated with NACT between 2001 and 2006, were used. Severe infection was febrile neutropenia or any other grade III-IV infective adverse event during NACT. The IRF7 signature was calculated from gene expression data available for 160 patients on a pre-NACT biopsy. Cox models for distant relapse-free interval (DRFI) investigated the effect of the severe infection and IRF7. Fine and Gray models studied the occurrence of bone metastases as first distant relapse.

Results: Median follow-up was 4.8 years. No association between severe infection and DFRI was observed in the entire population (n = 1615 eligible patients) hazard ratio [(HR] = 0.99, 90% CI, confidence interval [CI] = 0.81-1.20). For IRF7 (N = 160), a trend towards an association with DRFI was observed (HR = 0.89 for a 50 unit increase, 90% CI = 0.78-1.02, p = 0.081). Higher levels of the IRF7 signature were significantly associated with a decreased bone metastases risk: (HR = 0.76 for a 50 unit increase, 95% CI, 0.62-0.94, p = 0.012).

Conclusions: In this study it was shown that severe infection during NACT was not associated with decreased DRFI while high expression of the IRF7 gene signature was significantly associated with reduced bone relapse. This result may be useful for future adjuvant bisphosphonate/denosumab use.
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http://dx.doi.org/10.1016/j.ejca.2016.11.015DOI Listing
February 2017

Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis.

PLoS Med 2016 Dec 27;13(12):e1002201. Epub 2016 Dec 27.

INSERM Unit U981, Gustave Roussy, Villejuif, France.

Background: Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing.

Methods And Findings: Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9-155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2- mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival.

Conclusions: This work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations.
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http://dx.doi.org/10.1371/journal.pmed.1002201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189935PMC
December 2016

MICADo - Looking for Mutations in Targeted PacBio Cancer Data: An Alignment-Free Method.

Front Genet 2016 8;7:214. Epub 2016 Dec 8.

Centre de BioInformatique de Bordeaux, University of BordeauxBordeaux, France; Laboratoire Bordelais de Recherche en Informatique, Centre National de la Recherche Scientifique, University of BordeauxBordeaux, France.

Targeted sequencing is commonly used in clinical application of NGS technology since it enables generation of sufficient sequencing depth in the targeted genes of interest and thus ensures the best possible downstream analysis. This notwithstanding, the accurate discovery and annotation of disease causing mutations remains a challenging problem even in such favorable context. The difficulty is particularly salient in the case of third generation sequencing technology, such as PacBio. We present MICADo, a de Bruijn graph based method, implemented in python, that makes possible to distinguish between patient specific mutations and other alterations for targeted sequencing of a cohort of patients. MICADo analyses NGS reads for each sample within the context of the data of the whole cohort in order to capture the differences between specificities of the sample with respect to the cohort. MICADo is particularly suitable for sequencing data from highly heterogeneous samples, especially when it involves high rates of non-uniform sequencing errors. It was validated on PacBio sequencing datasets from several cohorts of patients. The comparison with two widely used available tools, namely VarScan and GATK, shows that MICADo is more accurate, especially when true mutations have frequencies close to backgound noise. The source code is available at http://github.com/cbib/MICADo.
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http://dx.doi.org/10.3389/fgene.2016.00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143680PMC
December 2016

GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients.

Oncotarget 2016 Nov;7(47):77358-77364

Hôpital Jean-Minjoz, Centre Hospitalier Universitaire, Boulevard Fleming, 25030 Besançon, France.

Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46×10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16×10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors.
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http://dx.doi.org/10.18632/oncotarget.12669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363591PMC
November 2016

The mammary ducts create a favourable microenvironment for xenografting of luminal and molecular apocrine breast tumours.

J Pathol 2016 11 29;240(3):256-261. Epub 2016 Sep 29.

INSERM U1218, Bergonie Cancer Institute, University of Bordeaux, 33076, Bordeaux, France.

There is a paucity of models for hormone receptor-positive (HR+) breast cancer because of the difficulty of establishing xenografts from these tumours. We show that this obstacle can be overcome by injecting human tumour cells directly into the mammary ducts of immunodeficient mice. Tumours from 31 patients were infected overnight with a lentiviral vector expressing tdTomato and injected through the nipple into the mammary ducts of NOD-SCID-IL2RG-/- mice. Tumours formed in the mice in 77% of cases after the first injection (6/8 luminal A, 15/20 luminal B, and 3/3 molecular apocrine). Four luminal A and one molecular apocrine graft were tested in secondary and tertiary grafts: all were successfully passaged in secondary and 4/5 in tertiary grafts. None of the samples engrafted when injected subcutaneously. The morphology, oestrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and Ki-67 profiles of the clinical samples were maintained in the tertiary grafts. We also show that the intraductal approach can be used to test the response to targeted therapy with fulvestrant and palbociclib, using a genetically defined ER+ model. We conclude that the mammary ducts create a microenvironment that is uniquely favourable to the survival and growth of tumours derived from mammary hormone-sensing cells. This approach opens the door to testing genomically targeted treatment of HR+ tumours in precision medicine programmes. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4772DOI Listing
November 2016

[Breast cancer screening: On our way to the future].

Bull Cancer 2016 09 26;103(9):753-63. Epub 2016 Jul 26.

Université de recherche Paris, sciences et lettres, institut Curie, 26, rue d'Ulm, 75005 Paris, France; Institut Curie, Saint-Cloud, 35, rue Dailly, 92210 Saint-Cloud, France; Université Versailles-Saint-Quentin, 78180 Montigny-le-Bretonneux, France.

Breast cancer remains a potentially lethal disease, which requires aggressive treatments and is associated with long-term consequences. Its prognosis is linked to both tumor biology and burden at diagnosis. Although treatments have allowed important improvements in prognosis over the past 20 years, breast cancer screening remains necessary. Mammographic screening allows earlier stage diagnoses and a decrease of breast cancer specific mortality. However, breast cancer screening modalities should be revised with the objective to address demonstrated limitations of mammographic screening (limited benefit, imperfect sensitivity and specificity, overdiagnoses, radiation-induced morbidity). Furthermore, both objective and perceived performances of screening procedures should be improved. Numerous large international efforts are ongoing, leading to scientific progresses that should have rapid clinical implications in this area. Among them is improvement of imaging techniques performance, development of real time diagnosis, and development of new non radiological screening techniques such as the search for circulating tumor DNA, development of biomarkers able to allow precise risk evaluation and stratified screening. As well, overtreatment is currently addressed by biomarker-based de-escalation clinical trials. These advances need to be associated with strong societal support, as well as major paradigm changes regarding the way health and cancer prevention is perceived by individuals.
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http://dx.doi.org/10.1016/j.bulcan.2016.06.005DOI Listing
September 2016