Publications by authors named "Etienne Brain"

98 Publications

New Frontiers for Fairer Breast Cancer Care in a Globalized World.

Eur J Breast Health 2021 Apr 31;17(2):86-94. Epub 2021 Mar 31.

Breast Center of Americas Integrated Oncology Center, Rio de Janeiro, Brazil.

In early 2020, the book "Breast cancer: Global Quality Care" was published by Oxford University Press. In the year since then, publications, interviews (by ecancer), presentations, webinars, and virtual congress have been organized to disseminate further the main message of the project: "A call for Fairer Breast Cancer Care for all Women in a Globalized World." Special attention is paid to increasing the "value-based healthcare" putting the patient in the center of the care pathway and sharing information on high-quality integrated breast cancer care. Specific recommendations are made considering the local resource facilities. The multidisciplinary breast conference is considered "the jewel in the crown" of the integrated practice unit, connecting multiple specializations and functions concerned with patients with breast cancer. Management and coordination of medical expertise, facilities, and their interfaces are highly recommended. The participation of two world-leading cancer research programs, the CONCORD program and Breast Health Global Initiative, in this project has been particularly important. The project is continuously under review with feedback from the faculty. The future plan is to arrive at an openaccess publication that is freely available to all interested people. This project is designed to help ease the burden and suffering of women with breast cancer across the globe.
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http://dx.doi.org/10.4274/ejbh.galenos.2021.2021-1-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025716PMC
April 2021

Phenotypic discordance between primary and metastatic breast cancer in the large-scale real-life multicenter French ESME cohort.

NPJ Breast Cancer 2021 Apr 16;7(1):41. Epub 2021 Apr 16.

Gustave Roussy Cancer Campus, Villejuif, France.

Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.
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http://dx.doi.org/10.1038/s41523-021-00252-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052407PMC
April 2021

Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study.

Genome Med 2021 Mar 15;13(1):44. Epub 2021 Mar 15.

Department of Medical Oncology, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005, Paris, France.

Background: Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use.

Methods: We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months).

Results: Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology.

Conclusions: Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse.

Trial Registration: The trial was registered at ClinicalTrials.gov ( NCT01956552 ).
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http://dx.doi.org/10.1186/s13073-021-00862-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962302PMC
March 2021

70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age.

Lancet Oncol 2021 04 12;22(4):476-488. Epub 2021 Mar 12.

European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.

Background: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age.

Methods: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing.

Findings: Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1]).

Interpretation: With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy.

Funding: European Commission Sixth Framework Programme.
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http://dx.doi.org/10.1016/S1470-2045(21)00007-3DOI Listing
April 2021

Individualizing Surveillance Mammography for Older Patients After Treatment for Early-Stage Breast Cancer: Multidisciplinary Expert Panel and International Society of Geriatric Oncology Consensus Statement.

JAMA Oncol 2021 Apr;7(4):609-615

Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts.

Importance: There is currently no guidance on how to approach surveillance mammography for older breast cancer survivors, particularly when life expectancy is limited.

Objective: To develop expert consensus guidelines that facilitate tailored decision-making for routine surveillance mammography for breast cancer survivors 75 years or older.

Evidence: After a literature review of the risk of ipsilateral and contralateral breast cancer events among breast cancer survivors and the harms and benefits associated with mammography, a multidisciplinary expert panel was convened to develop consensus guidelines on surveillance mammography for breast cancer survivors 75 years or older. Using an iterative consensus-based approach, input from clinician focus groups, and critical review by the International Society for Geriatric Oncology, the guidelines were refined and finalized.

Findings: The literature review established a low risk for ipsilateral and contralateral breast cancer events in most older breast cancer survivors and summarized the benefits and harms associated with mammography. Draft mammography guidelines were iteratively evaluated by the expert panel and clinician focus groups, emphasizing a patient's risk for in-breast cancer events, age, life expectancy, and personal preferences. The final consensus guidelines recommend discontinuation of routine mammography for all breast cancer survivors when life expectancy is less than 5 years, including those with a history of high-risk cancers; consideration to discontinue mammography when life expectancy is 5 to 10 years; and continuation of mammography when life expectancy is more than 10 years. Individualized, shared decision-making is encouraged to optimally tailor recommendations after weighing the benefits and harms associated with surveillance mammography and patient preferences. The panel also recommends ongoing clinical breast examinations and diagnostic mammography to evaluate clinical findings and symptoms, with reassurance for patients that these practices will continue.

Conclusions And Relevance: It is anticipated that these expert guidelines will enhance clinical practice by providing a framework for individualized discussions, facilitating shared decision-making regarding surveillance mammography for breast cancer survivors 75 years or older.
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http://dx.doi.org/10.1001/jamaoncol.2020.7582DOI Listing
April 2021

Management and outcome of male metastatic breast cancer in the national multicenter observational research program Epidemiological Strategy and Medical Economics (ESME).

Ther Adv Med Oncol 2020 23;12:1758835920980548. Epub 2020 Dec 23.

Department of Medical Oncology, ICO Institut de Cancerologie de l'Ouest - René Gauducheau, Saint-Herblain, France.

Background And Aims: Because of its low prevalence, metastatic breast cancer (MBC) in males is managed based on clinical experience with women. Using a real-life database, we aim to provide a comprehensive analysis of male MBC characteristics, management and outcome.

Methods: The Epidemiological Strategy and Medical Economics Data Platform collected data for all men and women ⩾18 years with MBC in 18 participating French Comprehensive Cancer Centers from January 2008 to November 2016. Demographic, clinical, and pathological characteristics were retrieved, as was treatment modality. Men were matched 1:1 to women with similar characteristics.

Results: Of 16,701 evaluable patients, 149 (0.89%) men were identified. These men were older (median age 69 years) and predominantly had hormone receptor HR+/HER2- disease (78.3%). Median overall survival (OS) was 41.8 months [95% confidence interval (CI: 26.9-49.7)] and similar to women. Median progression-free survival (PFS) with first-line therapy was 9.3 months [95% CI (7.4-11.5)]. In the HR+/HER2- subpopulation, endocrine therapy (ET) alone was the frontline treatment for 43% of patients, including antiestrogens ( = 19), aromatase inhibitors ( = 15) with luteinizing hormone-releasing hormone (LHRH) analogs ( = 3), and various sequential treatments. Median PFS achieved by frontline ET alone was similar in men [9.8 months, 95% CI (6.9-17.4)] and in women [13 months, 95% CI (8.4-30.9)] ( = 0.80). PFS was similar for HR+/HER2- men receiving upfront ET or chemotherapy: 9.8 months [95% CI (6.9-17.4)] 9.5 months [95% CI (7.4-11.7)] ( = 0.22), respectively.

Conclusion: MBC management in men and women leads to similar outcomes, especially in HR+/HER2- patients for whom ET should also be a cornerstone. Unsolved questions remain and successfully recruiting trials for men are still lacking.
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http://dx.doi.org/10.1177/1758835920980548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768846PMC
December 2020

Clinical utility of circulating tumour cell-based monitoring of late-line chemotherapy for metastatic breast cancer: the randomised CirCe01 trial.

Br J Cancer 2021 Mar 21;124(7):1207-1213. Epub 2021 Jan 21.

Department of Medical Oncology, Institut Curie, Paris, France.

Background: CirCe01 trial aimed to assess the clinical utility of circulating tumour cell (CTC)-based monitoring in metastatic breast cancer (MBC) patients beyond the third line of chemotherapy (LC).

Methods: CirCe01 was a prospective, multicentre, randomised trial (NCT01349842) that included patients with MBC after two systemic LC. Patients with ≥5 CTC/7.5 mL (CellSearch®) were randomised between the CTC-driven and the standard arm. In the CTC arm, changes in CTC count were assessed at the first cycle of each LC; patients in whom CTC levels predicted early tumour progression had to switch to a subsequent LC.

Results: Greater than or equal to 5 CTC/7.5 mL were observed in N = 101/204 patients. In the CTC arm (N = 51), 43 (83%) and 18 (44%) patients completed CTC monitoring in the third and fourth lines, respectively, and 18 (42%) and 11 (61%) of these patients, respectively, had no CTC response. Thirteen (72%) and 5 (46%) of these patients underwent early switch to the next LC. Overall survival was not different between the two arms (hazard ratio = 0.95, 95% confidence interval = [0.6;1.4], p = 0.8). In subgroup analyses, patients with no CTC response who switched chemotherapy experienced longer survival than patients who did not.

Conclusions: Due to the limited accrual and compliance, this trial failed to demonstrate the clinical utility of CTC monitoring.

Clinical Trial Registration: NCT, NCT01349842, https://clinicaltrials.gov/ct2/show/NCT01349842 , registered 9 May 2011.
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http://dx.doi.org/10.1038/s41416-020-01227-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007590PMC
March 2021

Priorities for the global advancement of care for older adults with cancer: an update of the International Society of Geriatric Oncology Priorities Initiative.

Lancet Oncol 2021 01;22(1):e29-e36

Department of Medical Oncology University Hospitals Leuven, Leuven, Belgium.

In 2011, the International Society of Geriatric Oncology (SIOG) published the SIOG 10 Priorities Initiative, which defined top priorities for the improvement of the care of older adults with cancer worldwide. Substantial scientific, clinical, and educational progress has been made in line with these priorities and international health policy developments have occurred, such as the shift of emphasis by WHO from communicable to non-communicable diseases and the adoption by the UN of its Sustainable Development Goals 2030. Therefore, SIOG has updated its priority list. The present document addresses four priority domains: education, clinical practice, research, and strengthening collaborations and partnerships. In this Policy Review, we reflect on how these priorities would apply in different economic settings, namely in high-income countries versus low-income and middle-income countries. SIOG hopes that it will offer guidance for international and national endeavours to provide adequate universal health coverage for older adults with cancer, who represent a major and rapidly growing group in global epidemiology.
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http://dx.doi.org/10.1016/S1470-2045(20)30473-3DOI Listing
January 2021

Impact of body mass index on overall survival in patients with metastatic breast cancer.

Breast 2021 Feb 1;55:16-24. Epub 2020 Dec 1.

Department of Cancer Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94800, Villejuif, France; Department of Medical Oncology, CHU de Limoges, 2 Avenue Martin Luther King, Limoges, France.

Background: High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC).

Methods: The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers.

Results: Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m (range 12.1-66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2-48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02-1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect.

Conclusion: Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor.
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http://dx.doi.org/10.1016/j.breast.2020.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725947PMC
February 2021

Impact of Mutation Status on Tumor Infiltrating Lymphocytes (TILs), Response to Treatment, and Prognosis in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

Cancers (Basel) 2020 Dec 8;12(12). Epub 2020 Dec 8.

Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.

Introduction: Five to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to status.

Material And Methods: Out of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses.

Results: Among 1199 BC patients: 46 were -deficient and 221 proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in deficient BC ( 0.001), and this association remained statistically significant only in the luminal BC subtype ( 0.006). The interaction test between BC subtype and status was nearly significant ( = 0.056). Pre and post-NAC TILs were not significantly different between deficient and proficient carriers; however, in the luminal BC group, post-NAC TILs were significantly higher in deficient BC. Survival analysis were not different between carriers and non-carriers.

Conclusions: mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC. -carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.
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http://dx.doi.org/10.3390/cancers12123681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764707PMC
December 2020

Trastuzumab Emtansine Plus Non-Pegylated Liposomal Doxorubicin in HER2-Positive Metastatic Breast Cancer (Thelma): A Single-Arm, Multicenter, Phase Ib Trial.

Cancers (Basel) 2020 Nov 25;12(12). Epub 2020 Nov 25.

Medical Department, Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ 07450, USA.

The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-naïve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m) in the "3 plus 3" dose-escalation part. During expansion, they received 60 mg/m of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3-67.7) with a median duration of response of 6.9 months (95%CI, 4.8-9.1). Clinical benefit rate was 66.7% (95%CI, 38.4-88.2) and median progression-free survival was 7.2 months (95%CI, 4.5-9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients.
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http://dx.doi.org/10.3390/cancers12123509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760511PMC
November 2020

VEGF-Related Germinal Polymorphisms May Identify a Subgroup of Breast Cancer Patients with Favorable Outcome under Bevacizumab-Based Therapy-A Message from COMET, a French Unicancer Multicentric Study.

Pharmaceuticals (Basel) 2020 Nov 23;13(11). Epub 2020 Nov 23.

Medical Oncology Department, Institut Curie, St Cloud, 92210 Paris, France.

The prospective multicenter COMET trial followed a cohort of 306 consecutive metastatic breast cancer patients receiving bevacizumab and paclitaxel as first-line chemotherapy. This study was intended to identify and validate reliable biomarkers to better predict bevacizumab treatment outcomes and allow for a more personalized use of this antiangiogenic agent. To that end, we aimed to establish risk scores for survival prognosis dichotomization based on classic clinico-pathological criteria combined or not with single nucleotide polymorphisms (SNPs). The genomic DNA of 306 patients was extracted and a panel of 13 SNPs, covering seven genes previously documented to be potentially involved in drug response, were analyzed by means of high-throughput genotyping. In receiver operating characteristic (ROC) analyses, the hazard model based on a triple-negative cancer phenotype variable, combined with specific SNPs in (rs833061), (rs9582036) and (rs1870377), had the highest predictive value. The overall survival hazard ratio of patients assigned to the poor prognosis group based on this model was 3.21 (95% CI (2.33-4.42); < 0.001). We propose that combining this pharmacogenetic approach with classical clinico-pathological characteristics could markedly improve clinical decision-making for breast cancer patients receiving bevacizumab-based therapy.
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http://dx.doi.org/10.3390/ph13110414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700430PMC
November 2020

Efficacy of Circulating Tumor Cell Count-Driven vs Clinician-Driven First-line Therapy Choice in Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: The STIC CTC Randomized Clinical Trial.

JAMA Oncol 2021 Jan;7(1):34-41

Department of Medical Oncology, Institut Curie, Université de Paris, Paris, France.

Importance: The choice between chemotherapy and endocrine therapy as first-line treatment for hormone receptor-positive, ERBB2 (also known as HER2)-negative metastatic breast cancer is usually based on the presence of clinical features associated with a poor prognosis. In this setting, a high circulating tumor cell (CTC) count (≥5 CTCs/7.5 mL) is a strong adverse prognostic factor for overall survival and progression-free survival (PFS).

Objective: To compare the efficacy of a clinician-driven treatment choice vs a CTC-driven choice for first-line treatment.

Interventions: In the CTC arm, patients received chemotherapy or endocrine therapy according to the CTC count (chemotherapy if ≥5 CTCs/7.5 mL; endocrine therapy if <5 CTCs/7.5 mL), whereas in the control arm, the choice was left to the investigator.

Design, Setting, And Participants: In the STIC CTC randomized, open-label, noninferiority phase 3 trial, participants were randomized to a clinician-driven choice of first-line treatment or a CTC count-driven first-line treatment choice. Eligible participants were premenopausal and postmenopausal women 18 years or older diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer. Data were collected at 17 French cancer centers from February 1, 2012, to July 28, 2016, and analyzed June 2019 to October 2019.

Main Outcome And Measures: The primary end point was the investigator-assessed PFS in the per-protocol population, with a noninferiority margin of 1.25 for the 90% CI of the hazard ratio.

Results: Among the 755 women in the per-protocol population, the median (range) age was 63 (30-88) years [64 (30-88) years for the 377 patients allocated to the CTC arm and 63 (31-87) years for the 378 patients allocated to the standard arm]; 138 (37%) and 103 (27%) received chemotherapy, respectively. Median PFS was 15.5 months (95% CI, 12.7-17.3) in the CTC arm and 13.9 months (95% CI, 12.2-16.3) in the standard arm. The primary end point was met, with a hazard ratio of 0.94 (90% CI, 0.81-1.09).

Conclusions And Relevance: This randomized clinical trial found that the CTC count may be a reliable biomarker method for guiding the choice between chemotherapy and endocrine therapy as the first-line treatment in hormone receptor-positive, ERBB2-negative metastatic breast cancer.

Trial Registration: ClinicalTrials.gov Identifier: NCT01710605.
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http://dx.doi.org/10.1001/jamaoncol.2020.5660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645742PMC
January 2021

Perspectives on cancer care in older patients in France.

Ecancermedicalscience 2020 15;14:1103. Epub 2020 Sep 15.

Senior Oncology Unit, Medical Oncology Department, Gustave Roussy Cancer Campus, Chevilly-Larue 94550, France.

In France, cancer is the leading cause of death. Its incidence is increasing due to the growing population and longer life expectancy. Although older adults represent most new cases, they remain underrepresented in clinical trials. Their prognosis is often worse due to delayed diagnosis and multimorbidities. Geriatric oncology has made great strides worldwide, highlighted by important studies implementing geriatric assessment in clinical research and supported by the successive national cancer plans. This paper reviews the most important actions taken in France during the last decade to improve the management of older patients with cancer.
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http://dx.doi.org/10.3332/ecancer.2020.1103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532034PMC
September 2020

Plasma thymidine kinase 1 activity and outcome of ER+ HER2- metastatic breast cancer patients treated with palbociclib and endocrine therapy.

Breast Cancer Res 2020 09 14;22(1):98. Epub 2020 Sep 14.

Department of Medical Oncology, Institut Curie, Saint-Cloud, 92210, Paris, France.

Purpose: Previous cohort studies have reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). In this prospective study, we report here the prognostic impact of pTKa in ER+/HER2- MBC patients treated with endocrine therapy and CDK4/6 inhibitor.

Experimental Design: Patients were included into the prospective, ethics committee-approved ALCINA study (NCT02866149). Eligibility criteria were patients with ER+/HER2- MBC treated at Institut Curie with endocrine therapy and palbociclib. Plasma samples were obtained at baseline and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden).

Results: From May 2016 to August 2018, 103 patients treated with endocrine therapy and palbociclib were included. Patients had received a median of two prior systemic therapies for MBC (range 0-14). Median follow-up was 13.8 months (range 6-31), with median PFS and OS of 9.6 months (95%CI [7.0-11.3]) and 28 months (95%CI [23-not reached]), respectively. Median baseline pTKa was 292 Du/L (range 20-27,312 Du/L, IQR [89-853]). After adjusting for other prognostic factors, baseline pTKa remained an independent prognostic factor for both PFS (HR = 1.3 95%CI [1.1-1.4], p = 0.0005) and OS (HR = 1.3 95%CI [1.2-1.6], p < 0.0001), and 4-week pTKa was associated with OS (HR = 1.6 95%CI [1.3-2], p < 0.0001). That survival prediction was significantly improved by the addition of baseline pTKa to clinicopathological characteristics. Adding pTKa changes at 4 weeks to baseline pTKa did not further increase survival prediction.

Conclusion: This study demonstrates the clinical validity of pTKa as a new circulating prognostic marker in ER+/HER2- MBC patients treated with endocrine therapy and palbociclib.
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http://dx.doi.org/10.1186/s13058-020-01334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489000PMC
September 2020

Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with -Mutant Metastatic Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 12 28;26(23):6242-6253. Epub 2020 Aug 28.

Centre de Biochimie Structurale (CBS), INSERM, CNRS, Université de Montpellier, Montpellier, France.

Purpose: The limited knowledge on the molecular profile of patients with -mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with -mutant NSCLC.

Experimental Design: This was a prospective study of 78 patients with advanced -mutant NSCLC, enrolled in 27 centers across France. Blood samples ( = 208) were collected from BRAF-TT-naïve patients ( = 47), patients nonprogressive under treatment ( = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.

Results: ctDNA was detected in 74% of BRAF-TT-naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as -mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in , and .

Conclusions: ctDNA sequencing is clinically relevant for the detection of -activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in -mutant NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1037DOI Listing
December 2020

Exclusive endocrine therapy or partial breast irradiation for women aged ≥70  years with luminal A-like early stage breast cancer (NCT04134598 - EUROPA): Proof of concept of a randomized controlled trial comparing health related quality of life by patient reported outcome measures.

J Geriatr Oncol 2021 Mar 29;12(2):182-189. Epub 2020 Jul 29.

Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, Florence, Italy; Azienda Ospedaliero Universitaria Careggi, Florence, Italy.

Background: Postoperative radiation therapy after breast conserving surgery in the older adult population is a matter of debate; although radiation therapy was shown to benefit these patients concerning local disease control, the absolute benefit was small and potentially negligible. Partial breast irradiation has been introduced as an alternative treatment approach for low-risk patients. Older adult patients with early breast cancer constitute a unique population with regards to prognosis and potential comorbidities, thus minimizing treatment to maintain health-related quality of life (HRQoL) without compromising survival is extremely important. Estimates of the patient's risk of benefit and/or harm with treatment should be performed together with an assessment of baseline comorbidities, life expectancy, and care preferences. Published data suggest that radiation therapy or endocrine therapy alone resulted in excellent disease control in older women with early breast cancer, and that the combination of both treatments has less incremental benefit than expected. Conversely, the toxicity profile of endocrine therapy is well known, often significantly impacting long term HRQoL of these potentially frail patients.

Methods: Patients older than 70  years receiving breast conserving surgery with T1N0, Luminal A-like tumors will be randomized to receive partial breast irradiation-alone or endocrine therapy-alone. The main objectives are to determine patient reported outcome measures in terms of HRQoL, as assessed by the EORTC QLQ-C30 using the global health status of patients, and to demonstrate a non-inferior local control rate between arms. Secondary endpoints are represented by individual scales from QLQ-C30 and module QLQ-BR45 scores; ELD14 questionnaire; geriatric COre DatasEt assessment; distant control rate, adverse events rates, breast cancer specific, and overall survival.

Discussion: The EUROPA trial is a new randomized trial focused on older adults (≥70  years) affected by good prognosis primary breast cancer. Our assumption is that postoperative radiation therapy-alone avoids the long-term toxicity of endocrine therapy and favorably impacts on HRQoL in this population. In the current report we present the trial's background and methods, focusing on perspectives in the field of precision medicine.

Trial Registration: The trial is registered with ClinicalTrial.gov Identifier NCT04134598 / EUROPA trial.
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http://dx.doi.org/10.1016/j.jgo.2020.07.013DOI Listing
March 2021

Adapting care for older cancer patients during the COVID-19 pandemic: Recommendations from the International Society of Geriatric Oncology (SIOG) COVID-19 Working Group.

J Geriatr Oncol 2020 11 16;11(8):1190-1198. Epub 2020 Jul 16.

Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

The COVID-19 pandemic poses a barrier to equal and evidence-based management of cancer in older adults. The International Society of Geriatric Oncology (SIOG) formed a panel of experts to develop consensus recommendations on the implications of the pandemic on several aspects of cancer care in this age group including geriatric assessment (GA), surgery, radiotherapy, systemic treatment, palliative care and research. Age and cancer diagnosis are significant predictors of adverse outcomes of the COVID-19 infection. In this setting, GA is particularly valuable to drive decision-making. GA may aid estimating physiologic reserve and adaptive capability, assessing risk-benefits of either providing or temporarily withholding treatments, and determining patient preferences to help inform treatment decisions. In a resource-constrained setting, geriatric screening tools may be administered remotely to identify patients requiring comprehensive GA. Tele-health is also crucial to ensure adequate continuity of care and minimize the risk of infection exposure. In general, therapeutic decisions should favor the most effective and least invasive approach with the lowest risk of adverse outcomes. In selected cases, this might require deferring or omitting surgery, radiotherapy or systemic treatments especially where benefits are marginal and alternative safe therapeutic options are available. Ongoing research is necessary to expand knowledge of the management of cancer in older adults. However, the pandemic presents a significant barrier and efforts should be made to ensure equitable access to clinical trials and prospective data collection to elucidate the outcomes of COVID-19 in this population.
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http://dx.doi.org/10.1016/j.jgo.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365054PMC
November 2020

Real-world Evaluation of Oral Vinorelbine in the Treatment of Metastatic Breast Cancer: An ESME-MBC Study.

Anticancer Res 2020 Jul;40(7):3905-3913

Biostatistics Department, Centre Léon Bérard, Lyon, France.

Background/aim: Vinorelbine is indicated for use in the treatment of MBC as a single agent or in combination but there is little real world data on this molecule and even less on its oral form. We exploited the Unicancer Epidemiology Strategy Medical-Economics (ESME) metastatic breast cancer (MBC) database to investigate current patterns of use of oral vinorelbine (OV), as well as outcomes of patients receiving this drug.

Patients And Methods: Data were collected retrospectively from women and men treated for MBC between 2008 and 2014 at one of 18 French Comprehensive Cancer Centres. The efficacy of OV was evaluated in terms of progression-free (PFS) and overall survival (OS) and treatment duration. The population and patterns of OV usage were also described.

Results: A total of 1806 patients (11% of the ESME MBC database) were included in this analysis. OV was prescribed as monotherapy (46%) or in combination (29%), especially with capecitabine. mainly in later treatment lines. Median PFS was 3.3 months: 2.9 months for single agent, 3.6 months for combination therapy. Median OS was 40.9 months.

Conclusion: Real-world data offer complementary results to the data from traditional clinical trials, but they concern a much larger population. In this ESME MBC cohort, OV was only prescribed to a small subset of MBC patients. OV was mainly given as single agent to patients with heavily pre-treated MBC; less commonly, it was co-administered with capecitabine or anti-HER2, in earlier lines of therapy. PFS was modest but in line with previous reports.
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http://dx.doi.org/10.21873/anticanres.14381DOI Listing
July 2020

Taking care of older patients with cancer in the context of COVID-19 pandemic.

Lancet Oncol 2020 05 14;21(5):e236. Epub 2020 Apr 14.

Department of Medical Oncology, Institut Bergonié, Université de Bordeaux, Inserm U1218, 33076 Bordeaux Cedex, France. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30229-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156244PMC
May 2020

Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008-2016.

Eur J Cancer 2020 04 2;129:60-70. Epub 2020 Mar 2.

Department of Cancer Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif, 94800, France. Electronic address:

Aim: Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC).

Methods: Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients' characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2-, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours.

Results: The median OS of the whole cohort was 39.5 months (95% confidence interval [CI], 38.7-40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p < 0.0001) with a median OS of 43.3 (95% CI, 42.5-44.5) in HR+/HER2-; 50.1 (95% CI, 47.6-53.1) in HER2+; and 14.8 months (95% CI, 14.1-15.5) in triple-negative subgroups, respectively. Beyond performance status, the following variables had a constant significant negative prognostic impact on OS in the whole cohort and among subtypes: older age at diagnosis of metastases (except for the triple-negative subtype), metastasis-free interval between 6 and 24 months, presence of visceral metastases and number of metastatic sites ≥ 3.

Conclusions: The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients. DATABASE REGISTRATION: clinicaltrials.gov Identifier NCT032753.
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http://dx.doi.org/10.1016/j.ejca.2020.01.016DOI Listing
April 2020

Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial.

J Clin Oncol 2020 04 21;38(11):1186-1197. Epub 2020 Feb 21.

Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal.

Purpose: MINDACT demonstrated that 46% of patients with early breast cancer at high clinical but low genomic risk on the basis of MammaPrint may safely avoid adjuvant chemotherapy. A second random assignment (R-C) compared docetaxel-capecitabine with an anthracycline-based regimen.

Patients And Methods: R-C randomly assigned patients 1:1 between standard anthracycline-based regimens, with or without taxanes (control) and experimental docetaxel 75 mg/m intravenously plus oral capecitabine 825 mg/m two times per day for 14 days (DC) every 3 weeks for 6 cycles. The primary end point was disease-free survival (DFS). Secondary end points included overall survival and safety.

Results: Of 2,832 patients, 1,301 (45%) were randomly assigned, and 97% complied with R-C assignment. In the control arm, 29.6% only received taxanes (0.5% of N0 patients). DFS events (n = 148) were much less than required (n = 422) as a result of a lower-than-expected accrual and event rate. At 5 years of median follow-up, DFS was not different between DC (n = 652) and control (n = 649; 90.7% [95% CI, 88% to 92.8%] 88.8% [95% CI, 85.9% to 91.1%]; hazard ratio [HR], 0.83 [95% CI, 0.60 to 1.15]; = .26). Overall survival (HR, 0.91 [95% CI, 0.54 to 1.53]) and DFS in the clinical high and genomic high-risk subgroup (86.1% 88.1%; HR, 0.83 [95% CI, 0.58 to 1.21]) were similar in both arms. DC led to more grade 1 neuropathy (27.1% 11.2%) and more grade 2 hand/foot syndrome (28.5% 3.3%) and diarrhea (13.7% 5.8%). Serious cardiac events occurred in 9 patients (control, n = 4; DC, n = 5). Fifty-three patients developed second cancers (control, n = 32; DC, n = 21; leukemia: 2 1). Five treatment-related deaths occurred (control, 2 [0.3%]; DC, 3 [0.5%]).

Conclusion: Although underpowered, this second randomization in MINDACT did not show any improvement in outcome or safety with the use of DC compared with anthracycline-based chemotherapy.
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http://dx.doi.org/10.1200/JCO.19.01371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840116PMC
April 2020

Reference values for the EORTC QLQ-C30 in early and metastatic breast cancer.

Eur J Cancer 2020 01 12;125:69-82. Epub 2019 Dec 12.

Department of Quality of Life, European Organization of Research and Treatment for Cancer, Brussels, Belgium. Electronic address:

Background: Considering the worldwide incidence of breast cancer (BC) and the importance of health-related quality of life (HRQoL) assessment, there is a growing need to have accurate and up-to-date reference values (RVs). RVs are useful for the design of randomised controlled trials (RCTs) and as benchmarks for comparison of cancer RCTs and health care interventions. This study aimed to provide RVs for the QLQ-C30 in early BC (EBC) and metastatic BC (MBC). General patterns of main results from the EORTC dataset (main dataset) were compared with the PDS dataset (comparison dataset) to see whether they would be consistent across pre-defined covariates.

Methods: European Organization for Research and Treatment of Cancer (EORTC) (main dataset) and Project Data Sphere (PDS) (comparison dataset) were searched to identify BC RCTs where baseline HRQoL (before treatment) was assessed with the QLQ-C30. RVs were calculated and stratified by disease stage, age, and when available, performance status (PS), comorbidity and region. RVs were reported using descriptive statistics.

Results: Data from three EORTC (n = 4115) and three PDS RCTs (n = 1406) were included in the analysis. While EBC patients presented better HRQoL with high baseline functioning scores and low prevalence of symptoms, MBC patients reported worse HRQoL with lower functioning scores and more prevalence of symptoms. In MBC, poor PS and presence of comorbidities reflected worse baseline HRQoL. No consistent differences were found for age and countries.

Conclusion: These up-to-date RVs for the EORTC QLQ-C30 in BC show differences in HRQoL scores between stages, PS, and comorbidities. These findings, supported by an independent dataset, will help the clinical interpretation of scores for BCpatients.
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http://dx.doi.org/10.1016/j.ejca.2019.10.031DOI Listing
January 2020

Treatment and outcomes in patients with central nervous system metastases from breast cancer in the real-life ESME MBC cohort.

Eur J Cancer 2020 01 10;125:22-30. Epub 2019 Dec 10.

Department of Research and Development, Unicancer, 101 Rue de Tolbiac, 75654, Paris, France.

Aim: The aims of the present study were to describe treatment patterns and survival outcomes in patients with central nervous system metastases (CNSM) selected among metastatic breast cancer (MBC) patients included in a retrospective study from the Epidemiological Strategy and Medical Economics (ESME) MBC cohort.

Methods: Neurological progression-free survival (NPFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Significant contributors to NPFS were determined using a multivariate Cox proportional hazards model.

Results: After a median follow-up of 42.8 months, of 16 701 patients included in the ESME MBC database, CNSM were diagnosed in 24.6% of patients. The most frequent treatments after diagnosis of CNSM were whole-brain radiotherapy (WBRT) (45.2%) and systemic treatment (59.3%). Median OS and NPFS were 7.9 months (95% CI: 7.2-8.4) and 5.5 months (95% CI: 5.2-5.8), respectively. In multivariate analysis, age >70 years (vs <50 years; HR = 1.40; 95% CI: 1.24-1.57), triple-negative tumours (vs HER2-/HR+; HR = 1.87; 95% CI: 1.71-2.06), HER2+/HR-tumours (vs HER2-/HR+; HR = 1.14; 95% CI: 1.02-1.27), ≥3 metastatic sites (vs < 3; HR = 1.32; 95% CI: 1.21-1.43) and ≥3 previous treatment lines (vs < 3; HR = 1.75; 95% CI: 1.56-1.96) were detrimental for NPFS. A time interval between selection and CNSM diagnosis superior to 18 months (vs <9 months; HR = 0.88; 95% CI: 0.78-0.98) was associated with longer NPFS.

Conclusions: This study describes current treatment patterns of MBC patients in a "real life" setting. Despite advances in stereotactic radiation therapy, most of the patients still received WBRT. More research is warranted to identify patient subsets for tailored treatment strategies.
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http://dx.doi.org/10.1016/j.ejca.2019.11.001DOI Listing
January 2020

Are Older Patients with Cervical Cancer Managed Differently to Younger Patients? An International Survey.

Cancers (Basel) 2019 Dec 6;11(12). Epub 2019 Dec 6.

Department of Medical Oncology, Institut Curie, Paris Science & Lettres Research University, 75005 Paris, France.

Although a quarter of cervical cancers occur after the age of 65 years, there is no treatment consensus for these patients. The aim of this work was to survey how physicians treat patients with advanced cervical cancer, focusing on treatment adjustments according to age and frailty status. Specialists were invited to an online survey. Data collected included information on respondent and treatment strategy in four cases (FIGO IIb, FIGO IVa, FIGO IVb, metastatic recurrence) with three age scenarios (45-year-old, 75-year-old and fit, 75-year-old and unfit). We received 237 responses of which 117 were fully completed. Thirty-four percent of respondents reported they had available access to a geriatric team and 25% used a frailty screening tool in routine. Therapeutic strategies did not differ between young and old fit patients. However, treatment modalities and intensity were different for old and unfit patients. Physicians answered that they would treat old fit patients as their younger counterparts but would reduce treatment intensity for old unfit patients. However, even if they were willing to adapt their treatment strategy based on frailty status, most of them do not use the tools that would allow distinguishing "fit" and "unfit" older patients, leaving room for improving accurate geriatric evaluation.
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http://dx.doi.org/10.3390/cancers11121955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966543PMC
December 2019

Actionability of HER2-amplified circulating tumor cells in HER2-negative metastatic breast cancer: the CirCe T-DM1 trial.

Breast Cancer Res 2019 11 14;21(1):121. Epub 2019 Nov 14.

Department of Medical Oncology, Institut Curie, PSL Research University, Saint Cloud, France.

Background: In this prospective phase 2 trial, we assessed the efficacy of trastuzumab-emtansine (T-DM1) in HER2-negative metastatic breast cancer (MBC) patients with HER2-positive CTC.

Methods: Main inclusion criteria for screening were as follows: women with HER2-negative MBC treated with ≥ 2 prior lines of chemotherapy and measurable disease. CTC with a HER2/CEP17 ratio of ≥ 2.2 by fluorescent in situ hybridization (CellSearch) were considered to be HER2-amplified (HER2). Patients with ≥ 1 HER2 CTC were eligible for the treatment phase (T-DM1 monotherapy). The primary endpoint was the overall response rate.

Results: In 154 screened patients, ≥ 1 and ≥ 5 CTC/7.5 ml of blood were detected in N = 118 (78.7%) and N = 86 (57.3%) patients, respectively. ≥1 HER2 CTC was found in 14 patients (9.1% of patients with ≥ 1 CTC/7.5 ml). Among 11 patients treated with T-DM1, one achieved a confirmed partial response. Four patients had a stable disease as best response. Median PFS was 4.8 months while median OS was 9.5 months.

Conclusions: CTC with HER2 amplification can be detected in a limited subset of HER2-negative MBC patients. Treatment with T-DM1 achieved a partial response in only one patient.

Trial Registration: NCT01975142, Registered 03 November 2013.
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http://dx.doi.org/10.1186/s13058-019-1215-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854749PMC
November 2019

Impact of breast cancer molecular subtypes on the incidence, kinetics and prognosis of central nervous system metastases in a large multicentre real-life cohort.

Br J Cancer 2019 12 13;121(12):991-1000. Epub 2019 Nov 13.

Department of Medical Oncology, Centre Léon Bérard, 28 Promenade Léa et Napoléon Bullukian, 69008, Lyon, France.

Background: Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses.

Methods: The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient's prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan-Meier method).

Results: CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2-/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR- (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8-92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5-17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18-3.75, triple-negative and HER2-/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2-8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50-0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65-0.81) for HER2+/HR-, 4.4 months (HR = 1.55, 95% CI: 1.42-1.69) for triple-negative and 7.1 months for HER2-/HR+ patients (p <0.0001).

Conclusions: Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients.

Clinical Trial Registration: NCT03275311.
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http://dx.doi.org/10.1038/s41416-019-0619-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964671PMC
December 2019

UCBG 2-04: Long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the human epidermal growth factor receptor 2-positive subgroup.

Eur J Cancer 2019 11 18;122:91-100. Epub 2019 Oct 18.

Medical Oncology Department, IUCT Claudius Regaud, Toulouse, France.

Purpose: We conducted a double-randomised phase III trial to evaluate a concomitant taxane-anthracycline regimen in node-positive breast cancer and the efficacy of trastuzumab in the human epidermal growth factor receptor 2 (HER2)-positive subpopulation.

Methods: A total of 3010 patients with node-positive breast cancer were randomly assigned to receive 6 cycles of 500 mg/m of fluorouracil, 100 mg/m of epirubicin and 500 mg/m of cyclophosphamide (FEC) or 75 mg/m of epirubicin and 75 mg/m of docetaxel (ED). Patients with HER2-positive tumours were secondary randomly assigned to either trastuzumab or observation. The primary end-point was disease-free survival (DFS) in the two chemotherapy arms.

Results: After a 115-month median follow-up, DFS was not significantly better in the ED arm (DFS: 70%, 95% confidence interval [CI]: 67-72) than in the FEC arm (DFS: 68%, 95% CI: 65-70; hazard ratio [HR] = 0.88, 95% CI: 0.77-1.01; p = 0.064). The OS was not different between FEC (OS: 80%, 95% CI: 78-83) and ED (OS: 81%, 95% CI: 79-83); HR = 0.97, 95% CI: 0.81-1.16; p = 0.729). ED appeared more toxic. In the 528 HER2-positive subset, there was trend for a higher DFS, in the intention-to-treat population, in the trastuzumab arm (DFS: 68%, 95% CI: 61-74) than in the observation arm (DFS: 60%, 95% CI: 54-66; HR = 0.77, 95% CI: 0.57-1.03; p = 0.079). In the per-protocol population, DFS was significantly higher in the trastuzumab arm (DFS: 70%, 95% CI: 63-76) than in the observation arm (DFS: 59%, 95% CI: 53-65; HR = 0.69, 95% CI: 0.51-0.94; p = 0.0156). The OS was not different between these 2 arms.

Conclusion: This study did not show superiority of the concomitant anthracycline-taxane arm which was more toxic in high-risk node-positive breast cancer patients. Long-term results of the HER2-positive subpopulation are in line with those of the other adjuvant trastuzumab trials but quantitatively less pronounced mostly because of lack of power.
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http://dx.doi.org/10.1016/j.ejca.2019.09.014DOI Listing
November 2019

Interaction between Molecular Subtypes and Stromal Immune Infiltration before and after Treatment in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

Clin Cancer Res 2019 11 12;25(22):6731-6741. Epub 2019 Sep 12.

Residual Tumor and Response to Treatment Laboratory, RT2Lab, INSERM, U932 Immunity and Cancer, Institut Curie, Paris, France.

Purpose: High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and -positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC.

Experimental Design: We assessed stromal TIL levels in 716 pre- and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group.

Results: Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, = 0.001). This was observed in luminal tumors and TNBCs, but not in -positive breast cancers ( = 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs ( = 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, < 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels ( = -0.80, < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner ( < 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in -positive breast cancers (HR, 1.04; confidence interval, 1.02-1.06; = 0.001), but not in luminal tumors or TNBCs ( = 0.04).

Conclusions: The associations of pre- and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3017DOI Listing
November 2019