Publications by authors named "Jean Sebastien Frenel"

54 Publications

Real-life prognosis of 5041 bone-only metastatic breast cancer patients in the multicenter national observational ESME program.

Ther Adv Med Oncol 2021 21;13:1758835920987657. Epub 2021 Jan 21.

Department of Medical Oncology, ICO René Gauducheau, Boulevard Jacques Monod, Saint Herblain, Pays de la Loire 44805, France.

Background: Bone-only (BO) metastatic breast cancer (MBC) is considered a more favorable entity than other MBC presentations. However, only few retrospective series and data from selected randomized controlled trials have been reported so far.

Methods: Using the French national multicenter ESME (Epidemiological Strategy and Medico Economics) Data Platform, the primary objective of our study was to compare the overall survival (OS) of patients with BO non-BO MBC at diagnosis, with adjustment on main prognostic factors using a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1), describe treatment patterns, and estimate factors associated with OS.

Results: Out of 20,095 eligible women, 5041 (22.4%) patients had BO disease [hormone-receptor positive (HR+)/human epidermal growth-factor-receptor-2 negative (HER2-),  = 4 102/13,229 (31%); HER2+,  = 644/3909 (16.5%); HR-/HER2-,  = 295/2 957 (10%)]. BO MBC patients had a better adjusted OS compared with non-BO MBC [52.1 months (95% confidence interval (CI) 50.3-54.1) 34.7 months (95% CI 34.0-35.6) respectively]. The 5-year OS rate of BO MBC patients was 43.4% (95% CI 41.7-45.2). They also had a better PFS1 [13.1 months (95% CI 12.6-13.8) 8.5 months (95% CI 8.3-8.7), respectively]. This observation could be repeated in all subtypes. BO disease was an independent prognostic factor of OS [hazard ratio 0.68 (95% CI 0.65-0.72),  < 0.0001]. Results were concordant in all analyses.

Conclusion: BO MBC patients have better outcomes compared with non-BO MBC, consistently, through all MBC subtypes.
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http://dx.doi.org/10.1177/1758835920987657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841864PMC
January 2021

Early Locoregional Breast Surgery and Survival in de novo Metastatic Breast Cancer in the Multicenter National ESME Cohort.

Ann Surg 2021 Feb 1. Epub 2021 Feb 1.

Department of Surgical Oncology, Institut de Cancérologie de Lorraine, Vandoeuvre-lès-Nancy, 6 Avenue de Bourgogne, 54519 Vandœuvre-lès-Nancy, France Department of Surgical Oncology, Institut Godinot, 1 Rue du Général Koenig, 51100 Reims, France Department of Biostatistics, Institut Claudius Regaud - IUCT Oncopole, 1 Avenue Irène-Joliot-Curie, 31059 Toulouse, France Department of Medical Oncology, Institut de Cancérologie de l'Ouest Nantes & Angers, 15 rue André Boquel, 49055 Angers, France Department of Medical Oncology, Centre François Baclesse, 3 Avenue du Général Harris, 14000 Caen, France Department of Plastic and Reconstructive Surgery, Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France Medical Oncology Department, Centre Oscar Lambret, 3 Rue Frédéric Combemale, 59000 Lille, France Department of Medical Oncology, Institut Bergonie, 229 Cours de l'Argonne, F-33000 Bordeaux, France Department of Surgical Oncology, Institut du Cancer de Montpellier, 208 Rue des Apothicaires, 34298 Montpellier, France Department of Medical Oncology, Centre Henri Becquerel, Rue d'Amiens, 76000 Rouen, France Department of Medical Oncology, Institut Paoli-Calmettes, 232 Boulevard de Sainte-Marguerite, 13009 Marseille Department of Surgical Oncology, Centre Georges François Leclerc, 1 rue Professeur Marion, 21079 Dijon, France Department of Surgical Oncology, Centre Eugène Marquis, Avenue de la Bataille Flandres-Dunkerque, 35000 Rennes, France Department of Medical Oncology, Centre Léon Bérard, 28 Prom. Léa et Napoléon Bullukian, 69008 Lyon, France Department of Medical Oncology, Centre Antoine Lacassagne, 33 Avenue de Valambrose, 06189 Nice, France Department of Medical Oncology, Institut Godinot, 1 Rue du Général Koenig, 51100 Reims, France Department of Medical Oncology, Centre Paul Strauss, 3 Rue de la Porte de l'Hôpital, 67000 Strasbourg, France Department of Medical Oncology, Institut Curie, 26 Rue d'Ulm, 75005 Paris & Saint-Cloud, France Department of Medical Oncology, Institut de Cancérologie de l'Ouest - René Gauducheau, Boulevard Professeur Jacques Monod, 44805 Nantes, France Department of Research and Development, R&D Unicancer, 101 Rue de Tolbiac, 75654 Paris, France Department of Medical Oncology, Institut Claudius Regaud - IUCT Oncopole, 1 Avenue Irène-Joliot-Curie, 31059 Toulouse, France.

Objective: The aim was to evaluate the impact of local surgery performed during the year following metastatic breast cancer (MBC) diagnosis on patients' outcomes from a large real-life cohort.

Summary Background Data: Locoregional treatment for patients with MBC at the time of diagnosis remains debated.

Methods: Women with newly diagnosed, de novo stage IV MBC and who started MBC treatment between January 2008 and December 2014 in one of the 18 French Comprehensive Cancer Centers were included (NCT03275311). The impact of local surgery performed during the first year on overall survival (OS) and progression-free survival (PFS) was evaluated by the Cox proportional hazards model in a 12 month-landmark analysis.

Results: Out of 16,703 patients in the ESME database, 1,977 had stage IV MBC at diagnosis, were alive and progression-free at 12 months and eligible for this study. Among them, 530 (26.8%) had received primary breast cancer surgery within 12 months. A greater proportion of patients who received surgery had less than 3 metastatic sites than the no-surgery group (90.8% vs 78.2%, p < 0.0001). Surgery within 12 months was associated with treatment with chemotherapy, HER2-targeted therapy (89.1% vs 69.6%, p < 0.0001) and locoregional radiotherapy (81.7% vs 32.5%, p < 0.0001). Multivariable analyses showed that surgery performed within 12 months was associated with longer OS and PFS (adjusted HR [95%CI] = 0.75 [0.61 - 0.92] and 0.72 [0.63 - 0.83], respectively), which were also affected by pattern and number of metastatic sites, histological subtype and age.

Conclusions: In the large ESME cohort, surgery within one year after de novo MBC diagnosis was associated with a significantly better OS and PFS.
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http://dx.doi.org/10.1097/SLA.0000000000004767DOI Listing
February 2021

Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial.

Cancer 2021 Jan 26. Epub 2021 Jan 26.

Institut Gustave Roussy, Villejuif, France.

Background: Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma.

Methods: Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively).

Results: After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression-free survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%).

Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.
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http://dx.doi.org/10.1002/cncr.33378DOI Listing
January 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

Characteristics and outcome of breast cancer-related microangiopathic haemolytic anaemia: a multicentre study.

Breast Cancer Res 2021 Jan 19;23(1). Epub 2021 Jan 19.

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

Background: Cancer-related microangiopathic haemolytic anaemia (MAHA) is a rare but life-threatening paraneoplastic syndrome. Only single cases or small series have been reported to date. We set up a retrospective multicentre study focusing on breast cancer-related MAHA.

Methods: Main inclusion criteria were known diagnosis of breast cancer, presence of schistocytes and either low haptoglobin or cytopenia and absence of any causes of MAHA other than breast cancer, including gemcitabine- or bevacizumab-based treatment. Patient characteristics, treatments and outcome were retrieved from digital medical records.

Results: Individual data from 54 patients with breast cancer-related MAHA were obtained from 7 centres. Twenty-three (44%) patients had a breast tumour with lobular features, and most primary tumours were low grade (grade I/II, N = 39, 75%). ER+/HER2-, HER2+ and triple-negative phenotypes accounted for N = 33 (69%), N = 7 (15%) and N = 8 (17%) cases, respectively. All patients had stage IV cancer at the time of MAHA diagnosis. Median overall survival (OS) was 28 days (range 0-1035; Q1:10, Q3:186). Independent prognostic factors for early death (≤ 28 days) were PS > 2 (OR = 7.0 [1.6; 31.8]), elevated bilirubin (OR = 6.9 [1.1; 42.6]), haemoglobin < 8.0 g/dL (OR = 3.7 [0.9; 16.7]) and prothrombin time < 50% (OR = 9.1 [1.2; 50.0]). A score to predict early death displayed a sensitivity of 86% (95% CI [0.67; 0.96]), a specificity of 73% (95% CI [0.52; 0.88]) and an area under the curve of 0.90 (95% CI [0.83; 0.97]).

Conclusions: Breast cancer-related MAHA appears to be a new feature of invasive lobular breast carcinoma. Prognostic factors and scores may guide clinical decision-making in this serious but not always fatal condition.
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http://dx.doi.org/10.1186/s13058-021-01386-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814553PMC
January 2021

Development of a Prognostic Tool to Guide the Decision to Extend Adjuvant Aromatase Inhibitors for up to Ten Years in Postmenopausal Early Breast Cancer Patients.

Cancers (Basel) 2020 Dec 11;12(12). Epub 2020 Dec 11.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Boulevard Professeur Jacques Monod, 44800 Saint-Herblain, France.

The selection of women with hormone receptor-positive (HR+) early breast cancer (EBC) at high risk of relapse after five years (yrs.) of adjuvant aromatase inhibitors (AIs) is crucial, as the benefit of extending AIs is counterbalanced by toxicity. We developed a clinicopathological tool to estimate the residual risk of relapse after five years of adjuvant AIs. The Institut de Cancérologie de l'Ouest (ICO) database was used to determine a prognostic score of post-five-year AI relapse. Cox regression models estimated our score's prognostic performance. In total, 1105 women were included. Median follow-up was 44 months (IQR = 21-70) post-AI treatment. From the Cox models, we designed a dichotomous prognostic score including the number of macrometastases, age (>70 yrs. vs. ≤70 yrs.), tumor size (≥T2 vs. not), and mitotic activity (≥2 vs. not). Overall, 77.5% of patients were classified as being at low risk and 22.5% at high risk of late recurrence. Low-risk patients had a five- to ten-year local or distant recurrence risk of 7.6% (95% CI, 5.4% to 10.6%) as compared with 26.9% (95% CI, 19.9% to 35.7%) for the high-risk roup. In this study, we developed a simple tool to identify women at high risk of relapse despite completing five years of AIs.
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http://dx.doi.org/10.3390/cancers12123725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763581PMC
December 2020

Anti-PD1 therapy induces lymphocyte-derived exosomal miRNA-4315 release inhibiting Bim-mediated apoptosis of tumor cells.

Cell Death Dis 2020 12 11;11(12):1048. Epub 2020 Dec 11.

CRCINA, INSERM, Université de Nantes, Nantes, France.

Anti-PD1 immunotherapy, as a single agent or in combination with standard chemotherapies, has significantly improved the outcome of many patients with cancers. However, resistance to anti-PD1 antibodies often decreases the long-term therapeutic benefits. Despite this observation in clinical practice, the molecular mechanisms associated with resistance to anti-PD1 antibody therapy have not yet been elucidated. To identify the mechanisms of resistance associated with anti-PD1 antibody therapy, we developed cellular models including purified T cells and different cancer cell lines from glioblastoma, lung adenocarcinoma, breast cancer and ovarian carcinoma. A murine model of lung cancer was also used. Longitudinal blood samples of patients treated with anti-PD1 therapy were also used to perform a proof-of-concept study of our findings. We found that anti-PD1 exposure of T-cell promotes an enrichment of exosomal miRNA-4315. We also noted that exosomal miRNA-4315 induced a phenomenon of apopto-resistance to conventional chemotherapies in cancer cells receiving exosomal miRNA-4315. At molecular level, we discern that the apopto-resistance phenomenon was associated with the miRNA-4315-mediated downregulation of Bim, a proapoptotic protein. In cellular and mice models, we observed that the BH3 mimetic agent ABT263 circumvented this resistance. A longitudinal study using patient blood showed that miRNA-4315 and cytochrome c can be used to define the time period during which the addition of ABT263 therapy may effectively increase cancer cell death and bypass anti-PD1 resistance.This work provides a blood biomarker (exosomal miRNA-4315) for patient stratification developing a phenomenon of resistance to anti-PD1 antibody therapy and also identifies a therapeutic alternative (the use of a BH3 mimetic drug) to limit this resistance phenomenon.
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http://dx.doi.org/10.1038/s41419-020-03224-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733505PMC
December 2020

A pharmacokinetic evaluation of alpelisib for the treatment of HR+, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer.

Expert Opin Drug Metab Toxicol 2021 Feb 8;17(2):139-152. Epub 2020 Dec 8.

Department of Medical Oncology, Institut de Cancérologie de l'Ouest - Pays de la Loire , France.

: In most cases, metastatic breast cancer remains an incurable disease. A PIK3CA mutation is detected in 30-40% of all hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancers. PIK3CA activating mutations have been linked to endocrine resistance. PI3K inhibitors therefore offer promising new therapeutic options for this disease. : This review discusses the pharmacologic properties, preclinical development, clinical efficacy, and safety profile of alpelisib, a PI3K inhibitor indicated in HR+/HER2 - PIK3CA-mutated advanced breast cancer, describing current therapeutic indication and open questions. : Following results of the SOLAR-1 trial, alpelisib became the first PI3K inhibitor approved by the U.S. Food and Drug Administration, in combination with fulvestrant, for postmenopausal women and men with HR+/HER2 - PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen. This trial showed a substantial improvement in progression-free survival. However, given the side effects of alpelisib, the treatment decision should follow a thorough benefit-risk assessment. The BYLieve trial suggests alpelisib-fulvestrant benefit after progression on CDK 4/6 inhibitors. The identification of patients that are likely to benefit the most from PI3K inhibitors is still eagerly sought.
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http://dx.doi.org/10.1080/17425255.2021.1844662DOI Listing
February 2021

Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer.

Ther Adv Med Oncol 2020 28;12:1758835920940939. Epub 2020 Jul 28.

Department of Medical Oncology, Institut de cancerologie de l'ouest site René Gauducheau, Saint Herblain, France.

Recently many therapeutic classes have emerged in advanced hormone receptor-positive breast cancer, which is the leading cause of cancer death in women. In absence of visceral crisis, treatment relies on endocrine therapy combined with cyclin dependent kinase 4 and 6 inhibitor. Many mechanisms lead to resistance to endocrine therapy, including the activation of intracellular signaling pathways critical for cell survival. Approximately 70% of breast tumors harbor an alteration in the phosphoinositide 3 kinase (PI3K)/Akt pathway, leading to its hyper activation. This pathway is involved in the regulation of growth, proliferation and cell survival as well as in angiogenesis and is consequently a major target in the oncogenesis. An aberrant mutation is a common phenomenon in breast cancer and found in approximately 40% of patients with advanced hormone receptor-positive breast cancer. For the moment, the only positive trials showing a progression free survival benefit in this population are BOLERO-2 (2012), SOLAR-1 (2019), which tested everolimus, a mammalian target of rapamycin inhibitor, and alpelisib, a PI3K inhibitor, and led to their marketing authorization. However, many other inhibitors of this pathway are promising; nevertheless their development is actually limited by toxicity, mainly cutaneous (rash), digestive (diarrhea) and endocrine (diabetes).
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http://dx.doi.org/10.1177/1758835920940939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388095PMC
July 2020

EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand.

Neurooncol Adv 2020 Jan-Dec;2(1):vdz051. Epub 2019 Dec 9.

Departments of Neurology, Erasmus MC, Rotterdam, The Netherlands.

Background: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.

Methods: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit.

Results: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy.

Conclusions: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.
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http://dx.doi.org/10.1093/noajnl/vdz051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212878PMC
December 2019

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

Radiotherapy-induced overexpression of exosomal miRNA-378a-3p in cancer cells limits natural killer cells cytotoxicity.

Epigenomics 2020 03 8;12(5):397-408. Epub 2020 Apr 8.

CRCINA, INSERM, Université de Nantes, Nantes 44000, France.

We here hypothesized that tumor-derived exosomal miRNA (TexomiR) released from irradiated tumors may play a role in the tumor cells escape to natural killer (NK) cells. Our study included the use of different cancer cell lines, blood biopsies of xenograph mice model and patients treated with radiotherapy. The irradiation of cancer cells promotes the TET2-mediated demethylation of miR-378 promoter, miR-378a-3p overexpression and its loading in exosomes, inducing the decrease of granzyme-B (GZMB) secretion by NK cells. An inverse correlation between TexomiR-378a-3p and GZMB was observed in murine and human blood samples. Our work identifies TexomiR-378a-3p as a molecular signature associated with the loss of NK cells cytotoxicity via the decrease of GZMB expression upon radiotherapy.
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http://dx.doi.org/10.2217/epi-2019-0193DOI Listing
March 2020

[Proton pump inhibitors and cancers: A hazardous association?]

Bull Cancer 2020 Apr 10;107(4):458-464. Epub 2020 Feb 10.

Institut de cancérologie de l'Ouest, département d'oncologie médicale, boulevard Professeur Jacques-Monod, 44800 Saint-Herblain, France.

Proton pump inhibitors, a major progress in gastro-enterology, are globally among the most widely prescribed drugs. But, due to their strong gastric acid inhibition, they can be responsible for side effects, particularly in cancer patients. They are involved in renal function impairment, bone fractures, digestive bacterial overgrowth, particularlyclostridium difficile infections, anemia and hypomagnesemia. Long term use can increase the risks of gastric, pancreatic and liver cancers. They decrease absorption of weak bases drugs, particularly tyrosine kinase inhibitors and capecitabine and are responsible for a poorer prognosis if taken concomitantly with erlotinib, gefitinib and pazopanib. Modification of cyclin dependent kinases is also possible as well as decrease of efficacy of immune check point inhibitors (microbiome modifications). Absoption and efficacy of capecitabine seem also poorer with negative prognosis effect on treatment of gastric and colon cancer. Their long term use, particularly in cancer patients, should probably be avoided.
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http://dx.doi.org/10.1016/j.bulcan.2019.12.009DOI Listing
April 2020

Cell-free circulating epimarks in cancer monitoring.

Epigenomics 2020 01 9;12(2):145-155. Epub 2020 Jan 9.

CRCINA, INSERM, Université de Nantes, Nantes, France.

Cancer numbers increasing, cases heterogeneity and the drug resistance emergence have pushed scientists to search for innovative solutions for patients and epimutations can be one. Methylated DNA, modified nucleosomes and noncoding RNAs are found in all cells, including tumor cells. They are intracellular actors but also have intercellular communication roles, being released in extracellular environment and in different body fluids. Here, we reviewed current literature on the use of these blood circulating epimarks in cancer monitoring. What stands out is that epimarkers must be considered as 'real time' images of the tumor, and can be isolated without invasive methods. In the future, the real challenge lies in the development of specific, sensitive, fast and clinically applicable detection and analysis methods of epimarkers.
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http://dx.doi.org/10.2217/epi-2019-0170DOI Listing
January 2020

[Retrospective study: Late surgery post chemotherapy versus after 3-4 cures in treatment of advanced ovarian cancer].

Bull Cancer 2020 Feb 16;107(2):157-170. Epub 2019 Dec 16.

Centre François-Baclesse, 2, avenue du Général-Harris, 14000 Caen, France.

Introduction: Treatment in locally advanced ovarian cancer is optimal surgery followed by chemotherapy. Patients with significant tumor spread, OMS>2, age>75 years old are poor candidates for aggressive primary surgery. Interval surgery, after neo-adjuvant chemotherapy, aims to achieve more complete surgery, increase survival, and reduce surgical morbidity. The primary endpoint was progression-free survival. Secondary outcomes were overall survival and postoperative morbidity and mortality.

Method: This is a retrospective study conducted in 2 French referral centers between January 2000 and December 2015. Patients who could not benefit from a complete initial surgery were operated after 3 cures of chemotherapy at the François Baclesse center and after least 5 cures at the center René Gauducheau.

Results: The population analyzed included 104 patients, 43 (41.0%) patients treated at the René Gauducheau center (group 1) and 61 (59.0%) patients treated at the François Baclesse center (group 2). Progression-free and overall survival were similar between the 2 groups, they were, respectively, 15.9 months and 34 months in group 1 vs. 15.4 months and 37.6 months in group 2 (P=0.72; P=0.65). Mean hospital stay and postoperative morbidity were similar in both groups.

Conclusion: For weak patients, to limit invasive surgery, doing more than 5 courses of chemotherapy may be a reasonable option.
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http://dx.doi.org/10.1016/j.bulcan.2019.10.004DOI Listing
February 2020

Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis.

EMBO J 2020 01 27;39(1):e102030. Epub 2019 Nov 27.

Team SOAP, CRCINA, Inserm, CNRS, Université de Nantes, Université d'Angers, Nantes, France.

Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-κB activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impairs autophagic flux, and culminates in lysosomal-mediated cell death, concomitantly with mTOR inactivation and dispersion from endo-lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.
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http://dx.doi.org/10.15252/embj.2019102030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939194PMC
January 2020

Glyphosate Primes Mammary Cells for Tumorigenesis by Reprogramming the Epigenome in a TET3-Dependent Manner.

Front Genet 2019 27;10:885. Epub 2019 Sep 27.

CRCINA, INSERM, Université de Nantes, Nantes, France.

The acknowledgment that pollutants might influence the epigenome raises serious concerns regarding their long-term impact on the development of chronic diseases. The herbicide glyphosate has been scrutinized for an impact on cancer incidence, but reports demonstrate the difficulty of linking estimates of exposure and response analysis. An approach to better apprehend a potential risk impact for cancer is to follow a synergistic approach, as cancer rarely occurs in response to one risk factor. The known influence of glyphosate on estrogen-regulated pathway makes it a logical target of investigation in breast cancer research. We have used nonneoplastic MCF10A cells in a repeated glyphosate exposure pattern over 21 days. Glyphosate triggered a significant reduction in DNA methylation, as shown by the level of 5-methylcytosine DNA; however, in contrast to strong demethylating agent and cancer promoter UP peptide, glyphosate-treated cells did not lead to tumor development. Whereas UP acts through a DNMT1/PCNA/UHRF1 pathway, glyphosate triggered increased activity of ten-eleven translocation (TET)3. Combining glyphosate with enhanced expression of microRNA (miR) 182-5p associated with breast cancer induced tumor development in 50% of mice. Culture of primary cells from resected tumors revealed a luminal B (ER+/PR-/HER2-) phenotype in response to glyphosate-miR182-5p exposure with sensitivity to tamoxifen and invasive and migratory potentials. Tumor development could be prevented either by specifically inhibiting miR 182-5p or by treating glyphosate-miR 182-5p-cells with dimethyloxallyl glycine, an inhibitor of TET pathway. Looking for potential epigenetic marks of TET-mediated gene regulation under glyphosate exposure, we identified and genes, the hypomethylation of which was sustained even after stopping glyphosate exposure for 6 weeks. Our findings reveal that low pressure but sustained DNA hypomethylation occurring the TET pathway primes cells for oncogenic response in the presence of another potential risk factor. These results warrant further investigation of glyphosate-mediated breast cancer risk.
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http://dx.doi.org/10.3389/fgene.2019.00885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777643PMC
September 2019

Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer.

Int J Cancer 2020 01 6;146(2):439-448. Epub 2019 Sep 6.

AGO and Department of Gynecology and Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.
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http://dx.doi.org/10.1002/ijc.32606DOI Listing
January 2020

Current options and future possibilities for the systemic treatment of hepatocellular carcinoma.

Hepat Oncol 2019 Jun 4;6(1):HEP11. Epub 2019 Jun 4.

Department of Medical Oncology, Institut Paoli-Calmettes, Cedex 9, Marseille 13000, France.

Most hepatocellular carcinoma patients could not benefit from or experience disease recurrence after curative treatments. In 2007 sorafenib demonstrated efficacy in first line treatment of advanced hepatocellular carcinoma. After a decade of negative trials, in early 2019 we now have another tyrosine kinase inhibitor available in first line, lenvatinib, three other targeted therapies in second line post-sorafenib (regorafenib, cabozantinib and ramucirumab) and promising data from two immunotherapies (nivolumab and pembrolizumab). Unfortunately, no biomarkers have been identified to help guide our choice. In this short review we summarize the results of these different therapies and propose a therapeutic algorithm based on subgroup analysis. It is most likely that we will not have head-to-head comparisons in second line trials.
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http://dx.doi.org/10.2217/hep-2019-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571544PMC
June 2019

Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data.

Cancer Manag Res 2019 15;11:4297-4312. Epub 2019 May 15.

Medical Oncology Department, Institut de Cancérologie de l'Ouest, Saint-Herblain 44800, France.

Pembrolizumab is a full-length human immunoglobulin G4 (IgG4) monoclonal antibody directed against the immune checkpoint PD-1 to remove its binding with PD-L1 and thus to restore an anti-tumor immune response of T cells. Pembrolizumab is one of the most advanced immune checkpoint inhibitors for cancer care. Apart from rare and serious adverse effects, its favorable tolerance profile enables to treat fragile patients who have often no other choice than best supportive care. The effective retained dose of pembrolizumab is a venous administration of 200 mg every 3 weeks until disease progression, intolerance or up to 24 months. Pembrolizumab has already proven its efficacy and thus obtained marketing authorization in so-called hot or hypermutated tumors or tumors expressing PD-L1 such as melanomas, non-small cell lung cancers, urothelial carcinomas, cervical cancer, etc. Pembrolizumab is also authorized in the United States in the treatment of mismatch repair-deficient tumors or with microsatellite instability. The current challenge is to expand its use in tumor types that are supposed to be less immunogenic, for example, by attempting to warm up the tumor microenvironment, or by combining pembrolizumab with other molecules. An acceptable toxicity profile of such combinations remains to explore. We review here the current indications of this drug, the main prognostic and predictive factors of its efficacy as well as the potential forthcoming indications.
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http://dx.doi.org/10.2147/CMAR.S151023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527794PMC
May 2019

Benefits versus risk profile of buparlisib for the treatment of breast cancer.

Expert Opin Drug Saf 2019 Jul;18(7):553-562

d Unité INSERM 1232, Equipe 8 CRCINA , ICO Nantes-Angers , Nantes , France.

: Activation of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways occurs in 70% of breast cancer, including PIK3CA activating mutations, PTEN loss and AKT mutation. It is associated with poor prognosis and resistance to anti-HER2 and endocrine therapy. PI3K inhibitors are promising anticancer targets that can reverse resistance to these therapies. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different solid tumors as monotherapy or in combination. : This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib. : Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α-selective PI3K inhibitors for ongoing and future trials.
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http://dx.doi.org/10.1080/14740338.2019.1623877DOI Listing
July 2019

Defining EGFR amplification status for clinical trial inclusion.

Neuro Oncol 2019 10;21(10):1263-1272

Department of Neurology, Erasmus Medical Center Cancer Institute, Rotterdam, Netherlands.

Background: Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no gold standard in determining the amplification status of EGFR or variant III (EGFRvIII) expression. Here, we aimed to determine which technique and which cutoffs are suitable to determine EGFR amplification status.

Methods: We compared fluorescence in-situ hybridization (FISH) and real-time quantitative (RT-q)PCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA).

Results: By using data from >1000 samples, we show that at least 50% of EGFR amplified nuclei should be present to define EGFR gene amplification by FISH. Gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with receiver operating characteristics analysis showing an area under the curve of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data show that EGFR copy numbers can strongly vary between tumors, with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level, FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII.

Conclusion: Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help define the optimal cutoff for various techniques to determine EGFR amplification for diagnostic purposes.
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http://dx.doi.org/10.1093/neuonc/noz096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784284PMC
October 2019

Pertuzumab for the treatment of breast cancer.

Expert Rev Anticancer Ther 2020 02 29;20(2):85-95. Epub 2019 Aug 29.

Medical Oncology, Institut de Cancérologie de l'Ouest, René Gauducheau, St Herblain, France.

: Pertuzumab, a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), inhibits the heterodimerization of HER2 with other HER receptors. It has been approved both by the Food and Drug Administration and the European Medicine Agency in the metastatic, neoadjuvant and adjuvant setting.: This review analyses and discusses preclinical and clinical studies of pertuzumab in breast cancer. In this article, we review the status of pertuzumab, the completed and ongoing trials, and its safety.: Pertuzumab is a key drug for the treatment of HER2-positive metastatic or early breast cancer. However, it is imperative to identify patients that will need dual-targeting and mechanisms of resistance. Moreover, the value of pertuzumab beyond progression needs to be evaluated.
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http://dx.doi.org/10.1080/14737140.2019.1596805DOI Listing
February 2020

Patient-centered simulations to assess the usefulness of the 70-gene signature for adjuvant chemotherapy administration in early-stage breast cancer.

Breast Cancer Res Treat 2019 Apr 2;174(2):537-542. Epub 2019 Jan 2.

INSERM UMR 1246 -SPHERE, Nantes University, Tours University, Nantes, France.

Purpose: From the MINDACT trial, Cardoso et al. did not demonstrate a significant efficacy for adjuvant chemotherapy (CT) for women with early-stage breast cancer presenting high clinical and low genomic risks. Our objective was to assess the usefulness of the 70-gene signature in this population by using an alternative endpoint: the number of Quality-Adjusted Life-Years (QALYs), i.e., a synthetic measure of quantity and quality of life.

Methods: Based on the results of the MINDACT trial, we simulated a randomized clinical trial consisting of 1497 women with early-stage breast cancer presenting high clinical and low genomic risks. The individual preferences for the different health states and corresponding decrements were obtained from the literature.

Results: The gain in terms of 5-year disease-free survival was 2.8% (95% CI from - 0.1 to 5.7%, from 90.4% for women without CT to 93.3% for women with CT). In contrast, due to the associated side effects, CT significantly reduced the number of QALYs by 62 days (95% CI from 55 to 70 days, from 4.13 years for women without CT to 3.96 years for women with CT).

Conclusion: Our results support the conclusions published by Cardoso et al. by providing additional evidence that the 70-gene signature can be used to avoid overtreatment by CT for women with high clinical risk but low genomic risk.
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http://dx.doi.org/10.1007/s10549-018-05107-6DOI Listing
April 2019

Pharmacokinetic drug evaluation of abemaciclib for advanced breast cancer.

Expert Opin Drug Metab Toxicol 2019 Feb 5;15(2):85-91. Epub 2019 Jan 5.

a Medical Oncology , Institut de Cancérologie de l'Ouest, René Gauducheau , St Herblain , France.

Introduction: The combination of cyclin-dependent kinases 4 and 6 (CDK 4 and 6) inhibitors with endocrine therapy represents a new standard of care for endocrine-receptor positive metastatic breast cancer. Currently, three compounds are approved. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration in view of the results of the MONARCH1 and 2 trials. Area covered: In this article, we review the preclinical and clinical development of abemaciclib in advanced breast cancer, describing current therapeutic indications and open questions. Expert opinion: Results of phase III trials investigating abemaciclib in patients with endocrine-receptor positive metastatic breast cancer have shown a substantial improvement in progression-free-survival, with a safe and manageable toxicity profile. In order to better select patients who will more likely respond to CDK4/6 inhibitors, biomarkers need to be identified. To optimize CDK4/6 targeting, combination therapies are being tested in several ongoing trials.
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http://dx.doi.org/10.1080/17425255.2019.1559816DOI Listing
February 2019

miR-370-3p Is a Therapeutic Tool in Anti-glioblastoma Therapy but Is Not an Intratumoral or Cell-free Circulating Biomarker.

Mol Ther Nucleic Acids 2018 Dec 13;13:642-650. Epub 2018 Sep 13.

Equipe Apoptose & Progression Tumorale, Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA), INSERM U1232, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France; LaBCT, Institut de Cancérologie de l'Ouest, Saint Herblain, France; Cancéropole Grand-Ouest, réseau Epigénétique (RepiCGO), Université de Nantes, Nantes, France; EpiSAVMEN Consortium (Région Pays de la Loire), Université de Nantes, Nantes, France; LabEX IGO, Université de Nantes, Nantes, France. Electronic address:

In the last decade, microRNAs (miRs) have been described as biomarkers and therapeutic agents. Based on this finding, our aim here is to know if (1) miRNA-370-3p can be used as a biomarker associated with a favorable survival and if (2) miRNA-370-3p can be used as a therapeutic tool that increases the efficiency of standard anti-GBM treatment. A first approach using the data available on the "Prognostic miRNA Database" indicated that the expression level of miRNA-370-3p in GBM (T-miR-370-3p) is not associated with a prognosis value for survival. A second approach quantifying the expression level of cell-free circulating miRNA-370-3p (cfc-miR-370-3p) also indicated that cfc-miR-370-3p is not associated with a prognosis value for survival. To investigate whether miR-370-3p can be used in vivo to increase the anti-GBM effect of TMZ, we then used the model of LN18-induced GBMs in mice. Our data indicated that the miRNA-370-3p/TMZ treatment was two times more efficient than the TMZ treatment for decreasing the tumor volume. In addition, our study correlated the decrease of tumor volume induced by the miRNA-370-3p/TMZ treatment with the decrease in FOXM1 and MGMT (i.e., two targets of miR-370-3p). Our data thus support the idea that miR-370-3p could be used as therapeutic tool for anti-glioblastoma therapy, but not as a biomarker.
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http://dx.doi.org/10.1016/j.omtn.2018.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258828PMC
December 2018

The self-reported perceptions of the repercussions of the disease and its treatments on daily life for young women with breast cancer and their partners.

J Psychosoc Oncol 2019 Jan-Feb;37(1):50-68. Epub 2018 Oct 8.

m Département de Sénologie , Centre Oscar Lambret , Lille , France.

Purpose: This study aimed to compare the self-reported perceptions of the repercussions of the disease and its treatments and emotional distress in young women with breast cancer and their partners.

Design: Cross-sectional study using self-reported questionnaires.

Sample: 491 couples in which women were aged <45 years when diagnosed with non-metastatic breast cancer in four different groups of treatment: during chemotherapy with or without Trastuzumab; under Trastuzumab with or without hormone therapy; during hormone therapy; and during the follow-up period.

Methods: Patients and partners completed a questionnaire assessing their self-reported perceptions of the disease and treatments (Patient YW-BCI and Partner YW-BCI for the partners) and their emotional distress (CESD; STAI).

Findings: Patients reported more difficulties than partners in the management of child(ren) and everyday life, body image and sexuality, negative affectivity about the disease and apprehension about the future, career management, and finances. While the difficulties were generally more marked in the chemotherapy and Trastuzumab groups than in the hormone therapy and follow-up groups, the negative affectivity about the disease and apprehension about the future was high in all four groups, especially in patients. The partners reported more difficulties in sharing with close relatives, and even more in those groups reflecting the latest treatment phases. No difference appeared between patients and partners in couple cohesion and deterioration of relationships with relatives. Partners were less anxious than patients but as depressed as them.

Conclusions: Difficulties of patients and partners seem particularly severe in the early care pathway, maybe reflecting better adjustment in women under surveillance and their partners. A longitudinal study will substantiate this finding and enable a better identification of some explanatory processes of these differences and similarities in the daily self-reported repercussions of the disease throughout the cancer care pathway. Implications for psychosocial oncology: It seems important to support young women with breast cancer and their partners, as our results evidence distress in both and differences according to the type of treatment the woman is currently receiving. Healthcare providers need consistent methods to identify and respond to couples' distress and reduce significant disparities in support.
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http://dx.doi.org/10.1080/07347332.2018.1479326DOI Listing
February 2020

Emerging PARP inhibitors for treating breast cancer.

Expert Opin Emerg Drugs 2018 09 29;23(3):211-221. Epub 2018 Sep 29.

a René Gauducheau , Institut de Cancérologie de l'Ouest , St Herblain , France.

Introduction: Some breast cancers harbor defects in DNA repair pathways, including BRCA1 and BRCA2 mutations, leading to a genomic instability. Compromised DNA-damage repair response is found in 11 to 42% of triple negative breast cancers, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors are a promising strategy in breast cancer exploiting Homologous Deficient Recombination deficiency (HRD) by a synthetic lethal approach. Several PARP inhibitors have currently reached early phase trials with studies on going in the adjuvant, neoadjuvant and metastatic setting. Area covered: Here, we review completed and ongoing trials with PARP inhibitors as well as their mechanisms of activity and acquired resistance. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance.
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http://dx.doi.org/10.1080/14728214.2018.1527900DOI Listing
September 2018

An Update on the Clinical Use of CDK4/6 Inhibitors in Breast Cancer.

Drugs 2018 Sep;78(13):1353-1362

Institut de Cancérologie de l'Ouest, René Gauducheau, St Herblain, France.

Deregulated cell division, resulting in aberrant cell proliferation, is one of the key hallmarks of cancer. Cyclin-dependent kinases (CDKs) play a central role in cell cycle progression in cancer, and the clinical development of the CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has changed clinical practice in the setting of endocrine-receptor positive breast cancer. Results of pivotal phase II and III trials investigating these CDK4/6 inhibitors in patients with endocrine receptor-positive, advanced breast cancer have demonstrated a significant improvement in progression-free survival, with a safe toxicity profile. No validated biomarkers of sensitivity or resistance exist at the moment. Future development of CDK4/6 inhibitors in breast cancer should focus on the identification of predictive biomarkers, the development of drug combinations to overcome resistance, and the application of CDK4/6 inhibitors to other breast cancer subtypes.
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http://dx.doi.org/10.1007/s40265-018-0972-9DOI Listing
September 2018

Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer.

Breast Cancer Res Treat 2018 Apr 15;168(2):559-566. Epub 2017 Dec 15.

Medical Oncology Department, Centre René Gauducheau, Institut de Cancérologie de l'Ouest (ICO), Saint-Herblain, France.

Background: Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population.

Methods: From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed.

Results: 60 patients were treated accordingly; median age was 61 years; 50 patients (83.3%) had visceral metastasis, and 10 (16.7%) had bone-only disease. Patients had previously received a median of 5 (1-14) lines of treatment, including ET (median 3) and chemotherapy (median 2); 28 (46.7%) received previously fulvestrant and all everolimus. With a median follow-up of 10.3 months, median progression-free survival (mPFS) was 5.8 months (95% CI 3.9-7.3). Patients pretreated with fulvestrant had a similar PFS of 6.4 months (HR 1.00; 95% CI 0.55-1.83; P = 1.00). The most common AEs (adverse events) were neutropenia (93%), anemia (65%), and thrombocytopenia (55%).

Conclusion: In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8 months with the same magnitude of benefit for fulvestrant-pretreated patients.
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http://dx.doi.org/10.1007/s10549-017-4623-8DOI Listing
April 2018