Publications by authors named "Fabrice Andre"

271 Publications

Tribbles Pseudokinase 3 Regulation and Contribution to Cancer.

Cancers (Basel) 2021 Apr 11;13(8). Epub 2021 Apr 11.

Inserm, UMR981, F-94805 Villejuif, France.

The first Tribbles protein was identified as critical for the coordination of morphogenesis in Drosophila melanogaster. Three mammalian homologs were subsequently identified, with a structure similar to classic serine/threonine kinases, but lacking crucial amino acids for the catalytic activity. Thereby, the very weak ATP affinity classifies TRIB proteins as pseudokinases. In this review, we provide an overview of the regulation of gene expression at both transcriptional and post-translational levels. Despite the absence of kinase activity, TRIB3 interferes with a broad range of cellular processes through protein-protein interactions. In fact, TRIB3 acts as an adaptor/scaffold protein for many other proteins such as kinase-dependent proteins, transcription factors, ubiquitin ligases, or even components of the spliceosome machinery. We then state the contribution of TRIB3 to cancer development, progression, and metastasis. TRIB3 dysregulation can be associated with good or bad prognosis. Indeed, as TRIB3 interacts with and regulates the activity of many key signaling components, it can act as a tumor-suppressor or oncogene in a context-dependent manner.
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http://dx.doi.org/10.3390/cancers13081822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070086PMC
April 2021

Unhealthy behaviors after breast cancer: Capitalizing on a teachable moment to promote lifestyle improvements.

Cancer 2021 Apr 22. Epub 2021 Apr 22.

INSERM Unit 981 - Molecular predictors and new targets in oncology, Gustave Roussy, Villejuif, France.

Background: This study assessed the prevalence and risk factors of unhealthy behaviors among survivors of early-stage breast cancer.

Methods: Women (n = 9556) from the CANcer TOxicity cohort (NCT01993498) were included. Physical activity (PA), tobacco and alcohol consumption, and body mass index were assessed at diagnosis and at years 1 and 2 after diagnosis. A behavior was defined as unhealthy if patients failed to meet PA recommendations (≥10 metabolic equivalent task hours per week), reduce/quit tobacco, or decrease alcohol consumption to less than daily, or if they gained substantial weight over time. Multivariable-adjusted generalized estimating equations explored associations with unhealthy behaviors.

Results: At diagnosis, 41.7% of patients were inactive, 18.2% currently used tobacco, 14.6% consumed alcohol daily, and 48.9% were overweight or obese. At years 1 and 2, unhealthy PA behavior was reported among 37.0% and 35.6% of patients, respectively, unhealthy tobacco use behavior was reported among 11.4% and 9.5%, respectively, and unhealthy alcohol behavior was reported among 13.1% and 12.6%, respectively. In comparison with the previous assessment, 9.4% and 5.9% of underweight and normal-weight patients had transitioned to the overweight or obese category at years 1 and 2, respectively, and 15.4% and 16.2% of overweight and obese patients had gained ≥5% of their weight at years 1 and 2, respectively. One in 3 current tobacco smokers and 1 in 10 daily alcohol users reported improved behaviors after diagnosis. Older women (5-year increment) were more likely to be inactive (adjusted odds ratio [aOR], 1.03; 95% confidence interval [CI], 1.01-1.05) and report unhealthy alcohol behavior (aOR, 1.28; 95% CI, 1.23-1.33) but were less likely to engage in unhealthy tobacco use (aOR, 0.81; 95% CI, 0.78-0.85). Being at risk for depression (vs not being at risk for depression) was associated with reduced odds of unhealthy tobacco use (aOR, 0.67; 95% CI, 0.46-0.97) and with a higher likelihood of unhealthy alcohol behavior (aOR, 1.58; 95% CI, 1.14-2.19). Women with a college education (vs a primary school education) less frequently reported an unhealthy PA behavior (aOR, 0.61; 95% CI, 0.51-0.73) and were more likely to report unhealthy alcohol behavior (aOR, 1.85; 95% CI, 1.37-2.49). Receipt of chemotherapy (vs not receiving chemotherapy) was associated with higher odds of gaining weight (aOR, 1.51; 95% CI, 1.23-1.87) among those who were overweight or obese at diagnosis.

Conclusions: The majority of women were adherent to healthy lifestyle behaviors at the time of their breast cancer diagnosis, but a significant subset was nonadherent. Unhealthy behaviors tended to persist after the breast cancer diagnosis, having varying clinical, psychological, sociodemographic, and treatment-related determinants. This study will inform more targeted interventions to promote optimal health.
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http://dx.doi.org/10.1002/cncr.33565DOI Listing
April 2021

Overcoming Resistance to Tumor-Targeted and Immune-Targeted Therapies.

Cancer Discov 2021 Apr;11(4):874-899

Paris Saclay University, Saint-Aubin, France.

Resistance to anticancer therapies includes primary resistance, usually related to lack of target dependency or presence of additional targets, and secondary resistance, mostly driven by adaptation of the cancer cell to the selection pressure of treatment. Resistance to targeted therapy is frequently acquired, driven by on-target, bypass alterations, or cellular plasticity. Resistance to immunotherapy is often primary, orchestrated by sophisticated tumor-host-microenvironment interactions, but could also occur after initial efficacy, mostly when only partial responses are obtained. Here, we provide an overview of resistance to tumor and immune-targeted therapies and discuss challenges of overcoming resistance, and current and future directions of development. SIGNIFICANCE: A better and earlier identification of cancer-resistance mechanisms could avoid the use of ineffective drugs in patients not responding to therapy and provide the rationale for the administration of personalized drug associations. A clear description of the molecular interplayers is a prerequisite to the development of novel and dedicated anticancer drugs. Finally, the implementation of such cancer molecular and immunologic explorations in prospective clinical trials could de-risk the demonstration of more effective anticancer strategies in randomized registration trials, and bring us closer to the promise of cure.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1638DOI Listing
April 2021

Patient-Reported Outcomes in Patients With -Mutated Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer From SOLAR-1.

J Clin Oncol 2021 Mar 29:JCO2001139. Epub 2021 Mar 29.

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

Purpose: In the phase III SOLAR-1 trial (NCT02437318), the PI3Kα-selective inhibitor and degrader alpelisib significantly improved median progression-free survival when added to fulvestrant in patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ()-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. We assessed health-related quality of life using patient-reported outcome measures in these patients.

Materials And Methods: In the -mutant cohort, 341 patients were randomly assigned 1:1 to receive alpelisib 300 mg daily or placebo plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Patient-reported outcomes were evaluated with the European Organisation for Research and Treatment of Cancer QoL of Cancer Patients and Brief Pain Inventory-Short Form questionnaires. Changes from baseline and time to 10% deterioration were analyzed using repeated measurement models and Cox models, respectively.

Results: Global Health Status/QoL and functional status were maintained from baseline (mean changes < 10 points) in the alpelisib (overall change from baseline [95% CI], -3.50 [-8.02 to 1.02]) and placebo arms (overall change from baseline [95% CI], 0.27 [-4.48 to 5.02]). Overall treatment effect in Global Health Status/QoL was not significantly different between arms (-3.77; 95% CI, -8.35 to 0.80; = .101). Time to 10% deterioration for Global Health Status/QoL was similar between arms (hazard ratio, 1.03; 95% CI, 0.72 to 1.48). Compared with placebo, deterioration in social functioning and in diarrhea, appetite loss, nausea or vomiting, and fatigue symptom subscales occurred with alpelisib. Numerical improvement in Worst Pain was observed with alpelisib versus placebo (42% 32%, week 24; = .090).

Conclusion: In SOLAR-1, there was no statistical difference in deterioration of Global Health Status/QoL between arms, whereas symptom subscales favored placebo for diarrhea, appetite loss, nausea or vomiting, and fatigue, known side effects of alpelisib. Treatment decisions must consider efficacy and tolerability; taken with clinical efficacy, these results support the benefit-risk profile of alpelisib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative -mutated advanced breast cancer.
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http://dx.doi.org/10.1200/JCO.20.01139DOI Listing
March 2021

Long-term patient reported outcomes and hematologic toxicity among patients who received Granulocyte-Colony Stimulating Factors during chemotherapy for early breast cancer.

Breast 2021 Jun 2;57:43-48. Epub 2021 Mar 2.

INSERM Unit 981 - Molecular predictors and new targets in oncology, Gustave Roussy, Villejuif, France. Electronic address:

We assessed long-term associations of Granulocyte-Colony Stimulating Factors (G-CSF) use with patient-reported outcomes (PROs) and hematologic toxicity among chemotherapy-treated, early-stage breast cancer patients in CANTO (NCT01993498). Among 2920 patients longitudinally followed-up until year-4 after diagnosis, 49% used G-CSF. In multivariable-adjusted mixed-models, EORTC QLQ-C30 pain and summary score were not substantially different between groups (overall adjusted mean difference, use vs no-use [95%CI]: +1.27 [-0.33 to +2.87] and -1.01 [-1.98 to -0.04], respectively). PROs were slightly worse at year-4 among patients receiving G-CSF, although differences were of trivial clinical significance. No major differences were observed in leukocyte or platelet count over time.
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http://dx.doi.org/10.1016/j.breast.2021.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970125PMC
June 2021

Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers.

Cell Death Dis 2021 03 11;12(3):258. Epub 2021 Mar 11.

Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, 94800, Villejuif, France.

The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient's plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
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http://dx.doi.org/10.1038/s41419-021-03540-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948172PMC
March 2021

Genomic alterations in PIK3CA-mutated breast cancer result in mTORC1 activation and limit sensitivity to PI3Kα inhibitors.

Cancer Res 2021 Mar 8. Epub 2021 Mar 8.

Department of Pathology, Memorial Sloan Kettering Cancer Center

PI3Kα inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER+) breast cancer patients. Using whole genome CRISPR/Cas9 sgRNA knockout screens, we identified and validated several negative regulators of mTORC1 whose loss confers resistance to PI3Kα inhibition. Among the top candidates were TSC1, TSC2, TBC1D7, AKT1S1, STK11, MARK2, PDE7A, DEPDC5, NPRL2, NPRL3, C12orf66, SZT2 and ITFG2. Loss of these genes invariably results in sustained mTOR signaling under pharmacological inhibition of the PI3K-AKT pathway. Moreover, resistance could be prevented or overcome by mTOR inhibition, confirming the causative role of sustained mTOR activity in limiting the sensitivity to PI3Kα inhibition. Cumulatively, genomic alterations affecting these genes are identified in about 15% of PIK3CA-mutated breast tumors and appear to be mutually exclusive. This study improves our understanding of the role of mTOR signaling restoration in leading to resistance to PI3Kα inhibition and proposes therapeutic strategies to prevent or revert this resistance.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3232DOI Listing
March 2021

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial.

Lancet Oncol 2021 04 4;22(4):499-511. Epub 2021 Mar 4.

International Breast Cancer Center, Quiron Group, Madrid and Barcelona, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Background: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer.

Methods: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657.

Findings: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax).

Interpretation: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(20)30754-3DOI Listing
April 2021

Prediction of Breast Cancer Treatment-Induced Fatigue by Machine Learning Using Genome-Wide Association Data.

JNCI Cancer Spectr 2020 Oct 11;4(5):pkaa039. Epub 2020 May 11.

Gustave Roussy, INSERM Unit 981, Villejuif, France.

Background: We aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data.

Methods: We accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and higher than quartile 3 at 1 year after primary treatment completion on European Organization for Research and Treatment of Cancer quality-of-life questionnaires for Overall Fatigue and on the multidimensional questionnaire for Physical, Emotional, and Cognitive fatigue. First, we tested univariate associations of each endpoint with clinical variables and genome-wide variants. Then, using preselected clinical (false discovery rate < 0.05) and genomic ( < .001) variables, a multivariable preconditioned random-forest regression model was built and validated on a hold-out subset to predict fatigue. Gene set enrichment analysis identified key biological correlates (MetaCore). All statistical tests were 2-sided.

Results: Statistically significant clinical associations were found only with Emotional and Cognitive Fatigue, including receipt of chemotherapy, anxiety, and pain. Some single nucleotide polymorphisms had some degree of association ( < .001) with the different fatigue endpoints, although there were no genome-wide statistically significant ( < 5.00 × 10) associations. Only for Cognitive Fatigue, the predictive ability of the genomic multivariable model was statistically significantly better than random (area under the curve = 0.59,  = .01) and marginally improved with clinical variables (area under the curve = 0.60,  = .005). Single nucleotide polymorphisms found to be associated ( < .001) with Cognitive Fatigue belonged to genes linked to inflammation (false discovery rate adjusted  = .03), cognitive disorders ( = 1.51 × 10), and synaptic transmission ( = 6.28 × 10).

Conclusions: Genomic analyses in this large cohort of breast cancer survivors suggest a possible genetic role for severe Cognitive Fatigue that warrants further exploration.
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http://dx.doi.org/10.1093/jncics/pkaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583150PMC
October 2020

Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: the randomized phase II SAFIR02-BREAST IMMUNO trial.

Nat Med 2021 02 18;27(2):250-255. Epub 2021 Jan 18.

Unicancer, Paris, France.

The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did not progress after six to eight cycles of chemotherapy. Patients (n = 199) were randomized to either durvalumab (10 mg kg every 2 weeks) or maintenance chemotherapy. In the overall population, durvalumab did not improve progression-free survival (adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.00-1.96; P = 0.047) or overall survival (OS; adjusted HR: 0.84, 95% CI: 0.54-1.29; P = 0.423). In an exploratory subgroup analysis, durvalumab improved OS in patients with triple-negative breast cancer (TNBC; n = 82; HR: 0.54, 95% CI: 0.30-0.97, P = 0.0377). Exploratory analysis showed that the HR of death was 0.37 (95% CI: 0.12-1.13) for patients with PD-L1 TNBC (n = 32) and 0.49 (95% CI: 0.18-1.34) for those with PD-L1 TNBC (n = 29). In patients with TNBC, exploratory analyses showed that the HR for durvalumab efficacy (OS) was 0.18 (95% CI: 0.05-0.71; log-rank test, P = 0.0059) in patients with CD274 gain/amplification (n = 23) and 1.12 (95% CI: 0.42-2.99; log-rank test, P = 0.8139) in patients with CD274 normal/loss (n = 32). Tumor infiltration by lymphocytes (CD8, FoxP3 and CD103 expressions) and homologous recombination deficiency did not predict sensitivity to durvalumab in exploratory analyses. This latter finding should be interpreted with caution since only one patient presented a germline BRCA mutation. The present study provides a rationale to evaluate single-agent durvalumab in maintenance therapy in patients with TNBC. Exploratory analyses identified CD274 amplification as a potential biomarker of sensitivity. Maintenance chemotherapy was more effective than durvalumab in patients with hormone receptor-positive and Her2-negative disease.
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http://dx.doi.org/10.1038/s41591-020-01189-2DOI Listing
February 2021

Immunodynamics of explanted human tumors for immuno-oncology.

EMBO Mol Med 2021 Jan 29;13(1):e12850. Epub 2020 Dec 29.

Institut Gustave Roussy, Villejuif, France.

Decision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay.
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http://dx.doi.org/10.15252/emmm.202012850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799366PMC
January 2021

Melanoma Persister Cells Are Tolerant to BRAF/MEK Inhibitors via ACOX1-Mediated Fatty Acid Oxidation.

Cell Rep 2020 11;33(8):108421

INSERM U981, Villejuif, France; Université Paris-Saclay, Kremlin-Bicêtre, France; Dermato-Oncology, Gustave Roussy Cancer Campus, Villejuif, France; Gustave Roussy Cancer Campus, Villejuif, France. Electronic address:

Emerging evidence indicates that non-mutational drug tolerance mechanisms underlie the survival of residual cancer "persister" cells. Here, we find that BRAF(V600E) mutant melanoma persister cells tolerant to BRAF/MEK inhibitors switch their metabolism from glycolysis to oxidative respiration supported by peroxisomal fatty acid β-oxidation (FAO) that is transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARα). Knockdown of the key peroxisomal FAO enzyme, acyl-CoA oxidase 1 (ACOX1), as well as treatment with the peroxisomal FAO inhibitor thioridazine, specifically suppresses the oxidative respiration of persister cells and significantly decreases their emergence. Consistently, a combination treatment of BRAF/MEK inhibitors with thioridazine in human-melanoma-bearing mice results in a durable anti-tumor response. In BRAF(V600E) melanoma samples from patients treated with BRAF/MEK inhibitors, higher baseline expression of FAO-related genes and PPARα correlates with patients' outcomes. These results pave the way for a metabolic strategy to overcome drug resistance.
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http://dx.doi.org/10.1016/j.celrep.2020.108421DOI Listing
November 2020

Body weight and return to work among survivors of early-stage breast cancer.

ESMO Open 2020 11;5(6):e000908

Prédicteurs moléculaires et nouvelles cibles en oncologie, INSERM Unit 981, Gustave Roussy, Villejuif, France; Medical Oncology, Gustave Roussy, Villejuif, France. Electronic address:

Background: Many breast cancer (BC) survivors are employed at diagnosis and are expected to return to work after treatment. Among them, around 50% are overweight or obese. There are limited data about the impact of body weight on their ability to return to work.

Methods: We used data from CANcer TOxicity (NCT01993498), a prospective, multicentre cohort of women with stage I-III BC. Professionally active women who were ≥5 years younger than retirement age were identified. Multivariable logistic regression models examined associations of body mass index (BMI) at diagnosis and subsequent weight changes with non-return to work 2 years after diagnosis, adjusting for psychosocial, treatment and behavioural characteristics.

Results: Among 1869 women, 689 were overweight or obese. Overall, 398 patients (21.3%) had not returned to work 2 years after diagnosis. Non-return to work was more likely for overweight or obese than underweight or normal weight patients (adjusted OR (aOR) 1.32; 95% CI, 1.01 to 1.75; p=0.045). Weight loss (≥5%) was observed in 15.7% overweight or obese and 8.7% underweight or normal weight patients and was associated with significant increases in physical activity only among overweight or obese patients (mean change, +4.7 metabolic-equivalent-of-task-hour/week; 95% CI +1.9 to +7.5). Overweight or obese patients who lost weight were more likely to return to work compared with those who did not lose weight (aOR of non-return-to-work, 0.48; 95% CI 0.24 to 0.97, p=0.0418), whereas weight loss was associated with increased odds of non-return to work among underweight or normal weight women (aOR 2.07; 95% CI 1.20 to 3.56, p=0.0086) (pBMI×weight changes=0.0002). The continuous trend of weight gain on non-return to work was significant for overweight or obese patients (aOR for one-percent-unit difference, 1.03; 95% CI 1.01 to 1.06, p=0.030).

Conclusions: Excess weight may be a barrier to return to work. Among overweight or obese BC survivors, weight loss was associated with higher rates of return to work, whereas further weight gain was associated with lower likelihood of return to work. Employment outcomes should be evaluated in randomised studies of weight management.
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http://dx.doi.org/10.1136/esmoopen-2020-000908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656950PMC
November 2020

AI-driven quantification, staging and outcome prediction of COVID-19 pneumonia.

Med Image Anal 2021 01 15;67:101860. Epub 2020 Oct 15.

Radiology Department, Hopital Avicenne - AP-HP.Hopitaux universitaires Paris Seine-Saint-Denis, 125 Rue de Stalingrad, Bobigny 93000, France; Université Sorbonne Paris Nord, 99 Avenue Jean Baptiste Clément, Villetaneuse 93430, France.

Coronavirus disease 2019 (COVID-19) emerged in 2019 and disseminated around the world rapidly. Computed tomography (CT) imaging has been proven to be an important tool for screening, disease quantification and staging. The latter is of extreme importance for organizational anticipation (availability of intensive care unit beds, patient management planning) as well as to accelerate drug development through rapid, reproducible and quantified assessment of treatment response. Even if currently there are no specific guidelines for the staging of the patients, CT together with some clinical and biological biomarkers are used. In this study, we collected a multi-center cohort and we investigated the use of medical imaging and artificial intelligence for disease quantification, staging and outcome prediction. Our approach relies on automatic deep learning-based disease quantification using an ensemble of architectures, and a data-driven consensus for the staging and outcome prediction of the patients fusing imaging biomarkers with clinical and biological attributes. Highly promising results on multiple external/independent evaluation cohorts as well as comparisons with expert human readers demonstrate the potentials of our approach.
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http://dx.doi.org/10.1016/j.media.2020.101860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558247PMC
January 2021

Differentiation of groups of patients with cognitive complaints at breast cancer diagnosis: Results from a sub-study of the French CANTO cohort.

Psychooncology 2021 Apr 31;30(4):463-470. Epub 2020 Oct 31.

Département Interdisciplinaire d'Organisation des Parcours Patients, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Objective: Cognitive complaints are more frequent in women with breast cancer (BC) than in healthy controls and can be present before any treatment. Findings regarding contributive factors remain inconsistent. This study aimed to identify different groups of patients with cognitive complaints at BC diagnosis and to determine whether these different groups were associated with demographic, medical, or psychological characteristics.

Methods: Cognitive complaints were assessed in a subset of 264 women from the French multicenter prospective CANTO cohort, at baseline before any treatment. Clustering analyzes were performed using the six-cognitive dimension Costa's scoring of the FACT-Cog V3. Univariable analyses were used to study how cognitive function (standardized neuropsychological tests, ICCTF), anxiety, depression, fatigue, and quality of life (HADS, FA12, QLQ-C30) were associated with specific cognitive complaints groups.

Results: Results included 263 women (54±11 years), newly diagnosed with BC (69% stages I-III). Four distinct groups emerged, ranged from "no complaints" (22.8%), "low complaints" (55.1), "mixed complaints" (14.5%), to "consistent complaints" (7.6%). No significant differences were found in terms of demographic and medical factors between the four groups. However, the groups with higher proportions of patients with complaints were found to have more impairment in executive function, higher scores of anxiety, depressive symptoms, and fatigue, and lower quality of life, than the groups with lower proportions of cognitive complaints.

Conclusion: Using complete cognitive assessment prior to BC treatment, we identified four distinct cognitive complaints groups with specific characteristics. This work provides valuable clinical basis to further investigations for a better understanding of cognitive complaints and their associates.
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http://dx.doi.org/10.1002/pon.5572DOI Listing
April 2021

A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency.

Cancer Discov 2021 Feb 12;11(2):408-423. Epub 2020 Oct 12.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris, France.

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of , calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of . These findings have potential implications for the clinical management of FPR1-deficient patients. SIGNIFICANCE: The loss-of-function variant rs867228 in , harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking , suggesting a personalized strategy for compensating for the FPR1 defect..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0465DOI Listing
February 2021

Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy.

NPJ Precis Oncol 2020 8;4:27. Epub 2020 Sep 8.

Experimental and Translational Pathology Platform (PETRA), Genomic Platform - Molecular Biopathology unit (BMO) and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.

Unravelling the biological processes driving tumour resistance is necessary to support the development of innovative treatment strategies. We report the design and feasibility of the MATCH-R prospective trial led by Gustave Roussy with the primary objective of characterizing the molecular mechanisms of resistance to cancer treatments. The primary clinical endpoints consist of analyzing the type and frequency of molecular alterations in resistant tumours and compare these to samples prior to treatment. Patients experiencing disease progression after an initial partial response or stable disease for at least 24 weeks underwent a tumour biopsy guided by CT or ultrasound. Molecular profiling of tumours was performed using whole exome sequencing, RNA sequencing and panel sequencing. At data cut-off for feasibility analysis, out of 333 inclusions, tumour biopsies were obtained in 303 cases (91%). From these biopsies, 278 (83%) had sufficient quality for analysis by high-throughput next generation sequencing (NGS). All 278 samples underwent targeted NGS, 215 (70.9%) RNA sequencing and 222 (73.2%) whole exome sequencing. In total, 163 tumours were implanted in NOD scid gamma (NSG) or nude mice and 54 patient-derived xenograft (PDX) models were established, with a success rate of 33%. Adverse events secondary to invasive tumour sampling occurred in 24 patients (7.6%). Study recruitment is still ongoing. Systematic molecular profiling of tumours and the development of patient-derived models of acquired resistance to targeted agents and immunotherapy is feasible and can drive the selection of the next therapeutic strategy.
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http://dx.doi.org/10.1038/s41698-020-00130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478969PMC
September 2020

Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer.

J Natl Cancer Inst 2021 Mar;113(3):309-317

Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

Background: There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i.

Methods: PALOMA-3 was a phase III, multicenter, double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor-positive (ER+) breast cancer. Pretreatment plasma samples from 459 patients were analyzed for mutations in 17 genes, copy number in 14 genes, and circulating tumor fraction. Progression-free survival (PFS) was compared in patients with circulating tumor fraction above or below a prespecified cutoff of 10% and with or without a specific genomic alteration. All statistical tests were 2-sided.

Results: Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.17 to 2.24; P = .004) and placebo plus fulvestrant (HR = 1.77, 95% CI = 1.21 to 2.59; P = .004). In multivariable analysis, high-circulating tumor fraction was associated with worse PFS (HR = 1.20 per 10% increase in tumor fraction, 95% CI = 1.09 to 1.32; P < .001), as was TP53 mutation (HR = 1.84, 95% CI = 1.27 to 2.65; P = .001) and FGFR1 amplification (HR = 2.91, 95% CI = 1.61 to 5.25; P < .001). No interaction with treatment randomization was observed.

Conclusions: Pretreatment ctDNA identified a group of high-risk patients with poor clinical outcome despite the addition of CDK4/6 inhibition. These patients might benefit from inclusion in future trials of escalating treatment, with therapies that may be active in these genomic contexts.
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http://dx.doi.org/10.1093/jnci/djaa087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936069PMC
March 2021

Immune responses during COVID-19 infection.

Oncoimmunology 2020 08 25;9(1):1807836. Epub 2020 Aug 25.

Immunology, Gustave Roussy, Villejuif, France.

Over the past 16 years, three coronaviruses (CoVs), severe acute respiratory syndrome CoV (SARS-CoV) in 2002, Middle East respiratory syndrome CoV (MERS-CoV) in 2012 and 2015, and SARS-CoV-2 in 2020, have been causing severe and fatal human epidemics. The unpredictability of coronavirus disease-19 (COVID-19) poses a major burden on health care and economic systems across the world. This is caused by the paucity of in-depth knowledge of the risk factors for severe COVID-19, insufficient diagnostic tools for the detection of SARS-CoV-2, as well as the absence of specific and effective drug treatments. While protective humoral and cellular immune responses are usually mounted against these , immune responses to SARS-CoV2 sometimes derail towards inflammatory tissue damage, leading to rapid admissions to intensive care units. The lack of knowledge on mechanisms that tilt the balance between these two opposite outcomes poses major threats to many ongoing clinical trials dealing with immunostimulatory or immunoregulatory therapeutics. This review will discuss innate and cognate immune responses underlying protective or deleterious immune reactions against these pathogenic coronaviruses.
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http://dx.doi.org/10.1080/2162402X.2020.1807836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480812PMC
August 2020

Pervasive chromosomal instability and karyotype order in tumour evolution.

Nature 2020 11 2;587(7832):126-132. Epub 2020 Sep 2.

Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland.

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2 breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.
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http://dx.doi.org/10.1038/s41586-020-2698-6DOI Listing
November 2020

Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage.

Science 2020 08;369(6506):936-942

Department of Physics of Complex Systems, ELTE Eötvös Loránd University, Budapest, Hungary.

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Mice bearing harboring this prophage mounted a TMP-specific H-2K-restricted CD8 T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.
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http://dx.doi.org/10.1126/science.aax0701DOI Listing
August 2020

Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19.

Cell 2020 09 5;182(6):1401-1418.e18. Epub 2020 Aug 5.

INSERM U1287, Gustave Roussy Cancer Campus, Villejuif 94800, France; Département d'Hématologie, Gustave Roussy Cancer Campus, Villejuif 94800, France.

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14CD16 monocytes, accumulation of HLA-DR classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10CD101CXCR4 neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.
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http://dx.doi.org/10.1016/j.cell.2020.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405878PMC
September 2020

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer.

Nat Commun 2020 07 30;11(1):3819. Epub 2020 Jul 30.

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.

Hormone receptor (HR) breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HRHER2 BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR BC.
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http://dx.doi.org/10.1038/s41467-020-17644-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393498PMC
July 2020

Progresses Toward Precision Medicine in -altered Solid Tumors.

Clin Cancer Res 2020 Dec 14;26(23):6102-6111. Epub 2020 Jul 14.

Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.

(rearranged during transfection) gene encodes a receptor tyrosine kinase essential for many physiologic functions, but aberrations are involved in many pathologies. While loss-of-function mutations are associated with congenital disorders like Hirschsprung disease and CAKUT, gain-of-function mutations and rearrangements are critical drivers of tumor growth and proliferation in many different cancers. -altered ( ) tumors have been hitherto targeted with multikinase inhibitors (MKI) having anti- activities, but they inhibit other kinase targets more potently and show limited clinical activities. The lack of target specificity and consequently increased side effects, responsible for dose reduction and drug discontinuation, are critical limitations of MKIs in the clinics. New selective inhibitors, selpercatinib and pralsetinib, are showing promising activities, improved response rates, and more favorable toxicity profiles in early clinical trials. This review critically discusses the oncogenic activation of and its role in different kinds of tumors, clinical features of tumors, clinically actionable genetic alterations and their diagnosis, and the available data and results of nonselective and selective targeting of .
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1587DOI Listing
December 2020

Cognitive Impairment in Patients with Breast Cancer before Surgery: Results from a CANTO Cohort Subgroup.

Cancer Epidemiol Biomarkers Prev 2020 Sep 1;29(9):1759-1766. Epub 2020 Jul 1.

Clinical Research Department, Centre François Baclesse, Caen, France.

Background: Twenty to 30% of patients with breast cancer have cognitive impairment after surgery and before adjuvant treatment, but very few studies have focused on cognition before any treatment. This study used a subgroup of women with newly diagnosed breast cancer from the French cancer and toxicities (CANTO) cohort to describe cognition before any treatment in comparison with a group of healthy controls (HC).

Methods: Cognitive assessment was performed before any breast cancer treatment (surgery or neoadjuvant treatment) on women with newly diagnosed invasive stage I-III breast cancer and HCs. Objective cognitive performance, cognitive complaints, anxiety, depression, and fatigue were assessed. Objective cognitive impairment was defined according to International Cognition and Cancer Task Force recommendations.

Results: Of the 264 included patients with breast cancer (54 ± 11 years) and 132 age-matched HCs (53 ± 9 years), overall objective cognitive impairment was observed in 28% of patients with breast cancer and 8% of HCs ( < 0.001). Cognitive complaints were reported by 24% of patients versus 12% of HCs ( < 0.01). Patients reported significantly more anxiety and emotional and cognitive fatigue than HCs ( < 0.01). After adjustment, significantly more patients with breast cancer had overall objective cognitive impairment than HCs [OR = 3.01; 95% confidence interval (CI): 1.31-6.88] without significant difference between groups for cognitive complaints (OR = 1.38; 95% CI: 0.65-2.92). Cognitive complaints were positively associated with fatigue (OR = 1.03; 95% CI: 1.02-1.05).

Conclusions: In this prospective study, compared with HCs, patients with localized breast cancer had more objective cognitive impairment before any treatment. Cognitive complaints were mostly related to fatigue.

Impact: Baseline assessment before treatment is important to assess the impact of each cancer treatment on cognition.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0346DOI Listing
September 2020

Serum Detection of Nonadherence to Adjuvant Tamoxifen and Breast Cancer Recurrence Risk.

J Clin Oncol 2020 08 22;38(24):2762-2772. Epub 2020 Jun 22.

Institut Gustave Roussy, Villejuif, France.

Purpose: Nonadherence to long-term treatments is often under-recognized by physicians and there is no gold standard for its assessment. In breast cancer, nonadherence to tamoxifen therapy after surgery constitutes a major obstacle to optimal outcomes. We sought to evaluate the rate of biochemical nonadherence to adjuvant tamoxifen using serum assessment and to examine its effects on short-term, distant disease-free survival (DDFS).

Patients And Methods: We studied 1,177 premenopausal women enrolled in a large prospective study (CANTO/NCT01993498). Definition of biochemical nonadherence was based on a tamoxifen serum level < 60 ng/mL, assessed 1 year after prescription. Self-reported nonadherence to tamoxifen therapy was collected at the same time through semistructured interviews. Survival analyses were conducted using an inverse probability weighted Cox proportional hazards model, using a propensity score based on age, staging, surgery, chemotherapy, and center size.

Results: Serum assessment of tamoxifen identified 16.0% of patients (n = 188) below the set adherence threshold. Patient-reported rate of nonadherence was lower (12.3%). Of 188 patients who did not adhere to the tamoxifen prescription, 55% self-reported adherence to tamoxifen. After a median follow-up of 24.2 months since tamoxifen serum assessment, patients who were biochemically nonadherent had significantly shorter DDFS (for distant recurrence or death, adjusted hazard ratio, 2.31; 95% CI, 1.05 to 5.06; = .036), with 89.5% of patients alive without distant recurrence at 3 years in the nonadherent cohort versus 95.4% in the adherent cohort.

Conclusion: Therapeutic drug monitoring may be a useful method to promptly identify patients who do not take adjuvant tamoxifen as prescribed and are at risk for poorer outcomes. Targeted interventions facilitating patient adherence are needed and have the potential to improve short-term breast cancer outcomes.
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http://dx.doi.org/10.1200/JCO.19.01758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430219PMC
August 2020

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer.

NPJ Breast Cancer 2020 12;6:17. Epub 2020 May 12.

32Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH USA.

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.
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http://dx.doi.org/10.1038/s41523-020-0156-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217863PMC
May 2020

Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAF non-small cell lung cancer.

Eur J Cancer 2020 06 6;132:211-223. Epub 2020 May 6.

Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France.

Introduction: BRAF is a confirmed therapeutic target in non-small cell lung cancer (NSCLC), as the BRAF inhibitor dabrafenib, in combination with the MEK inhibitor trametinib, is approved for the treatment of NSCLC harbouring BRAF V600E mutation. Scant evidence is available concerning the mechanisms of resistance to BRAF/MEK inhibitors in BRAF NSCLC.

Patients And Methods: Patients with BRAF NSCLC with acquired resistance to BRAF/MEK inhibitors were included in the institutional, prospective MATCH-R (from "Matching Resistance") trial and underwent tumour and liquid biopsies at the moment of radiological progression. Extensive molecular analyses were performed, including targeted next-generation sequencing (NGS), whole-exome sequencing (WES), RNA sequencing and comparative genomic hybridisation (CGH) array.

Results: Of the 11 patients included, eight had progressed on dabrafenib-trametinib combination, two on dabrafenib monotherapy and one on vemurafenib (BRAF inhibitor). Complete molecular analyses were available for seven patients, whereas an additional case had only targeted NGS and CGH array data. Among these eight patients, acquired molecular events potentially responsible for resistance were detected in three who progressed on dabrafenib-trametinib combination, that is, MEK1 K57N, RAS viral (v-ras) oncogene homolog (NRAS) Q61R and rat sarcoma viral oncogene homolog (KRAS) Q61R mutations. One patient progressing on dabrafenib monotherapy developed a PTEN frameshift mutation. No molecular hints addressing resistance emerged in the remaining four patients with analyses performed. Tumour mutational burden, evaluated by WES in seven patients, was low (median = 2.06 mutations/megabase, range = 1.57-3.75 mut/Mb).

Conclusions: Novel resistance mechanisms to BRAF/MEK inhibitors in BRAF NSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.
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http://dx.doi.org/10.1016/j.ejca.2020.03.025DOI Listing
June 2020