Publications by authors named "Etienne Rouleau"

98 Publications

Combination of targeted therapy and immune checkpoint blocker in a patient with xeroderma pigmentosum presenting an aggressive angiosarcoma and a recurrent non-resectable basal cell carcinoma.

Eur J Cancer 2021 Jun 23;150:130-132. Epub 2021 Apr 23.

Dermatology Unit, Gustave Roussy Cancer Campus, Villejuif, France; Inserm U981, Gustave Roussy Cancer Campus, Villejuif, France; University Paris-Saclay, Faculty of Medicine, Kremlin-Bicêtre, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2021.03.022DOI Listing
June 2021

Tumor mutation burden testing: a survey of the International Quality Network for Pathology (IQN Path).

Virchows Arch 2021 Apr 15. Epub 2021 Apr 15.

Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori - IRCCS - "Fondazione G. Pascale", Via Mariano Semola, 80131, Napoli, Italy.

While tumour mutation burden (TMB) is emerging as a possible biomarker for immune-checkpoint inhibitors (ICI), methods for testing have not been standardised as yet. In April 2019, the International Quality Network for Pathology (IQN Path) launched a survey to assess the current practice of TMB testing. Of the 127 laboratories that replied, 69 (54.3%) had already introduced TMB analysis for research purposes and/or clinical applications. Fifty laboratories (72.5%) used targeted sequencing, although a number of different panels were employed. Most laboratories tested formalin-fixed paraffin-embedded material (94.2%), while 18/69 (26%) tested also cell-free DNA. Fifty-five laboratories used both single nucleotide variants and indels for TMB calculation; 20 centers included only non-synonymous variants. In conclusion, the data from this survey indicate that multiple global laboratories were capable of rapidly introducing routine clinical TMB testing. However, the variability of testing methods raises concerns about the reproducibility of results among centers.
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http://dx.doi.org/10.1007/s00428-021-03093-7DOI Listing
April 2021

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

Concordance between Tumor and Germline BRCA Status in High-Grade Ovarian Carcinoma Patients in the Phase III PAOLA-1/ENGOT-ov25 Trial.

J Natl Cancer Inst 2020 Dec 29. Epub 2020 Dec 29.

Centre Léon Bérard and University, Claude Bernard Lyon 1, Lyon, GINECO, France.

Background: PAOLA1 is a phase III study assessing olaparib maintenance therapy in advanced high-grade ovarian carcinoma patients responding to first-line platinum-taxane-based chemotherapy plus bevacizumab as standard of care. Randomization was stratified by treatment outcome and tumor BRCA1/2 status (tBRCA) at screening.

Methods: tBRCA was tested on FFPE tumor blocks on 5 French platforms using 2 Next-Generation Sequencing methods based either on hybrid capture or amplicon technology. One of the exploratory objectives was to assess the concordance between germline (gBRCA) and tBRCA testing in French patients. gBRCA testing was performed on blood samples on the same platforms.

Results: From May 2015 to July 2017, tBRCA tests were performed for 1,176 screened patients. Only 52 (4.4%) tumor samples were non-contributive. The median interval between reception of the tumor sample and availability of the tBRCA status result was 37 days (range =8-260). A pathogenic variant (PV) was reported in 27.1% tumor samples (319 of 1,176 screened patients). tBRCA and gBRCA testing were both performed for 451 French patients with negative results for both tests in 306 patients (67.8%) and positive results for both tests in 85 patients (18.8%). Only one large genomic rearrangement of BRCA1 was detected, exclusively in the blood sample. Interestingly, tBRCA testing revealed 6.4% of PV (29 of 451) not detected by gBRCA testing.

Conclusions: tBRCA testing is an appropriate tool with an acceptable turnaround time for clinical practice and a low failure rate, ensuring reliable identification of patients likely to benefit from PARPi therapy.
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http://dx.doi.org/10.1093/jnci/djaa193DOI Listing
December 2020

Chronic Plasma Exposure to Kinase Inhibitors in Patients with Oncogene-Addicted Non-Small Cell Lung Cancer.

Cancers (Basel) 2020 Dec 14;12(12). Epub 2020 Dec 14.

Cancer Medicine Department, Gustave Roussy, 94805 Villejuif, France.

Kinase inhibitors (KI) have dramatically improved the outcome of treatment in patients with non-small cell lung cancer (NSCLC), which harbors an oncogene addiction. This study assesses KI plasma levels and their clinical relevance in patients chronically exposed to KIs. Plasma samples were collected in NSCLC patients receiving erlotinib, gefitinib, osimertinib, crizotinib, or dabrafenib (with or without trametinib) for at least three months between November 2013 and February 2019 in a single institution. KI drug concentrations were measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry and compared to published data defining optimal plasma concentration. The main outcome was the rate of samples with suboptimal KI plasma concentrations. Secondary outcomes included its impact on mutation emergence in patients receiving a first-generation epidermal growth factor receptor (EGFR) KI. Fifty-one samples were available from 41 patients with advanced NSCLC harboring driver genetic alterations, including , v-Raf murine sarcoma viral oncogene homolog B (), anaplastic lymphoma kinase () or ROS proto-oncogene 1 (), and who had an available evaluation of chronic KI plasma exposure. Suboptimal plasma concentrations were observed in 51% (26/51) of cases. In -mutant cases failing first-generation KIs, exon 20 p.T790M mutation emergence was detected in 31% (4/13) of samples in optimal vs. none in suboptimal concentration (0/5). Suboptimal plasma concentrations of KIs are frequent in advanced NSCLC patients treated with a KI for at least three months and might contribute to treatment failure.
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http://dx.doi.org/10.3390/cancers12123758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764991PMC
December 2020

Outcomes of patients with metastatic gastrointestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib as first-line treatment.

ESMO Open 2020 11;5(6):e001082

Sarcoma Group, Gustave Roussy, Villejuif, France.

Background: Imatinib is the standard first-line therapy in metastatic gastrointestinal stromal tumours (GIST). Investigational multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result either in increased survival or in early emergence of resistance to approved MKIs.

Methods: To assess whether using MKIs other than imatinib in first line decreases imatinib efficacy in second line for patients with GIST, a retrospective chart review was performed from 2005 to 2011 in two French tertiary centres of patients with GIST who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by imatinib as second line.

Results: Of 46 patients, (55% women, median age 55 years (range 24-81)), 22 (47%) had a exon 11 mutation, 1 a exon 9 mutation (2%), 1 a mutation (2%). Out of 46 patients, 21 (46%) received masitinib, 17 (37%) received dasatinib and 8 (17%) received nilotinib as first-line treatment with a median progression-free survival of 18.0 months (95% CI: 8.5 to 25.5). Median time to imatinib failure was 19.7 months (95% CI: 13.5 to 29.0). Median time to second relapse was 48.7 months (95% CI: 31.2 to 72.0). Median overall survival from time of initial metastasis diagnosis was 5.7 years (95% CI: 4.5 to 7.4).

Conclusions: Patients with GIST who received investigational MKIs as first-line treatment and imatinib as second line had a time to second relapse longer than that observed historically with imatinib in first line, suggesting that using MKIs other than imatinib in first line does not decrease the efficacy of subsequent treatment lines.
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http://dx.doi.org/10.1136/esmoopen-2020-001082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703411PMC
November 2020

Comparison of Pathogenicity Prediction Tools on Somatic Variants.

J Mol Diagn 2020 12 1;22(12):1383-1392. Epub 2020 Oct 1.

Departments of Medical Biology and Pathology, Gustave Roussy Institute, Villejuif, France. Electronic address:

Genomic sequencing is increasingly used in managing patients with cancer. Interpretation of somatic variants and their pathogenicity is often complex. Pathogenicity prediction tools are commonly used as part of the expert interpretation of somatic variants, but most of these tools were initially developed for germline variants. Our aim was to benchmark their performance for somatic variants. A gold standard list was assembled of 4319 somatic single-nucleotide variants, classified as oncogenic (n = 2996) or neutral (n = 1323), based on their presence in curated databases or on their allele frequency in the general population. These variants were annotated with the most commonly used prediction tools [Database for Nonsynonymous SNPs' Functional Predictions (dbNSFP) and Universal Mutation Database Predictor (UMD-Predictor)] and computed performance calculations. Stratification of the prediction tools based on Matthews correlation coefficient and area under the receiver operating characteristic curve allowed the identification of the top-performing ones, namely, Combined Annotation-Dependent Depletion (CADD), Eigen or Eigen Principal Components (Eigen-PC), Polymorphism Phenotyping version 2 (PolyPhen-2), Protein Variation Effect Analyzer (PROVEAN), UMD-Predictor, and Rare Exome Variant Ensemble Learner (REVEL). Interestingly, Sorting Intolerant From Tolerant (SIFT), which is a commonly used prediction tool for somatic variants, was ranked in the second performance category. Combining tools two by two only marginally improved performances, mainly because of the occurrence of discordant predictions.
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http://dx.doi.org/10.1016/j.jmoldx.2020.08.007DOI Listing
December 2020

Clinical Relevance of an Amplicon-Based Liquid Biopsy for Detecting and Fusion and Resistance Mutations in Patients With Non-Small-Cell Lung Cancer.

JCO Precis Oncol 2020 2;4. Epub 2020 Apr 2.

Department of Medical Oncology, Centre Léon Bérard Lyon, France.

Purpose: Liquid biopsy specimen genomic profiling is integrated in non-small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with -positive NSCLC and its impact on outcomes.

Patients And Methods: Patients with advanced -positive NSCLC were prospectively enrolled in the study by researchers at eight French institutions. Plasma samples were analyzed using InVisionFirst-Lung and correlated with clinical outcomes.

Results: Of the 128 patients included in the study, 101 were positive for and 27 for alterations. Blood samples (N = 405) were collected from 29 patients naïve for treatment with tyrosine kinase inhibitors (TKI) or from 375 patients under treatment, including 105 samples collected at disease progression (PD). Sensitivity was 67% (n = 18 of 27) for fusion detection. Higher detection was observed for fusions at TKI failure (n = 33 of 74; 46%) versus in patients with therapeutic response (n = 12 of 109; 11%). -resistance mutations were detected in 22% patients (n = 16 of 74) overall; 43% of the total -resistance mutations identified occurred after next-generation TKI therapy. was the most common mutation detected (n = 7 of 16). Heterogeneity of resistance was observed. resistance was detected in 30% (n = 3 of 10). The absence of circulating tumor DNA mutations at TKI failure was associated with prolonged median overall survival (105.7 months). Complex -resistance mutations correlated with poor overall survival (median, 26.9 months NR for single mutation; = .003) and progression-free survival to subsequent therapy (median 1.7 6.3 months; = .003).

Conclusion: Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy.
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http://dx.doi.org/10.1200/PO.19.00281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448797PMC
April 2020

Rare DICER1 and Absent FOXL2 Mutations Characterize Ovarian Juvenile Granulosa Cell Tumors.

Am J Surg Pathol 2021 02;45(2):223-229

Departments of Pathology.

FOXL2 somatic mutation occurs in a high percentage of ovarian adult granulosa cell tumors and DICER1 mutations in a high proportion of Sertoli-Leydig cell tumors. These mutations have only been studied in a limited number of juvenile granulosa cell tumors (JGCTs), and their occurrence and frequency in these neoplasms is controversial. We aimed to determine the frequency of FOXL2 and DICER1 mutations in a large cohort of 50 JGCTs, and to evaluate the prognostic impact of these mutations. A FOXL2 hotspot mutation was found in 2/50 JGCTs. Review of these 2 cases reclassified them as adult granulosa cell tumors. Thus, FOXL2 mutation was absent from our large cohort of JGCTs. DICER1 mutations in the RNase IIIb domain were found in 4 cases. After review of the mutated cases, 1 was reclassified as a gynandroblastoma with a prominent JGCT component. Thus, DICER1 mutations were detected in 3/47 (6%) of pathologically confirmed JGCTs. Our results show that FOXL2 mutations are not present in JGCT, whereas a small percentage of these neoplasms exhibit DICER1 mutations.
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http://dx.doi.org/10.1097/PAS.0000000000001582DOI Listing
February 2021

Predictive molecular pathology in non-small cell lung cancer in France: The past, the present and the perspectives.

Cancer Cytopathol 2020 09;128(9):601-610

UMR-1138, INSERM, Département de Biologie, Hôpital Européen Georges-Pompidou, Paris, France.

The advent of molecular targets for novel therapeutics in oncology, notably for non-small cell lung carcinoma (NSCLC), led the French National Cancer Institute (INCa) to establish a national network of 28 hospital Molecular Genetics Centers for Cancer (MGCC) in 2007. In each University in France, laboratories were established to develop molecular biology testing to evaluate a few genomic alterations, initially a selection of genes, by using specific targeted polymerase chain reaction (PCR) assays. In a second phase, the number of studied genes was increased. In 2015, the MGCC benefited from an additional dedicated budget from the INCa to develop next-generation sequencing (NGS) technology. In the meantime, a new financial regulation for innovative testing has been established for the acts out of nomenclature. Consequently, all private and public laboratories in France have access to funding for molecular biology testing in oncology. The gene-based PCR assays or NGS tests have benefitted from reimbursement of cost testing by the INCa. Today, the laboratories consider this reimbursement to be only partial, and its use to be complex. In 2018, a strategic plan for medical genomic analyses (France Médecine Génomique 2025) was implemented to introduce more systematic sequencing into the health care pathway and oncology practice. The large panel of molecular tests should be centralized to a limited number of molecular genetic centers. This review describes the evolution of the different stages of implementation of molecular pathology testing for NSCLC patients over the last few years in France.
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http://dx.doi.org/10.1002/cncy.22318DOI Listing
September 2020

Long-term Outcomes of Oral Vinorelbine in Advanced, Progressive Desmoid Fibromatosis and Influence of Mutational Status.

Clin Cancer Res 2020 12 1;26(23):6277-6283. Epub 2020 Sep 1.

Department of International Patients Care, Gustave Roussy Cancer Institute, Villejuif, Paris, France.

Purpose: Desmoid-type fibromatosis (DF) are locally aggressive neoplasms, with a need for effective systemic treatment in case of progression to avoid the short- and long-term complications of local treatments.

Experimental Design: We retrospectively analyzed the outcomes of adult patients with DF treated with oral vinorelbine (90 mg once weekly) at Gustave Roussy Cancer Institute (Villejuif, Paris, France). Only patients with documented progressive disease according to RECIST v1.1 for more than 3 months (±2 weeks) before treatment initiation were included.

Results: From 2009 to 2019, 90 out of 438 patients with DF were eligible for this analysis. Vinorelbine was given alone in 56 patients (62%), or concomitantly with endocrine therapy in 34 patients, for a median duration of 6.7 months. A partial response was observed in 29% and stable disease in another 57%. With a median follow-up of 52.4 months, the median time to treatment failure (TTF) was not reached. Progression-free rates at 6 and 12 months were 88.7% and 77.5%, respectively. Concomitant endocrine therapy was associated with longer TTF in women [HR, 2.16; 95% confidence interval (CI), 1.06-4.37; = 0.03). Among 64 patients with documented mutational status, p.S45F or p.S45P mutations were associated with longer TTF compared with p.T41A or wild-type tumors (HR, 2.78; 95% CI, 1.23-6.27; = 0.04). Toxicity profile was favorable, without grade 3-4 toxicity, except for one grade 3 neutropenia.

Conclusions: Oral vinorelbine is an effective, affordable, and well-tolerated regimen in patients with advanced, progressive DF. Prolonged activity was observed in patients with tumors harboring p.S45F or p.S45P mutations.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1847DOI Listing
December 2020

Co-occurrence of germline and pathogenic variants.

J Med Genet 2021 Jun 23;58(6):357-361. Epub 2020 Jun 23.

Department of Genetics, Institut Curie, Paris, France.

Introduction: We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both and genes. To the best of our knowledge, this is the first report of such an association.Family description: The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer.

Results: A large deletion of from exons 1 to 7 and two pathogenic variants were identified.

Conclusion: This complex situation is challenging for genetic counselling and management of at-risk individuals.
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http://dx.doi.org/10.1136/jmedgenet-2020-106972DOI Listing
June 2021

Outcomes in oncogenic-addicted advanced NSCLC patients with actionable mutations identified by liquid biopsy genomic profiling using a tagged amplicon-based NGS assay.

PLoS One 2020 11;15(6):e0234302. Epub 2020 Jun 11.

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

Circulating tumor DNA (ctDNA)-based molecular profiling is rapidly gaining traction in clinical practice of advanced cancer patients with multi-gene next-generation sequencing (NGS) panels. However, clinical outcomes remain poorly described and deserve further validation with personalized treatment of patients with genomic alterations detected in plasma ctDNA. Here, we describe the outcomes, disease control rate (DCR) at 3 months and progression-free survival (PFS) in oncogenic-addicted advanced NSCLC patients with actionable alterations identified in plasma by ctDNA liquid biopsy assay, InVisionFirst®-Lung. A pooled retrospective analysis was completed of 81 advanced NSCLC patients with all classes of alterations predicting response to current FDA approved drugs: sensitizing common EGFR mutations (78%, n = 63) with T790M (73%, 46/63), ALK / ROS1 gene fusions (17%, n = 14) and BRAF V600E mutations (5%, n = 4). Actionable driver alterations detected in liquid biopsy were confirmed by prior tissue genomic profiling in all patients, and all patients received personalized treatment. Of 82 patients treated with matched targeted therapies, 10% were at first-line, 41% at second-line, and 49% beyond second-line. Acquired T790M at TKI relapse was detected in 73% (46/63) of patients, and all prospective patients (34/46) initiated osimertinib treatment based on ctDNA results. The 3-month DCR was 86% in 81 evaluable patients. The median PFS was of 14.8 months (12.1-22.9m). Baseline ctDNA allelic fraction of genomic driver did not correlate with the response rate of personalized treatment (p = 0.29). ctDNA molecular profiling is an accurate and reliable tool for the detection of clinically relevant molecular alterations in advanced NSCLC patients. Clinical outcomes with targeted therapies endorse the use of liquid biopsy by amplicon-based NGS ctDNA analysis in first line and relapse testing for advanced NSCLC patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289417PMC
August 2020

in Breast and Ovarian Cancers.

Int J Mol Sci 2020 May 28;21(11). Epub 2020 May 28.

Department of Medical Biology and Pathology, Gustave Roussy, Cancer Genetics Laboratory, Gustave Roussy, 94800 Villejuif, France.

Ovarian and breast cancers are currently defined by the main pathways involved in the tumorigenesis. The majority are carcinomas, originating from epithelial cells that are in constant division and subjected to cyclical variations of the estrogen stimulus during the female hormonal cycle, therefore being vulnerable to DNA damage. A portion of breast and ovarian carcinomas arises in the context of DNA repair defects, in which genetic instability is the backdrop for cancer initiation and progression. For these tumors, DNA repair deficiency is now increasingly recognized as a target for therapeutics. In hereditary breast/ovarian cancers (HBOC), tumors with mutations present an impairment of DNA repair by homologous recombination (HR). For many years, mutations were only screened on germline DNA, but now they are also searched at the tumor level to personalize treatment. The reason of the inactivation of this pathway remains uncertain for most cases, even in the presence of a HR-deficient signature. Evidence indicates that identifying the mechanism of HR inactivation should improve both genetic counseling and therapeutic response, since they can be useful as new biomarkers of response.
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http://dx.doi.org/10.3390/ijms21113850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312125PMC
May 2020

Non-small cell lung carcinomas with CTNNB1 (beta-catenin) mutations: A clinicopathological study of 26 cases.

Ann Diagn Pathol 2020 Jun 20;46:151522. Epub 2020 Apr 20.

Department of Pathology, Marie Lannelongue Hospital, 133 avenue de la Résistance, 92350 Le Plessis Robinson, France.

Beta-catenin, encoded by the CTNNB1 gene, plays an important role in cell proliferation. Mutations of CTNNB1 are oncogenic in several tumor types and are often associated with a nuclear abnormal expression. However, such mutations have only rarely been reported in non-small cell lung carcinomas and their clinical signification is not well described. Our study was conducted on 26 CTNNB1-mutated non-small cell lung carcinomas. Tumors were routinely tested by next generation sequencing for mutations in exon 3 of CTNNB1 gene. Twenty three cases were from a series of 925 tumors (2.48%). The hospital files and pathological data, from surgical samples (n = 16), small biopsies (n = 5) and trans-bronchial fine needle aspirations (n = 5), were reviewed. Immunohistochemistry was performed with an anti-beta-catenin antibody. There were 10 female and 16 male patients aged 52 to 83. Eleven of 25 patients were no-smoking or light smokers. Three cases were diagnosed while under treatment with EGFR tyrosine kinase inhibitor. There were 25 adenocarcinomas and 1 squamous cell carcinoma. Most adenocarcinomas had a papillary component and were TTF1-positive. One case was a well-differentiated fetal adenocarcinoma. Eleven cases (42%) with CTNNB1 mutations showed associated EGFR mutations. The frequency of CTNNB1 mutations was higher among EGFR mutated carcinomas. Immunohistochemistry showed heterogeneous nuclear or cytoplasmic abnormal expression. Our study shows that CTNNB1 mutations mostly occur in TTF1-positive adenocarcinomas with a papillary pattern. These mutations are often associated with EGFR mutations and possibly interfer in the mechanism of resistance to tyrosine kinase inhibitors. Our experience suggests that immuno-histochemistry cannot be used for screening.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151522DOI Listing
June 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

Sensitive detection methods are key to identify secondary EGFR c.2369C>T p.(Thr790Met) in non-small cell lung cancer tissue samples.

BMC Cancer 2020 May 1;20(1):366. Epub 2020 May 1.

Department of Pathology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1, PO Box 30001, 9700, RB, Groningen, the Netherlands.

Background: Correct identification of the EGFR c.2369C>T p.(Thr790Met) variant is key to decide on a targeted therapeutic strategy for patients with acquired EGFR TKI resistance in non-small cell lung cancer. The aim of this study was to evaluate the correct detection of this variant in 12 tumor tissue specimens tested by 324 laboratories participating in External Quality Assessment (EQA) schemes.

Methods: Data from EQA schemes were evaluated between 2013 and 2018 from cell lines (6) and resections (6) containing the EGFR c.2369C>T p.(Thr790Met) mutation. Adequate performance was defined as the percentage of tests for which an outcome was available and correct. Additional data on the used test method were collected from the participants. Chi-squared tests on contingency tables and a biserial rank correlation were applied by IBM SPSS Statistics version 25 (IBM, Armonk, NY, USA).

Results: In 26 of the 1190 tests (2.2%) a technical failure occurred. For the remaining 1164 results, 1008 (86.6%) were correct, 151 (12.9%) were false-negative and 5 (0.4%) included incorrect mutations. Correct p.(Thr790Met) detection improved over time and for repeated scheme participations. In-house non-next-generation sequencing (NGS) techniques performed worse (81.1%, n = 293) compared to non-NGS commercial kits (85.2%, n = 656) and NGS (97.0%, n = 239). Over time there was an increase in the users of NGS. Resection specimens performed worse (82.6%, n = 610 tests) compared to cell line material (90.9%, n = 578 tests), except for NGS (96.3%, n = 344 for resections and 98.6%, n = 312 for cell lines). Samples with multiple mutations were more difficult compared to samples with the single p.(Thr790Met) variant. A change of the test method was shown beneficial to reduce errors but introduced additional analysis failures.

Conclusions: A significant number of laboratories that offer p.(Thr790Met) testing did not detect this relevant mutation compared to the other EQA participants. However, correct identification of this variant is improving over time and was higher for NGS users. Revising the methodology might be useful to resolve errors, especially for resection specimens with low frequency or multiple variants. EQA providers should include challenging resections in the scheme.
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http://dx.doi.org/10.1186/s12885-020-06831-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193365PMC
May 2020

Association of metastatic pattern and molecular status in stage IV non-small cell lung cancer adenocarcinoma.

Eur Radiol 2020 Sep 23;30(9):5021-5028. Epub 2020 Apr 23.

Imaging Department, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.

Objectives: The aim of our study was to investigate the association between driver oncogene alterations and metastatic patterns on imaging assessment, in a large cohort of metastatic lung adenocarcinoma patients.

Methods: From January 2010 to May 2017, 550 patients with stage IV lung adenocarcinoma with molecular analysis were studied retrospectively including 135 EGFR-mutated, 81 ALK-rearrangement, 47 BRAF-mutated, 141 KRAS-mutated, and 146 negative tumors for these 4 mutations (4N). After review of the complete imaging report by two radiologists (junior and senior) to identify metastatic sites, univariate correlation analyzes were performed.

Results: We found differences in metastatic tropism depending on the molecular alteration type when compared with the non-mutated 4N group: in the EGFR group, pleural metastases were more frequent (32% versus 20%; p = 0.021), and adrenal and node metastases less common (6% versus 23%; p < 0.001 and 11% versus 23%; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% versus 29%; p = 0.043 and 37% versus 24%; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (respectively 47% versus 20%; p < 0.001 and 11% versus 3%; p = 0.04) and bone metastases were rarer (21% versus 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK, and BRAF groups (respectively 6%, 7%, and 15% versus 1%); p = 0.016; p = 0.009; and p < 0.001.

Conclusion: The application of these correlations between molecular status and metastatic tropism in clinical practice may lead to earlier and more accurate identification of patients for targeted therapy.

Key Points: • Bone and brain metastasis are the most common organs involved in lung adenocarcinoma but the relative incidence of each metastatic site depends on the molecular alteration. • EGFR-mutated tumors preferentially spread to the pleura and less commonly to adrenals, ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones and have a serous (pericardial ad pleural) tropism. • These correlations could help in the clinical management of patients with metastatic lung adenocarcinoma.
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http://dx.doi.org/10.1007/s00330-020-06784-yDOI Listing
September 2020

Association of TERT, OGG1, and CHRNA5 Polymorphisms and the Predisposition to Lung Cancer in Eastern Algeria.

Pulm Med 2020 20;2020:7649038. Epub 2020 Mar 20.

Laboratoire de Biologie Moléculaire et Cellulaire, University Frères Mentouri Constantine 1, Constantine 25000, Algeria.

Lung cancer remains the most common cancer in the world. The genetic polymorphisms (rs2853669 in TERT, rs1052133 in OGG1, and rs16969968 in CHRNA5 genes) were shown to be strongly associated with the risk of lung cancer. Our study's aim is to elucidate whether these polymorphisms predispose Eastern Algerian population to non-small-cell lung cancer (NSCLC). To date, no study has considered this association in the Algerian population. This study included 211 healthy individuals and 144 NSCLC cases. Genotyping was performed using TaqMan probes and Sanger sequencing, and the data were analyzed using multivariate logistic regression adjusted for covariates. The minor allele frequencies (MAFs) of TERT rs2853669, CHRNA5 rs16969968, and OGG1 rs1052133 polymorphisms in controls were C: 20%, A: 31%, and G: 29%, respectively. Of the three polymorphisms, none shows a significant association, but stratified analysis rs16969968 showed that persons carrying the AA genotype are significantly associated with adenocarcinoma risk (pAdj = 0.03, ORAdj = 2.55). Smokers with an AA allele have a larger risk of lung cancer than smokers with GG or GA genotype (pAdj = 0.03, ORAdj = 3.91), which is not the case of nonsmokers. Our study suggests that CHRNA5 rs16969968 polymorphism is associated with a significant increase of lung adenocarcinoma risk and with a nicotinic addiction.
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http://dx.doi.org/10.1155/2020/7649038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109590PMC
March 2020

High Prevalence of Somatic Oncogenic Driver Alterations in Patients With NSCLC and Li-Fraumeni Syndrome.

J Thorac Oncol 2020 07 14;15(7):1232-1239. Epub 2020 Mar 14.

Clinical Genetic Unit, Cancer Medicine Department, Gustave Roussy, Villejuif, France. Electronic address:

Introduction: Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown.

Methods: Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants.

Results: Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation.

Conclusions: Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.
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http://dx.doi.org/10.1016/j.jtho.2020.03.005DOI Listing
July 2020

Circulating Tumor DNA Analysis for Patients with Oncogene-Addicted NSCLC With Isolated Central Nervous System Progression.

J Thorac Oncol 2020 03 13;15(3):383-391. Epub 2019 Dec 13.

Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France; Paris-Sud University, Orsay, France. Electronic address:

Introduction: In patients with oncogene-addicted NSCLC and isolated central nervous system progression (iCNS), tissue biopsy is challenging, and the clinical utility of plasma liquid biopsy (i.e., circulating tumor DNA [ctDNA]) is unknown.

Methods: Patients with advanced NSCLC with known baseline genomic alteration (GA) (EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, PIK3CA, STK11, TP53) on tissue were divided into three groups on the basis of their disease progression pattern: iCNS, extra-CNS only (noCNS), or both (cCNS). All patients with available plasma ctDNA were included and were analyzed by next-generation sequencing InVisionFirst-Lung. ctDNA was considered positive if at least one GA was detected. Cell-free tumor DNA was analyzed in cerebrospinal fluid when available.

Results: Out of 517 patients screened, 247 were included: 54 had iCNS, 99 had noCNS, and 94 had cCNS progressive disease (64, 128, and 110 ctDNA samples, respectively). CtDNA was positive in 52% iCNS versus 84% in noCNS and 92% in cCNS (p < 0.00001), with lower detection of driver (37% versus 77% and 73%, respectively) and resistance alterations (6% versus 45% and 44%). Patients with iCNS and positive ctDNA were more at risk of extra-CNS progression (32% versus 7%, p = 0.026). In 12 patients with iCNS, ctDNA was positive in six (50%) plasma and in 10 (83%) paired cerebrospinal fluid (p = 0.193).

Conclusions: Although tagged amplicon-based next-generation sequencing has high detection rates of GA in plasma ctDNA in patients with NSCLC with extra-CNS disease, detection rate of GAs (52%) is lower in the subset of patients with iCNS disease. Complementary tests such as cerebrospinal fluid cell-free DNA may be useful. Further evidence would be beneficial to understand the genomic landscape in patients with NSCLC and iCNS.
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http://dx.doi.org/10.1016/j.jtho.2019.11.024DOI Listing
March 2020

BRAF exon 11 mutant melanoma and sensitivity to BRAF/MEK inhibition: Two case reports.

Eur J Cancer 2019 Nov 27;121:109-112. Epub 2019 Sep 27.

Department of Dermatology, Gustave Roussy, 114 Rue Edouard-Vaillant, 94800, Villejuif, France; Paris-Sud University, 63 Rue Gabriel Péri, 94276, Le Kremlin-Bicêtre, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2019.08.029DOI Listing
November 2019

Variation in nomenclature of somatic variants for selection of oncological therapies: Can we reach a consensus soon?

Hum Mutat 2020 01 14;41(1):7-16. Epub 2019 Oct 14.

Department of Public Health and Primary Care, Biomedical Quality Assurance Research Unit, University of Leuven, Leuven, Belgium.

A standardized nomenclature for reporting oncology biomarker variants is key to avoid misinterpretation of results and unambiguous registration in clinical databases. External quality assessment (EQA) schemes have revealed a need for more consistent nomenclature use in clinical genetics. We evaluated the propensity of EQA for improvement of compliance with Human Genome Variation Society (HGVS) recommendations for reporting of predictive somatic variants in lung and colorectal cancer. Variant entries between 2012 and 2018 were collected from written reports and electronic results sheets. In total, 4,053 variants were assessed, of which 12.1% complied with HGVS recommendations. Compliance improved over time from 2.1% (2012) to 22.3% (2018), especially when laboratories participated in multiple EQA schemes. Compliance was better for next-generation sequencing (20.9%) compared with targeted techniques (9.8%). In the 1792 reports, HGVS recommendations for reference sequences were met for 31.9% of reports, for 36.0% of noncommercial, and 26.5% of commercial test methods. Compliance improved from 16.7% (2012) to 33.1% (2018), and after repeated EQA participation. EQA participation improves compliance with HGVS recommendations. The residual percentage of errors in the most recent schemes suggests that laboratories, companies, and EQA providers need to collaborate for additional improvement of harmonization in clinical test reporting.
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http://dx.doi.org/10.1002/humu.23926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973115PMC
January 2020

Implementing TMB measurement in clinical practice: considerations on assay requirements.

ESMO Open 2019 24;4(1):e000442. Epub 2019 Jan 24.

Department of Biopathology, Centre Jean Perrin, Clermont-Ferrand, France.

Clinical evidence demonstrates that treatment with immune checkpoint inhibitor immunotherapy agents can have considerable benefit across multiple tumours. However, there is a need for the development of predictive biomarkers that identify patients who are most likely to respond to immunotherapy. Comprehensive characterisation of tumours using genomic, transcriptomic, and proteomic approaches continues to lead the way in advancing precision medicine. Genetic correlates of response to therapy have been known for some time, but recent clinical evidence has strengthened the significance of high tumour mutational burden (TMB) as a biomarker of response and hence a rational target for immunotherapy. Concordantly, immune checkpoint inhibitors have changed clinical practice for lung cancer and melanoma, which are tumour types with some of the highest mutational burdens. TMB is an implementable approach for molecular biology and/or pathology laboratories that provides a quantitative measure of the total number of mutations in tumour tissue of patients and can be assessed by whole genome, whole exome, or large targeted gene panel sequencing of biopsied material. Currently, TMB assessment is not standardised across research and clinical studies. As a biomarker that affects treatment decisions, it is essential to unify TMB assessment approaches to allow for reliable, comparable results across studies. When implementing TMB measurement assays, it is important to consider factors that may impact the method workflow, the results of the assay, and the interpretation of the data. Such factors include biopsy sample type, sample quality and quantity, genome coverage, sequencing platform, bioinformatic pipeline, and the definitions of the final threshold that determines high TMB. This review outlines the factors for adoption of TMB measurement into clinical practice, providing an understanding of TMB assay considerations throughout the sample journey, and suggests principles to effectively implement TMB assays in a clinical setting to aid and optimise treatment decisions.
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http://dx.doi.org/10.1136/esmoopen-2018-000442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350758PMC
January 2019

Clinical utility of tumor mutational burden in patients with non-small cell lung cancer treated with immunotherapy.

Transl Lung Cancer Res 2018 Dec;7(6):647-660

Department of Cancer Medicine, Gustave Roussy, Institut d'Oncologie Thoracique (IOT), Gustave Roussy, Villejuif, France.

Anti-programmed death (ligand)-1 [anti-PD-(L)1] therapies such as pembrolizumab, nivolumab or atezolizumab have become standard of care for non-small cell lung cancer (NSCLC) patients either in first line or beyond. PD-L1 expression level allows enriching the treated population with responders, but it is still not an optimal biomarker. Even in patients with PD-L1 tumor proportion score (TPS) levels of ≥50% treated with first line pembrolizumab overall response rate (ORR) is only 44.8% and overall survival at one year is 70%. Moreover, in combination trials with chemotherapy and anti-PD-(L)1 therapy, a significant proportion of patients does not respond (ORR ranges from 45.3% to 64.0%), regardless of PD-L1 expression. Furthermore, PD-L1 expression level is not associated with improved benefit in patients treated with combinations of anti-PD-(L)1 and anti-cytotoxic T-lymphocyte-associated antigen (anti-CTLA4) therapy. One of the new promising biomarkers is tumor mutational burden (TMB). It has been discovered that especially tumor types with a known high mutation rate such as NSCLC and melanoma respond best to immune checkpoint inhibitors (ICIs). An explanation is that this high mutation rate makes it more likely that neoantigens arise that are targeted by activated immune cells, but it is not feasible to determine neoantigen load in daily practice. However, TMB of a certain tumor type is associated with neoantigen load and outcome on ICIs. In this comprehensive review, we discuss the TMB analysis methods, the rationale to use TMB as a predictive biomarker and the clinical utility of TMB in NSCLC patients treated with ICIs.
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http://dx.doi.org/10.21037/tlcr.2018.09.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249615PMC
December 2018

Non-Coding Variants in and Genes: Potential Impact on Breast and Ovarian Cancer Predisposition.

Cancers (Basel) 2018 Nov 16;10(11). Epub 2018 Nov 16.

Institut Gustave Roussy, 94805 Villejuif, France.

and are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to / exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of and are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of genes and their role on breast and ovarian cancer predisposition.
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http://dx.doi.org/10.3390/cancers10110453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266896PMC
November 2018

Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas.

Clin Cancer Res 2019 02 9;25(3):1087-1097. Epub 2018 Nov 9.

Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics.

Experimental Design: Fresh tumor tissue was prospectively collected from 36 endometrial cancers, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double-strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next-generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of -associated genomic scars, a surrogate marker for HRD, was determined in the The Cancer Genome Atlas (TCGA) endometrial cancer cohort.

Results: Most endometrial cancers included in the final analysis ( = 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24% ( = 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, = 0.014). All but 1 of the HRD cases harbored either a pathogenic variant or high somatic copy-number (SCN) losses of HR genes. Analysis of TCGA cases supported these results, with -associated genomic scars present in up to 48% (63/132) of NEEC versus 12% (37/312) of EEC ( < 0.001).

Conclusions: HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, -mutant endometrial cancers. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1443DOI Listing
February 2019