Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

To date, most BC GWASs have been performed Background Polygenic risk score (PRS), calculated in individuals of European (EUR) ancestry, and based on genome-wide association studies (GWASs), the generalisation of EUR-based PRS to other can improve breast cancer (BC) risk assessment. populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.</p

Tumor‐infiltrating lymphocyte transfusion in a patient with treatment refractory triple negative breast cancer

Abstract Background Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that is treated with chemotherapy. Recently, programmed death 1 (PD1) inhibition, as well as antibody‐drug conjugates, have been added to the available treatment regimen, yet metastatic disease is fatal. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TILs) has been well described in melanoma, but less data is available on other solid malignancies. Case Herein, we present a case of a 31‐year‐old patient diagnosed with Breast Cancer gene 1 (BRCA1) positive, TNBC. The patient's disease rapidly progressed while under standard treatment protocols. As a result, additional genetic testing of the tumor was carried out and revealed loss of BRCA1 heterozygosity, a double Tumor Protein 53 (TP53) mutation, and MYC amplification. Due to resistance to conventional therapy, an experimental approach was attempted using tumor‐infiltrating lymphocytes in November 2021 at Hadassah University Medical Center. While receiving this treatment, the patient exhibited a reported subjective clinical improvement including a month spent out of the hospital. However, the final result, presumably due to Interleukin 2 (IL‐2) toxicity, was the patient's passing. Conclusion This case is unique and peculiar regarding the treatment modality chosen, due to the extremely refractory disease the patient suffered from. After standard therapies rapidly failed, adoptive cell therapy was attempted with the infusion of TILs. This treatment has been shown effective in melanoma, however, there is an extreme paucity of data on other solid tumors, including TNBC. Although the patient ultimately demised presumably due to treatment side effects, brief clinical benefit was apparent. Further studies are warranted

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel.

Peer reviewed: TrueFunder: Statistics NetherlandsFunder: Lower Saxonian Cancer SocietyFunder: Lise Boserup FundFunder: Heidelberger Zentrum für Personalisierte Onkologie Deutsches Krebsforschungszentrum In Der Helmholtz-Gemeinschaft; FundRef: http://dx.doi.org/10.13039/100018027Funder: Komen FoundationFunder: Claudia von Schilling Foundation for Breast Cancer ResearchFunder: Ligue Contre le Cancer; FundRef: http://dx.doi.org/10.13039/501100004099Funder: Sigrid Juselius FoundationFunder: Kuopion Yliopistollinen Sairaala; FundRef: http://dx.doi.org/10.13039/501100004092Funder: Sheffield Experimental Cancer Medicine CentreFunder: Stockholm läns landsting; FundRef: http://dx.doi.org/10.13039/501100011727Funder: Department of Health and Human Services (USA)Funder: Stichting Tegen Kanker; FundRef: http://dx.doi.org/10.13039/501100005026Funder: David F. and Margaret T. Grohne Family Foundation; FundRef: http://dx.doi.org/10.13039/100009769Funder: Sundhed og Sygdom, Det Frie Forskningsråd; FundRef: http://dx.doi.org/10.13039/100008392Funder: Stavros Niarchos FoundationFunder: Institute of the Ruhr University BochumFunder: Institute of Cancer Research; FundRef: http://dx.doi.org/10.13039/501100000027Funder: Fondation du cancer du sein du Québec; FundRef: http://dx.doi.org/10.13039/100016328Funder: Institut National de la Santé et de la Recherche Médicale; FundRef: http://dx.doi.org/10.13039/501100001677Funder: Institute for Prevention and Occupational MedicineFunder: K.G. Jebsen Centre for Breast Cancer ResearchFunder: Research Centre for Genetic Engineering and BiotechnologyFunder: Robert and Kate Niehaus Clinical Cancer Genetics InitiativeFunder: Rudolf Bartling FoundationFunder: Karolinska Institutet; FundRef: http://dx.doi.org/10.13039/501100004047Funder: Robert Bosch Stiftung; FundRef: http://dx.doi.org/10.13039/501100001646Funder: Intramural Research Funds of the National Cancer Institute (USA)Funder: Intramural Research Program of the Division of Cancer Epidemiology and GeneticsFunder: Centre International de Recherche sur le Cancer; FundRef: http://dx.doi.org/10.13039/100008700Funder: Queensland Cancer FundFunder: Red Temática de Investigación Cooperativa en CáncerFunder: Intramural Research Program of the National Institutes of HealthFunder: National Health Service (UK)Funder: Ministerie van Volksgezondheid, Welzijn en Sport; FundRef: http://dx.doi.org/10.13039/501100002999Funder: Märit and Hans Rausings Initiative Against Breast CancerFunder: Associazione Italiana per la Ricerca sul Cancro; FundRef: http://dx.doi.org/10.13039/501100005010Funder: Fundación Científica Asociación Española Contra el Cáncer; FundRef: http://dx.doi.org/10.13039/501100002704Funder: Agence Nationale de la Recherche; FundRef: http://dx.doi.org/10.13039/501100001665Funder: Dutch Prevention Funds,Funder: Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du TravailFunder: American Cancer Society; FundRef: http://dx.doi.org/10.13039/100000048Funder: Dutch Zorg OnderzoekFunder: Alexander von Humboldt-Stiftung; FundRef: http://dx.doi.org/10.13039/100005156Funder: Ministerio de Economia y Competitividad (Spain)Funder: Against Breast Cancer; FundRef: http://dx.doi.org/10.13039/100013129Funder: Mutuelle Générale de l’Education NationaleFunder: Dietmar-Hopp Foundation,Funder: Division of Cancer Prevention, National Cancer Institute; FundRef: http://dx.doi.org/10.13039/100007316Funder: World Cancer Research Fund; FundRef: http://dx.doi.org/10.13039/501100000321Funder: Genome QuébecFunder: National Cancer Research NetworkFunder: Berta Kamprad Foundation FBKSFunder: Biomedical Research Centre at Guy’s and St ThomasFunder: Genome Canada; FundRef: http://dx.doi.org/10.13039/100008762Funder: Friends of Hannover Medical SchoolFunder: Breast Cancer Research Foundation; FundRef: http://dx.doi.org/10.13039/100001006Funder: Breast Cancer NowFunder: UK National Institute for Health Research Biomedical Research CentreFunder: University of Crete; FundRef: http://dx.doi.org/10.13039/501100004429Funder: National Breast Cancer Foundation (Finland)Funder: European Regional Development Fund; FundRef: http://dx.doi.org/10.13039/501100008530Funder: National Breast Cancer Foundation (Australia)Funder: Directorate-General XII, Science, Research, and Development; FundRef: http://dx.doi.org/10.13039/501100012517Funder: Baden Württemberg Ministry of Science, Research and ArtsFunder: VicHealth; FundRef: http://dx.doi.org/10.13039/501100001231Funder: Victorian Breast Cancer Research Consortium.Funder: Finnish Cancer FoundationFunder: Fomento de la Investigación Clínica IndependienteFunder: the Cancer Biology Research Center (CBRC), Djerassi Oncology CenterFunder: Tel Aviv University Center for AI and Data ScienceFunder: University of OuluFunder: National Breast Cancer Foundation (JS)Funder: Safra Center for BioinformaticsFunder: Fondation de France, Institut National du CancerFunder: University of Utah; FundRef: http://dx.doi.org/10.13039/100007747Funder: National Cancer Center Research and Development Fund (Japan)Funder: Oak Foundation; FundRef: http://dx.doi.org/10.13039/100001275Funder: New South Wales Cancer CouncilFunder: North Carolina University Cancer Research FundFunder: Kreftforeningen; FundRef: http://dx.doi.org/10.13039/100008730Funder: Northern California Breast Cancer Family RegistryFunder: Institut Gustave RoussyFunder: Huntsman Cancer Institute, University of Utah; FundRef: http://dx.doi.org/10.13039/100010638Funder: Ovarian Cancer Research Fund; FundRef: http://dx.doi.org/10.13039/100001282Funder: NIHR Oxford Biomedical Research Centre; FundRef: http://dx.doi.org/10.13039/501100013373Funder: Hellenic Health Foundation; FundRef: http://dx.doi.org/10.13039/501100018706Funder: Oulun Yliopistollinen Sairaala; FundRef: http://dx.doi.org/10.13039/501100018949Funder: Helmholtz SocietyFunder: Herlev and Gentofte HospitalFunder: PSRSIIRI-701Funder: Helsinki University Hospital Research FundFunder: Cancer Council Victoria; FundRef: http://dx.doi.org/10.13039/501100000951Funder: National Research Council (Italy)Funder: Cancer Council Tasmania; FundRef: http://dx.doi.org/10.13039/501100001169Funder: Cancer Council Western Australia; FundRef: http://dx.doi.org/10.13039/501100001170Funder: Hamburger Krebsgesellschaft; FundRef: http://dx.doi.org/10.13039/100018515Funder: Gustav V Jubilee foundationFunder: National Program of Cancer RegistriesFunder: Cancer Council South Australia; FundRef: http://dx.doi.org/10.13039/501100000950Funder: Cancer Council NSW; FundRef: http://dx.doi.org/10.13039/501100001102Funder: Guy's & St. Thomas' NHS Foundation TrustFunder: Cancer Institute NSW; FundRef: http://dx.doi.org/10.13039/501100001171Funder: Cancer Foundation of Western AustraliaFunder: Netherlands Cancer Registry (NKR),Funder: Cancer Fund of North SavoBACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

International audienceTo date, most BC GWASs have been performed Background Polygenic risk score (PRS), calculated in individuals of European (EUR) ancestry, and based on genome-wide association studies (GWASs), the generalisation of EUR-based PRS to other can improve breast cancer (BC) risk assessment. populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women