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Clinical Studies

Efficacy of front-line treatment for hormone receptor-positive HER2-negative metastatic breast cancer with germline BRCA1/2 mutation

British Journal of Cancer volume 128, pages 2072–2080 (2023)Cite this article

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Abstract

Background

Efficacy of endocrine therapy in HR+/HER2− metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation.

Methods

The ESME metastatic breast cancer platform (NCT03275311) is a French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1).

Results

A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR [95% CI] 1.26 [1.03–1.55]). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR [95% CI] = 1.54 [1.03–2.32]) and PFS1 (adjusted HR [95% CI] 1.58 [1.17–2.12]) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 [0.88–1.41], p = 0.350; PFS1: 1.09 [0.90–1.31], p = 0.379).

Conclusion

In this large cohort of HR+/HER2− MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.

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Fig. 1
Fig. 2: Overall survival and first-line progression-free survival according to gBRCA groups at treatment initiation and type of first-line treatment.

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Data availability

All data are contained in the ESME database, which is managed by Unicancer (http://www.unicancer.fr/). However, the ESME database is not publicly available for the following reason: in the ESME Research programme, public data sharing is not automatic in order to ensure that only trained users can analyse the ESME datasets. The analysis datasets will be made available only under data transfer and use agreements executed between Unicancer and the potential licensee. Interested parties should contact the corresponding author. Amélie Lusque had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data supporting the findings of this study are available from UNICANCER but restrictions apply to the availability of these data, which was used under licence for this study and is therefore not publicly available. However, the data are available from the authors upon reasonable request and with permission from UNICANCER.

Code availability

Codes used to generate the data are available upon reasonable request.

References

  1. Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomark Prev. 2012;21:134–47.

    Article  CAS  Google Scholar 

  2. Aleskandarany M, Caracappa D, Nolan CC, Macmillan RD, Ellis IO, Rakha EA, et al. DNA damage response markers are differentially expressed in BRCA-mutated breast cancers. Breast Cancer Res Treat. 2015;150:81–90.

    Article  CAS  PubMed  Google Scholar 

  3. Halpern N, Sonnenblick A, Uziely B, Divinsky L, Goldberg Y, Hamburger T, et al. Oncotype Dx recurrence score among BRCA1/2 germline mutation carriers with hormone receptors positive breast cancer. Int J Cancer. 2017;140:2145–9.

    Article  CAS  PubMed  Google Scholar 

  4. De Talhouet S, Peron J, Vuilleumier A, Friedlaender A, Viassolo V, Ayme A, et al. Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes. Sci Rep. 2020;10:7073.

    Article  CAS  PubMed  Google Scholar 

  5. Metcalfe K, Lynch HT, Foulkes WD, Tung N, Olopade OI, Eisen A, et al. Oestrogen receptor status and survival in women with BRCA2-associated breast cancer. Br J Cancer. 2019;120:398–403.

    Article  CAS  PubMed  Google Scholar 

  6. Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N. Engl J Med. 2018;379:753–63.

    Article  CAS  PubMed  Google Scholar 

  7. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl J Med. 2017;377:523–33.

  8. Cardoso F, Paluch-Shimon S, Senkus E, Curigliano G, Aapro MS, Andre F, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol: Off J Eur Soc Med Oncol / ESMO. 2020;31:1623–49.

    Article  CAS  Google Scholar 

  9. Andre F, Su F, Solovieff N, Arteaga CL, Hortobagyi GN, Chia SKL, et al. Pooled ctDNA analysis of the MONALEESA (ML) phase III advanced breast cancer (ABC) trials. J Clin Oncol. 2020;38:1009.

    Article  Google Scholar 

  10. Frenel JS, Dalenc F, Pistilli B, de La Motte Rouge T, Levy C, Mouret-Reynier MA, et al. 304P ESR1 mutations and outcomes in BRCA1/2 or PALB2 germline mutation carriers receiving first line aromatase inhibitor + palbociclib (AI+P) for metastatic breast cancer (MBC) in the PADA-1 trial. Ann Oncol. 2020;31:S364.

    Article  Google Scholar 

  11. Collins JM, Nordstrom BL, McLaurin KK, Dalvi TB, McCutcheon SC, Bennett JC, et al. A real-world evidence study of CDK4/6 inhibitor treatment patterns and outcomes in metastatic breast cancer by germline BRCA mutation status. Oncol Ther. 2021;9:575–89.

    Article  PubMed  Google Scholar 

  12. Bruno L, Ostinelli A, Waisberg F, Enrico D, Ponce C, Rivero S, et al. Cyclin-dependent kinase 4/6 inhibitor outcomes in patients with advanced breast cancer carrying germline pathogenic variants in DNA repair-related genes. JCO Precis Oncol. 2022;6:e2100140.

    Article  PubMed  Google Scholar 

  13. Gobbini E, Ezzalfani M, Dieras V, Bachelot T, Brain E, Debled M, et al. Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort. Eur J Cancer. 2018;96:17–24.

    Article  PubMed  Google Scholar 

  14. Deluche E, Antoine A, Bachelot T, Lardy-Cleaud A, Dieras V, Brain E, et al. Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008–2016. Eur J cancer. 2020;129:60–70.

    Article  CAS  PubMed  Google Scholar 

  15. Quek RGW, Mardekian J. Clinical outcomes, treatment patterns, and health resource utilization among metastatic breast cancer patients with germline BRCA1/2 mutation: a real-world retrospective study. Adv Ther. 2019;36:708–20.

    Article  CAS  PubMed  Google Scholar 

  16. Baretta Z, Mocellin S, Goldin E, Olopade OI, Huo D. Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis. Med (Baltim). 2016;95:e4975.

    Article  CAS  Google Scholar 

  17. Rennert G, Bisland-Naggan S, Barnett-Griness O, Bar-Joseph N, Zhang S, Rennert HS, et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med. 2007;357:115–23.

    Article  CAS  PubMed  Google Scholar 

  18. Verhoog LC, Brekelmans CT, Seynaeve C, van den Bosch LM, Dahmen G, van Geel AN, et al. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 1998;351:316–21.

    Article  CAS  PubMed  Google Scholar 

  19. Huzarski T, Byrski T, Gronwald J, Gorski B, Domagala P, Cybulski C, et al. Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2013;31:3191–6.

    Article  Google Scholar 

  20. Bordeleau L, Panchal S, Goodwin P. Prognosis of BRCA-associated breast cancer: a summary of evidence. Breast Cancer Res Treat. 2010;119:13–24.

    Article  CAS  PubMed  Google Scholar 

  21. van den Broek AJ, Schmidt MK, van ‘t Veer LJ, Tollenaar RA, van Leeuwen FE. Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: what’s the evidence? A systematic review with meta-analysis. PloS One. 2015;10:e0120189.

    Article  PubMed  Google Scholar 

  22. Schmidt MK, van den Broek AJ, Tollenaar RA, Smit VT, Westenend PJ, Brinkhuis M, et al. Breast cancer survival of BRCA1/BRCA2 mutation carriers in a hospital-based cohort of young women. J Natl Cancer Inst. 2017;109. https://doi.org/10.1093/jnci/djw329.

  23. Copson ER, Maishman TC, Tapper WJ, Cutress RI, Greville-Heygate S, Altman DG, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19:169–80.

    Article  CAS  PubMed  Google Scholar 

  24. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2008;26:4282–8.

    Article  Google Scholar 

  25. Goodwin PJ, Phillips KA, West DW, Ennis M, Hopper JL, John EM, et al. Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an international prospective breast cancer family registry population-based cohort study. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30:19–26.

    Article  Google Scholar 

  26. Fasching PA, Yadav S, Hu C, Wunderle M, Haberle L, Hart SN, et al. Mutations in BRCA1/2 and other panel genes in patients with metastatic breast cancer -association with patient and disease characteristics and effect on prognosis. J Clin Oncol: Off J Am Soc Clin Oncol. 2021;39:1619–30.

    Article  CAS  Google Scholar 

  27. Niyazov A, Quek RGW, Lewis K, Kemp J, Rider A. 161P - BRCA status, treatment patterns and outcomes in HER2- advanced breast cancer (ABC): A multi-country real-world study. Ann Oncol. 2019;30:iii51–iii2.

    Article  Google Scholar 

  28. Safonov A, Bandlamudi C, Tallon de Lara P, Ferraro E, Derakhshan F, Will M et al. Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance. Presented at SABCS 2021; December 7–10, 2021; San Antonio, TX. Abstract GS4-08.

  29. Bertucci F, Ng CKY, Patsouris A, Droin N, Piscuoglio S, Carbuccia N, et al. Genomic characterization of metastatic breast cancers. Nature 2019;569:560–4.

    Article  CAS  PubMed  Google Scholar 

  30. Lips EH, Debipersad RD, Scheerman CE, Mulder L, Sonke GS, van der Kolk LE, et al. BRCA1-mutated estrogen receptor-positive breast cancer shows BRCAness, suggesting sensitivity to drugs targeting homologous recombination deficiency. Clin Cancer Res: Off J Am Assoc Cancer Res. 2017;23:1236–41.

    Article  CAS  Google Scholar 

  31. Marra A, Gazzo A, Gupta A, Selenica P, Da Silva EM, Pareja F, et al. 210O Mutational signature analysis reveals patterns of genomic instability linked to resistance to endocrine therapy (ET) +/− CDK 4/6 inhibition (CDK4/6i) in estrogen receptor-positive/HER2-negative (ER+/HER2-) metastatic breast cancer (MBC). Ann Oncol. 2022;33:S632.

    Article  Google Scholar 

  32. Park YH, Im S-A, Park K, Wen J, Min A, Bonato V, et al. Prospective longitudinal multi-omics study of palbociclib resistance in hormone receptor+/HER2- metastatic breast cancer. J Clin Oncol. 2021;39:1013.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the 18 French Comprehensive Cancer Centres for providing the data and each ESME local coordinator for managing the project at the local level. 18 Participating French Comprehensive Cancer Centres (FCCC):; I. Curie, Paris/ Saint-Cloud, G. Roussy, Villejuif, I. Cancérologie de l’Ouest, Angers/Nantes, C. F. Baclesse, Caen, ICM Montpellier, C. L. Bérard, Lyon, C. G-F Leclerc, Dijon, C. H. Becquerel, Rouen; I. C. Regaud, Toulouse; C. A. Lacassagne, Nice; Institut de Cancérologie de Lorraine, Nancy; C. E. Marquis, Rennes; I. Paoli-Calmettes, Marseille; C. J. Perrin, Clermont Ferrand; I. Bergonié, Bordeaux; C. P. Strauss, Strasbourg; I. J. Godinot, Reims; C. O. Lambret, Lille. Moreover, we thank the ESME Scientific Group, the Strategic Committee, and the ESME coordination team for their ongoing support. Prior presentations This work has been presented at the ESMO meeting as a poster in 2021.

Funding

The ESME MBC database receives financial support from an industrial consortium (Roche, Pfizer, AstraZeneca, MSD, Eisai, and Daiichi Sankyo). Data collection, analysis, and publication are managed entirely by UNICANCER independently of the industrial consortium.

Author information

Authors and Affiliations

  1. Medical Oncology, ICO Institut de Cancerologie de l’Ouest René Gauducheau, Saint-Herblain, France

    J.-S. Frenel

  2. Biostatistics & Health Data Science Unit, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France

    A. Lusque

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

    S. Delaloge

  4. Medical Oncology, Centre Antoine Lacassagne, Nice, France

    J.-M. Ferrero

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

    T. Bachelot

  6. Medical Oncology, Centre Georges-François Leclerc (Dijon), Dijon, France

    I. Desmoulins

  7. Medical Oncology, Centre Francois Baclesse, Caen, France

    C. Levy

  8. Medical Oncology, Institut Jean Godinot, Reims, France

    J.-C. Eymard

  9. Medical Oncology Department, Institute Paoli Calmettes, Marseille, France

    A. Gonçalves

  10. Medical Oncology Department, ICO - Institut de cancerologie de l’Ouest - Site Paul Papin, Angers, France

    A. Patsouris

  11. Medical Oncology, Jean Perrin Center, Clermont-Ferrand, France

    M. A. Mouret Reynier

  12. Medical Oncology, Centre Henri Becquerel, Rouen, France

    M. J.-C. Thery

  13. Bas-Rhin, Centre Paul Strauss Centre de Lutte contre le Cancer, Strasbourg, France

    T. Petit

  14. Medical Oncology, Hôpital René Huguenin - Institut Curie, Saint-Cloud, France

    L. Cabel

  15. Medical Oncology, Institut de Cancerologie de Lorraine - Alexis Vautrin, Vandoeuvre Les Nancy, France

    L. Uwer

  16. Medical Oncology, Institut Bergonié, Bordeaux, France

    M. Debled

  17. Department of Real World Data, UNICANCER, Paris, France

    M. Chevrot

  18. Medical Oncology, Centre Oscar Lambret, Lille, France

    A. Mailliez

  19. Medical Oncology Department, ICM Regional Cancer Institute of Montpellier, Montpellier University, INSERM U1194, Montpellier, France

    W. Jacot

  20. Medical Oncology, Centre Eugene - Marquis, Rennes, France

    T. de La Motte Rouge

Authors
  1. J.-S. Frenel
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Contributions

Conceptualisation JSF, AL, SD, AMa, WJ, TDLM. Formal analysis JSF, AL, SD, AMa, WJ, TDLM. Project administration MC. Investigation JSF, AL, SD, JMF, TB, ID, CL, JCE, AG, AP, MAM, JCT, TP, LC, LU, MD, MC, WJ, TDLM. Writing original draught JSF, AL, SD, AMa, WJ, TDLM. Writing review and editing JSF, AL, SD, JMF, TB, ID, CL, JCE, AG, AP, MAM, JCT, TP, LC, LU, MD, MC, WJ, TDLM

Corresponding author

Correspondence to J.-S. Frenel.

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Competing interests

JSF reports personal fees from Roche Genentech, personal fees and non-financial support from SeattleGenetics, personal fees and non-financial support from Novartis, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Lilly, personal fees and non-financial support from Novartis, personal fees and non-financial support from GSK, personal fees and non-financial support from Clovis oncoloy, personal fees and non-financial support from Astra Zeneca, personal fees and non-financial support from Daiichi Sankyo, personal fees and non-financial support from Gilead, personal fees and non-financial support from MSD, personal fees and non-financial support from Pierre Fabre, personal fees and non-financial support from Amgen, outside the submitted work. AL has declared no conflict of interest. SD reports grants and non-financial support from Pfizer, grants from Novartis, grants and non-financial support from Astra Zeneca, grants and non-financial support from Roche Genentech, grants from Lilly, grants from Puma, grants from Myriad, grants from Orion, grants from Amgen, grants from Sanofi, grants from Genomic Health, grants from GE, grants from Servier, grants from MSD, grants from BMS, grants from Pierre Fabre, grants from Seagen, grants from Exact Sciences, grants from Rappta, grants from Besins, grants from European Commission, grants from French government grants, grants from Fondation ARC, outside the submitted work. JMF reports personal fees from Pfizer, Novartis, Pierre Fabre, Lilly. TB reports personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Astra Zeneca, grants, personal fees and non-financial support from Pfizer, grants and personal fees from SeaGen, grants, personal fees and non-financial support from Novartis, outside the submitted work; ID has declared no conflict of interest. CL has received reports personal fees from Daiichi, Astra Zeneca, Lilly, MSD. JCE has declared no conflict of interest. AG has declared no conflict of interest. AP reports from Lilly, other from Daiichi-Sankyo, other from Pfizer, other from Pierre Fabre, outside the submitted work; MAM has declared no conflict of interest. JCT has received reports personal fees from PFIZER, personal fees from MSD, personal fees from ASTRAZENECA, non-financial support from NOVARTIS, outside the submitted work. TP eports personal fees and non-financial support from Pfizer, personal fees from Lilly, personal fees and non-financial support from Novartis, personal fees and non-financial support from Astra-Zeneca, personal fees from Seagen, personal fees and non-financial support from Daiichi Sankyo, personal fees from Pierre Fabre, outside the submitted work. LC has declared no conflict of interest. LU has declared no conflict of interest. MD has declared no conflict of interest. MC has declared no conflict of interest. AM has declared no conflict of interest. WJ reports personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from Astra Zeneca, personal fees and non-financial support from Roche Genentech, personal fees and non-financial support from Lilly, non-financial support from Sanofi, personal fees from Daiichi Sankyo, personal fees from MSD, personal fees from Rain Pharmaceuticals, non-financial support from Pierre Fabre, personal fees from Seagen, personal fees from BMS, personal fees and non-financial support from Eisai, personal fees and non-financial support from Pfizer, non-financial support from Glaxo Smithkline, non-financial support from Chugai Pharma, outside the submitted work. TDLM reports grants from Novartis, grants, personal fees and non-financial support from Astra Zeneca, personal fees and non-financial support from Roche Genentech, grants and personal fees from MSD, grants from Seagen, personal fees from Eisai, grants, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Glaxo Smithkline, personal fees and non-financial support from CLOVIS ONCOLOGY, outside the submitted work.

Ethics approval and consent to participate

ESME MBC database was authorised by the French data protection authority (Registration ID 1704113 and authorisation N°DE-2013.-117).

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Frenel, JS., Lusque, A., Delaloge, S. et al. Efficacy of front-line treatment for hormone receptor-positive HER2-negative metastatic breast cancer with germline BRCA1/2 mutation. Br J Cancer 128, 2072–2080 (2023). https://doi.org/10.1038/s41416-023-02248-4

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