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Cancer treatment according to BRCA1 and BRCA2 mutations

Nature Reviews Clinical Oncology volume 9, pages 520–528 (2012)Cite this article

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Abstract

Identification of germline mutations associated with significant cancer susceptibility has the potential to change all aspects of an individual's care, from screening to cancer treatment. For example, women with germline mutations in BRCA1 and BRCA2 have markedly elevated risks of breast and ovarian cancer and the identification of these germline mutations has led to specific screening and prevention strategies. More recently, advances in the understanding of the biological function of BRCA1 and BRCA2 have led to clinical trials testing targeted therapies in this population, particularly poly(ADP-ribose) polymerase (PARP) inhibitors. Unfortunately, the development of PARP inhibitors has not been as rapid as anticipated and has been more challenging than expected. Somatic mutations identified in many cancer types have allowed the development of therapeutics that target these mutated genes, and many of these agents obtained rapid regulatory approval and are currently in widespread clinical practice. Diagnostic testing has a central role in targeted cancer therapeutics for both somatic and germline mutations. Although the era of molecular medicine and targeted therapies has led to significant changes in the practice of oncology, new challenges continue to arise.

Key Points

  • Subtypes of cancers can be defined by inherited (BRCA1 and BRCA2 in breast and ovarian cancer) and somatic mutations (ALK mutations in lung cancer)

  • Identification of a BRCA1 or BRCA2 mutation has significant clinical implications for screening and treatment

  • Understanding of the function of BRCA1 and BRCA2 has led to the investigation of targeted agents, namely PARP inhibitors, in this patient population

  • Diagnostic tests are necessary to identify BRCA1 or BRCA2 carriers who may benefit from targeted therapies; the regulatory issues regarding companion diagnostics are evolving

  • Development of drugs targeting molecularly defined subtypes is feasible and can lead to rapid regulatory approval; however, the example of PARP inhibitors in BRCA-mutated cancers illustrates potential challenges

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Acknowledgements

We thank Roger Cohen for helpful discussions and the MacDonald Family Foundation for funding for this effort.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, University of Pennsylvania, 3400 Spruce Street, 16 Penn Tower, Philadelphia, 19104, PA, USA

    Kara N. Maxwell

  2. Basser Research Center, Abramson Cancer Center, University of Pennsylvania, 3 West Perelman Center, 3400 Civic Center Boulevard, Philadelphia, 19104, PA, USA

    Susan M. Domchek

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Both authors were involved in the research of data and the writing of the article, and provided substantial contributions to the discussion of content as well as editing the manuscript ahead of submission.

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Correspondence to Susan M. Domchek.

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S. M. Domchek had received funding for clinical trials from Abbott Pharmaceuticals and AstraZeneca. K. N. Maxwell declares no competing interests.

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Maxwell, K., Domchek, S. Cancer treatment according to BRCA1 and BRCA2 mutations. Nat Rev Clin Oncol 9, 520–528 (2012). https://doi.org/10.1038/nrclinonc.2012.123

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