Germline PALB2 Variants and PARP Inhibitors in Endometrial Cancer

View More View Less
  • 1 Department of Medical Oncology, Flinders Medical Centre, Adelaide, SA;
  • | 2 Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA;
  • | 3 Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA;
  • | 4 Adelaide Medical School, University of Adelaide, Adelaide, SA;
  • | 5 Gynaecological Oncology, FlindersMedical Centre, Adelaide, SA;
  • | 6 The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW; and
  • | 7 Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, SA, Australia.

PARP inhibitors are orally administered antineoplastic agents that affect the homologous recombination (HR) repair pathway, and are approved by the FDA for the treatment of ovarian, breast, pancreatic, and prostate cancers. This report presents a case of recurrent endometrial carcinoma occurring in a woman with a germline pathogenic PALB2 whole-exon deletion. This uncommon finding in a patient with endometrial carcinoma provided the opportunity to use a management strategy of PARP inhibition with olaparib, resulting in a prolonged response to treatment; however, disease progression eventually occurred. Further studies are required to elucidate the mechanisms underlying resistance to PARP inhibition, and the potential future treatment options in this setting. Current recommendations for risk management of female carriers of PALB2 variants focus on breast and ovarian cancer risk. This case raises the additional question of a potential role for risk-reducing hysterectomy in female carriers of PALB2 variants.

Submitted January 11, 2021; final revision received June 8, 2021; accepted for publication June 8, 2021.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Correspondence: Michael A. Cilento, MBBS, Department of Medical Oncology, Flinders Medical Centre, Flinders Drive, Bedford Park, SA 5042, Australia. Email: michael.cilento@sa.gov.au
  • 1.

    Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer 2016;16:110120.

  • 2.

    Ducy M, Sesma-Sanz L, Guitton-Sert L, et al. The tumor suppressor PALB2: inside out. Trends Biochem Sci 2019;44: 226240.

  • 3.

    Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913917.

  • 4.

    Hoang LN, Kinloch MA, Leo JM, et al. Interobserver agreement in endometrial carcinoma histotype diagnosis varies depending on the cancer genome atlas (TCGA)-based molecular subgroup. Am J Surg Pathol 2017;41:245252.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405424.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin 2021;71:733.

  • 7.

    Resnick KE, Hampel H, Fishel R, et al. Current and emerging trends in Lynch syndrome identification in women with endometrial cancer. Gynecol Oncol 2009;114:128134.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Tian W, Bi R, Ren Y, et al. Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes. Int J Cancer 2019;145:12901298.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Lu C, Xie M, Wendl MC, et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun 2015;6:10086.

  • 10.

    Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:6773.

  • 11.

    Le Gallo M, O’Hara AJ, Rudd ML, et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet 2012;44:13101315.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov 2017;7:818831.

    • Search Google Scholar
    • Export Citation
  • 13.

    Matanes E, Volodarsky-Perel A, Eisenberg N, et al. Endometrial cancer in germline BRCA mutation carriers: a systematic review and meta-analysis. J Minim Invasive Gynecol 2021;28:947956.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Jiang X, Li X, Li W, et al. PARP inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms. J Cell Mol Med 2019;23:23032313.

  • 15.

    Li H, Liu ZY, Wu N, et al. PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol Cancer 2020;19:107.

  • 16.

    Horak P, Weischenfeldt J, von Amsberg G, et al. Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance. Cold Spring Harb Mol Case Stud 2019;5:a003657.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Gomez MK, Illuzzi G, Colomer C, et al. Identifying and overcoming mechanisms of PARP inhibitor resistance in homologous recombination repair-deficient and repair-proficient high grade serous ovarian cancer cells. Cancers (Basel) 2020;12:1503.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Daly MB, Pilarski R, Yurgelun MB, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020. J Natl Compr Canc Netw 2020;18:380391.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Yang X, Leslie G, Doroszuk A, et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J Clin Oncol 2020;38:674685.

    • Crossref
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 833 833 833
PDF Downloads 525 525 525
EPUB Downloads 0 0 0