Cowden Syndrome and Breast Cancer

  • PTEN is a tumor suppressor gene:
    • Inherited mutations in this gene can be associated with Cowden’s syndrome
  • Cowden’s syndrome is associated with increased risk of multiple types of cancer including:
    • Breast
    • Endometrial
    • Thyroid
    • Colorectal
    • Melanoma
  • PTEN mutations carriers:
    • Tend to develop cancers at younger ages than individuals with sporadic malignancies
    • Lifetime breast cancer risk with this syndrome is:
      • Up to 85%, as reported by Tan el al:
        • Although it is noted given the limitations in reported studies of women with Cowden’s syndrome:
          • Risk estimates are not stable
    • Hamartomas on the skin or mucous membranes:
      • Are extremely common in this syndrome
    • Macrocephaly:
      • May also be seen
    • PTEN mutations are inherited in an autosomal dominant pattern:
      • With an estimated frequency of 1 in 200,000 people
    • Loss of PTEN gene expression:
      • At the somatic or germline level may affect response to HER2-directed therapies
      • Low levels of the protein in stromal cells:
        • Have been associated with increased risk of recurrence related to radiation in pre-clinical models
    • Moderate risk genes associated with varying levels are breast cancer risk with the following relative risks reported from a meta-analysis: 
      • PALB2:
        • RR 5.3
      • CDH1:
        • RR 6.6
      • CHEK2 truncating mutations:
        • RR 3.0
      • ATM:
        • RR 2.8
  • References
    • Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3(9):1190-1196.
    • Gustafson S, Zbuk KM, Scacheri C, Eng C. Cowden syndrome. Semin Oncol. 2007;34(5):428-434.
    • Ngeow J, Sesock K, Eng C. Breast cancer risk and clinical implications for germline PTEN mutation carriers. Breast Cancer Res Treat.2017;165(1):1-8.
    • Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400-407.
    • Weiss A, Garber JE, King T. Breast cancer surgical risk reduction for patients with inherited mutations in moderate penetrance genes. JAMA Surg. 2018;153(12):1145-1146.
    • Kim C, Lee CK, Chon HJ, et al. PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer. Oncotarget. 2017;8(69):113494-113501.
    • Sizemore GM, Balakrishnan S, Thies KA, et al. Stromal PTEN determines mammary epithelial response to radiotherapy. Nat Commun. 2018;9(1):2783.
    • Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med.2015;372(23):2243-2257.

#Arrangoiz #BreastSurgeon #CancerSurgeon #BreastCancer #SurgicalOncologist #CASO #CenterforAdvancedSurgicalOncology #PalmettoGeneralHospital

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