Endometrial Cancer Risk Among Germline / Pathogenic Variant Carriers: Review of Our Current Understanding and Next Steps

Overview

Journal JCO Precis Oncol

Specialty Oncology

Date 2023 Dec 7

PMID 38061009

Authors

Kimia Sorouri

Filipa Lynce

Colleen M Feltmate

Michelle R Davis

Michael G Muto

Panagiotis A Konstantinopoulos

Elizabeth H Stover

Allison W Kurian

Sarah J Hill

Ann H Partridge

Sara M Tolaney

Judy E Garber

Brittany L Bychkovsky

Affiliations

Soon will be listed here.

Abstract

Purpose: To review the literature exploring endometrial cancer (EC) risk among surgical candidates with germline pathogenic variants (PVs) to guide decisions around risk-reducing (rr) hysterectomy in this population.

Design: A comprehensive review was conducted of the current literature that influences clinical practice and informs expert consensus. We present our understanding of EC risk among PV carriers, the risk-modifying factors specific to this patient population, and the available research technology that may guide clinical practice in the future. Limitations of the existing literature are outlined.

Results: Patients with PVs, those with a personal history of tamoxifen use, those who desire long-term hormone replacement therapy, and/or have an elevated BMI are at higher risk of EC, primarily endometrioid EC and/or uterine papillary serous carcinoma, and may benefit from rr-hysterectomy. Although prescriptive clinical guidelines specific to PV carriers could inform decisions around rr-hysterectomy, limitations of the current literature prevent more definitive guidance at this time. A large population-based study of a contemporary cohort of PV carriers with lifetime follow-up compared with cancer-gene negative controls would advance this topic and facilitate care decisions.

Conclusion: This review validates a potential role for rr-hysterectomy to address EC risk among surgical candidates with PVs. Evidence-based clinical guidelines for rr-hysterectomy in PV carriers are essential to ensure equitable access to this preventive measure, supporting insurance coverage for patients with either or PVs to pursue rr-hysterectomy. Overall, this review highlights the complexity of EC risk in PV carriers and offers a comprehensive framework to shared decision making to inform rr-hysterectomy for PV carriers.

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References

Cicchillitti L, Corrado G, De Angeli M, Mancini E, Baiocco E, Patrizi L . Circulating cell-free DNA content as blood based biomarker in endometrial cancer. Oncotarget. 2018; 8(70):115230-115243. PMC: 5777767. DOI: 10.18632/oncotarget.23247. View

Bogani G, Cromi A, Serati M, DI Naro E, Casarin J, Pinelli C . Laparoscopic and vaginal approaches to hysterectomy in the obese. Eur J Obstet Gynecol Reprod Biol. 2015; 189:85-90. DOI: 10.1016/j.ejogrb.2015.02.035. View

Portela S, Cunningham A, Laios A, Hutson R, Theophilou G . Breast Cancer Patients at Increased Risk of Developing Type II Endometrial Cancer: Relative and Absolute Risk Estimation and Implications for Counseling. Cureus. 2021; 13(1):e12981. PMC: 7920226. DOI: 10.7759/cureus.12981. View

Shu C, Pike M, Jotwani A, Friebel T, Soslow R, Levine D . Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations. JAMA Oncol. 2016; 2(11):1434-1440. PMC: 5594920. DOI: 10.1001/jamaoncol.2016.1820. View

. Committee opinion no. 619: Gynecologic surgery in the obese woman. Obstet Gynecol. 2015; 125(1):274-278. DOI: 10.1097/01.AOG.0000459870.06491.71. View

Casey M, Bewtra C, Lynch H, Snyder C, Stacey M . Endometrial cancers in mutation carriers from hereditary breast ovarian cancer syndrome kindreds: report from the Creighton University Hereditary Cancer Registry with review of the implications. Int J Gynecol Cancer. 2015; 25(4):650-6. DOI: 10.1097/IGC.0000000000000402. View

Boretto M, Maenhoudt N, Luo X, Hennes A, Boeckx B, Bui B . Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nat Cell Biol. 2019; 21(8):1041-1051. DOI: 10.1038/s41556-019-0360-z. View

Beiner M, Finch A, Rosen B, Lubinski J, Moller P, Ghadirian P . The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study. Gynecol Oncol. 2006; 104(1):7-10. DOI: 10.1016/j.ygyno.2006.08.004. View

Bland A, Calingaert B, Secord A, Lee P, Valea F, Berchuck A . Relationship between tamoxifen use and high risk endometrial cancer histologic types. Gynecol Oncol. 2008; 112(1):150-4. DOI: 10.1016/j.ygyno.2008.08.035. View

10.

. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019; 394(10204):1159-1168. PMC: 6891893. DOI: 10.1016/S0140-6736(19)31709-X. View

11.

Kwon J, Lenehan J, Carey M, Ainsworth P . Prolonged survival among women with BRCA germline mutations and advanced endometrial cancer: a case series. Int J Gynecol Cancer. 2007; 18(3):546-9. DOI: 10.1111/j.1525-1438.2007.01030.x. View

12.

Bie Y, Zhang Z . Diagnostic value of serum HE4 in endometrial cancer: a meta-analysis. World J Surg Oncol. 2014; 12:169. PMC: 4050396. DOI: 10.1186/1477-7819-12-169. View

13.

Nappi R, Tiranini L, Martini E, Bosoni D, Righi A, Cucinella L . Medical Treatment of Female Sexual Dysfunction. Urol Clin North Am. 2022; 49(2):299-307. DOI: 10.1016/j.ucl.2022.02.001. View

14.

Reitsma W, Mourits M, de Bock G, Hollema H . Endometrium is not the primary site of origin of pelvic high-grade serous carcinoma in BRCA1 or BRCA2 mutation carriers. Mod Pathol. 2012; 26(4):572-8. DOI: 10.1038/modpathol.2012.169. View

15.

Lee S, Chou Y, Tantoh D, Hsu S, Nfor O, Tyan Y . Risk of uterine leiomyoma based on BET1L rs2280543 single nucleotide polymorphism and vegetarian diet. BMC Womens Health. 2022; 22(1):139. PMC: 9044639. DOI: 10.1186/s12905-022-01721-1. View

16.

Bafligil C, Thompson D, Lophatananon A, Smith M, Ryan N, Naqvi A . Association between genetic polymorphisms and endometrial cancer risk: a systematic review. J Med Genet. 2020; 57(9):591-600. PMC: 7476276. DOI: 10.1136/jmedgenet-2019-106529. View

17.

Byrd L, Shenton A, Maher E, Woodward E, Belk R, Lim C . Better life expectancy in women with BRCA2 compared with BRCA1 mutations is attributable to lower frequency and later onset of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2008; 17(6):1535-42. DOI: 10.1158/1055-9965.EPI-07-2792. View

18.

Kotsopoulos J, Gronwald J, Karlan B, Huzarski T, Tung N, Moller P . Hormone Replacement Therapy After Oophorectomy and Breast Cancer Risk Among BRCA1 Mutation Carriers. JAMA Oncol. 2018; 4(8):1059-1065. PMC: 6143051. DOI: 10.1001/jamaoncol.2018.0211. View

19.

Schrag D, Kuntz K, Garber J, Weeks J . Decision analysis--effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations. N Engl J Med. 1997; 336(20):1465-71. DOI: 10.1056/NEJM199705153362022. View

20.

Zhang Y, Liu H, Yang S, Zhang J, Qian L, Chen X . Overweight, obesity and endometrial cancer risk: results from a systematic review and meta-analysis. Int J Biol Markers. 2013; 29(1):e21-9. DOI: 10.5301/jbm.5000047. View