Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Seppälä, Toni T.; Dominguez‐Valentin, Mev; Crosbie, Emma; Engel, Christoph; Aretz, Stefan; Macrae, Finlay; Winship, Ingrid; Capellà, Gabriel; Thomas, Huw; Hovig, Eivind; Nielsen, Maartje; Sijmons, Rolf H.; Bertario, Lucio; Bonanni, Bernardo; Tibiletti, Maria Grazia; Cavestro, Giulia Martina; Mints, Miriam; Gluck, Nathan; Katz, Lior H.; Heinimann, Karl; Vaccaro, Carlos; Green, Kate; Lalloo, Fiona; Hill, James A.; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Strauß, Hans; Tecklenburg, Johanna; Holinski‐Feder, Elke; Steinke‐Lange, Verena; Mecklin∥, Jukka–Pekka; Plazzer, John Paul; Pineda, Marta; Navarro, Matilde; Vida, Joan B.; Kariv, Revital; Rosner, Guy; Piñero, Tamara Alejandra; Pavicic, Walter Hernán; Kalfayan, Pablo; Broeke, Sanne W. ten; Jenkins, Mark A.; Sunde, Lone; Bernstein, Inge; Burn, John; Greenblatt, Marc S.; Cappel, Wouter H. de Vos tot Nederveen; Valle, Adriana Della; Lopez-Koestner, Francisco; Büttner, Reinhard; Görgens, Heike; Morak, Monika; Holzapfel, Stefanie; Hüneburg, Robert; Doeberitz, Magnus von Knebel; Loeffler, Markus; Redler, Silke; Weitz, Jürgen; Pylvänäinen, Kirsi; Renkonen–Sinisalo, Laura; Lepistö, Anna; Hopper, John L.; Win, Aung Ko; Lindor, Noralane M.; Gallinger, Steven; Marchand, Loı̈c Le; Newcomb, Polly A.; Figueiredo, Jane C.; Thibodeau, Stephen N.; Therkildsen, Christina; Wadt, Karin; Mourits, Marian J.E.; Ketabi, Zohreh; Denton, Oliver G.; Rødland, Einar Andreas; Vasen, Hans F. A.; Neffa, Florencia; Esperón, Patricia; Tjandra, Douglas; Möslein, Gabriela; Rokkones, Erik; Sampson, Julian R.; Evans, D. Gareth; Møller, Pål

doi:10.1016/j.ejca.2021.02.022

Cited by 13 publications

(17 citation statements)

References 20 publications

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“…The timing and options of RRS can be individualized based on childbearing potential, comorbidities, menopause status, family history and types of germline PVs. 43,109 As mentioned above, the risks of LS-EC varied based on the types of germline PVs, and the median age at onset in path_MSH6 carriers was higher than that in path_MLH1 and path_MSH2 carriers. 17,22 Path_MSH6 carriers are recommended to undergo RRS after 40 years of age, while either path_MLH1 or path_MSH2 carriers might consider risk-reducing surgery at approximately 35 years of age when they no longer need to be fertile.…”

Section: Preventive Surgerymentioning

confidence: 92%

“…Considering the lower risk of EC in path_PMS2 carriers, the role of RRS for path_PMS2 carriers needs further evaluation. Seppälä et al 109 indicated that hysterectomy and/or BSO were performed in 32%, 30%, 18% and 13% of path_MLH1 , path_MSH2 , path_MSH6 and path_PMS2 carriers aged 40‐49 years, respectively, which showed that the uptake of RRS was low and did not correspond well with the current guidelines and age or gene‐associated predicted risks. In addition, a newly published study indicated that little clinical benefit was gained by performing RRS before 40 years old, and there was no significant survival benefit to performing BSO in premenopausal path_MSH6 and path_PMS2 carriers, 110 indicating that guidelines need to be updated consistently based on new data to facilitate optimal individual clinical decision.…”

Section: Preventionmentioning

confidence: 97%

“…The timing and options of RRS can be individualized based on childbearing potential, comorbidities, menopause status, family history and types of germline PVs 43,109 . As mentioned above, the risks of LS‐EC varied based on the types of germline PVs, and the median age at onset in path_MSH6 carriers was higher than that in path_MLH1 and path_MSH2 carriers 17,22 .…”

Section: Preventionmentioning

confidence: 99%

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Endometrial cancer in Lynch syndrome

Zhao

Chen

Zang

et al. 2021

Intl Journal of Cancer

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Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS‐associated endometrial cancer (LS‐EC) is the most common extraintestinal sentinel cancer caused by germline PVs in MMR genes, including MLH1, MSH2, MSH6 and PMS2. The clinicopathologic features of LS‐EC include early age of onset, lower body mass index (BMI), endometrioid carcinoma and lower uterine segment involvement. There has been significant progress in screening, diagnosis, surveillance, prevention and treatment of LS‐EC. Many studies support universal screening for LS among patients with EC. Screening mainly involves a combination of traditional clinical criteria and molecular techniques, including MMR‐immunohistochemistry (MMR‐IHC), microsatellite instability (MSI) testing, MLH1 promoter methylation testing and gene sequencing. The effectiveness of endometrial biopsy and transvaginal ultrasound (TVS) for clinical monitoring of asymptomatic women with LS are uncertain yet. Preventive strategies include hysterectomy and bilateral salpingo‐oophorectomy (BSO) as well as chemoprophylaxis using exogenous progestin or aspirin. Recent research has revealed the benefits of immunotherapy for LS‐EC. The NCCN guidelines recommend pembrolizumab and nivolumab for treating patients with advanced or recurrent microsatellite instability‐high (MSI‐H)/mismatch repair‐deficient (dMMR) EC.

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Section: Preventive Surgerymentioning

confidence: 92%

Section: Preventionmentioning

confidence: 97%

Section: Preventionmentioning

confidence: 99%

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Endometrial cancer in Lynch syndrome

Zhao

Chen

Zang

et al. 2021

Intl Journal of Cancer

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“…In Lynch syndrome, risk reducing hysterectomy and salpingo-oophorectomy is cost effective at age 4046 and prevents 13–45% of endometrial cancers if performed at age 40 years, and 4–18% if performed at age 60 3. Despite this, uptake by 50 years of age is low, at 9–28% for hysterectomy and 13–26% for salpingo-oophorectomy,47 and centers across the world vary in their approach to recommending risk reducing surgery 48. Female Lynch syndrome carriers regard cancer surveillance to be very important, and would opt for more regular investigations if offered 49.…”

Section: Discussionmentioning

confidence: 99%

Screening and risk reducing surgery for endometrial or ovarian cancers in Lynch syndrome: a systematic review

Lim

Hickey

Young

et al. 2022

Int J Gynecol Cancer

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ObjectiveLynch syndrome is a hereditary cancer syndrome caused by mismatch repair gene mutations, and female carriers are at an increased risk of endometrial and ovarian cancer. The best approach to screening is not yet clear and practice varies across countries and centers. We aimed to provide evidence to inform the best approach to screening and risk reduction.MethodsA systematic search of the literature was conducted (Medline, Embase, PubMed). Studies evaluating the following were included: women with Lynch syndrome (by mismatch repair mutation or Amsterdam II criteria), screening methods for endometrial and/or ovarian cancer, intervention included endometrial biopsy, transvaginal ultrasound, or serum cancer antigen 125 (CA-125), outcomes evaluated were number of cancers and/or endometrial hyperplasia.ResultsA total of 18 studies of Lynch syndrome carriers which screened for endometrial cancer using transvaginal ultrasound and/or hysteroscopy/endometrial biopsy revealed an incidence of 3.9% at the time of screening. Most (64.1%) endometrial cancers detected were from screening, with the balance detected in symptomatic women at the first screening visits, regular review, or between screening intervals. In mismatch repair carriers, the overall sensitivity of endometrial screening was 66.7%, and the number needed to screen ranged between 4 and 38 (median 7). The sensitivity of endometrial biopsy was 57.1% and the number needed to screen was 23–380 (median 78). The sensitivity of transvaginal ultrasound was 34.4% and the number needed to screen was 35–973 (median 170). Fourteen studies which screened for ovarian cancer using transvaginal ultrasound and/or CA-125 revealed an incidence of 1.3% at the time of screening and 42.9% of ovarian cancers were detected at asymptomatic screening. The sensitivity of ovarian screening was 54.6%, and the number needed to screen was 9–191 (median 23) in mismatch repair carriers. Thirteen studies reported 5.8% incident endometrial cancers and 0.5% ovarian cancers at time of risk reducing surgery.ConclusionsThere is limited evidence to support screening for endometrial and ovarian cancer in Lynch syndrome and data on mortality reduction are not available. Further prospective, randomized trials comparing targeted screening methods are needed. Risk reducing surgery remains the most reliable way to reduce endometrial and ovarian cancer risk in Lynch syndrome.

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“… 43 However, Seppala et al observed that uptake of risk-reducing gynecological surgery in LS aligned poorly regarding gene- and age-associated risk and did not correspond well with current clinical guidelines. 44 …”

Section: Hereditary Gynecologic Cancer Syndromesmentioning

confidence: 99%