Are prediction models for Lynch syndrome valid for probands with endometrial cancer?

Abstract

Currently, three prediction models are used to predict a patient's risk of having Lynch syndrome (LS). These models have been validated in probands with colorectal cancer (CRC), but not in probands presenting with endometrial cancer (EMC). Thus, the aim was to determine the performance of these prediction models in women with LS presenting with EMC. Probands with EMC and LS were identified. Personal and family history was entered into three prediction models, PREMM(1,2), MMRpro, and MMRpredict. Probabilities of mutations in the mismatch repair genes were recorded. Accurate prediction was defined as a model predicting at least a 5% chance of a proband carrying a mutation. From 562 patients prospectively enrolled in a clinical trial of patients with EMC, 13 (2.2%) were shown to have LS. Nine patients had a mutation in MSH6, three in MSH2, and one in MLH1. MMRpro predicted that 3 of 9 patients with an MSH6, 3 of 3 with an MSH2, and 1 of 1 patient with an MLH1 mutation could have LS. For MMRpredict, EMC coded as "proximal CRC" predicted 5 of 5, and as "distal CRC" three of five. PREMM(1,2) predicted that 4 of 4 with an MLH1 or MSH2 could have LS. Prediction of LS in probands presenting with EMC using current models for probands with CRC works reasonably well. Further studies are needed to develop models that include questions specific to patients with EMC with a greater age range, as well as placing increased emphasis on prediction of LS in probands with MSH6 mutations.

Performance of PREMM1,2,6, MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases

“…The only other study looking at LS prediction models among EC cases examined the sensitivity of PREMM 1,2 , MMRpredict, and MMRpro in 13 population-based EC cases with LS and showed that these models performed reasonably well in EC cases, with sensitivities ranging from 64 to 100%. 24 Our larger analysis supports the high yield in sensitivity but also reveals that the predictive models tend to assign greater weight to a diagnosis of EC compared with CRC (e.g., just the presence of an EC diagnosis in a proband results in a PREMM 1,2,6 score above the 5% cut-off point).…”

Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study

“…Cancer family risk (our categories or PREMM 1,2,6 scores) did not reliably predict germline mutation, and several mutation carriers had no history of LACs in relatives ( Table 4 ), confirming reports that family history fails to identify Lynch carriers. 30 – 33 As noted, some women with a previous history of cancer were excluded from the GOG210 study.…”

Brief family history questionnaire to screen for Lynch syndrome in women with newly diagnosed non-serous, non-mucinous ovarian cancers

“…There are newer clinical prediction tools, such as PREMM5, MMRpredict, and MMRpro, mostly developed using the colorectal cancer population; unfortunately, these tools have limited clinical utility for gynecological malignancies 20–22. These prediction tools have lower discriminative ability to distinguish mutation carriers from non-carriers in endometrial cancer, and no such tools exist in ovarian cancer 21 23. More importantly, these tools take time, and rely on detailed and accurate history taking, which is often impractical in busy clinical settings.…”