4 Refining pathologic interpretation of endometrial carcinomas: lessons learned from a nationwide study in a new era of molecular classification

Thompson, Emily F.; Huvila, Jutta; Leung, Samuel; Irving, Julie; Westhuizen, Nicholas van der; Kinloch, Mary; Lytwyn, Alice; Sur, Monalisa; Parra‐Herran, Carlos; Yasmeen, Amber; Gougeon, F.; Morin, Carol; Grondin, Katherine; Offman, Saul; Salisbury, Taylor; He, E; Lawson, Julia M.; Broek, J Vanden; Bell, Cliff; Ennour‐Idrissi, Kaoutar; Wohlmuth, Christoph; Vicus, Danielle; Gotlieb, Walter H.; Helpman, Limor; Lum, Amy; Senz, Janine; Dg, Huntsman; Mcalpine, J

doi:10.1136/ijgc-2020-igcs.4

Cited by 5 publications

(11 citation statements)

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“…10,11 A recent countrywide initiative in Canada found that despite universal tumor testing, LS was underdiagnosed. 12 Mutations in cancer susceptibility genes (CSGs) other than those associated with LS are thought to play a smaller role in EC risk. 13 Although multigene panel testing (MGPT) studies performed for women with EC have identified PVs in other CSGs, [14][15][16] the true burden of PVs in other CSGs remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

Levine

Pearlman

Hampel

et al. 2021

JCO Precision Oncology

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PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

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Section: Introductionmentioning

confidence: 99%

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

Levine

Pearlman

Hampel

et al. 2021

JCO Precision Oncology

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“…The proportion of p53abn tumours for each histotype was assessed recently using pooled data from several EC cohorts that have been classified molecularly as follows; serous carcinoma 93%, carcinosarcoma 85%, clear cell carcinoma 38%, grade 3 endometrioid EC 22% and grade 1-2 endometrioid EC 5%. 7,[9][10][11][12][13][14][18][19][20][21]44 Conventional adjuvant therapy The importance of conventional platinum-based chemotherapy in p53abn EC was demonstrated with the retrospective molecular analysis of PORTEC-3 trial for high-risk EC. This showed that patients with p53abn EC had significantly improved outcomes when chemotherapy was used in addition to pelvic radiation, with 5-year recurrence-free survival of 59% with chemotherapy and radiation versus 36% with radiation alone (p = 0.019).…”

Section: Immune Checkpoint Blockade Therapymentioning

confidence: 99%

Section: P53abn Endometrial Cancermentioning

confidence: 99%

“…Further, this is a subset of women in whom better treatment options and opportunities to improve survival statistics are desperately needed. The evidence that p53abn molecular subtype is found in up to 5% of grade 1 and 2 endometrioid endometrial carcinomas 7 , 45 highlights why it is important that molecular features are integrated into pathology classification and stratification of care. Patients with stage I and grade 1–2 endometrioid EC without LVI would otherwise be considered low risk by historical EC risk stratification systems, and might be treated by surgery alone.…”

Section: P53abn Endometrial Cancermentioning

confidence: 99%

“…What is also concerning is the significant variation in clinical practice that is currently observed in administering adjuvant therapy in EC. 7 A recent National Cancer Database review showed out of 19,594 EC patients who met the national guidelines criteria for adjuvant radiation, 47% did not receive radiation, which was associated with worse overall survival. Omission of adjuvant radiation was more common among African-American, Hispanic and Asian patients, and patients with lower household income, lack of health insurance and treatment at non-academic hospitals.…”

Section: Introductionmentioning

confidence: 99%

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The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

2021

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Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing ( POLE) and immunohistochemistry (mismatch repair and p53 proteins) to assign patients with EC to one of four molecular subtypes: POLEmut, MMRd, p53abn and NSMP (no specific molecular profile). Unlike histopathological evaluation, the molecular subtyping of EC offers an objective and reproducible classification system that has been shown to have prognostic value and therapeutic implications. It is an exciting time in EC care where we have moved beyond treatment based on histomorphology alone, and molecular classification will now finally allow assessment of treatment efficacy within biologically similar tumours. It is now recommended that molecular classification should be considered for all ECs, and should be performed routinely in all high grade tumours. It is also recommended to incorporate molecular classification into standard pathology reporting and treatment decision-making algorithms. In this review, we will discuss how the molecular classification of EC can be used to guide both conventional and targeted therapy in this new molecular era.

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Implementing universal upfront multi-gene panel testing in endometrial cancer: From cost to practical considerations

Levine

Barrington

Hampel

et al. 2022

Gynecologic Oncology

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4 Refining pathologic interpretation of endometrial carcinomas: lessons learned from a nationwide study in a new era of molecular classification

Cited by 5 publications

References 0 publications

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

Implementing universal upfront multi-gene panel testing in endometrial cancer: From cost to practical considerations

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