Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer

Soumerai, Tara E.; Donoghue, Mark T.A.; Bandlamudi, Chaitanya; Srinivasan, Preethi; Chang, Matthew T.; Zamarin, Dmitriy; Cadoo, Karen A.; Grisham, Rachel N.; O’Cearbhaill, Roisin E.; Tew, William P.; Konner, Jason; Hensley, Martee L.; Makker, Vicky; Sabbatini, Paul; Spriggs, David R.; Troso-Sandoval, Tiffany A.; Charen, Alexandra Snyder; Friedman, Claire F.; Gorsky, Mila; Schweber, Sarah J.; Middha, Sumit; Murali, Rajmohan; Chiang, Sarah; Park, Kay J.; Soslow, Robert A.; Ladanyi, Marc; Li, Bob T.; Mueller, Jennifer J.; Weigelt, Britta; Zehir, Ahmet; Berger, Michael F.; Abu‐Rustum, Nadeem R.; Aghajanian, Carol; DeLair, Deborah F.; Solit, David B.; Taylor, Barry S.; Hyman, David M.

doi:10.1158/1078-0432.ccr-18-0412

Cited by 107 publications

(86 citation statements)

References 23 publications

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“…Reasons hypothesized for the difficulty in demonstrating the activity of anti–HER2 agents in endometrial cancer include the selection of heavily pretreated patients, the activation of pathways that may confer resistance to trastuzumab (eg, PI3K‐Akt), and high levels of HER2 extracellular domain shedding . Immunoconjugates may bypass some of these issues, and a patient with HER2 ‐amplified serous carcinoma has been reported to have a complete response to trastuzumab emtansine …”

Section: Therapy For Recurrent or Metastatic Diseasementioning

confidence: 99%

“…A recent report noted a 16% rate of HER2 amplification as well as a smaller number of HER2 mutations in a series of 197 advanced/metastatic endometrial cancers. 124 Rates are highest in serous and clear cell tumors. However, a benefit to anti-HER2 therapy has been difficult to demonstrate in this tumor type.…”

Section: Anti-her2 Therapymentioning

confidence: 99%

“…127 Immunoconjugates may bypass some of these issues, and a patient with HER2amplified serous carcinoma has been reported to have a complete response to trastuzumab emtansine. 124 There is also a suggestion of promise for trastuzumab in the front-line setting. Fader et al randomized women with primary stage III and IV or recurrent HER2-positive (defined as 2+ or 3+ overexpression and confirmed amplification by fluorescence in situ hybridization) serous endometrial cancer to receive either carboplatin and paclitaxel or carboplatin, paclitaxel, and trastuzumab.…”

Section: Anti-her2 Therapymentioning

confidence: 99%

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Current recommendations and recent progress in endometrial cancer

Brooks

Fleming

Lastra

et al. 2019

CA A Cancer J Clinicians

414

372

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Endometrial cancer is the most common gynecologic cancer in the United States, and its incidence is rising. Although there have been significant recent advances in our understanding of endometrial cancer biology, many aspects of treatment remain mired in controversy, including the role of surgical lymph node assessment and the selection of patients for adjuvant radiation or chemotherapy. For the subset of women with microsatellite‐instable, metastatic disease, anti– programmed cell death protein 1 immunotherapy (pembrolizumab) is now approved by the US Food and Drug Administration, and numerous trials are attempting to build on this early success.

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Section: Therapy For Recurrent or Metastatic Diseasementioning

confidence: 99%

Section: Anti-her2 Therapymentioning

confidence: 99%

Section: Anti-her2 Therapymentioning

confidence: 99%

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Current recommendations and recent progress in endometrial cancer

Brooks

Fleming

Lastra

et al. 2019

CA A Cancer J Clinicians

414

372

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“…'POLE ultramutated' EC (POLEmut EC) has therefore been proposed as a distinct clinical entity that can be diagnosed in the presence of a pathogenic POLE exonuclease domain mutation (EDM) [8]. For the five most common POLE mutations (P286R, V411L, S297F, A456P, and S459F), pathogenicity (in this sense meaning causal for tumour ultramutation) has been confirmed [4][5][6][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]; however, the classification of other, less frequent POLE variants is currently challenging. This is becoming an urgent problem, as POLE sequencing for molecular EC classification is rapidly entering clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Interpretation of somatic POLE mutations in endometrial carcinoma

León‐Castillo

Britton

McConechy³

et al. 2020

The Journal of Pathology

223

207

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Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours (‘POLE‐ultramutated’) within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole‐exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE‐score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE‐ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non‐EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI‐H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co‐existent with MSI‐H showed genomic alterations characteristic of POLE‐ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI‐H and a pathogenic POLE EDM had a 5‐year recurrence‐free survival (RFS) of 92.3%, comparable to previously reported POLE‐ultramutated ECs. Additionally, 14 cases with non‐pathogenic POLE EDM and MMRd/MSI‐H had a 5‐year RFS of 76.2%, similar to MMRd/MSI‐H, POLE wild‐type ECs, suggesting that these should be categorised as MMRd, rather than POLE‐ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Endometrial carcinomas are among the tumor types with the highest frequency of genomic activation of the PI3K/ mTOR pathway. [5][6][7] Specifically, alterations in PTEN, PIK3CA, and PIK3R1 occur in endometrial carcinomas at estimated frequencies of 65%, 50%, and 31%, respectively, with variation depending on various cohort factors. 8 In addition to genetic alterations, PI3K pathway activation is also affected by hyperinsulinemia and increased insulin signaling.…”

Section: Introductionmentioning

confidence: 99%

Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway

Rubinstein

Hyman

Caird

et al. 2019

Cancer

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Background PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. Methods We conducted a single‐arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1‐4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss‐of‐function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. Results Twenty‐eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1‐3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy‐evaluable patients, the ORR was 16% (90% CI, 7%‐100%), and the clinical benefit rate was 28% (90% CI, 16%‐100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression‐free survival and overall survival were 2.5 months (95% CI, 1.2‐3.0) and 9.2 months (95% CI, 5.0‐15.9), respectively. The most common all‐grade treatment‐related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. Conclusion In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single‐agent activity and a manageable safety profile.

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Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer

Cited by 107 publications

References 23 publications

Current recommendations and recent progress in endometrial cancer

Current recommendations and recent progress in endometrial cancer

Interpretation of somatic POLE mutations in endometrial carcinoma

Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway

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