Systematic Next Generation Sequencing is feasible in clinical practice and identifies opportunities for targeted therapy in women with uterine cancer: Results from a prospective cohort study

Arend, Rebecca C.; Goel, Nidhi; Roane, B.M.; Foxall, McKenzie E.; Dholakia, Jhalak; Londoño, Angelina I.; Wall, Jaclyn; Leath, Charles A.; Huh, Warner K.

doi:10.1016/j.ygyno.2021.07.017

Cited by 11 publications

(8 citation statements)

References 32 publications

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“…Though the utility of NGS testing is gaining popularity in oncology clinical practice, there have been few studies evaluating its impact on treatment response or patient survival. In the literature, the benefits in gynecologic cancer treatment have been viewed as debatable [ 8 , 19 , 20 , 21 ]. This could be due to various reasons, including: (a) differences in the rate of utilization of the NGS test depending on whether the test is performed in-house or is outsourced; (b) low frequency of actionable mutations in gynecologic tumors; (c) optimal timing, whether the tumor is newly diagnosed, recurrent or metastatic as patterns of genomic alterations may differ; (d) patient clinical status or how well the patient can tolerate targeted therapy and whether they had been previously heavily treated; (e) broader or narrower sequencing approaches; (f) diversity of tumor types; (g) accessibility of the targetable drugs (often off-label drugs), and (h) intra- and inter-patient heterogeneity, among others.…”

Section: Discussionmentioning

confidence: 99%

The Clinical Utility and Impact of Next Generation Sequencing in Gynecologic Cancers

maruthi

Khazaeli

Jeyachandran

et al. 2022

Cancers

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Next generation sequencing (NGS) has facilitated the identification of molecularly targeted therapies. However, clinical utility is an emerging challenge. Our objective was to identify the clinical utility of NGS testing in gynecologic cancers. A retrospective review of clinico-pathologic data was performed on 299 gynecological cancers where NGS testing had been performed to identify (1) recognition of actionable targets for therapy, (2) whether the therapy changed based on the findings, and (3) the impact on survival. High grade serous carcinoma was the most common tumor (52.5%). The number of genetic alterations ranged from 0 to 25 with a mean of 2.8/case. The most altered genes were TP53, PIK3CA, BRCA1 and BRCA2. Among 299 patients, 100 had actionable alterations (79 received a targeted treatment (Group1), 29 did not receive treatment (Group 2), and there were no actionable alterations in 199 (Group3). The death rate in groups 1, 2 and 3 was 54.4%, 42.8% and 50.2%, with an average survival of 18.6, 6.6 and 10.8 months, respectively (p = 0.002). In summary, NGS testing for gynecologic cancers detected 33.4% of actionable alterations with a high clinical action rate. Along with the high clinical utility of NGS, testing also seemed to improve survival for patients who received targeted treatment.

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Section: Discussionmentioning

confidence: 99%

The Clinical Utility and Impact of Next Generation Sequencing in Gynecologic Cancers

maruthi

Khazaeli

Jeyachandran

et al. 2022

Cancers

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“…Recent studies demonstrate the relevance of PPP2R1A somatic alterations that may contribute to poor prognosis in patients with advance stage endometrial cancer independent of the histological subtype [ 45 ]. On the other hand, the endometrial endometrioid carcinoma was mainly characterized by somatic mutations in the PTEN gene (71%) which is the most common genomic aberration in this concrete subtype, occurring between 63% and 82% of endometrioid affected cases [ 14 , 46 ]. The PIK3CA gene was situated as the second more altered gene (60%), which is in accordance with described molecular genetics data in endometrial carcinomas [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors

et al. 2022

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Gynecological cancer accounts for an elevated incidence worldwide requiring responsiveness regarding its care. The comprehensive genomic approach agrees with the classification of certain tumor types. We evaluated 49 patients with gynecological tumors undergoing high-throughput sequencing to explore whether identifying alterations in cancer-associated genes could characterize concrete histological subtypes. We performed immune examination and analyzed subsequent clinical impact. We found 220 genomic aberrations mostly distributed as single nucleotide variants (SNV, 77%). Only 3% were classified as variants of strong clinical significance in BRCA1 and BRCA2 of ovarian high-grade serous (HGSC) and uterine endometrioid carcinoma. TP53 and BRCA1 occurred in 72% and 28% of HGSC. Cervical squamous cell carcinoma was entirely HPV-associated and mutations occurred in PIK3CA (60%), as well as in uterine serous carcinoma (80%). Alterations were seen in PTEN (71%) and PIK3CA (60%) of uterine endometrioid carcinoma. Elevated programmed death-ligand 1 (PD-L1) was associated with high TILs. Either PD-L1 augmented in deficient mis-matched repair (MMR) proteins or POLE mutated cases when compared to a proficient MMR state. An 18% received genotype-guided therapy and a 4% immunotherapy. The description of tumor subtypes is plausible through high-throughput sequencing by recognizing clinically relevant alterations. Additional concomitant assessment of immune biomarkers identifies candidates for immunotherapy.

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“…Previous studies identified that 75% of Black patients with EC had TP53 alteration compared with 40% for White patients with EC . TP53 is used as a biomarker to identify high-risk patients for treatment intensification, and POLE sequencing is rapidly entering clinical practice for treatment de-escalation .…”

Section: Discussionmentioning

confidence: 99%

“…More recent studies utilized immunohistochemistry staining for p53, finding that this is a cost-effective surrogate for identification of the CN-high group, which has the poorest prognosis . TP53 alteration is significantly more common in Black patients with EC than in White patients (75% vs 40%) . The presence of other more favorable biomarkers may allow for tailored treatment de-escalation of treatment among patients with EC.…”

Section: Introductionmentioning

confidence: 99%

Race, Prevalence of POLE and POLD1 Alterations, and Survival Among Patients With Endometrial Cancer

Zheng,

Donnelly,

Strauss

2024

JAMA Netw Open

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ImportanceBlack patients with endometrial cancer (EC) in the United States have higher mortality than patients of other races with EC. The prevalence of POLE and POLD1 pathogenic alterations in patients of different races with EC are not well studied.ObjectiveTo explore the prevalence of and outcomes associated with POLE and POLD1 alterations in differential racial groups.Design, Setting, and ParticipantsThis retrospective cohort study incorporated the largest available data set of patients with EC, including American Association for Cancer Research Project GENIE (Genomics Evidence Neoplasia Information Exchange; 5087 participants), Memorial Sloan Kettering–Metastatic Events and Tropisms (1315 participants), and the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (517 participants), collected from 2015 to 2023, 2013 to 2021, and 2006 to 2012, respectively. The prevalence of and outcomes associated with POLE or POLD1 alterations in EC were evaluated across self-reported racial groups.ExposurePatients of different racial groups with EC and with or without POLE or POLD1 alterations.Main Outcomes and MeasuresThe main outcome was overall survival. Data on demographic characteristics, POLE and POLD1 alteration status, histologic subtype, tumor mutation burden, fraction of genome altered, and microsatellite instability score were collected.ResultsA total of 6919 EC cases were studied, of whom 444 (6.4%), 694 (10.0%), and 4869 (70.4%) patients were self-described as Asian, Black, and White, respectively. Within these large data sets, Black patients with EC exhibited a lower weighted average prevalence of pathogenic POLE alterations (0.5% [3 of 590 cases]) compared with Asian (6.1% [26 of 424]) or White (4.6% [204 of 4520]) patients. By contrast, the prevalence of POLD1 pathogenic alterations was 5.0% (21 cases), 3.2% (19 cases), and 5.6% (255 cases) in Asian, Black, and White patients with EC, respectively. Patients with POLD1 alterations had better outcomes regardless of race, histology, and TP53 alteration status. For a total of 241 clinically annotated Black patients with EC, a composite biomarker panel of either POLD1 or POLE alterations identified 7.1% (17 patients) with positive outcomes (1 event at 70 months follow up) in the small sample of available patients.Conclusions and RelevanceIn this retrospective clinicopathological study of patients of different racial groups with EC, a composite biomarker panel of either POLD1 or POLE alteration could potentially guide treatment de-escalation, which is especially relevant for Black patients.

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Systematic Next Generation Sequencing is feasible in clinical practice and identifies opportunities for targeted therapy in women with uterine cancer: Results from a prospective cohort study

Cited by 11 publications

References 32 publications

The Clinical Utility and Impact of Next Generation Sequencing in Gynecologic Cancers

The Clinical Utility and Impact of Next Generation Sequencing in Gynecologic Cancers

Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors

Race, Prevalence of POLE and POLD1 Alterations, and Survival Among Patients With Endometrial Cancer

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