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PARP Inhibitor in Advanced Endometrial Carcinoma Beyond BRCA and Related Genetic Mutations

To the Editor:

Nakamura et al1 reported a durable clinical response to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in a patient with advanced high-grade serous endometrial carcinoma harboring a BRIP1 somatic mutation. The authors stated that there are currently no trials of PARP inhibitors in endometrial carcinoma, mainly because mutations in BRIP1, BRCA1, BRCA2, and other homologous recombination (HR)–related genes are too rare, being reported overall in < 5% of cases.2
In fact, the French group GINECO (Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens) is conducting a national randomized phase II trial evaluating olaparib as maintenance therapy in platinum-sensitive advanced uterine carcinoma (UTOLA trial; ClinicalTrials.gov identifier: NCT03745950; Fig 1) versus placebo. We anticipate that patients with endometrial tumors might benefit from a PARP inhibitor, even in cases of no BRCA or related genetic mutations.
Fig 1. The UTOLA trial design. The primary end point is progression-free survival (PFS). The secondary end points are overall survival, response rate, quality of life, safety, time from random assignment to first and second subsequent therapies, and time from random assignment to second disease progression or death. The sample size calculation was based on the following hypothesis: 66.7% relative increase in median first PFS rate in olaparib arm (from 4.5 to 7.5 months), 5% type I error (one tailed), and 20% type II error. Exploratory analyses included homologous recombination–deficient (HRD) phenotype and multiple-gene next-generation sequencing, including BRCA1 and BRCA2 and other HRD-related genes (TP53, PTEN, POLE, and ARID1A), and microsatellite instability status. FIGO, International Federation of Gynecology and Obstetrics; PD, progressive disease. (*) Stratification factors: immunophenotype TP53 (yes v no) and mismatch repair (yes v no), response to chemotherapy (objective response v stable disease), and center.
The HR-deficient (HRD) phenotype was initially characterized in approximately 50% of high-grade serous ovarian carcinomas, and 20% to 25% of these had no BRCA1 or BRCA2 mutations.3 Importantly, this phenotype is associated with clinical activity of platinum and PARP inhibitors in platinum-sensitive ovarian carcinomas regardless of BRCA mutations.4,5
According to The Cancer Genome Atlas data, the HRD phenotype was also recently reported in 25% of uterine endometrial carcinomas.6 It is almost exclusively found in the serous-like, TP53-mutated subtype, in which it represents nearly 50% of cases.7 Molecular alterations responsible for the HRD phenotype in endometrial carcinoma have not been largely explored and remain to be identified, because BRCA1 promoter methylation seems uncommon.7 Finally, HR deficiency could be induced by platinum-based chemotherapy; a recent study showed decreased expression of Rad51 protein, a key partner of HR, after neoadjuvant chemotherapy in a subset of patients with ovarian cancer.8 In TP53 wild-type endometrioid carcinoma, common molecular alterations such as PTEN or ARID1A loss have been also associated in vitro with significant PARP inhibitor activity.9,10
According to these preliminary data, inclusion criteria in the UTOLA trial are not restricted to specific molecular alterations; rather, patients could be enrolled if their disease is platinum sensitive, a well-recognized landmark of the HRD phenotype. Patients are stratified according to MRR and TP53 immuno-phenotypes, and a large screening of molecular alterations, including HRD profile, will be conducted to determine the best candidates for PARP inhibitor maintenance.
In conclusion, we agree with Nakamura et al1 that PARP inhibitors should be explored in patients with advanced endometrial carcinoma, beyond those with rare mutations in BRCA or related genes. The UTOLA trial will help to answer this question.
A reply to this Correspondence was not provided.

Acknowledgment

Written on behalf of the French GINECO (Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens) group.

Authors' Disclosures of Potential Conflicts of Interest

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
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Jérôme Alexandre

Honoraria: Roche/Genentech, AstraZeneca, Novartis, Sanofi/Aventis, Ipsen, MSD Oncology, GlaxoSmithKline
Consulting or Advisory Role: Roche, Sanofi, Novartis, AstraZeneca, Ipsen
Research Funding: Janssen (Inst), MSD Oncology (Inst)
Travel, Accommodations, Expenses: Janssen, Novartis

Isabelle Ray-Coquard

Honoraria: Roche, PharmaMar, AstraZeneca, Clovis Oncology, Tesaro, MSD Oncology, Genmab, AbbVie, Pfizer, Bristol Myers Squibb
Consulting or Advisory Role: Pfizer, AbbVie, Genmab, Roche, AstraZeneca, Tesaro, Clovis Oncology, PharmaMar, MSD Oncology, Bristol Myers Squibb, Deciphera, Mersana, GlaxoSmithKline
Research Funding: MSD Oncology, Bristol Myers Squibb
Travel, Accommodations, Expenses: Roche, AstraZeneca, Tesaro, PharmaMar, GlaxoSmithKline, Clovis Oncology, Bristol Myers Squibb, Advaxis
Uncompensated Relationships: GINECO, Inca National Cancer Institute France

Florence Joly

Consulting or Advisory Role: AstraZeneca, Janssen, Roche, Sanofi, Ipsen, Pfizer, MSD Oncology, Bristol Myers Squibb, GlaxoSmithKline, Astellas Pharma
Research Funding: Astellas Pharma, Janssen
Travel, Accommodations, Expenses: Roche, Janssen, AstraZeneca, Ipsen, GlaxoSmithKline, Bristol Myers Squibb
No other potential conflicts of interest were reported.

References

1.
Nakamura K, Aimono E, Tanishima S, et al: Olaparib monotherapy for BRIP1-mutated high-grade serous endometrial cancer. JCO Precis Oncol 4:283-290, 2020
2.
Heeke AL, Pishvaian MJ, Lynce F, et al: Prevalence of homologous recombination-related gene mutations across multiple cancer types. JCO Precis Oncol 2:1-13, 2018
3.
Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature 474:609-615, 2011 [Erratum: Nature 490:298, 2012]
4.
Ray-Coquard I, Pautier P, Pignata S, et al: Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 381:2416-2428, 2019
5.
Mirza MR, Monk BJ, Herrstedt J, et al: Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 375:2154-2164, 2016
6.
Marquard AM, Eklund AC, Joshi T, et al: Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs. Biomark Res 3:9, 2015
7.
de Jonge MM, Auguste A, van Wijk LM, et al: Frequent homologous recombination deficiency in high-grade endometrial carcinomas. Clin Cancer Res 25:1087-1097, 2019
8.
Kubelac P, Genestie C, Auguste A, et al: Changes in DNA damage response markers with treatment in advanced ovarian cancer. Cancers (Basel) 12:707-719, 2020
9.
Dedes KJ, Wetterskog D, Mendes-Pereira AM, et al: PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med 2:53ra75, 2010
10.
Shen J, Peng Y, Wei L, et al: ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov 5:752-767, 2015

Information & Authors

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Published In

JCO Precision Oncology
Pages: 1025 - 1026
PubMed: 35050765

History

Published online: September 04, 2020

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Jérôme Alexandre, MD, PhD [email protected]
Jérôme Alexandre, MD, PhD, Service d’Oncologie Médicale, Cochin–Port Royal, Assistance Publique–Hôpitaux de Paris Centre Université de Paris, Cancer Research for Personalized Medicine, Paris, France; Isabelle Ray-Coquard, MD, PhD, Service d’Oncologie Médicale, Centre Léon Bérard, Université de Lyon, Lyon, France; and Florence Joly, MD, PhD, Medical Oncology Department, Centre François Baclesse, University of Caen–Normandie, Caen, France
Isabelle Ray-Coquard, MD, PhD
Jérôme Alexandre, MD, PhD, Service d’Oncologie Médicale, Cochin–Port Royal, Assistance Publique–Hôpitaux de Paris Centre Université de Paris, Cancer Research for Personalized Medicine, Paris, France; Isabelle Ray-Coquard, MD, PhD, Service d’Oncologie Médicale, Centre Léon Bérard, Université de Lyon, Lyon, France; and Florence Joly, MD, PhD, Medical Oncology Department, Centre François Baclesse, University of Caen–Normandie, Caen, France
Florence Joly, MD, PhD
Jérôme Alexandre, MD, PhD, Service d’Oncologie Médicale, Cochin–Port Royal, Assistance Publique–Hôpitaux de Paris Centre Université de Paris, Cancer Research for Personalized Medicine, Paris, France; Isabelle Ray-Coquard, MD, PhD, Service d’Oncologie Médicale, Centre Léon Bérard, Université de Lyon, Lyon, France; and Florence Joly, MD, PhD, Medical Oncology Department, Centre François Baclesse, University of Caen–Normandie, Caen, France

Notes

Jérôme Alexandre, MD, PhD, Department of Medical Oncology, Cochin Hospital, 123 Bld de Port Royal, Paris, France 75014; e-mail: [email protected].

Author Contributions

Conception and design: All authors
Administrative support: Jérôme Alexandre
Collection and assembly of data: Jérôme Alexandre, Florence Joly
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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Jérôme Alexandre, Isabelle Ray-Coquard, Florence Joly
JCO Precision Oncology 2020 :4, 1025-1026

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