Somatic BRCA1/2 Recovery as a Resistance Mechanism After Exceptional Response to Poly (ADP-ribose) Polymerase Inhibition

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Bibliographische Detailangaben
Zeitschriftentitel:	Journal of Clinical Oncology
Personen und Körperschaften:	Lheureux, Stephanie, Bruce, Jeff P., Burnier, Julia V., Karakasis, Katherine, Shaw, Patricia A., Clarke, Blaise A., Yang, S.Y. Cindy, Quevedo, Rene, Li, Tiantian, Dowar, Mark, Bowering, Valerie, Pugh, Trevor J., Oza, Amit M.
In:	Journal of Clinical Oncology, 35, 2017, 11, S. 1240-1249
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Society of Clinical Oncology (ASCO)
Schlagwörter:	Cancer Research Oncology

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Zusammenfassung:	<jats:sec><jats:title>Purpose</jats:title><jats:p> Durable and long-term responses to the poly (ADP-ribose) polymerase inhibitor olaparib are observed in patients without BRCA1/2 mutations. However, beyond BRCA1/2 mutations, there are no approved biomarkers for olaparib in high-grade serous ovarian cancer (HGSOC). To determine mechanisms of durable response and resistance to olaparib therapy, we performed an analysis of HGSOC tumors from three patients without germline BRCA1/2 mutations who experienced exceptional responses to olaparib. </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> We performed integrated exome, low-pass genome, and RNA sequence analysis of tumors at diagnosis and upon relapse from patients with platinum-sensitive HGSOC recurrence who were treated > 5 years with olaparib therapy as a single agent. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> We observed somatic disruption of BRCA1/2 in all three patients at diagnosis, followed by subsequent BRCA recovery upon progression by copy number gain and/or upregulation of the remaining functional allele in two patients. The third patient with ongoing response (> 7 years) had a tumor at diagnosis with biallelic somatic deletion and loss-of-function mutation, thereby lacking a functional allele for recovery of BRCA1 activity and indicating a potential cure. </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> Olaparib has durable benefit for patients with ovarian cancer beyond germline BRCA1/2 carriers. These data suggest that biallelic loss of BRCA1/2 in cancer cells may be a potential marker of long-term response to poly (ADP-ribose) polymerase inhibition and that restoration of homologous repair function may be a mechanism of disease resistance. </jats:p></jats:sec>
Umfang:	1240-1249
ISSN:	0732-183X 1527-7755
DOI:	10.1200/jco.2016.71.3677