title: Somatic BRCA1/2 Recovery as a Resistance Mechanism After Exceptional Response to Poly (ADP-ribose) Polymerase Inhibition.
abstract: Purpose 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. Patients and Methods 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. Results 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. Conclusion 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.
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lheureux
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Jeff P
authors.initials: JP
authors.lastname: Bruce
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Julia V
authors.initials: JV
authors.lastname: Burnier
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Karakasis
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Shaw
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: S Y Cindy
authors.initials: SY
authors.lastname: Yang
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Rene
authors.initials: R
authors.lastname: Quevedo
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Li
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Dowar
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Valerie
authors.initials: V
authors.lastname: Bowering
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.affiliation: Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059472:Exome; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010793:Phthalazines / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D059767:Recombinational DNA Repair; D017423:Sequence Analysis, RNA; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib