Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer

Bang, Yung Jue; Im, Seock Ah; Lee, Moon Hyoung; Cho, Jae Yong; Song, Eun Kee; Lee, Kyung Hee; Kim, Yeul Hong; Park, Joon Oh; Chun, Hoo G.; Zang, Dae Young; Fielding, Anitra; Rowbottom, Jacqui; Hodgson, Darren; O'Connor, Mark J.; Yin, Xiaolu; Kim, Woo Ho

doi:10.1200/jco.2014.60.0320

Cited by 244 publications

(173 citation statements)

References 33 publications

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“…Furthermore, a phase II double-blind study of paclitaxel with or without olaparib for patients with gastric cancer stratified patients between low or undetectable ATM levels versus normal ATM levels. A greater improvement in overall survival was seen in the ATM-low subgroup, consistent with the preclinical observations (73).…”

Section: Parp Inhibitorssupporting

confidence: 79%

ATM Mutations in Cancer: Therapeutic Implications

Choi¹,

Kipps²,

Kurzrock³

2016

Molecular Cancer Therapeutics

390

318

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Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors. Such mutations may result in chemotherapy resistance and adverse prognosis, but may also be exploited by existing or emerging targeted therapies that produce synthetic lethal states.

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Section: Parp Inhibitorssupporting

confidence: 79%

ATM Mutations in Cancer: Therapeutic Implications

Choi¹,

Kipps²,

Kurzrock³

2016

Molecular Cancer Therapeutics

390

318

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show abstract

“…Mutations in ATM (found in 8% of the ICGC cohort described by Waddell et al) may predict sensitivity to targeted DNA damaging agents (e.g. PARPinhibitors or ATR inhibitors), however it remains to be determined whether ATM mutation, gene expression or immunohistochemistry is the ideal predictive biomarker for response in this patient sub-group (62). There is growing evidence that mutations in chromatin remodeling pathways (e.g.…”

Section: Targeting Ddr Deficiencymentioning

confidence: 99%

“…There is growing evidence that mutations in chromatin remodeling pathways (e.g. ARID1A mutations) can be targeted using PARP-or ATR-inhibitors (40,55,60,(62)(63)(64). These mutations are associated with the poor prognostic squamous sub-type and may provide a therapeutic strategy to target this sub-set of patients(10).…”

Section: Targeting Ddr Deficiencymentioning

confidence: 99%

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Dreyer

Chang

Bailey

et al. 2017

Clinical Cancer Research

146

114

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Pancreatic cancer has become the 3 rd leading cause of cancer death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet, only 20% will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers, and beyond that a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient sub-groups. With the development of next generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection.Incorporating pre-clinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development.3

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“…Some of these treatments include the previously mentioned HER2 targeted agent pertuzumab, which when combined with trastuzumab and docetaxel in the first-line HER2 positive mBC cancer setting, was not a cost-effective strategy when compared to trastuzumab and docetaxel alone (74). However, a criticism of this analysis was that it failed to account for the sequential (as opposed to one time) drug prescribing practice that is commonly employed in patients with metastatic disease (75).…”

Section: Future Approvalsmentioning

confidence: 99%

Cost-effectiveness of precision medicine in gastrointestinal stromal tumor and gastric adenocarcinoma

Zeichner

Goldstein

Kohn

et al. 2017

J. Gastrointest. Oncol.

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Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer

Abstract: Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.

Cited by 244 publications

References 33 publications

ATM Mutations in Cancer: Therapeutic Implications

ATM Mutations in Cancer: Therapeutic Implications

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Cost-effectiveness of precision medicine in gastrointestinal stromal tumor and gastric adenocarcinoma

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