TP53 mutational status is predictive of pazopanib response in advanced sarcomas

Koehler, Kenna; Liebner, David A.; Chen, J.L.

doi:10.1093/annonc/mdv598

Cited by 61 publications

(61 citation statements)

References 12 publications

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“…8 Several recent studies from our group and others have suggested that patients with TP53 mutations may have better outcomes when treated with anti-angiogenesis agents, perhaps because TP53 alterations result in increased VEGF-A levels. [9][10][11][12] We have also reported that patients with TP53 alterations who were treated with anti-VEGF/VEGR agents-with no other matches-had higher rates of response, PFS, and OS compared with patients with wild-type TP53. 12 We therefore performed subanalyses to determine outcomes if groups of matched patients included TP53 matched to VEGF/VEGFR inhibitors (groups 2, 4, and 5; Table 1 and Fig 1).…”

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson precision medicine study.

Tsimberidou

Hong

Cartwright

et al. 2017

JCO

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Purpose-Genomic profiling is increasingly used in the management of cancer. We have previously reported preliminary results of our precision medicine program. Here, we present response and survival outcomes for 637 additional patients who were referred for phase I trials and were treated with matched targeted therapy (MTT) when available.Patients and Methods-Patients with advanced cancer who underwent tumor genomic analyses were treated with MTT when available.Results-Overall, 1,179 (82.1%) of 1,436 patients had one or more alterations (median age, 59.7 years; men, 41.2%); 637 had one or more actionable aberrations and were treated with MTT (n = 390) or non-MTT (n = 247). Patients who were treated with MTT had higher rates of complete and partial response (11% v 5%; P = .0099), longer failure-free survival (FFS; 3.4 v 2.9 months; P = . 0015), and longer overall survival (OS; 8.4 v 7.3 months; P = .041) than did unmatched patients. Two-month landmark analyses showed that, for MTT patients, FFS for responders versus nonresponders was 7.6 versus 4.3 months (P < .001) and OS was 23.4 versus 8.5 months (P < . 001), whereas for non-MTT patients (responders v nonresponders), FFS was 6.6 versus 4.1 months (P = .001) and OS was 15.2 versus 7.5 months (P = .43). Patients with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase pathway alterations matched to PI3K/Akt/mammalian target of rapamycin axis inhibitors alone demonstrated outcomes comparable to unmatched patients. Conclusion-Ourresults support the use of genomic matching. Subset analyses indicate that matching patients who harbor a PI3K and mitogen-activated protein kinase pathway alteration to only a PI3K pathway inhibitor does not improve outcome. We have initiated IMPACT2, a randomized trial to compare treatment with and without genomic selection.

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Section: Discussionmentioning

confidence: 88%

“…A patient's tumor was considered matched with a targeted therapy if a drug was known to inhibit the aberration at low nanomolar concentrations or if an antibody targeted the alteration product, per literature data [9][10][11][12] (Appendix). Subset analyses are listed in Table 1.…”

Section: Definition Of Matched Therapymentioning

confidence: 99%

Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson precision medicine study.

Tsimberidou

Hong

Cartwright

et al. 2017

JCO

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“…However, the same effect was not seen amongst patients with TP53 wild-type malignancies. In addition, another recent study documents that patients with sarcomas who respond to the VEGFR inhibitor pazopanib harbored TP53 mutations (33). TP53 is also potentially targetable with the WEE1 inhibitor currently in clinical development (AZ1775, NCT01748825) (34).…”

Section: Discussionmentioning

confidence: 99%

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

et al. 2017

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Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated interrogated 54–70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66%, ≥ 1 characterized alteration(s) excluding variants of unknown significance. TP53-associated genes were most commonly altered (37.8%) followed by genes involved in the MAPK pathway (31.2%), PI3K signaling (18.1%) and the cell cycle machinery (10.4%). Distinct genomic profiles were observed in 87.9% of CUP cases with 99.7% exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of non-invasive liquid biopsies in next-generation clinical trials.

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“…Our current data support the concept that TP53 status may represent a ready biomarker for response to anti-angiogenesis agents, with multivariate analysis demonstrating significant improvement in all outcome parameters when individuals with TP53-mutant, but not TP53 wildtype, advanced neoplasms were treated with anti-angiogenesis agents. Recently, TP53 mutational status was also shown to be predictive of response to the VEGFR inhibitor pazopanib in advanced sarcomas (45). The underlying mechanism of response may relate to TP53 mutations being associated with upregulation of VEGF-A and VEGFR2 expression (7,(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

TP53Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics

Wheler

Janků

Naing

et al. 2016

Molecular Cancer Therapeutics

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TP53 mutational status is predictive of pazopanib response in advanced sarcomas

Abstract: Mutations in TP53 may serve as a predictive biomarker of response to VEGFR inhibition in patients with advanced sarcoma. Larger, prospective studies are necessary to confirm these findings.

Cited by 61 publications

References 12 publications

Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson precision medicine study.

Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson precision medicine study.

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

TP53Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics

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