P53 Mutations in Advanced Cancers: Clinical Characteristics, Outcomes, and Correlation between Progression-Free Survival and Bevacizumab-Containing Therapy

Said, Rabih; Hong, David S.; Warneke, Carla L.; Lee, John; Wheler, Jennifer J.; Janků, Filip; Naing, Aung; Falchook, Gerald S.; Fu, Siqing; Piha-Paul, Sarina A.; Tsimberidou, Apostolia M.; Kurzrock, Razelle

doi:10.18632/oncotarget.974

Cited by 102 publications

(98 citation statements)

References 40 publications

(35 reference statements)

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“…We found that 96% of our patients demonstrated at least one molecular alteration, and 85% had two or more alterations. The most frequent alteration was TP53 mutation, found in 44% of our patients, similar to previous reports (16).…”

Section: Discussionsupporting

confidence: 92%

On the Road to Precision Cancer Medicine: Analysis of Genomic Biomarker Actionability in 439 Patients

Schwaederlé¹,

Daniels²,

Piccioni³

et al. 2015

Molecular Cancer Therapeutics

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Despite the increased use of molecular diagnostics, the extent to which patients who have these tests harbor potentially actionable aberrations is unclear. We retrospectively reviewed 439 patients with diverse cancers, for whom next-generation sequencing (mostly 236-gene panel) had been performed. Data pertaining to the molecular alterations identified, as well as associated treatment suggestions (on-or off-label, or experimental), were extracted from molecular diagnostic reports. Most patients (420/ 439; 96%) had at least one molecular alteration: 1,813 alterations (in 207 distinct genes) were identified [the majority being mutations (62%) or amplifications (29%)]. The three most common gene abnormalities were TP53 (44%), KRAS (16%), and PIK3CA (12%). The median number of alterations per patient was 3 (range, 0-16). Nineteen patients (4%) had no alterations; 48

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Section: Discussionsupporting

confidence: 92%

On the Road to Precision Cancer Medicine: Analysis of Genomic Biomarker Actionability in 439 Patients

Schwaederlé¹,

Daniels²,

Piccioni³

et al. 2015

Molecular Cancer Therapeutics

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“…In contrast, patients with TP53 mutations exhibited a higher rate of clinical benefit with VEGF/R inhibitors, a finding observed in our previous work (27). Possible explanations include a role of TP53 mutations in promoting vascularization.…”

Section: Discussionsupporting

confidence: 56%

Synergy Between VEGF/VEGFR Inhibitors and Chemotherapy Agents in the Phase I Clinic

Tang

Hess

Jardim

et al. 2014

Clinical Cancer Research

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Purpose: We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies. Experimental Design: Patients treated on phase I protocols between December 2004 and July 2013 (n = 1,498) were included in this analysis. The primary outcome was clinical benefit, defined as stable disease ≥6 months, complete response, or partial response. Two odds ratios (OR) for achieving clinical benefit were calculated: one for patients treated with VEGF/R inhibitors (OR with VEGF/R) and another for patients treated without (OR without VEGF/R). To compare these two ORs, an interaction term was included in the multivariate model: (chemotherapy/factor of interest)×(VEGF/R). We took significant interaction terms (Pinteraction < 0.05) to suggest effect modification (either synergy or antagonism) with VEGF/R inhibitors. Results: All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [OR = 1.9; 95% confidence interval (CI), 1.5–2.4; P < 0.0001]. Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [OR with VEGF/R = 1.6 (95% CI, 1.1–2.5) vs. OR without VEGF/R = 0.4 (95% CI, 0.3–0.6), Pinteraction = 0.02]. Specifically, the antimetabolite class was associated with the greatest increase in OR for clinical benefit [OR with VEGF/R = 2.7 (95% CI, 1.5–4.7) vs. OR without VEGF/R = 0.2 (95% CI 0.1–0.3), Pinteraction = 0.004]. Conclusions: VEGF/R inhibitor was found to synergize with chemotherapeutics. This effect was most pronounced with the antimetabolite class. Clin Cancer Res; 20(23); 5956–63. ©2014 AACR.

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“…Kara and colleagues (15) examined only 34 patients and analyzed p53 expression, not mutational status; Ince and colleagues (16) examined survival, not PFS. In contrast, the multivariate analysis demonstrating that a bevacizumab-containing regimen was an independent factor associated with better outcomes in TP53-mutated patients included a variety of tumors and analyzed PFS (5).…”

Section: Resultsmentioning

confidence: 99%

VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

Schwaederlé¹,

Lazar

Validire³

et al. 2015

Cancer Research

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Bevacizumab is one of the most widely used antiangiogenic drugs in oncology, but the overall beneficial effects of this VEGF-A targeting agent are relatively modest, in part due to the lack of a biomarker to select patients most likely to respond favorably. Several molecular aberrations in cancer influence angiogenesis, including mutations in the tumor suppressor gene TP53, which occur frequently in many human malignancies. In this study, we present a multiple regression analysis of transcriptomic data in 123 patients with non-small cell lung cancer (NSCLC) showing that TP53 mutations are associated with higher VEGF-A expression (P ¼ 0.006). This association was interesting given a recent retrospective study showing longer progression-free survival in patients with diverse tumors who receive bevacizumab, if tumors harbor mutant TP53 instead of wild-type TP53. Thus, our current findings linking TP53 mutation with VEGF-A upregulation offered a mechanistic explanation for why patients exhibit improved outcomes after bevacizumab treatment when their tumors harbor mutant TP53 versus wild-type TP53. Overall, this work warrants further evaluation of TP53 as a ready biomarker to predict bevacizumab response in NSCLC and possibly other tumor types. Cancer Res; 75(7);

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P53 Mutations in Advanced Cancers: Clinical Characteristics, Outcomes, and Correlation between Progression-Free Survival and Bevacizumab-Containing Therapy

Abstract: ABSTRACT:Background: Mutations in the p53 gene are amongst the most frequent

Cited by 102 publications

References 40 publications

On the Road to Precision Cancer Medicine: Analysis of Genomic Biomarker Actionability in 439 Patients

On the Road to Precision Cancer Medicine: Analysis of Genomic Biomarker Actionability in 439 Patients

Synergy Between VEGF/VEGFR Inhibitors and Chemotherapy Agents in the Phase I Clinic

VEGF-A Expression Correlates with TP53 Mutations in Non–Small Cell Lung Cancer: Implications for Antiangiogenesis Therapy

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