Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent <i>KRAS</i> and <i>TP53</i> hotspot mutant cancer

Wang, Zhijie; Piha-Paul, Sarina A.; Janků, Filip; Subbiah, Vivek; Shi, Naiyi; Gong, Jing; Wathoo, Chetna; Shaw, Kenna; Hess, Kenneth R.; Broaddus, Russell R.; Naing, Aung; Hong, David S.; Tsimberidou, Apostolia M.; Karp, Daniel D.; Yao, James C.; Meric‐Bernstam, Funda; Fu, Siqing

doi:10.18632/oncotarget.16840

Cited by 5 publications

(7 citation statements)

References 37 publications

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“…Additionally, patients with KRAS hotspot mutations at locations other than codon G12 had significantly worse OS than did patients with KRAS hotspot mutations at codon G12 and KRAS - patients. This finding is consistent with our and others’ previous findings that patients harboring mutations at codon G13 had significantly worse OS than did those without mutations at this codon [ 28 , 35 , 36 ]. This finding may enhance future drug development targeting KRAS mutations to differentiate subgroups of KRAS -mutant NSCLC.…”

Section: Discussionsupporting

confidence: 93%

“…We previously reported on an outcome analysis of patients with metastatic KRAS and TP53 hotspot-mutant solid tumors in a phase 1 trial center [ 28 ]. In the present study, we focused on the impact of KRAS and/or TP53 hotspot mutations on patients with metastatic NSCLC as well as the impact of phase 1 clinical trial therapy on their survival.…”

Section: Discussionmentioning

confidence: 99%

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Outcome analysis of Phase I trial patients with metastaticKRASand/orTP53mutant non-small cell lung cancer

Wang

Piha-Paul

et al. 2018

Oncotarget

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KRAS and TP53 mutations, which are the most common genetic drivers of tumorigenesis, are still considered undruggable targets. Therefore, we analyzed these genetic aberrations in metastatic non-small cell lung cancer (NSCLC) for the development of potential therapeutics. One hundred eighty-five consecutive patients with metastatic NSCLC in a phase 1 trial center were included. Their genomic aberrations, clinical characteristics, survivals, and phase 1 trial therapies were analyzed. About 10%, 18%, 36%, and 36% of the patients had metastatic KRAS+/TP53+, KRAS+/TP53-,KRAS-/TP53+, and KRAS-/TP53- NSCLC, respectively. The most common concurrent genetic aberrations beside KRAS and/or TP53 (>5%) were KIT, epidermal growth factor receptor, PIK3CA, c-MET, BRAF, STK11, ATM, CDKN2A, and APC. KRAS+/TP53+ NSCLC did not respond well to the phase 1 trial therapy and was associated with markedly worse progression-free (PFS) and overall (OS) survivals than the other three groups together. KRAS hotspot mutations at locations other than codon G12 were associated with considerably worse OS than those at this codon. Gene aberration-matched therapy produced prolonged PFS and so was anti-angiogenesis in patients with TP53 mutations. Introduction of the evolutionary action score system of TP53 missense mutations enabled us to identify a subgroup of NSCLC patients with low-risk mutant p53 proteins having a median OS duration of 64.5 months after initial diagnosis of metastasis. These data suggested that patients with metastatic dual KRAS+/TP53+ hotspot-mutant NSCLC had poor clinical outcomes. Further analysis identified remarkably prolonged survival in patients with low-risk mutant p53 proteins, which warrants confirmatory studies.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Outcome analysis of Phase I trial patients with metastaticKRASand/orTP53mutant non-small cell lung cancer

Wang

Piha-Paul

et al. 2018

Oncotarget

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“…16 Additional studies have demonstrated statistically significant improvements in clinical outcomes (such as response rate, progression-free survival, and overall survival) among TP53-mutant patients treated with anti-VEGF or anti-VEGFR therapies, compared to TP53-wild-type populations. [17][18][19][20] The increased expression of VEGFA may explain the improved response to VEGF/ VEGFR inhibitors in TP53-mutant populations, but to date, datasets have only interrogated a relatively small number of patients. Herein, we present an analysis of TP53 mutation status and VEGF/VEGFR expression in a large pan-cancer cohort, using a collection of 7525 tumor samples from The Cancer Genome Atlas (TCGA).…”

Section: Introductionmentioning

confidence: 99%

MutatedTP53is a marker of increasedVEGFexpression: analysis of 7,525 pan-cancer tissues

Boichard

Kurzrock

2019

Cancer Biology & Therapy

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Anti-angiogenic therapies are an important class of anti-cancer treatment drugs. However, their efficacy is limited to certain tumors and would benefit from identifying a biomarker predictive of therapeutic response. TP53 (tumor protein p53) is a tumor suppressor gene frequently mutated in cancer and implicated in cell-cycle regulation, apoptosis, and angiogenesis. Data from 7,525 unique tumor samples (representing 30 tumor cohorts) were retrieved from the TCGA database to analyze the relationship between TP53-mutation status and VEGFA (vascular endothelial growth factor A) expression. Univariate analyses were done using a Mann-Whitney univariate test or Fisher's exact test. Parameters with a p-value (p)≤0.1 in univariate analysis were selected for follow-up multivariate analyses, including TP53mutation status, cancer cohorts, cancer subtypes, and VEGFA expression. Our analysis demonstrates statistically significant increases in VEGFA mRNA tissue expression in TP53-mutated adenocarcinomas (but not in squamous cancers) compared to TP53 wild-type tumors. This association holds true in multivariate analyses and remains independent of HIF-1α and MDM2 overexpression. Our findings provide additional evidence that TP53 mutations are linked to the VEGF pathway, potentially offering insight into the mechanism behind increased sensitivity to anti-angiogenic therapies observed in some TP53-mutant tumors.

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“…Archival formalin-fixed, paraffin-embedded tissue blocks, core biopsy specimens, or surgical resection specimens were used for TP53 mutation assessment. TP53 mutation assessment was performed in a Clinical Laboratory Improvement Amendment−certified molecular diagnostic laboratory at MD Anderson Cancer Center (for hotspots 2 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] , as well as at Foundation Medicine (for the entire coding sequence), as described previously [47][48][49] .…”

Section: Evaluation Of Toxicity and Efficacymentioning

confidence: 99%

“…In cancer cells, TP53 mutations are associated with elevated HIF-1α levels, which augment the HIF-1α−dependent transcriptional activation of the VEGF gene in response to tumor hypoxia 15 , and mediate resistance to cancer therapy 16 . In addition, we found that among cancer patients receiving VEGF inhibition− based therapies, the progression-free survival (PFS) durations of patients with mutated TP53 were significantly longer than those of patients with wild-type TP53 [16][17][18][19] .…”

mentioning

confidence: 99%

Phase I studies of vorinostat with ixazomib or pazopanib imply a role of antiangiogenesis-based therapy for TP53 mutant malignancies

Wang

Janků

Piha-Paul

et al. 2020

Sci Rep

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We performed two phase i trials of the histone deacetylase inhibitor vorinostat combined with either the vascular endothelial growth factor inhibitor pazopanib (NCT01339871) or the proteasome inhibitor ixazomib (NCT02042989) in patients with metastatic TP53 mutant solid tumors. Both trials followed a 3 + 3 dose-escalation design allowing for a dose expansion cohort of up to 14 additional patients with a specific tumor type. Patients had to have a confirmed TP53 mutation to be enrolled in NCT02042989. Among patients enrolled in NCT01339871, TP53 mutation status was determined for those for whom tumor specimens were available. The results of NCT01339871 were reported previously. Common treatment-related adverse events in NCT02042989 included anemia, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea. Compared with patients with metastatic TP53 hotspot mutant solid tumors who were treated with ixazomib and vorinostat (n = 59), those who were treated with pazopanib and vorinostat (n = 11) had a significantly higher rate of clinical benefit, defined as stable disease lasting ≥6 months or an objective response (3.4% vs. 45%; p < 0.001), a significantly longer median progression-free survival duration (1.7 months [95% confidence interval (CI), 1.1-2.3] vs. 3.5 months [95% CI, 1.7-5.2]; p = 0.002), and a longer median overall survival duration (7.3 months [95% CI, 4.8-9.8] vs. 12.7 months [95% CI, 7.1-18.3]; p = 0.24). Our two phase I trials provide preliminary evidence supporting the use of antiangiogenisis-based therapy in patients with metastatic TP53 mutant solid tumors, especially in those with metastatic sarcoma or metastatic colorectal cancer.

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Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent KRAS and TP53 hotspot mutant cancer

Cited by 5 publications

References 37 publications

Outcome analysis of Phase I trial patients with metastaticKRASand/orTP53mutant non-small cell lung cancer

Outcome analysis of Phase I trial patients with metastaticKRASand/orTP53mutant non-small cell lung cancer

MutatedTP53is a marker of increasedVEGFexpression: analysis of 7,525 pan-cancer tissues

Phase I studies of vorinostat with ixazomib or pazopanib imply a role of antiangiogenesis-based therapy for TP53 mutant malignancies

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