Mutated p53 portends improvement in outcomes when bevacizumab is combined with chemotherapy in advanced/recurrent endometrial cancer: An NRG Oncology study

Leslie, Kimberly K.; Filiaci, Virginia L.; Mallen, Adrianne; Thiel, Kristina W.; Devor, Eric J.; Moxley, Katherine M.; Richardson, Debra L.; Mutch, David G.; Secord, Angeles Alvarez; Tewari, Krishnansu S.; McDonald, Megan; Mathews, Cara; Cosgrove, Casey; Dewdney, Summer B.; Casablanca, Yovanni; Jackson, Amanda; Rose, Peter G.; Zhou, Xun; McHale, Michael; Lankes, Heather A.; Levine, Douglas A.; Aghajanian, Carol

doi:10.1016/j.ygyno.2021.01.025

Cited by 49 publications

(53 citation statements)

References 38 publications

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“…We originally hypothesized that the mutations in p53, a well-established controller of the G1/S and G2/M cell cycle checkpoints, would predict for enhanced synergy. This hypothesis follows our recently published translational study of GOG-86P in which patients with mutations in TP53 had significantly improved outcomes when bevacizumab was combined with chemotherapy as compared to other experimental agents [3]. However, the majority of endometrial organoid models used in this study had wild-type (WT) p53 (Figure 2), precluding a definitive analysis of the role of p53 in sensitivity.…”

Section: Discussionsupporting

confidence: 68%

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Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Dixit

Zhang

et al. 2021

Pharmaceuticals

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Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models. The cellular effects of bevacizumab and cediranib were examined in endometrial cancer cell lines using extracellular signal-related kinase (ERK) phosphorylation, ligand shedding, cell viability, and cell cycle progression as readouts. Cellular viability was also tested in eight patient-derived organoid models of endometrial cancer. Finally, we performed a phosphoproteomic array of 875 phosphoproteins to define the signaling changes related to bevacizumab versus cediranib. Cediranib but not bevacizumab blocked ligand-mediated ERK activation in endometrial cancer cells. In both cell lines and patient-derived organoids, neither bevacizumab nor cediranib alone had a notable effect on cell viability. Cediranib but not bevacizumab promoted marked cell death when combined with chemotherapy. Cell cycle analysis demonstrated an accumulation in mitosis after treatment with cediranib + chemotherapy, consistent with the abrogation of the G2/M checkpoint and subsequent mitotic catastrophe. Molecular analysis of key controllers of the G2/M cell cycle checkpoint confirmed its abrogation. Phosphoproteomic analysis revealed that bevacizumab and cediranib had both similar and unique effects on cell signaling that underlie their shared versus individual actions as anti-angiogenic agents. An anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy.

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Section: Discussionsupporting

confidence: 68%

“…Recent progress has been made in defining the molecular biology of endometrial carcinoma, which has led to the use of targeted agents to treat this disease. The addition of targeted therapies including anti-angiogenics in conjunction with chemotherapy may be more effective than chemotherapy alone, as we have recently reported [ 3 ].…”

Section: Introductionmentioning

confidence: 96%

Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Dixit

Zhang

et al. 2021

Pharmaceuticals

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“…There is mounting evidence, including a recent report from the NRG Oncology cooperative group, demonstrating that mutated TP53 predicts response to VEGF pathway inhibitors (VEGFi), including bevacizumab and pazopanib [ 21 – 23 , 25 , 26 ]. The reason for this relationship appears to be upregulation of the VEGF/VEGFR axis as one of the consequences of TP53 mutations [ 21 – 23 , 25 , 26 ]. However, we performed a post hoc analysis to determine if eliminating patients matched on the basis of this relationship would impact the study results.…”

Section: Resultsmentioning

confidence: 99%

Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study

et al. 2021

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Background Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study. Methods A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS). Results Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0–15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01–10.83), P = 0.048], PFS [HR 0.55 (0.28–1.07), P = 0.08], and OS [HR 0.42 (0.21–0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups. Conclusions Personalized combination therapies targeting a majority of a patient’s molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies. Trial registration I-PREDICT (NCT02534675) was registered on August 25, 2015.

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“…In a post hoc analysis, assessment of TP53 mutation status showed that women with TP53 mutant EC had both improved progression free- and overall survival when treated with bevacizumab and chemotherapy, whereas women with TP53 wild-type tumours showed no difference in outcomes. 63 The authors concluded p53/ TP53 could be used as a biomarker to help predict patients with EC more likely to respond to bevacizumab treatment.…”

Section: P53abn Endometrial Cancermentioning

confidence: 99%

The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

2021

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Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing ( POLE) and immunohistochemistry (mismatch repair and p53 proteins) to assign patients with EC to one of four molecular subtypes: POLEmut, MMRd, p53abn and NSMP (no specific molecular profile). Unlike histopathological evaluation, the molecular subtyping of EC offers an objective and reproducible classification system that has been shown to have prognostic value and therapeutic implications. It is an exciting time in EC care where we have moved beyond treatment based on histomorphology alone, and molecular classification will now finally allow assessment of treatment efficacy within biologically similar tumours. It is now recommended that molecular classification should be considered for all ECs, and should be performed routinely in all high grade tumours. It is also recommended to incorporate molecular classification into standard pathology reporting and treatment decision-making algorithms. In this review, we will discuss how the molecular classification of EC can be used to guide both conventional and targeted therapy in this new molecular era.

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Mutated p53 portends improvement in outcomes when bevacizumab is combined with chemotherapy in advanced/recurrent endometrial cancer: An NRG Oncology study

Cited by 49 publications

References 38 publications

Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study

The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

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