Angiotensin System Inhibitors and Survival Outcomes in Patients with Metastatic Renal Cell Carcinoma

McKay, Rana R.; Rodriguez, Gustavo E.; Lin, Xun; Kaymakcalan, Marina D.; Hamnvik, Ole-Petter R; Sabbisetti, Venkata; Bhatt, Rupal S.; Simantov, Ronit; Choueiri, Toni K.

doi:10.1158/1078-0432.ccr-14-2332

Cited by 120 publications

(99 citation statements)

References 39 publications

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“…The current study did not support a protective effect for ASI in ccRCC (Tables 4 and 5). However, other studies have found that ASIs may offer survival benefits in kidney cancer in the targeted treatment era [11, 27]. Possibilities for this discrepancy include insufficient power in the current study to detect a benefit from ASIs.…”

Section: Discussionmentioning

confidence: 62%

“…However, further clinical description, for example the anatomic metastatic pattern, of these patient cohorts is lacking. Furthermore, while evidence emerges that comorbidities and their treatment may influence kidney cancer outcomes [10, 11], the distribution of these among ccA and ccB patients remain to be addressed. These are analyses which may prove important in understanding the biology and clinical relevance of these ccRCC molecular subtypes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities

Haake

Brooks

Welsh

et al. 2016

Urologic Oncology: Seminars and Original Investigations

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Purpose The 34-gene classifier, ClearCode34, identifies prognostically distinct molecular subtypes of clear cell renal cell carcinoma (ccRCC) termed ccA and ccB. The primary objective of this study was to describe clinical characteristics and comorbidities of relevance in patients stratified by ClearCode34. Patients and Methods In this retrospective analysis, 282 patients from Moffitt Cancer Center with ccRCC with gene expression analyses of the primary tumor were identified and ClearCode34 was applied to identify tumors as ccA or ccB. The medical record and institutional databases were queried to define patient characteristics, comorbidities, and outcomes. Results We validated in this external cohort the superior overall survival (OS), cancer specific survival (CSS), and recurrence-free survival of ccA patients relative to ccB patients (p<0.001). Addressing other clinical characteristics, the ccA patients were more likely to be obese (48% versus 34%, p=0.021) and diabetic (26% versus 13%, p=0.035). The ccA patients also trended towards having been more frequent users of angiotensin system inhibitors (ASIs) (71% versus 52%, p=0.055). In multivariate analyses, ccB status is independently associated with inferior CSS (HR 3.26, 95% CI 1.84–5.79) and OS (HR 2.50, 95% CI 1.53–4.08). Conclusions ClearCode34, after considering distinct patterns of comorbidities in each molecular subtype, remains a strong prognostic tool in ccRCC patients. Obesity and DM emerged as factors that may influence ccRCC phenotypes and further studies investigating the impact of these metabolic conditions functionally onto tumor biology are warranted. Additionally, use of ASI could be studied in the context of ccRCC molecular classification in future studies to better understand its impact on ccRCC outcomes.

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities

Haake

Brooks

Welsh

et al. 2016

Urologic Oncology: Seminars and Original Investigations

View full text Add to dashboard Cite

show abstract

“…If antihypertensive agents are required to control high BP, treatment guidance (e.g., European Society of Cardiology guidelines) [52] should be followed. However, angiotensin system inhibitors may now be the treatment of choice, following analyses of data from Izzedine et al [53] and McKay et al [54] showing that concomitant use of angiotensin system inhibitors is associated with significant improvements in survival outcomes in patients with mRCC. Dose escalation is currently not recommended if a patient is already hypertensive/taking antihypertensive medication according to the axitinib summary of product characteristics [13], but frequently occurs (with appropriate monitoring and treatment) in real-world clinical practice.…”

Section: Proactive Management Of Aesmentioning

confidence: 99%

Individualized Dosing with Axitinib: Rationale and Practical Guidance

et al. 2017

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Axitinib is a potent, selective, vascular endothelial growth factor receptor inhibitor with demonstrated efficacy as second-line treatment for metastatic renal cell carcinoma. Analyses of axitinib drug exposures have demonstrated high interpatient variability in patients receiving the 5 mg twice-daily (b.i.d.) starting dose. Clinical criteria can be used to assess whether individual patients may benefit further from dose modifications, based on their safety and tolerability data. This review provides practical guidance on the 'flexible dosing' method, to help physicians identify who would benefit from dose escalations, dose reductions or continuation with manageable toxicity at the 5 mg b.i.d. dose. This flexible approach allows patients to achieve the best possible outcomes without compromising safety. Rationale for individualized dosingBefore the development of molecular targeted therapy, most available anticancer drugs, with hormone therapies and immunotherapies being notable exceptions, were chemotherapy agents: chemicals aimed at having a cytotoxic effect on cancer cells [1,2]. These drugs were dosed according to a patient's weight or body surface area, based on the observation that patients with a greater body size generally have a greater volume of distribution and require higher doses than smaller patients to reach equal drug concentrations [3]. It was thought this approach would deliver consistent systemic drug exposure, thereby optimizing treatment outcomes. This dosing approach was also chosen based on a lack of a better option at that time. However, it was known that multiple factors beyond patient size (including age, sex, renal function, hepatic function, concomitant medication, disease state and genetics) could have an impact on the actual concentration of a drug in an individual's bloodstream [4]. Consequently, there remains high variability between patients (interpatient variability) in systemic drug concentrations, even when normalized for weight/body surface area [5].When molecular targeted agents were first introduced for use in metastatic renal cell carcinoma (mRCC), these drugs were recommended at a fixed dose, based on an assumption that the maximum tolerated fixed dose would result in the best efficacy and that this same high dose would be appropriate for all patients. However, most tyrosine kinase inhibitors (TKIs) demonstrate high interpatient variability in drug exposure (depending on oral bioavailability and first-pass liver metabolism of drugs); therefore, the subsequent therapeutic effect and toxicity for the same administered dose may vary [6]. As a result, fixed dosing may result in suboptimal efficacy for some patients or excessive toxicity in others [7]. In addition, higher-than-needed doses may be excessive if therapeutic effects are already achieved at lower doses.

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“…proteinuria, could further enhance the predictive role of hypertension. Moreover, there is early evidence that the use of specific blood pressure lowering drugs might improve cancer outcomes in patients receiving anti-VEGF drugs [32]. Potential interactions between blood pressure lowering drugs and specific anti-VEGF drugs might be relevant in this context [33].…”

Section: Anti-vegf-induced Hypertension and Cancer Outcomes: Translatmentioning

confidence: 99%

Anti-VEGF-induced hypertension and cancer outcomes: translating research into clinical practice

Mangoni

Woodman

Kichenadasse

et al. 2016

Expert Review of Precision Medicine and Drug Development

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Angiotensin System Inhibitors and Survival Outcomes in Patients with Metastatic Renal Cell Carcinoma

Cited by 120 publications

References 39 publications

Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities

Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities

Individualized Dosing with Axitinib: Rationale and Practical Guidance

Anti-VEGF-induced hypertension and cancer outcomes: translating research into clinical practice

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