Precision Oncology: Identifying Predictive Biomarkers for the Treatment of Metastatic Renal Cell Carcinoma

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Abstract

The recent FDA approval of multiple new pharmaceutical agents for metastatic renal cell carcinoma (RCC) has left physicians with several options for first- and second- line therapy. With limited head-to-head comparisons, however, there is a paucity of evidence to recommend the use of one agent over another. To address this knowledge gap, Voss et al. identified serum biomarkers from specimens collected during the RECORD-3 trial, a comparative study of first-line sunitinib versus first-line everolimus. Of the biomarkers identified, the 5 most strongly associated with first-line everolimus progression-free survival (PFS1L) were combined to form a composite biomarker score (CBS). The CBS was significantly associated with everolimus PFS1L in multivariate regression analysis. This study is an example of the additional value offered by a randomized trial with prospective biospecimen collection and a significant step towards identifying predictive biomarkers for the treatment of metastatic RCC. As further comparative trials are performed, it will be essential that biomarkers are appropriately identified and validated in order to further the goal of precision oncology.

Keywords: Carcinoma, Renal Cell, Biomarker
Therapeutic options for patients with metastatic renal cell carcinoma (RCC) are expanding rapidly. Currently, eleven FDA-approved agents are available for the treatment of RCC. The majority of these disrupt metabolic or proliferative pathways such as vascular endothelial growth factor (VEGF; bevacizumab), its receptor (VEGFR; axitinib, pazopanib, sorafenib, sunitinib, cabozantinib, lenvatinib), or the mammalian target of rapamycin (mTOR; everolimus, temsirolimus) while two others (nivolumab and interleukin-2) bolster the patient’s anti-tumor immune response (Table 1) (1–13). Unfortunately, the overall survival (OS) and progression free survival (PFS) benefits of these agents in the first-line setting have largely been demonstrated with respect to either placebo or interferon-alpha monotherapy as the comparator arm in phase III randomized controlled trials (RCTs)(3–6, 8, 9, 13) (Table 1). To date, only two phase III RCTs have directly compared tyrosine kinase inhibitors (TKI) in treatment-naïve metastatic RCC and both trials failed to identify a single best choice for first-line therapy(14, 15).

Table 1
Table 1
FDA approved therapies for RCC with their pivotal trial parameters.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986829/

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Circulating angiogenic factor levels correlate with extent of disease and risk of recurrence in patients with soft tissue sarcoma

https://www.google.com/amp/s/www.resear ... arcoma/amp

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Circulating angiogenic factor levels correlate with extent of disease and risk of recurrence in patients with soft tissue sarcoma


Background: Tumor angiogenesis, or new blood vessel formation, is regulated by a balance between pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and anti-angiogenic factors such as endostatin.

Patients and methods: To investigate this angiogenic balance in soft tissue sarcomas (STS), blood samples were collected from 76 STS patients and 15 healthy controls, and analyzed for VEGF, bFGF and endostatin using quantitative enzyme-linked immunosorbent assays (ELISA).

Results: Forty-one patients (54%) had primary tumors, 20 (26%) had local recurrences and 15 (20%) had metastatic disease with or without local disease. Levels of all three angiogenic factors were highly variable in STS patients. Mean levels of VEGF and bFGF were 12 and 14 times higher, respectively, in patients compared with controls (P<0.0001). VEGF levels correlated with size of tumor, with the highest levels found in tumors >10 cm in size. Patients with metastases had endostatin levels 45% lower than patients without metastases (P=0.047). In 54 patients who underwent resection of primary disease or local recurrence, low pre-operative bFGF level was associated with a higher risk of subsequent recurrence (P=0.044).

Conclusions: STS secrete widely variable levels of angiogenic factors, and levels of specific factors may correlate with extent of disease, predict risk of recurrence and possibly guide the use of anti-angiogenic agents.



https://pubmed.ncbi.nlm.nih.gov/15277268/