Elevated plasma interleukin 6 predicts poor response in patients treated with sunitinib for metastatic clear cell renal cell carcinoma.

INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) is the most common type among renal cell carcinomas, and anti-angiogenic treatment is currently first line therapy in metastatic ccRCC (mccRCC). Response rates and duration of response show considerable variation, and adverse events have major influence on patient's quality of life. The need for predictive biomarkers to select those patients most likely to respond to receptor tyrosine kinase inhibitors (rTKI) upfront is urgent. We investigated the predictive value of plasma interleukin-6 (pIL6), interleukin-6 receptor α (pIL6Rα) and interleukin 6 signal transducer (pIL6ST) in mccRCC patients treated with sunitinib. MATERIAL AND METHODS: Forty-six patients with metastatic or non-resectable ccRCC treated with sunitinib were included. Full blood samples were collected at baseline before start of sunitinib and after every second cycle of treatment during the study time. pIL6, pIL6R and pIL6ST at baseline and week 12 samples were analysed by ELISA. The predictive potential of the candidate markers was assessed by correlation with response rates (RECIST). In addition, progression free survival (PFS) and overall survival (OS) were analysed. RESULTS: Low pIL6 at baseline was significantly associated with improved response to sunitinib (Fisher's exact test, p < 0.01). Furthermore, low pIL6 at baseline was significantly associated with improved PFS (log rank, p = 0.04). In addition, patients with a decrease in concentration of pIL6R between baseline and week 12 showed significantly improved PFS (log rank, p = 0.04) and patients with high pIL6ST at baseline showed significantly improved OS (log rank, p = 0.03). CONCLUSION: Low pIL6 at baseline in mccRCC patients treated with sunitinib predicts improved treatment response, and might represent a candidate predictive marker.

Tumour cell expression of interleukin 6 receptor α is associated with response rates in patients treated with sunitinib for metastatic clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and anti-angiogenic treatment is currently first line therapy for metastatic ccRCC (mccRCC). Response rates and duration of response show considerable variation, and adverse events have a major influence on patient quality of life. The need for predictive biomarkers to select responders to receptor tyrosine kinase inhibitors upfront is urgent. We investigated the predictive value of immunohistochemical biomarkers associated with angiogenesis and systemic inflammation in mccRCC. Forty-six patients with metastatic or non-resectable ccRCC treated with sunitinib were included. Metastatic and/or primary tumour tissue was stained by immunohistochemistry for selected markers related to angiogenesis [vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR2), platelet-derived growth factor receptor ß (PDGFRß), and heat shock protein 27 (HSP27)] and immune responses [Interleukin 6 receptor α (IL6Rα), interleukin-6 (IL6), and jagged1 (JAG1)]. The predictive potential of the candidate markers was assessed by correlations with response rates (RECIST). In addition, progression free survival (PFS) and overall survival (OS) were analysed. Low tumour cell expression of IL6Rα was significantly associated with improved response to sunitinib (Fisher's exact test, p = 0.03), but not with PFS or OS. Median/high expression of IL6Rα showed significant association with median/high expression of VEGF-A and HSP27. Furthermore, low expression of IL6 was significantly associated with improved PFS, but not OS or response rates. High expression of IL6 was significantly associated with high expression of JAG1, VEGF-A, VEGFR2, and PDGFRß. Loss of tumour cell expression of IL6Rα in mccRCC patients treated with sunitinib predicts improved treatment response, and might represent a candidate predictive marker.

Predictive value of C-reactive protein in patients treated with sunitinib for metastatic clear cell renal cell carcinoma.

BACKGROUND: Sunitinib has become mainstay first line treatment for patients with metastatic renal clear cell carcinoma (mRCC). Still, useful predictive markers of response are lacking and urgently needed for clinical decision making. METHODS: In the present study we investigated the predictive value of standard serum markers as well as clinical markers, including C-reactive protein (CRP), Neutrophil to Lymphocyte ratio (NLR) and early hypertension (eHTN) in an unselected prospective patient population treated with sunitinib for mRCC. Forty-six patients were enrolled in a prospective single-arm study of predictive markers for sunitinib response. Response rates according to RECIST 1.1 were used as primary end-point. Secondary objectives were to evaluate prognostic value of the candidate markers with regard to progression free survival (PFS) and overall survival (OS). In addition, toxicity rates and quality of life was recorded. RESULTS: Median PFS and OS was 9.1 months and 15.0 months, respectively. Of 38 patients evaluable for response, 1 patient had complete response (CR), 7 had partial response (PR), 18 had stable disease (SD) and 12 had progressive disease (PD). Normal CRP at baseline was significantly associated with objective response (CR + PR) (p = 0.01). Normal CRP was also significantly associated with improved PFS and OS (Log rank, p = 0.05 and <0.01, respectively). Early hypertension, NLR and IMDC risk score were not significantly associated with response rates or survival. CONCLUSION: Baseline CRP was a significant predictive factor of sunitinib response and a prognostic factor of survival. Baseline CRP might be a useful biomarker in the treatment planning of mRCC. Due to the relatively small sample size, our results need to be confirmed in larger studies.

Differences in metastatic patterns in relation to time between primary surgery and first relapse from breast cancer suggest synchronized growth of dormant micrometastases.

A significant variation in the metastatic pattern among breast cancer patients exists. Clinical observations suggest that these differences are related to time to recurrence (TTR), thus suggesting a common systemic growth signal at the time of surgery. Our goal was to identify a marker for synchronized growth of micrometastases. To quantify the metastatic pattern at first relapse, 180 patients with metastatic breast cancer were studied. Standard deviation (SD) of lesions size and lesion number was calculated and served as a marker for variation. Patients with low SD (multiple/similar sized lesions) were assumed to have synchronized growth, whereas patients with high SD were assumed to have unsynchronized growth. Patients were grouped according to TTR; early (< 3 years-) or late (> 3 years- after surgery). In patients not receiving systemic adjuvant treatment, median SD was significantly lower in the early group (2.5 mm) compared with 6.4 mm in the late group (p = 0.005). In node negative patients, median SD was significantly lower in the early group (3.0 mm) when compared with the late group (5.7 mm, p = 0.02). An additional drop in SD was observed immediately after end of adjuvant endocrine therapy. Our results identify SD as a marker of synchronized metastatic growth in breast cancer. A metastatic phenotype characterized by multiple similar sized metastases, suggesting synchronized onset of growth of micrometastases was predominantly found in patients recurring early after surgery and was counteracted by adjuvant treatment. Systemic growth signals caused by surgery might be antagonized during the time window following surgery.