Zeki Surmeli

Prognostic factors for survival in metastatic renal cell carcinoma patients with brain metastases receiving targeted therapy

Background: The primary objective of our study was to examine the clinical outcomes and prognosis of patients with metastatic renal cell carcinoma (mRCC) with brain metastases (BMs) receiving targeted therapy. Patients and methods: Fifty-eight patients from 16 oncology centers for whom complete clinical data were available were retrospectively reviewed. Results: The median age was 57 years (range 30-80). Most patients underwent a nephrectomy (n = 41; 70.7%), were male (n = 42; 72.4%) and had clear-cell (CC) RCC (n = 51; 87.9%). Patients were treated with first-line suni-tinib (n = 45; 77.6%) or pazopanib (n = 13; 22.4%). The median time from the initial RCC diagnosis to the diagnosis of BMs was 9 months. The median time from the first occurrence of metastasis to the development of BMs was 7 months. The median overall survival (OS) of mRCC patients with BMs was 13 months. Time from the initial diagnosis of systemic metastasis to the development of BMs (<12 months; p = 0.001), histological subtype (non-CC; p<0.05) and number of BMs (>2; p<0.05) were significantly associated with OS in multivariate analysis. There were no cases of toxic death. One mRCC patient with BMs (1.7%) experienced treatment-related cerebral necrosis. All other toxicities included those commonly observed with VEGF-TKI therapy. Conclusions: The time from the initial diagnosis of systemic metastasis to the development of BMs (<12 months), a non-CC histological subtype, and a greater number of BMs (>2) were independent risk factors for a poor prognosis.

The Impact of Subtype Distribution in Inflammatory Breast Cancer Outcome

Objective Inflammatory breast cancer (IBC) has an unfavourable prognosis despite the advances made in the treatment of breast cancer. Our study aimed to define immunohistochemistry-based surrogate subtype distribution to determine whether the breast cancer subtype accompanied survival outcome differences in IBC. Materials and Methods Medical records of female breast cancer patients with non-metastatic inflammatory breast cancer admitted to our clinic between March 2000 and December 2015 were retrospectively reviewed. Patient demographics, clinical and pathological feature of the primary tumour, adjuvant treatment options and survival data were analysed. Intrinsic breast cancer subtypes were defined according to ER, PR, HER-2 and ki-67 status. Results We identified 129 non-metastatic inflammatory breast cancer patients. Median follow-up was 73 months. 10 (7.7%) were luminal A-like, 67 (51.9%) were luminal B-like, 37 (28.6%) were HER-2 positive, and 15 (11.6%) were triple negative (TNBC) by immunohistochemistry. There were no statistically significant differences between subtypes in terms of histological type, grade, tumour size and lymph node status. Median disease-free survival was 47 months (95% confidence interval [CI] 29.2-82.6) and median overall survival was 75 months (95% CI 64.7-90.8). Triple negative breast cancer showed poorer outcome than other subgroups. Presence of TNBC disease was associated with poorer outcome compared to luminal A (HR: 0.19, 95% CI 0.04-0.92, p: 0.039), luminal B (HR: 0.34, 95% CI 0.15-0.74, p: 0.007) and HER-2 positive subgroups (HR: 0.40, 95% CI 0.17-0.94, p:0.037). Luminal A patients had a trend to have a better overall survival which did not reach to a statistical significant difference. Conclusion Our study put forth that IBC have a poor prognosis irrespective of breast cancer surrogate subtype distribution. Luminal A, the most frequent subtype of breast cancer was the least common in our IBC patient group. TNBC had the worst outcome when compared to other breast cancer subtypes.

Combination of zoledronic acid and serine/threonine phosphatase inhibitors induces synergistic cytotoxicity and apoptosis in human breast cancer cells via inhibition of PI3K/Akt pathway

The aim of this study was to investigate the cytotoxic and apoptotic effects of zoledronic acid (ZA) in combination with serine/threonine protein phosphatase inhibitors, calyculin-A (CA) and okadaic acid (OA), in human MCF-7 and MDA-MB-231 breast cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. DNA fragmentation and caspase-3/7 activity assays were performed to evaluate apoptosis. Activities of phosphatase 1 (PP1) and phosphatase 2A (PP2A) were measured by serine/threonine phosphatase ELISA kit. Expression levels of PI3K, p-PI3K, Akt, p-Akt, Bcl-2, p-Bcl-2, Bad, and p-Bad proteins were evaluated by Western blot analysis. Combination of ZA with either CA or OA showed synergistic cytotoxicity and apoptosis as compared to any agent alone in both MCF-7 and MDA-MB-231 breast cancer cells. Combination treatment also resulted in inhibition of both PP1 and PP2A activities. Both agents used alone or in combination did not induce significant changes in total PI3K, Akt, Bcl-2, and Bad expressions, while p-PI3K, p-Akt, p-Bcl-2, and p-Bad levels were reduced by the combination treatment as compared to agents alone. Moreover, apoptotic effect of combination treatment was significantly inhibited in the presence of LY294002, a specific PI3K inhibitor, in both breast cancer cell lines. In conclusion, synergistic apoptotic effect of the combination treatment is correlated with the block of the PI3K/Akt signal pathway in breast cancer cells.

1121PPROGNOSTIC EFFECT OF PRIMARY TUMOR CHARACTERISTICS IN METASTATIC MELANOMA

ABSTRACT Aim: Prognostic effect of pathological and clinical parameters of the primary tumor is well-defined in localized melanoma. In this study we analyzed the effect of these parameters on survival duration in metastatic melanoma. Methods: Records of cutaneous metastatic melanoma patients diagnosed between 2006 - 2013 in our center were reviewed. Patients with pathological data of the primary melanoma lesion were included in the study. We analyzed the effect of pathological and clinical parameters on disease-specific survival (DSS). DSS was measured from diagnosis of metastatic melanoma to death. Results: 140 patients were included in the study. At a median follow-up duration of 28 months, 88 deaths were observed. DSS of the patient population was 16 months (95% CI: 13.3–18.7). Male patients had a shorter median DSS (14.4 vs. 19.4 months, p: 0.046). DSS was similar in patients aged under and over 60 years. Presence of ulceration of the primary lesion was associated with worse median survival duration (15 vs. 22.3 months, p: 0.006). Mitotic count of less than 5/mm2 was associated with longer median DSS compared with 5 or more mitoses/mm2 (22.3 vs. 13.2, p: 0.013). Breslow thickness (≤2 mm vs. >2 mm) was not found to have a prognostic effect; however, patients with regional lymph node metastases at the time of diagnosis had shorter median DSS duration (13.5 vs. 23 months, p: 0.035). Localization of the primary tumor, histological subtype and presence of regression were not associated with DSS in metastatic melanoma. In multivariate analysis, presence of ulceration (HR: 2.54, 95%CI: 1.2–5.3), and mitotic count of 5 or more (HR: 2.43, 95%CI: 1.1–5.4) were associated with decreased DSS. Conclusions: Presence of ulceration, high mitotic count (≥5/mm2) and presence of regional lymph node metastases at the time of diagnosis are among the well-known prognostic factors in localized melanoma. Our results support that these factors may portend poor prognosis also in metastatic melanoma. These parameters may be associated with tumor biology and may indicate more aggressive disease. Disclosure: All authors have declared no conflicts of interest.

383PCOMPARISON OF MOLECULAR SUBTYPES OF BREAST CANCER IN WOMEN ≤35 YEARS AND > 35 YEARS: DOES AGE MATTER?

ABSTRACT Aim: Primary objective was to evaluate the impact of age, on determining molecular subgroups and whether the different outcome of patients ≤35 years and ≥35 years of age is related to the diversity of molecular subgroups. Methods: A total of 216 patients ≤35 years and randomly selected 212 patients of all patients ≥35 years presented to Ege University Faculty of Medicine Department of Oncology between 2000 and 2011 diagnosed with breast cancer were enrolled in the study. Demographic data, clinico-pathological characteristics and treatment modalities were reviewed and recorded for each patient. Molecular subtyping was based on estrogen, progesteron receptors (ER, PR), cerb-B2 and Ki-67 proliferation index. Luminal A disease was defined as ER (+), PR (+), cerb-B2(-), Ki-67 ≤ %15. Cases that were ER/PR (+), cerb-B2 (-)/(+), Ki-67 ≥ %15 were classified as Luminal B. If all three receptors were negative, then it was accepted as triple negative disease and Her-2 positive disease was characterized by lack of hormon receptors and presence of cerb-B2. Results: 166 of 216 patients ≤35 years of age, and 154 of 212 patients ≥35 years were found to be appropriate and pathologically have been assessed for molecular subtyping. Accordingly, 87 patients (%40.3) in younger group were Luminal B and 32 patients (%14.8) were triple negative, which composed the largest proportion of all very young group. 29 patients (%13.4) were Luminal A, 18 patients (%8.3) were Her-2 positive. Among the ≥35 years group the majority was Luminal B (%28.3) as similar in very young population,however followed by Luminal A (%22.6) that has favorable prognostic features. 28 patients (%13.2) were triple negative, 18 patients (%8.5) were Her-2 positive. There was no statistically significant difference in molecular subtypes between the two age groups. However, triple negative subtype and Ki-67≥ %15 which is associated with poorer prognosis was numerically higher among ≤ 35 years group. Conclusions: In our study there was no statistically significant difference in molecular subtypes between two diverse age groups. This could be explained by small size of the study population, but also could be an indication that age is an independent prognostic factor apart from all other clinico-pathologic features. Further studies based on genotypic analyses with larger patient series are required. Disclosure: All authors have declared no conflicts of interest.