Alexandra Karadimou

Immune Response in Ovarian Cancer: How Is the Immune System Involved in Prognosis and Therapy: Potential for Treatment Utilization

Ovarian cancer is one of the leading causes of cancer-related death among women. Resistance to the disease occurs in more than 70% of the cases even after treated with chemotherapy agents such as paclitaxel- and platinum-based agents. The immune system is increasingly becoming a target for intense research in order to study the hosts immune response against ovarian cancer. T cell populations, including NK T cells and Tregs, and cytokines have been associated with disease outcome, indicating their increasing clinical significance, having been associated with prognosis and as markers of disease progress, respectively. Harnessing the immune system capacity in order to induce antitumor response remains a major challenge. This paper examines the recent developments in our understanding of the mechanisms of development of the immune response in ovarian cancer as well as its prognostic significance and the existing experience in clinical studies.

Prechemotherapy serum levels of CD105, transforming growth factor beta2, and vascular endothelial growth factor are associated with prognosis in patients with advanced epithelial ovarian cancer treated with cytoreductive surgery and platinum-based chemotherapy.

Background: Serum CD105 has been associated with angiogenic activity in cancer, and low CD105 expression has been associated with improved prognosis. The present study evaluated the prognostic significance of serum levels of CD105 and related factors in patients with epithelial ovarian cancer (EOC) after cytoreductive surgery and chemotherapy. Patients and Methods: Eighty-six patients with stages IIC to IV EOC treated postoperatively with platinum-based chemotherapy were included. The enzyme-linked immunosorbent assay was used to measure prechemotherapy serum levels of CD105, transforming growth factor &bgr;1/2 (TGF-&bgr;1/2), angiopoietin 2, vascular endothelial growth factor, and tumor necrosis factor-&agr;. Results: High levels of TGF-&bgr;2 (>8908.86 pg/mL) and CD105 (>4.25 ng/mL) were independently associated with improved overall survival (not reached vs 39 months, P = 0.009 and 75 vs 39 months, P = 0.029, respectively), whereas a high level of TGF-&bgr;2 and a low level of vascular endothelial growth factor (<219.04 pg/mL) were independently associated with improved progression-free survival (49 vs 17 months, P = 0.022 and 57 vs 16 months, P = 0.023, respectively). Among patients with favorable (>4.25 ng/mL) CD105 levels, only patients with low TGF-&bgr;1 levels (<177.1 ng/mL) had superior survival than patients with low CD105 levels. Conclusions: Our study confirms the prognostic significance of angiogenesis in EOC and supports a biological interaction between CD105 and TGF-&bgr;1. High angiogenic activity may be associated by increased efficacy of postoperative chemotherapy.

Leukocytoclastic vasculitis after long-term treatment with sunitinib: a case report.

We report on a 63-year-old woman, previously in good health, who had undergone nephrectomy for clear cell renal cell carcinoma in 2002. Because of systemic relapse with multiple lung metastases in 2006, the patient was treated with sunitinib 50 mg daily on a 4-weeks on-/2-weeks off-schedule. After 3 years of treatment, she developed a purpuric rash on her feet and trunk. Biopsy revealed leukocytoclastic vasculitis. No other organ involvement was diagnosed. She was started on oral prednisone 30 mg daily with rapid resolution of the vasculitic skin lesions. Sunitinib was temporally discontinued and reintroduced at the same dose level. Reappearance of a less serious vasculitis after 2 cycles of re-treatment was resolved in the weeks off-treatment and by reducing the dose of sunitinib along with 5 mg of prednisone daily. One year after the diagnosis, the patient is still on this therapy. Oncology providers should be aware of this rare but potentially serious, possible adverse effect of sunitinib.

Prognostic impact of baseline serum C-reactive protein in metastatic renal cell carcinoma treated with sunitinib.

425 Background: The aim of our study was to determine whether baseline serum C-reactive protein (CRP) level could predict outcome of patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib in first-line setting. METHODS We reviewed the charts of 187 consecutive patients in three hospitals in Belgium and France who started sunitinib as first targeted treatment between 2005 and 2012. Data were collected from each individual patient file on known prognostic factors for mRCC and anatomical location of metastatic sites, response rate, progression free survival (PFS), and overall survival (OS). RESULTS 187 eligible patients were identified by retrospective chart review. Median PFS was 26 months in the group with baseline CRP within normal limits (≤5 mg/l) versus 8 months in the group with elevated baseline CRP (>5 mg/l) (p < 0.0001). Median OS was 50 versus 12 months respectively (p < 0.0001). In the group with normal baseline CRP, 69% of patients experienced a partial response (PR) compared to 31% of patients in the group with elevated baseline CRP (p < 0.0001). On multivariate analysis, taking into account baseline neutrophil count, platelet count, ECOG PS, serum lactate dehydrogenase (LDH) activity, hemoglobin levels, corrected serum calcium levels, interval between initial diagnosis of RCC and start of systemic therapy </≥12 months, presence/absence of liver metastases or bone metastases and prior nephrectomy, baseline serum CRP-level was found to be an independent variable associated with poor PFS (p = 0.01) and OS (p < 0.0001). CONCLUSIONS Baseline serum CRP level is an independent parameter correlated with ORR, PFS and OS in mRCC patients treated with sunitinib in first-line. [Table: see text].

A pharmacogenomic scoring system predicting median time to progression (mTTP) on sunitinib (SUN) as first-line treatment in patients (pts) with metastatic renal cell carcinoma (mRCC).

359 Background: There are no established biomarkers predicting outcome of SUN treatment in mRCC. METHODS We assessed 30 single nucleotide polymorphisms (SNPs) in 10 genes on fresh frozen clear cell RCC nephrectomy specimens originating from pts who developed metastatic disease. RESULTS We processed 79 samples. In 49 pts, normal kidney tissue adjacent to the tumor was used, in 30 pts only tumoral tissue was available. After nephrectomy and in presence of synchronous or metachronous metastasis, all pts received SUN as 1st line treatment. We observed associations between several SNPs and mTTP: In the promotor region of the gene encoding for IL-8 (proangiogenic growth factor): rs4073: TT or TA versus (vs) AA variant: mTTP 12 mo vs not reached (NR) (p=0.02). In ABCB1 (involved in drug transport): rs2032582: TA or TT vs GT/GA or GG: 9 vs 16 mo (p=0.03). rs1128503: TT vs CT or CC: 9 vs 16 mo (p=0.02). In VEGFR3 (a target of SUN): rs307826 : GA vs AA: 9.3 vs 18 mo (p=0.01). rs307821 : GT vs GG: 10 vs 16 mo (p=0.08). rs448012 : CC/CG vs GG: 12 mo vs NR (p=0.02). In NR1/2 (promotor leading to increased CYP3A4 expression): rs3814055: TT vs CC/CT: 13 vs 18 mo (p=0.02). rs1054190: CC vs CT: 14 vs 20 mo (p=0.14). In PDGFR-alpha (another SUN target): rs1800812: TT vs GG/GT: 3.5 vs 16 mo (p<0.0001). A scoring system combining 7 non-overlapping SNPs was build and pts were classified in a favorable, intermediate and unfavorable SNP profile group. A link with mTTP and response rate was found, but not with established clinical prognostic scores (MSKCC). CONCLUSIONS SNPs in genes linked to the pharmacokinetics and -dynamics of SUN can probably predict outcome of SUN treatment in mRCC. Our results confirm in part previous observations made by other groups in pazopanib or SUN (in IL-8, VEGFR3 and NR1/2) and highlight the potential role of other SNPs (in ABCB1, NR1/2 and PDGFR). Extension of the series and univariate/multivariate validation are ongoing. [Table: see text].

Association of ERCC1 SNPs with outcome in platinum-treated patients with advanced urothelial cancer: a Hellenic Cooperative Oncology Group study

AIM The association between two polymorphisms of ERCC1 and treatment outcomes after platinum-based chemotherapy in patients with advanced urothelial cancer (UC) was examined. MATERIALS & METHODS Genotyping of 19007C>T and 8092C>A polymorphisms was determined by PCR amplification and RFLP in 113 advanced UC patients, treated with platinum-based chemotherapy. RESULTS Seventy eight patients (69%) were carriers of the 19007T polymorphic allele: 51 (45%) heterozygotes and 27 (24%) homozygotes. Fifty three (47%) patients were carriers of the 8092A polymorphic allele: the frequencies of C/A and A/A genotypes were 37% and 10%, respectively. The T/T genotype was independently associated with prolonged median cancer-specific survival (not-reached vs 14.8 months; p = 0.026). There was no interaction between T/T or any other genotype with the type of platinum derivative (cisplatin/carboplatin). CONCLUSION 19007C>T, especially in its homozygotic state, but not 8092C>A polymorphism, could be a useful prognostic marker in advanced UC treated with platinum-based chemotherapy.

A Risk-Adapted Strategy of Adjuvant Paclitaxel/Carboplatin in Early-Stage Ovarian Cancer: Time-Dependent Effect of 4 versus 6 Cycles on Outcome

Objective: We investigated the efficacy of risk-adapted adjuvant paclitaxel/carboplatin chemotherapy in early-stage ovarian carcinoma. Methods: Fifty-three patients were treated according to the risk of relapse: patients with stages IA or IB or with grade 1 (low risk) received 4 cycles of paclitaxel and carboplatin; patients with IC/IIA and grade 2 or 3 (high risk) received 6 cycles of chemotherapy. The outcome was compared with that of 95 patients who were all treated with 4 cycles. Results: Median follow-up was 88, 113 and 42 months for the whole cohort, non-risk-adapted and risk-adapted treatment, respectively. Five-year relapse-free and disease-specific survival was 86 and 93% for the whole population, 96 and 97% for low-risk and 81 and 91% for high-risk patients. Risk classification was the only significant prognostic factor for relapse-free (p = 0.011) and disease-specific survival (p = 0.039). Among high-risk patients, the administration of 6 cycles was associated with a significantly lower relapse rate after censoring events, which occurred beyond 2 years (3 vs. 18%; p = 0.013), but this difference was diminished at 5 years (23 vs. 25%; p = 0.797). Conclusions: Six cycles of chemotherapy reduced the risk of relapse within 2 years, but the benefit from two additional cycles beyond this time is questionable.

The role of high-dose chemotherapy in the treatment of testicular cancer

Testicular cancer is a highly curable neoplasm, even in the case of extragonadal disease. Nevertheless, patients with adverse prognostic features or relapsing after first-line cisplatin-based chemotherapy have a worse prognosis with a death rate greater than 50%. High-dose chemotherapy (HDC) has long been used in this group of patients. The introduction of stem cells, instead of bone marrow, as the source of hemopoietic cells and the use of leukocyte growth factors have substantially reduced the mortality and morbidity of this procedure although the role of HDC is not well defined. This review summarizes the available data, focusing on published randomized studies. The problems associated with the design of these studies and the interpretation of data are discussed. Currently this HDC approach is mainly used in patients who relapse after first-line chemotherapy. Nevertheless, selection of patients likely to benefit from this treatment remains an issue of intense clinical research.

ERCC1 polymorphisms in patients with advanced bladder cancer treated with platinum-based chemotherapy.

e15066 Background: Platinum-based combination chemotherapy represents the standard treatment for advanced urothelial cancer. Determination of prognosis is based on clinical characteristics: ECOG PS...