Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†.

BACKGROUND: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, ß = 0.8) 379 events had to be observed in the bevacizumab arms. RESULTS: With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. CONCLUSIONS: Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. CLINICAL TRIAL NUMBER: NCT 00567554, www.clinicaltrials.gov.

Pattern and clinical predictors of lymph node metastases in epithelial ovarian cancer.

Para-aortic lymphadenectomy is part of staging in early epithelial ovarian cancer (EOC) and could be part of therapy in advanced EOC. However, only a minority of patients receive therapy according to guidelines or have attendance to a specialized unit. We analyzed pattern of lymphatic spread of EOC and evaluated if clinical factors and intraoperative findings reliably could predict lymph node involvement, in order to evaluate if patients could be identified in whom lymphadenectomy could be omitted and who should not be referred to a center with capacity of performing extensive gynecological operations. Retrospective analysis was carried out of all patients with EOC who had systematic pelvic and para-aortic lymphadenectomy during primary cytoreductive surgery. One hundred ninety-five patients underwent systematic pelvic and para-aortic lymphadenectomy. Histologic lymph node metastases were found in 53%. The highest frequency was found in the upper left para-aortic region (32% of all patients) and between vena cava inferior and abdominal aorta (36%). Neither intraoperative clinical diagnosis nor frozen section of pelvic nodes could reliably predict para-aortic lymph node metastasis. The pathologic diagnosis of the pelvic nodes, if used as diagnostic tool for para-aortic lymph nodes, showed a sensitivity of only 50% in ovarian cancer confined to the pelvis and 73% in more advanced disease. We could not detect any intraoperative tool that could reliably predict pathologic status of para-aortic lymph nodes. Systematic pelvic and para-aortic lymphadenectomy remains part of staging in EOC. Patients with EOC should be offered the opportunity to receive state-of-the-art treatment including surgery.

Cisplatinum rechallenge in relapsed ovarian cancer patients with platinum reinduction therapy and carboplatin hypersensitivity.

Hypersensitivity reactions have been reported as limiting side effect in patients re-exposed to carboplatin for relapsed gynecologic malignancy. This study analyzed the incidence, clinical features, management, and outcome of carboplatin-associated hypersensitivity reactions. We performed a retrospective study and analyzed medical records of all gynecological cancer patients treated with carboplatin in our institution from 2000 to 2003. No hypersensitivity reactions were observed in 171 patients during the first carboplatin-containing chemotherapy. All six carboplatin-associated hypersensitivity reactions occurred in 69 patients who were re-exposed to carboplatin (9%). The median number of carboplatin cycles prior to hypersensitivity reaction was nine (range, 8-13). Cisplatin rechallenge was performed in five patients, and no hypersensitivity occurred. An increase in neurotoxicity (National Cancer Institute Common Toxicity Criteria grade 2) was documented in two patients who had residual neurotoxicity grade 1 due to prior taxane treatment. Cisplatinum rechallenge is a feasible strategy to overcome carboplatin hypersensitivity. However, close monitoring of neurotoxicity is necessary, particularly in patients with residual neurotoxicity due to prior platinum- and taxane-containing chemotherapy.

Human cationic amino acid transporter hCAT-3 is preferentially expressed in peripheral tissues.

At least five distinct carrier proteins form the family of mammalian cationic amino acid transporters (CATs). We have cloned a cDNA containing the complete coding region of human CAT-3. hCAT-3 is glycosylated and localized to the plasma membrane. Transport studies in Xenopus laevis oocytes revealed that hCAT-3 is selective for cationic L-amino acids and exhibits a maximal transport activity similar to other CAT proteins. The apparent substrate affinity and sensitivity to trans-stimulation of hCAT-3 resembles most closely hCAT-2B. This is in contrast to rat and murine CAT-3 proteins that have been reported to display a very low activity and to be inhibited by neutral and anionic L-amino acids as well as D-arginine (Hosokawa, H., et al. (1997) J. Biol. Chem. 272, 8717-8722; Ito, K., and Groudine, M. (1997) J. Biol. Chem. 272, 26780-26786). Also, in adult rat and mouse, CAT-3 has been found exclusively in central neurons. Human CAT-3 expression is not restricted to the brain, in fact, by far the highest expression was found in thymus. Also in other peripheral tissues, hCAT-3 expression was equal to or higher than in most brain regions, suggesting that hCAT-3 is not a neuron-specific transporter.