Phase IB Study of Induction Chemotherapy With XELOX, Followed by Radiation Therapy, Carboplatin, and Everolimus in Patients With Locally Advanced Esophageal Cancer.

PURPOSE: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation. MATERIALS AND METHODS: Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used. RESULTS: Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively. CONCLUSIONS: The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.

Association between cytosolic expression of BRCA1 and metastatic risk in breast cancer.

BACKGROUND: Although BRCA1 has been extensively studied for its role as a tumour-suppressor protein, the role of BRCA1 subcellular localisation in oncogenesis and tumour progression has remained unclear. This study explores the impact of BRCA1 mislocalisation on clinical outcomes in breast cancer. METHODS: Tissue microarrays assembled from a cohort of patients with all stages of breast cancer were analysed for BRCA1 localisation and correlated with patient survival. Tissue microarrays of patients who had breast cancer that had metastasised to the lung were assembled from an independent cohort of patients. These were analysed for BRCA1 subcellular expression. In vitro studies using cultured human breast cancer cells were conducted to examine the effect of cytosolic BRCA1 on cell migration and efficiency of invasion. RESULTS: An inverse association was found between cytosolic BRCA1 expression and metastasis-free survival in patients aged >40 years. Further analysis of BRCA1 subcellular expression in a cohort of breast cancer patients with metastatic disease revealed that the cytosolic BRCA1 content of breast tumours that had metastasised to the lung was 36.0% (95% CI=(31.7%, 40.3%), which was markedly higher than what is reported in the literature (8.2-14.8%). Intriguingly, these lung metastases and their corresponding primary breast tumours demonstrated similarly high cytosolic BRCA1 distributions in both paired and unpaired analyses. Finally, in vitro studies using human breast cancer cells demonstrated that genetically induced BRCA1 cytosolic sequestration (achieved using the cytosol-sequestering BRCA1 5382insC mutation) increased cell invasion efficiency. CONCLUSIONS: Results from this study suggest a model where BRCA1 cytosolic mislocalisation promotes breast cancer metastasis, making it a potential biomarker of metastatic disease.

Survival Benefit of Adjuvant Radiation Therapy for Gastric Cancer following Gastrectomy and Extended Lymphadenectomy.

Purpose. Although randomized trials suggest a survival benefit of adjuvant chemotherapy and radiation therapy (XRT) for gastric adenocarcinoma, its use in patients who undergo an extended lymphadenectomy is less clear. The purpose of this study was to determine if a survival benefit exists in gastric cancer patients who receive adjuvant XRT following resection with extended lymphadenectomy. Methods. The SEER registry was queried for records of patients with resected gastric adenocarcinoma from 1988 to 2007. Multivariable Cox regression models were used to assess independent prognostic factors affecting overall survival (OS) and disease-specific survival (DSS). Results. Of 15,060 patients identified, 3,208 (21%) received adjuvant XRT. Adjuvant XRT was independently associated with improved OS (HR 0.67, CI 0.64-0.71) and DSS (HR 0.69, CI 0.65-0.73) in stages IB through IV (M0). This OS and DSS benefit persisted regardless of the extent of lymphadenectomy. Furthermore, lymphadenectomy with >25 LN resected was associated with improved OS and DSS compared with <15 LN or 15-25 LN. Conclusion. This population-based study shows a survival benefit of adjuvant XRT following gastrectomy that persists in patients who have an extended lymphadenectomy. Furthermore, removal of >25 LNs results in improved OS and DSS compared with patients who have fewer LNs resected.

Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature.

Radiation can be used to guide drugs to specific sites such as neoplasms or aberrant blood vessels. When blood vessels are treated with ionizing radiation, they respond by expressing a number of cell adhesion molecules and receptors that participate in homeostasis. Examples of radiation-induced molecules in blood vessels include ICAM-1, E-selectin, P-selectin and the beta(3) integrin. We have observed that the endothelium and blood components respond to oxidative stress in a similar, if not identical manner in all tumor models. Although we have identified several other radiation-induced molecules within tumor blood vessels, the beta(3) target for drug delivery achieves the greatest site-specific peptide binding within irradiated tumor blood vessels. We have focused on peptides and antibodies that bind to integrin beta(3). beta(3)-binding proteins have been conjugated to fluorochromes and radionuclides to study the site specificity and microscopic distribution. We have found immunofluorescent and immunohistochemical staining of beta(3) within the lumen of blood vessels immediately following irradiation. To determine whether it is feasible to guide drug delivery to irradiated tumors, we studied ligands to alpha(2b)beta(3) (fibrinogen). Peptides within fibrinogen that bind to alpha(2b)beta(3) includes the dodecapeptide, HHLGGAKQAGDV and the RGD peptide. We utilized 131I conjugation to these ligands to study the biodistribution in tumor bearing mice. Our clinical trial consists of the RGD peptidomimetic, biapcitide, labeled with 99mTc. This study shows that it is feasible to guide drugs to human neoplasms by use of radiation-guided peptides. These studies have shown that peptides that bind to these integrins bind to tumors following exposure to ionizing radiation.