Faculty Bibliography

Background: TRC093 is a humanized monoclonal antibody that specificallybinds cleaved collagen and has been shown to inhibit angiogenesisand tumor growth in preclinical studies. TRC093 is currentlybeing evaluated in a phase I clinical study for the treatment of metastatic human tumors (Gordon et al. EJC Supp 6, abs #414, pp130, 2008). Interestingly, one of the patients in this studywith granulosa cell carcinoma of the ovary with progressivedisease had a mixed response in the liver after 2 months of treatment. Given these encouraging results, we began to examinethe biological relevance of the cryptic epitope recognized byTRC093 in ovarian carcinoma and whether a soluble form of thiscryptic collagen epitope may represent a clinically useful markerfor patients at risk for ovarian and breast cancer. To thisend, we have adapted an ELISA assay for the detection of theshed collagen cryptic epitope that is defined by this antibodyto examine a patient population at risk for ovarian and breastcancer. Methods: To begin to assess the relevance of the cryptic collagenepitope recognized by TRC093 in ovarian tumor growth, humanSKOV3 ovarian carcinoma cells were injected subcutaneously intonude mice. Six days later when detectable tumors were observed,mice were treated (i.p.) 3x per week with TRC093 over a doserange up to 250 mug/injection for a period of 28 days.To assess the relevance of a shed soluble form of the crypticcollagen epitope in a patient population at risk for ovarianand breast cancer, serum samples from a group of high-risk womenvolunteers prospectively enrolled at the NYU School of Medicinewere analyzed for TRC093 epitope concentration by ELISA as previouslydescribed (Ng et al., Clin Can Res, 14:6253). Results: TRC093 significantly (p< 0.05) inhibited SKOV3 tumorgrowth at 100 mug and 250 mug/injection as comparedto control. These findings suggest that theTRC093 cryptic collagenepitope may represent a relevant therapeutic target for ovariancarcinoma. In a group of 23 high-risk women identified withrespect to their clinical status, a mean mu SEM of 42.9mu 9.8 mug/ml was determined for the patients withovarian/ breast cancer history compared with a mean of 15.3mu 2.9 mug/ml for normal women in this study population(p = 0.0254). Conclusions: The TRC093 shed serum epitope can distinguish betweena high-risk population of women with breast or ovarian cancerand normal clinical status. We are expanding the sample sizewith more ovarian surgical patients. The xenograft studies providefurther support for the potential use of the SKOV3 human ovariancarcinoma model to examine the effect of TRC093 in combinationwith cisplatin and or bevacizumab. The TRC093 epitope may representa key therapeutic target in ovarian cancer

BACKGROUND: We have previously established the recommended phase II dose (RPTD) of ixabepilone as 40 mg/m(2) administered over 1 h repeated every 3 weeks with neuropathy as a cumulative dose-limiting toxicity. We expanded the cohort at the RPTD to include detailed assessment of nerve damage in these patients. We report our findings on vibration perception threshold (VPT) and neuropathy. PATIENTS AND METHODS: Forty-four patients were treated with a median (range) of three (1-14) cycles of ixabepilone. The VPT (5-min duration) and nerve conduction test (NCT, 10-min duration) were carried out in the office, before ixabepilone dosing, and every two cycles thereafter. RESULTS: Neuropathy (grade 1 and grades 2-3) was observed in 17 (38.6%) and 11 (25%) patients, respectively. The mean increase in VPT as a function of grade 0-1 versus grades 2-3 neuropathy was 0.235 +/- 0.03 versus 0.869 +/- 0.09 (P = 0.049) vibration units. The F-wave frequency and distal motor latency, as assessed using the NCT, did not correlate with clinical neurotoxicity. CONCLUSION: The change in VPT is observed early and likely reflects early vibration perception change. Mean change in VPT correlates with the severity of clinical neuropathy. Whether VPT change predicts onset of severe neuropathy warrants prospective testing and validation.

BACKGROUND: Concurrent radiation therapy (RT) and chemotherapy represents the standard treatment of locally advanced cervical cancer. This study was designed to determine the feasibility and toxicity of concomitant administration of RT with twice per week paclitaxel and carboplatin. MATERIALS AND METHODS: Nine women with cervical cancer stage IB2-IVA were treated with standard RT and twice per week paclitaxel at a dose of 30 mg/m2 with carboplatin in escalating doses starting at an AUC of 5. RESULTS: One out of the four patients who received carboplatin at AUC 5 developed grade III toxicity according to the National Cancer Institute (NCI) grading system. Two out of the five patients who received carboplatin at AUC 6 developed grade III toxicity. A clinical response was achieved in 8 patients (89%), with a complete response (CR) in 5 patients (56%). CONCLUSION: Combining RT with twice weekly paclitaxel (30 mg/m2) and carboplatin (AUC of 6) is a tolerated regimen, active in controlling locally advanced cervical cancer

BACKGROUND: Topotecan 14-day infusion combined with cisplatin was highly active in ovarian cancer, but too myelosuppressive. We therefore sought to evaluate the feasibility of substituting oxaliplatin for cisplatin to improve safety. METHODS: Ovarian and primary peritoneal cancer patients, pretreated with at least one prior platinum-containing regimen, performance status (PS) 0-1, without prior pelvic radiation were eligible. Topotecan was continuously infused days 1-15; oxaliplatin was given days 1 and 15; cycles were repeated every 28 days. Five dose levels were explored: topotecan (mg/m2/day)/oxaliplatin (mg/m2) doses: (1) 0.2/65; (2) 0.2/75; (3) 0.2/85; (4) 0.3/85; (5) 0.4/85. RESULTS: Twenty-three patients (20 ovarian, 1 tubal, and 2 peritoneal) were entered: median age 56 years (range, 37-77); PS: 0=12 and 1=11; histology: papillary serous 7, serous 4, adenocarcinoma 8, poorly differentiated 2. Median of 4 cycles were delivered. Grade 3 neutropenia occurred in 3 of 7 patients at level 5 (with fever at levels 4 and 5), without grade 4 neutropenia or thrombocytopenia. Other toxicities were mild and reversible (mainly gastrointestinal), except one grade 3 neuropathy and one oxaliplatin-related grade 3 hypersensitivity reaction. Six objective responses (five of them complete) were documented among 22 patients spanning several dose levels. CONCLUSION: Topotecan continuous infusion, combined with oxaliplatin, was associated with no grade 4 hematologic toxicity and evidence of activity. The recommended phase II dose is topotecan 0.4 mg/m2/day continuous infusion d1-15 with oxaliplatin 85 mg/m2 on days 1 and 15. A phase II evaluation as second-line treatment for both platinum-sensitive and -resistant ovarian cancer recurrences is ongoing

Chemotherapeutic agents that disrupt the assembly or disassembly of microtubules, including paclitaxel and docetaxel, are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapy is limited principally by problems with formulation, slow administration, cumulative neurotoxicity, and resistance in part through induction of P-glycoprotein. The broad-spectrum anticancer activity of taxane therapy has encouraged investigators to identify a class of structurally novel microtubulin-stabilizing agents that could produce comparable outcomes with fewer problems. Preclinical studies indicate that epothilones have a broad spectrum activity in paclitaxel-resistant breast cancer models. Several epothilone analogues have displayed promising antitumor activity in initial clinical trials. Ixabepilone, an epothilone derivative in the later stages of clinical development, has exhibited antitumor activity in breast cancers, with or without previous taxane therapy. The most common adverse events associated with ixabepilone are reversible sensory neuropathy and neutropenia. This review briefly outlines the basic science behind microtubule-targeting agents and examines the preclinical studies of several of these agents in breast cancer models. Also discussed are results from clinical trials of epothilones alone and in combination in patients with breast cancer

PURPOSE: To identify factors predictive of poor prognosis in a similarly treated population of women with stage IV epithelial ovarian cancer (EOC). PATIENTS AND METHODS: A retrospective review of 360 patients with International Federation of Gynecology and Obstetrics stage IV EOC who underwent primary surgery followed by six cycles of intravenous platinum/paclitaxel was performed. A proportional hazards model was used to assess the association of potential prognostic factors with progression-free survival (PFS) and overall survival (OS). RESULTS: The median PFS and OS for this group of stage IV ovarian cancer patients was 12 and 29 months, respectively. Multivariate regression analysis revealed that histology, malignant pleural effusion, intraparenchymal liver metastasis, and residual tumor size were significant prognostic variables. Whereas patients with microscopic residual disease had the best outcome, patients with 0.1 to 1.0 cm residual disease and patients with 1.1 to 5.0 cm residual disease had similar PFS and OS. Patients with a residual size more than 5 cm had a diminished PFS and OS when compared with all other groups. Median OS for microscopic, 0.1 to 5.0 cm, and more than 5.0 cm residual disease was 64, 30, and 19 months, respectively. CONCLUSION: Patients with more than 5 cm residual disease have the shortest PFS and OS, whereas patients with 0.1 to 1.0 and 1.1 to 5.0 cm have similar outcome. These findings suggest that ultraradical cytoreductive procedures might be targeted for selected patients in whom microscopic residual disease is achievable. Patients with less than 5.0 cm of disease initially and significant disease and/or comorbidities precluding microscopic cytoreduction may be considered for alternative therapeutic options other than primary cytoreduction

The co-existence of breast and ovarian cancers in the same individual should raise suspicion of a hereditary process. Patients with either BRCA1 or BRCA2 germ-line mutations have an average risk of 39% and 11% respectively of developing ovarian cancer by the age of 70; they have a risk of 35-85% of developing breast cancer in their lifetime. We report here unusual pathologic features in a BRCA2 germ-line mutation carrier recently diagnosed with synchronous breast and ovarian cancers, and summarize the findings in six other women who were diagnosed with ovarian cancer either simultaneously with the diagnosis of breast cancer or at varying times after the diagnosis. While in most instances this may be a coincidental occurrence in highly susceptible individuals, the patient we highlight raises the provocative hypothesis that at times breast cancer metastasizes to the ovaries of mutation carriers and stimulates the development of an ovarian cancer as well as other cancers. In addition, these ovarian cancers may have different mechanisms of metastases predisposing them to travel to unusual sites