Faculty Bibliography

This conference opened with Franco Muggia, host and principal organizer, thanking Joseph Landolph, co-Chair of the International Scientific Organizing Committee and its members (Franco Muggia, co-Chair, Max Costa, Steven Burakoff, Howard Hochster, Eliezer Huberman, John Bertram, Peter Danenberg, and Richard Moran); the members of the Local Organizing Committee (Drs. Costa, Guttenplan, Geacintov, and Hochster); and the Charles and Patricia Heidelberger Foundation for Cancer Research for developing the scientific program and for working to help him create this special symposium honoring the late Charles Heidelberger, former president of the American Association for Cancer Research, member of the National Academy of Sciences, and extraordinary scientist in the fields of carcinogenesis and cancer chemotherapy. It was most appropriate to commemorate the 50th anniversary of the patent obtained by him for 5-fluorouracil (5FU), a drug that came to symbolize the promise chemotherapy of nonhematologic malignancies. After this compound was shown to be helpful in the treatment of colorectal and breast cancers, Dr. Heidelberger proceeded to develop other fluoropyrimidines and to inspire Ph.D. students and postdoctoral fellows to investigate their mechanisms of action and to develop assays applicable to clinical specimens (what we now refer to as translational science). Steven Burakoff, director of the NYU Cancer Institute (2000 to 2008), followed with welcoming remarks. Dr. Burakoff pointed to his personal fortuitous connection to the Symposium: The famous immunologist, Michael Heidelberger, Charles' father, who was known as the Father of Immunochemistry, trained Elvin Kabat while at Columbia, who trained Baruch Benacerraf, who moved from NYU to Harvard and subsequently became Burakoff's mentor. The renowned NYU Division of Immunology carries the name Michael Heidelberger because he spent more than 30 years in the Department of Pathology at the NYU School of Medicine after retiring from Columbia University. [Mol Cancer Ther 2009;8(5):992-9]

BACKGROUND:: There are limited data regarding unique clinical or laboratory features associated with advanced clear cell (CC) and mucinous (MU) epithelial ovarian cancers (EOC), particularly the relationship between CA-125 antigen levels and prognosis. METHODS:: A retrospective review of 7 previously reported Gynecologic Oncology Group phase 3 trials in patients with stage III/IV EOC was conducted. A variety of clinical parameters were examined, including the impact of baseline and changes in the CA-125 level after treatment of CC and MU EOC on progression-free (PFS) and overall survival (OS). RESULTS:: Clinical outcomes among patients with advanced CC and MU EOC were significantly worse when compared with other cell types (median PFS, 9.7 vs 7.0 vs 16.7 months, respectively, P < .001; median OS, 19.4 vs 11.3 vs 40.5 months, respectively, P < .001). Suboptimal debulking was associated with significantly decreased PFS and OS among both. Although baseline CA-125 values were lower in CC (median, 154 mu/mL) and MU (100 mu/mL), compared with other cell types (275 mu/mL), this level did not appear to influence outcome among these 2 specific subtypes of EOC. However, an elevated level of CA-125 at the end of chemotherapy was significantly associated with decreased PFS and OS (P < .01 for all). CONCLUSIONS:: Surgical debulking status is the most important variable at prechemotherapy predictive of prognosis among advanced CC and MU EOC patients. Changes in the CA-125 levels at the end treatment as compared with baseline can serve as valid indicators of PFS and OS, and likely the degree of inherent chemosensitivity. Cancer 2009. (c) 2009 American Cancer Society

To date, the presence of a hereditary background has not influenced the selection of drug treatment in breast cancer. However, increasingly, negative hormone receptors and Her2 (often referred to as 'triple negative') or a medullary carcinoma histology has been reported in BRCA mutation carriers. Accordingly, such patients are often considered for adjuvant protocols based on chemotherapy (and not based on endocrine manipulations or trastuzumab). Mouse models introducing a conditional BRCA-null expression in the breast have recently provided powerful support for cisplatin-based treatment and have implications for the design of adjuvant studies in these patients.

BACKGROUND:: The objective of the current study was to determine the prognostic significance of a pretreatment serum CA 125 level in patients with advanced epithelial ovarian carcinoma (EOC) who received treatment with a standard chemotherapy regimen. METHODS:: Patients with International Federation of Gynecology and Obstetrics stage III/IV ovarian carcinoma who were on 1 of 7 Gynecologic Oncology Group (GOG) phase 3 trials and received treatment with a standard regimen of intravenous cisplatin and paclitaxel were included. A Cox regression model was used to assess the impact of CA 125 levels drawn before the initiation of chemotherapy on progression-free survival (PFS) both overall and by subgroup, including surgical debulking status, disease stage, and histologic subtype. RESULTS:: In total, 1299 patients who were on the cisplatin/paclitaxel arms of the GOG trials were eligible. The median CA 125 level was 246 U/mL. Only 7.6% of patients had a normal CA 125 level (</=35 U/mL). The lowest median CA 125 level was observed in the group with mucinous tumors; however, 69% of women who had mucinous tumors had abnormal CA 125 levels. Shorter PFS was observed with increasing CA 125 and persisted in multivariate analysis. Overall and in the serous subgroup, a 1-fold increase in CA 125 level was associated with a 7% increase in the hazard of disease progression (P < .001). This association was even more pronounced in patients who had stage III disease that was debulked to microscopic disease (15%; P = .003) and in patients who had endometrioid tumors (17%; P = .001). CONCLUSIONS:: A normal CA 125 level in the setting of advanced EOC was rare even after surgical debulking. The pretreatment CA 125 level was an independent predictor of PFS in patients with advanced EOC who received a standard chemotherapy regimen, particularly in the setting of disease that was debulked to a microscopic residual and in the serous or endometrioid subtypes. Cancer 2009. (c) 2009 American Cancer Society

Cisplatin and carboplatin have dominated the drug therapy of ovarian cancer and other gynecologic malignancies during the past three decades. This review, based on a recent international conference on metal coordination compounds, highlights advances in our understanding of their mechanisms of action and resistance. Two emerging areas are of special importance: 1) the role of transporters and exporters (first identified in the regulation of copper) in imparting the special selectivity of platinum drugs (also including oxaliplatin) for specific tumors; and 2) the relevance of inactivated DNA repair pathways, and in particular those related to BRCA genes in determining sensitivity of tumors to platinum drugs. The status of DNA repair pathways may become relevant to response to platinums and to the treatment of ovarian cancer in general: repair inhibitors are under testing alone or in combination with cytotoxic drugs for cancer

OBJECTIVE: This phase II study evaluated the efficacy and tolerability of dacarbazine in combination with thalidomide in metastatic melanoma patients. METHODS: Chemotherapy-naive patients with histologically confirmed, measurable metastatic melanoma with no evidence of brain metastases and adequate hematologic and organ function received dacarbazine (1,000 mg/m(2) i.v. every 3 weeks) and thalidomide (starting dose of 200 mg/day orally at night, escalated every 3 weeks) as tolerated. The primary endpoint was objective tumor response, evaluated after every 3 cycles of treatment. Fifteen patients, age range 29-77 years, were accrued for this study. All had stage IV disease (1 M1a, 5 M1b, 9 M1c). Nine patients had had no prior adjuvant therapy, 6 had received prior immunotherapy. The median number of cycles was 5 (range 1-18), with 8 patients receiving >or=3 cycles. The median thalidomide dose administered was 200 mg/day with a maximum tolerated dose of 400 mg/day. RESULTS: Of the 13 patients evaluable for response, 1 patient had a partial response, 3 patients had stable disease and 9 patients had progressive disease. No complete responses were seen. Two patients were not evaluable for response: 1 withdrew due to toxicity and 1 died of unrelated causes. Grade III neutropenia, thrombocytopenia and nausea were attributed to dacarbazine. Grade III/IV constipation, peripheral neuropathy, fatigue, edema and rash were attributed to thalidomide. CONCLUSION: The addition of thalidomide to dacarbazine in metastatic melanoma yielded activity insufficient to proceed with additional trials of this combination. Thalidomide dose escalation beyond 200 mg/day was limited by unacceptable toxicity. Therefore, this combination does not warrant further investigation

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