TESI DI DOTTORATO: Hereditary and familial breast and ovarian cancer: spectrum of related tumors. CANDIDATO: M.Pensabene. RELATORE: S.Pepe

This dissertation is focused on the evaluation of cancer spectrum related to hereditary and familial breast cancer. In BRCA1 mutation carriers, mean cumulative risk at age 70 years is 57% (95% CI, 47% to 66%) for breast cancer and 40% (95% CI, 35% to 46%) for ovarian cancer. Moreover, in BRCA2 mutation carriers mean cumulative risk at age 70 years is 49% (95% CI, 40% to 57%) for breast cancer and 18% (95% CI, 13% to 23%) for ovarian cancer. Various studies reported contradictory data concerning risk of cancer at sites different than breast and ovary in both of carriers of mutations in BRCA1 and BRCA2 genes. We selected families referred to “Screening and follow-up for hereditary and familial cancers” Unit of University “Federico II” in Naples for oncogenetic counseling. Families were analyzed in order to evaluate the cancer spectrum related with inherited and familial breast and ovarian cancer. We examined 104 pedigrees for a total of 4100 individuals (2117 females, 1983 males), all of Caucasian ethnicity. Based on family history of breast cancer and/or ovarian cancer and on clinical characteristics at diagnosis, pedigrees were classified according to Modena model in: hereditary with clustering (41 families; 39%), hereditary without clustering (27 families; 26%) and familial (36 families; 35%). A total of 587 independent events of cancer have been detected in the 104 families on study. In particular among the three major categories in which individuals have been grouped, 294 cases (17.6%) of tumors were registered in the category of hereditary with clustering constituted of a cohort of 1670 individuals, 103 cases (9.8%) of tumors in the category of hereditary without clustering constituted of a cohort of 1053 individuals and 190 cases (13.8%) of tumors in the familial category constituted of a cohort of 1377 individuals. In the hereditary with clustering group a high frequency emerges for cancer of ovary (2%), uterus (1,4%), prostate (1,4%) and lung (0,9%). A moderate frequency emerges for colon-rectum (0,8%) and stomach (0,7%) cancers. In the hereditary without clustering group a similar association has not been revealed except for colon-rectum cancer ((0,8%). In the familial group a high frequency has been registered for cancers of ovary (1,3%), uterus (2%), and colon-rectum (1,3%). A moderate frequency has been registered for prostate cancer (0,9%). We also determined frequency of tumors in families with mutations of BRCA1/2 genes. In the 10 families with BRCA1 mutations, 76 events of cancers have been detected in a total of 486 individuals. It emerges a clustering with ovarian (4.9%), uterine (1.2%) and bladder cancer (0.8%). In the 6 families with BRCA2 genotype, 33 events of cancers have been registered in a total of 185 individuals. It emerges a clustering with ovarian (2.8%), uterine (2,8%), colon-rectum (1%) and prostate cancers (2,6%). At least, the statistical analysis have not revealed a typical cancer spectrum, because differences of statistical value have not been gained for any specific site other than breast in our series among risk categories and sex

PRECLINICAL AND PHASE I STUDY OF OXALIPLATIN AND TOPOTECAN IN COMBINATION IN HUMAN CANCER.

BACKGROUND: DNA damage caused by platinum agents is frequently followed by induction of topoisomerase I, providing a rationale for use of platinum-based compounds with topoisomerase I inhibitors. MATERIALS AND METHODS: We studied the effect of a sequential schedule of oxaliplatin on day I and topotecan on days 2-5, in human colon and ovarian cancer cells in vitro, in nude mice bearing human cancer xenografts and finally in cancer patients in a phase I trial. RESULTS: We demonstrated a supra-additive effect of this combination on inhibition of colony formation and induction of apoptosis in vitro. We then demonstrated that the two agents in combination markedly inhibit tumor growth in nude mice. We translated these results into a clinical setting, conducting a phase I study in cancer patients with oxaliplatin 85 mg/m2 on day 1 and topotecan at doses escalating from 0.5 to 1.5 mg/m2 on days 2-5. Sixty cycles of treatment were administered to 18 patients affected prevalently by ovarian and colorectal cancer. Combination with topotecan 1.5 mg/m2 caused a dose-limiting toxicity. Therefore the maximum tolerated dose of topotecan was 1.25 mg/m2, at which six patients experienced a mild hematological and gastrointestinal toxicity. We also obtained evidence of clinical activity, particularly in ovarian cancer. CONCLUSIONS: Our results provide a solid biological and clinical rationale for a phase II trial at the recommended doses of oxaliplatin 85 mg/m2 and topotecan 1.25 mg/m2, possibly in ovarian cancer patients