TESI DI DOTTORATO:Gefitinib and Radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck. CANDIDATO: C.Romano. RELATORE: S.Pepe.

Introduction: Gefitinib, an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces growth arrest in squamous cancer cell carcinoma of head and neck (SCCHN) cell lines mainly by blocking cells in G1 and preventing them from entering the cell cycle. Clinical studies have demonstrated the activity of gefitinib monotherapy in SCCHN. Preclinical studies have shown that the combination of radiotherapy (RT) and drugs interfering with the EGF pathway may result in radiosensitization in squamous cell carcinomas that over express EGFR. Purpose: Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer who have neiver received radiotherapy or chemotherapy or undergone surgery for head and neck carcinoma, with the aim of finding the maximum tolerated dose and assessing the toxicity and activity of the combination. Patients and methods: The standard “3+3” design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than a third of patients of a given cohort had dose limiting toxicity (DLT). Results: DLT was observed in 3 out of 4 patients treated at the dose of 500 mg and included grade 3 stomatitis in 3 patients and grade 3 liver toxicities in 1 patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Four patients had a complete response, which was confirmed in three cases; eight patients had a partial response, which was not confirmed in six patients. Stable disease and disease progression were observed in one and three patients, respectively. Median duration of response was 5.4 (range: 1–21) months. The observed stable disease lasted 7.4 months. The median progression free-survival was 6.7 months (95% CI: 4.5–12.1) and the median OS was 8.5 months. Conclusion: Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge

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