We present the first characterisation of the mutational spectrum of the entire coding sequences and exon-intron boundaries of the BRCA1 and BRCA2 genes as well as large BRCA1 rearrangements in Portuguese families with inherited predisposition to breast/ovarian cancer. Of the 100 probands studied, pathogenic mutations were identified in 22 (24.7%) of 89 breast and/or ovarian cancer families with more than one affected member (15 in BRCA1 and seven in BRCA2), but in none of the 11 patients without family history of cancer. One (6.7%) of the BRCA1 mutations is a large deletion involving exons 11-15. Seven pathogenic point mutations are novel: 2088C>T, 2156delinsCC, and 4255_4256delCT in BRCA1 and 4608_4609delTT, 5036delA, 5583_5584insT, and 8923C>T in BRCA2. The novel 2156delinsCC was identified in three probands from different families and probably represents a founder mutation in our population. We also found a previously reported 3450_3453del4 mutation in three unrelated patients. In addition to the 22 pathogenic mutations, we identified 19 missense mutations of uncertain pathogenic significance, three of them (5241G>C in BRCA1 and IVS6+13C>T and 3731T>C in BRCA2) previously undescribed. The percentage of cases with truncating mutations in BRCA1 and BRCA2 was higher in breast/ovarian cancer (37.0%, mostly BRCA1) and male breast cancer (40%, all BRCA2) families than in families with only female breast cancer (17.5%). Interestingly, we found evidence for genetic anticipation regarding age at diagnosis of both breast and ovarian cancer in those families presenting affected members in more than one generation. These findings should be taken into consideration while planning screening and prophylactic measures in families with inherited predisposition to breast and ovarian cancer.

1084 Background: Gemcitabine plus cisplatin have synergistic activity and have been tested in several schedules and doses in metastatic breast cancer. Our objectives were to assesss the efficacy and toxicity of gemcitabine and cisplatin in pretreated patients. Methods: Measurable disease and at least two prior anthracycline and /or taxane-containing regimen in either metastatic or adjuvant setting was required. Treatment consisted of gemcitabine 700mg/m(2) IV infusion over 30 min plus cisplatin 30mg(2) given on day1 and 8 every 3 weeks. Results: Seventy four patients with median age of 48 years (range 26- 73) were recruited. A median of six cycles of the study treatment was delivered. The overal response rate was 30% (95% confidence interval, 12–53%). Median time to progreesion was 30.6 weeks (95%CI, 12.6–44 weeks). Median survival was 73.2 weeks (95% CI, 47.1–93.2 weeks). Toxicities included grade 3 and 4 leukopenia in 27(36.4%), anemia in 19 (25.6%) and oral mucositis in 4 (5.4%). No grade 3 or 4 peripheral neurophaty, hepatic or renal dysfunction was observed. No treatment-related death ocurred. Conclusions: Gemcitabine plus cisplatin is a well tollerated and active treatment in heavily pretreated patients with metastatic breast cancer. No significant financial relationships to disclose.

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