Overall survival in BRCA-associated ovarian cancer: case-control study of an Italian series.

About 10% of all ovarian cancers are due to BRCA 1 and/or BRCA 2 mutations. Some studies have shown that patients belonging to this group have a better survival compared to sporadic groups but data are still inconclusive. The aim of this study was to investigate overall survival in patients with ovarian cancer and germ-line mutations in the BRCA1/2 genes in comparison to high-risk patients, defined as patients with ovarian cancer and a strong family history of breast and ovarian cancer, but who tested negative for the BRCA mutation. We collected all the clinical features and did follow-up. The two groups showed similar characteristics concerning age at diagnosis, histological type and stage. Grade 3 was more frequent in the BRCA group. Survival data did not show any advantage for the BRCA mutated group.

Large genomic deletions inactivate the BRCA2 gene in breast cancer families.

BACKGROUND: BRCA1 and BRCA2 are the two major genes responsible for the breast and ovarian cancers that cluster in families with a genetically determined predisposition. However, regardless of the mutation detection method employed, the percentage of families without identifiable alterations of these genes exceeds 50%, even when applying stringent criteria for family selection. A small but significant increase in mutation detection rate has resulted from the discovery of large genomic alterations in BRCA1. A few studies have addressed the question of whether BRCA2 might be inactivated by the same kinds of alteration, but most were either done on a relatively small number of samples or employed cumbersome mutation detection methods of variable sensitivity. OBJECTIVE: To analyse 121 highly selected families using the recently available BRCA2 multiplex ligation dependent probe amplification (MLPA) technique. RESULTS: Three different large genomic deletions were identified and confirmed by analysis of the mutant transcript and genomic characterisation of the breakpoints. CONCLUSIONS: Contrary to initial suggestions, the presence of BRCA2 genomic rearrangements is worth investigating in high risk breast or ovarian cancer families.

Lack of association between androgen receptor CAG polymorphism and familial breast/ovarian cancer.

The human androgen receptor (AR) gene contains a highly polymorphic CAG repeat in exon 1 that is inversely correlated with AR transcriptional activity in vitro. Several studies have shown that fewer CAG repeats are associated with an increased risk as well as more aggressive forms of prostate cancer. More recently, AR allele length was also inversely correlated with the histological grade of breast cancer, but no association was found between the AR-CAG polymorphism and the risk of either breast or ovary cancer. On the contrary, it was proposed that a longer CAG repeat sequence might be associated with an increased risk of breast cancer in BRCA1 mutation carriers, thus suggesting a different role of the AR-CAG polymorphism in sporadic and inherited breast cancers. With the intent of better understanding the role of the AR-CAG polymorphism as a cancer risk modifier, we defined the AR genotype of 151 patients (101 with breast and 50 with ovary cancer) belonging to high-risk breast/ovary cancer families. No difference in CAG repeat length was found between either breast and ovary cancer patients or age at diagnosis of both tumors. These results were also confirmed in a sub-group of 47 breast cancer cases, that either carried a BRCA gene mutation (11 cases) or were identified by very stringent operational criteria as hereditary breast cancers. Even though a substantially larger sample size would be required to reach conclusive evidence, our findings suggest that the AR-CAG polymorphism does not act as a modifier of tumor onset or tumor phenotype in breast/ovarian cancer families.

Phase II study of 4'epi-doxorubicin.

Sixty-five patients with advanced solid tumors were treated with 4'epi-doxorubicin, a new analogue of doxorubicin (DXR). Forty-three of 61 evaluable patients had not received previous chemotherapy and/or hormonal treatment. 4'Epi-doxorubicin has been administered at the dose of 75 mg/m2 i.v. once every 21 days, for a minimum of 2 courses. The pattern of acute toxicity was similar to that of DXR. Transient electrocardiographic abnormalities were found in about 50% of patients. The ratio of pre-ejection period to the left ventricular ejection time (PEP/LVET) increased within 1 h after drug injection and returned to near basal values after 24 h. Three patients received a total dose of more than 550 mg/m2, still maintaining a baseline PEP/LVET ratio near to pretreatment values. Up to now, no patient has developed clinical signs of heart failure. Partial responses were seen in patients with tumors generally sensitive to DXR such as breast carcinoma (6 of 14) and soft tissue sarcomas (2 of 6), and in patients with tumors generally resistant to DXR such as melanoma (1 of 9), colorectal carcinoma (3 of 18) and pancreatic carcinoma (1 of 2). These data suggest that 4'epi-doxorubicin may have a broader spectrum of antitumor activity than DXR.

Phase II evaluation of 4'epi-doxorubicin in patients with metastatic colorectal carcinoma.

Thirty-four evaluable patients with metastatic colorectal carcinoma (13 rectal primary and 21 colonic primary, 4 pretreated and 30 untreated) received 4'epi-doxorubicin at the dose of 75 mg/m2 i.v. once every 21 days, for a minimum of 2 courses. Symptomatic toxicity (mainly confined to gastrointestinal complaints) was short-lived and easily managed. Hematologic toxicity was mild. Transient electrocardiographic abnormalities were found in 50% of patients, without signs of significant cumulative cardiotoxicity. Three previously untreated patients achieved a partial response (lasting 16, 12 and 12 weeks, respectively) with a response rate of 9% (3%-23%, 95% confidence interval). More interestingly, all responsive patients had rectal cancer: further studies of 4'epi-doxorubicin confined to the rectal localization seem warranted.

Multicenter phase II study of trastuzumab in combination with epirubicin and docetaxel as first-line treatment for HER2-overexpressing metastatic breast cancer.

The primary objective of study is to evaluate cardiac safety of trastuzumab in combination with epirubicin and docetaxel. HER2-overexpressing metastatic breast cancer patients were enrolled in a two-stage, multicenter phase II trial with weekly trastuzumab (4 and then 2 mg/kg) with epirubicin and docetaxel (either 75 mg/m(2)) on day 1 every 3 weeks. After eight courses of chemotherapy, trastuzumab was continued as a single agent. To assess cardiotoxicity, patients were evaluated for left ventricular ejection fraction (LVEF) at baseline, every two cycles during chemotherapy and trastuzumab, and every 3 months during trastuzumab alone. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure (CHF) and/or an absolute decrease in LVEF of >or=20 units or a decline to

Localized ovarian cancer: surgery plus chemotherapy.

Fifty-four patients were referred to Medical Oncology after operation for "limited" ovarian cancer; 7 were excluded because immediate restaging showed evidence of macroscopic spread to structures outside the true pelvis, and 10 will be considered separately because of microscopic spread shown only by cytology. Thirty-seven patients (31 stage I and 6 stage II) were accordingly accepted as "localized", because peritoneal cytology and diaphragm and omental plus parietal peritoneum histology could rule out the spread to the large abdominal cavity. Some of the referred patients had been operated in nearby hospitals; the Padua GYN Cin. performed 14 of the 37 first surgery operations and 30 of the 37 second look operations. All patients soon after surgery underwent first-line chemotherapy with 5 courses of high dose adriamycin plus cyclophosphamide for 4 months, then surgical second look, and second-line non-cross-resistant chemotherapy for 3 months. During the second look the organ and tissue removal was completed in those 21 patients having received "limited" first surgery. Two patients died within 5 years from admission, so that the overall 5 year actuarial survival from referral is 93% for the entire group with 11 patients still at risk; 87% are disease free 5 years after the second look with 7 at risk. Subdivision of the patients according to "adequate" vs. "limited" first surgery, may select a group (the "adequate" one, composed of 16 patients) completely free from relapses, up to now. The complex therapeutic program described seems to offer long term relapse-free survival to the majority of patients, while the few failures seem closely related with inadequacies of the initial surgical procedure.

Peptichemio in pretreated patients with ovarian cancer.

From January 1978 to October 1982, 47 patients with histological diagnosis of epithelial cancer of the ovary received peptichemio (PTC) at a dose of 70 mg/m2 (maximum, 120 mg total) every 15 days. Forty-two patients are now evaluable: 27 with stage III and 15 with stage IV disease. All patients but four with stage IV disease had been pretreated and had received at least one drug combination (median, three drugs per patient, including alkylating agents). Before the administration of PTC, the tumor extension in the abdomen was carefully assessed in all patients: ten patients had residual tumor less than 2 cm in diameter, while 32 patients had tumor greater than 2 cm in diameter. Objective responses were obtained in ten patients (23.8%): six complete remissions and one partial remission were observed in stage III patients and one complete remission and two partial remissions were observed in stage IV patients. Of the ten responding patients, eight had tumors less than 2 cm in diameter before receiving PTC. The median duration of response was 16 months. The most frequent side effects were myelosuppression and phlebosclerosis. Bone marrow depression was a common finding after the third course in heavily pretreated patients. Accordingly, in these patients a schedule interval of 3 weeks should be more appropriate. Since most of the responders were in the "small tumor" category, PTC appears to be an active drug in patients with ovarian cancer having small tumors (less than 2 cm). On the other hand, the response rate in a nonselected population of patients remains to be clearly defined with further studies.