Hereditary and non-hereditary branches of family eligible for BRCA test: cancers in other sites.

BACKGROUND: The analysis of relationships of BRCA alterations with cancer at sites other than breast/ovary may provide innovative information concerning BRCA pathogenic role and support additional clinical decisions. Aim of this study is to compare presence of cancers in other sites in members of hereditary (H) and not-hereditary (nH) branches of families of patients eligible to BRCA test. METHODS: We retrospectively analyzed the incidence of cancer in other sites in members of 136 families eligible for hereditary breast/ovarian cancer genetic counseling at Centro Studi Tumori Eredo-familiari of our Institute; we compared the frequency of other cancer types in 1156 members of the H-branch with respect to 1062 members of nH-Branch. The families belonging to a proband case and with informative members in at least three generation entered the present study. RESULTS: The frequency of other Cancers in members of H-branch was significantly higher than that in members of nH-branch (161 vs 75 cancers; p < 0.0001). In specific, members of H-branch had a significantly higher probability to have more lung cancer (38 vs 9;p < 0.0006), kidney cancer (23 vs 5;p < 0.0005), liver cancer (13 vs 3;p < 0.02) and larynx cancer (14 vs 4;p < 0.03). Interestingly, to belong to H-branch resulted significantly associated with a higher probability of lung cancer (OR 4.5; 2.15-9.38 95%C.I.), liver cancer (OR: 4.02; 1.14-14.15 95% C.I.) and larynx cancer (OR:3.4; 1.12-10.39 95%C.I.) independently from Gender and Age. CONCLUSIONS: Members belonging to the H-branch of families of patients eligible to BRCA test have a higher risk of tumors in lung, larynx and liver. Clinicians should consider the increased risk for these cancers to activate prevention/early diagnosis practices in members of families with breast/ovarian familial cancer syndrome.

Expression of base excision repair key factors and miR17 in familial and sporadic breast cancer.

Understanding of BRCA1/2 interaction with the base excision repair (BER) pathway could improve therapy based on 'synthetic lethality', whose effectiveness is based on homologous recombination deficiency in cells lacking functional BRCA genes. However, poly (ADP-ribose) polymerase (PARP) inhibitors failed in some patients and for this reason we explored BER key enzyme expression. In this study, the expression of BER enzymes (redox factor 1/apurinic-apyrimidinic endonuclease 1 (REF1/APEX1), NTH endonuclease III-like 1 (NTHL1), 8-oxoguanine DNA glycosylase (OGG1), PARP1) and of the scaffold protein XRCC1 (X-ray repair complementing defective repair in Chinese hamster cells 1) were investigated in familial (BRCA-related and not) and sporadic breast cancer cases. Furthermore, miR17 expression was measured because of its role in the epigenetic regulation of BRCA1. Gene expression was evaluated in BRCA1-mutated cell lines, SUM149PT and SUM1315MO2, and in a BRCA1-proficient triple-negative MDA-MB-231 cell line. A cohort of 27 familial and 16 sporadic breast cancer patients was then examined to confirm results obtained from the cell line model. APEX1/REF1 was found to be upregulated in familial BRCA-wild-type and sporadic cases, indicating this enzyme as a potential therapeutic target. Furthermore, XRCC1 was overexpressed in BRCAX patients; consequently, we suggest to test the effectiveness of inhibitors targeting two different BER components in preclinical studies. XRCC1, which is also involved in the non-homologous end-joining pathway, was found to be downregulated in BRCA2-related patients concurrently with no change in PARP1 expression. Interestingly, no difference in PARP1 and miR17 expression was found in BRCA-related and sporadic breast cancer cases. PARP1 and miR17 could therefore be further investigated as molecular biomarkers of 'BRCAness' phenotype, indicating patients which could really benefit from PARP inhibitor therapies.

BRCAness: a deeper insight into basal-like breast tumors.

The molecular scenario of breast cancer has become more complex in the last few years. Distinguishing between BRCA-associated, sporadic, HER2-enriched and triple-negative tumors is not sufficient to allow effective clinical management. Basal-like breast cancer, a subtype of triple-negative breast cancer, differs from others grouped under this heading. Commonalities between BRCA-related tumors and basal-like breast cancers (BRCAness phenotype) are highly relevant to ongoing clinical trials, in particular those investigating targeted therapies (e.g. PARP inhibitors) in sporadic breast tumors. The 'gold standard' to identify basal-like phenotype is DNA microarray, but integrated results could provide a panel of biomarkers helpful in identifying 'BRCAness' tumors (e.g. copy number aberrations, abnormal protein localization and altered transcriptional levels) and other molecular targets, such as APE1,the inhibition of which is emerging as an attractive breast cancer treatment in certain therapeutic settings.

Oral vinorelbine plus capecitabine (oral vincap) combination in patients with advanced breast cancer (ABC). A phase II study of the GOIM (Gruppo Oncologico dell'Italia Meridionale).

BACKGROUND: Vinorelbine i.v. and capecitabine are two of the most effective single agents in previously treated advanced breast cancer (ABC). A number of studies have been reported with the combination of these agents. Actually, the availability of oral formulation for vinorelbine allows a full oral combination of the two agents. The aim of this study was to evaluate the activity and toxicity of this novel combination. PATIENTS AND METHODS: Thirty-eight advanced breast cancer patients refractory to anthracyclines and taxanes were included in this study. Treatment consisted of vinorelbine 60 mg/m(2) (days 1 + 8), and capecitabine 2000 mg/m(2) (days 2-7 and 9-16) every 3 weeks. RESULTS: A total of 228 courses were given with a mean of three cycles/patient (range 1-12). Five patients (13.1%) had no toxicity at all. Hematologic side-effects were: neutropenia grade 2-3 in seven patients (18.9%) and grade 4 in one patient (2.7%), anemia grade 1 in 11 patients (29.7%), grade 2-3 in five patients (13.5%), thrombocytopenia grade 1 in six patients (16.2%) and grade 3 in one patient (2.7%). Non-hematologic side-effects were: fatigue grade 1 in five patients (13.5%), hand-foot syndrome grade 1 in two patients (5.4%) and grade 2 in two patients (5.4%), nausea/vomiting grade 1 in two patients (5.4%), grade 2 in three patients (8.1%) and grade 3 in one patient (2.7%), constipation grade 1 in two patients (5.4%), peripheral neurotoxicity grade 1 in three patients (8.1%) and grade 2 in one patient (2.7%), gastric pain grade 1 in two patients (5.4%), stomatitis grade 1 in three patients (8.1%) and grade 2 in one patient (2.7%). Out of 38 patients assessable, we observed two (5.4%) CR, 13 (34 %) PR, 14 (37.8%) SD and nine (26.3%) PD. The median time to progression was 4.5 months (range 1-18 months), the median response duration was 7 months (range 2-18 months) and the median survival duration was 10 months (range 2-26+). CONCLUSIONS: The oral vincap should be considered as an alternative to single agent capecitabine or vinorelbine in ABC refractory to antra-taxane combination.

Phase I/II study of gemcitabine plus mitoxantrone as salvage chemotherapy in metastatic breast cancer.

The purpose of this study was to determine the maximum-tolerated dose of gemcitabine plus mitoxantrone in women with metastatic breast cancer (MBC) and to evaluate activity and toxicity of this combination in a phase II trial. Sixty-three patients with MBC, previously treated with chemotherapy including anthracycline and/or taxanes, were treated with mitoxantrone 10 or 12 mg m(-2) intravenously on day 1 plus gemcitabine in escalating doses from 600 to 1200 mg m(-2) intravenously on days 1 and 8, every 3 weeks. In phase I, on 23 patients entered on study, dose-limiting toxicity occurred at the dosage of 1200 mg m(-2) gemcitabine and 10 mg m(-2) mitoxantrone, with three out of five patients developing grade 4 neutropenia. In phase II, with gemcitabine administered at 1000 mg m(-2) and mitoxantrone at 10 mg m(-2), 12 (30%) out of 40 assessable patients responded, even if no complete response was obtained. Moreover, stable disease was observed in eight (20%) patients. The median time to treatment failure was 22 weeks (range, 2-33), and median survival was 42 weeks (range, 2-92). Grade 3 and 4 neutropenia were observed in 12 (30%) and one (2.5%) cases respectively; grade 3 thrombocytopenia was observed in two patients (5%), grade 2 mucositis in two patients (5%), grade 3 anaemia in two patients (5%), grade 3 alopecia in one patient (2.5%) and asymptomatic cardiotoxicity in three patients (8%), respectively. In conclusion, the doses of 10 mg m(-2) (day 1) for mitoxantrone and 1000 mg m(-2) for gemcitabine (days 1-8) every 3 weeks resulted active and safe in MBC. Further investigations in less heavily pretreated patients are warranted.

Phase I/II study of paclitaxel, gemcitabine and vinorelbine as first-line chemotherapy of non-small-cell lung cancer.

BACKGROUND: The aim of our study was to determine the maximum tolerated dose of paclitaxel combined with a fixed dose of gemcitabine and vinorelbine in the treatment of non-small-cell lung cancer (NSCLC) and to evaluate in a phase II trial the efficacy of this combination. PATIENTS AND METHODS: Sixty-two patients with stage IIIB/IV NSCLC were treated with paclitaxel in escalating doses from 40-80 mg/m(2) combined with gemcitabine and vinorelbine at fixed doses of 1000 mg/m(2) and 25 mg/m(2), respectively. All drugs were given intravenously on day 1 and 8 every 3 weeks. RESULTS: In a phase I trial, carried out on 21 patients, grade 4 neutropenia, as dose-limiting toxicity, occurred at the dosage level of paclitaxel 80 mg/m(2). In a phase II trial, with paclitaxel administered at 70 mg/m(2), 27 out of 41 (66%) assessable patients responded (10% complete responses and 56% partial responses). Objective response was observed in 13 of 16 patients (81%) with stage IIIB disease and in 14 of 25 (56%) with stage IV disease. The median time to treatment failure was 26 weeks (range 3-72 weeks; 32 weeks and 20 weeks for stages IIIB and IV, respectively) and median survival 62 weeks (range 4-176 weeks; 72 weeks and 56 weeks for stages IIIB and IV, respectively). One-year survival was 64% for all patients (72% for patients with stage IIIB and 52% for those with stage IV). Grade 3 and 4 neutropenia were observed in 11 (27%) and seven (17%) cases, respectively; grade 3 thrombocytopenia was observed in three patients (7%) and grade 3 anemia in four patients (10%). The most relevant non-hematological toxicity was grade 2/3 asthenia, which was observed in 12 patients (29%). Alopecia was almost universal, whereas nausea and vomiting were absent. CONCLUSIONS: The combination of paclitaxel, gemcitabine and vinorelbine is effective and tolerable in the treatment of NSCLC. The high activity and low toxicity of this regimen warrant randomized studies with platinum-containing combinations.

Epithelial ovarian cancer: second and third line chemotherapy (review).

Standard therapy for patients affected with advanced epithelial ovarian cancer is cytoreductive surgery followed by combination chemotherapy. With this treatment, most patients obtain clinical complete or partial response, nevertheless, relapse is common and salvage chemotherapy is often needed. The probability of response to second line chemotherapy following platinum-based treatments is usually related to the platinum-free interval, even if recent studies have reported some other clinical features as having prognostic value, such as tumour burden and histology. Salvage monochemotherapy is generally used, but when the platinum-free interval is longer than 24 months, re-treatment with platinum compounds and/or taxanes is indicated. Moreover, a number of new agents with demonstrated activity in ovarian cancer are currently available. Sequentially used in recurrent disease, these agents may improve survival and/or quality of life. Among these new drugs, the most promising are: topotecan, doxil, gemcitabine and platinum analogues such as oxaliplatin, nedaplatin, satraplatin, BBR3464 and ZD0473. However, the real aim of salvage chemotherapy in relapsed ovarian cancer still remains palliative care, because complete responses are very rarely reported and long lasting responses are very seldom observed.

Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study.

A potential way to improve the results obtained with the standard carboplatin/cisplatin (CDDP)-paclitaxel treatment regimen in advanced ovarian cancer is to incorporate a modulating agent such as lonidamine (LND). In fact, LND has been shown to revert the resistance to cisplatin and to potentiate cisplatin activity experimental models and in clinical studies. 35 consecutive patients with advanced ovarian cancer, not previously treated with chemotherapy were treated with paclitaxel at a dose of 135 mg/m(2) intravenously (i.v.) on day 1 (in a 3 h infusion) and cisplatin at a dose of 75 mg/m(2) iv on day 2 plus LND orally (p.o.) at a dose of 450 mg/die for 6 consecutive days starting two days before chemotherapy, every 3 weeks for six cycles. Complete plus partial responses were observed in 8 (80%) out of the 10 women with measurable disease. In the 25 patients with evaluable disease, only four clinical progressions were observed (16%). Median progression-free survival (PFS) and overall survival (OS) were 28.5 (95% confidence interval (CI) 22.2-34.8) and 46.5 (95% CI 32.4-60.00) months respectively. Grade 3-4 neutropenia was observed in 9 (26%) patients. Alopecia, nausea and vomiting (Grade 3) were observed in 33 (94%) and 5 (14%) patients, respectively. In conclusion, the combination of CDDP/paclitaxel plus LND is active and tolerable in the treatment of advanced ovarian cancer.

New aromatase inhibitors in the treatment of advanced breast cancer.

New aromatase inhibitors are an exciting treatment option for postmenopausal women with hormone sensitive breast cancer. They have been shown to reduce tumors in a significant number of patients, and exhibit definite antitumor activity at a relatively low daily dose, and are highly potent, highly selective, and well-tolerated. Results from recent clinical phase III studies have confirmed their efficacy and the key role they have in the therapy for advanced breast cancer in postmenopausal women. The agents available for clinical use are: letrozole, anastrozole, and exemestane. These drugs have demonstrated high activity in women failing tamoxifen in locally advanced or metastatic disease. This communication reviews the clinical use of aromatase inhibitors, particularly in second and first line hormonal treatment of advanced breast cancer.