Abstract Retinoids have been studied as chemopreventive compounds because of their role in regulating cell growth, differentiation and apoptosis in preclinical models. Induction of apoptosis is a unique feature of fenretinide (4-hydroxyphenylretinamide, 4-HPR) the most studied retinoid in clinical trials of breast cancer (BC) prevention for its selective accumulation in the breast tissue and its low toxicity. Fenretinide is effective in inhibiting the growth of BRCA1 mutated BC cell lines. Recent studies showed that it modulates gene expression in ovarian cells, with an up-regulation of expression of proapoptotic genes in OVCA433 cells. The fifteen-year follow up of a randomized phase III trial of fenretinide to prevent second BC indicates that it induced a 17% reduction of second BC incidence. More importantly, when stratified by menopausal status, the analysis showed a 38%, statistically significant reduction of second BC in premenopausal women and this effect persisted for up to 15 years. Interestingly, the younger were the women (≤ 40 years), the greater was the trend of benefit by fenretinide. When considering the protective activity of fenretinide on second BC and a similar trend on ovarian cancer (OC) it appears that young women at high risk for both diseases such as carriers of germline BRCA1 and BRCA2 mutations or those with a high family risk may be ideal candidates for further investigation on this retinoid. Since a reduction of second BC might be a surrogate marker of primary prevention, a favorable effect of fenretinide provides strong rationale for a primary prevention trial in unaffected women at high-risk for BC. The European Institute of Oncology (IEO, Milan, Italy) has promoted a multi-centric (15 centres nationwide), randomized phase III placebo-controlled study with fenretinide in healthy young women: 758 healthy women, 25-44 years old, at increased BC risk (BRCA1/2 mutation carriers or subjects with mutation probability ≥20% acc. to BRCAPRO), will be randomized to 4-HPR 200 mg/day vs placebo for 5 years followed by a 10 years follow up period. We will perform a clinical examination every 6 months, and annual breast ultrasound and breast MRI. For subjects ≥ 35 years old also an annual mammography is requested. All subjects will undergo a transvaginal ultrasound at least once a year. At each visit, safety tests (β-HCG, AST, ALT, blood count, creatinine, glycemia, lipid profile, CA-125), and blood samples for biomarkers evaluation at baseline, 12, 36, and 60 months. Enrollment started at the IEO in December 2009. The other centers are expected to start within early 2011. The primary endpoint of the trial is to assess the efficacy of fenretinide in reducing the incidence of invasive BC and ductal intraepithelial neoplasia (DIN). Secondary endpoints are the incidence of non-invasive breast disorders, OC, other cancers and the study of various risk biomarkers. In particular, we will evaluate the change in circulating biomarkers of the IGF system, androgens, retinol binding protein (RBP-4), insulin, blood glucose and VEGF. Genotyping of single nucleotide polymorphisms (SNPs) linked to BC risk (MTHFR, COMT, GH, IGFBP-3, AR, TGF-β genes), degree of methylation of RASSAF1 and RARβ and circulating progranulin will be assessed. The results will be correlated with mammographic instrumental measurements, plasma and tissue biomarkers after 1 year treatment. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A71.
The prognostic role of the site of the primary breast cancer has not been clarified. This study aimed to gather more information about this issue from a large series of patients with long-term follow-up data.Data from 2,396 patients treated for early breast cancer with a conservative approach were reviewed (1973 to 1989). In 1,619 patients, the tumor had a lateral site, while in 777 cases, it was situated in the internal/central quadrants. The characteristics of the two groups were well balanced, apart from axillary nodal metastases, which were more frequent for lateral tumors (38.1% v 26.3%).Analysis of distant metastases indicated that the regression coefficient associated with tumor site was significant and the hazards ratio estimate was 1.291, which indicates the risk of distant metastases was increased by approximately 30% for internal/central tumors. The analysis of overall survival yielded a significant coefficient and a hazards ratio of 1.192, which indicates an approximately 20% increase of mortality for internal/central tumors.Early breast cancers situated in central/ internal quadrants have a worse prognosis compared with those in lateral quadrants, in terms of distant metastases and survival. Irradiation of the internal mammary chain for internal/medial tumors could be suggested, but, to date, the therapeutic strategy is still controversial.
Abstract Purpose: In a continuous effort to seek for anticancer treatments with minimal side effects, we aim at proving the feasibility of the Intraoperative Avidination for Radionuclide Therapy, a new procedure for partial breast irradiation. Experimental Design: To assess doses of 90Y-DOTA-biotin to target (i.e., breast tumor bed) and nontarget organs, we did simulation studies with 111In-DOTA-biotin in 10 candidates for conservative breast surgery. Immediately after quadrantectomy, patients were injected with 100-mg avidin in the tumor bed. On the following day, patients were given 111In-DOTA-biotin (∼111 MBq) i.v. after appropriate chase of biotinylated albumin (20 mg) to remove circulating avidin. Biokinetic studies were done by measuring radioactivity in scheduled blood samples, 48-h urine collection, and through scintigraphic images. The medical internal radiation dose formalism (OLINDA code) enabled dosimetry assessment in target and nontarget organs. Results: Images showed early and long-lasting radioactive biotin uptake in the operated breast. Rapid blood clearance (<1% at 12 h) and urine excretion (>75% at 24 h) were observed. Absorbed doses, expressed as mean ± SD in Gy/GBq, were as low as 0.15 ± 0.05 in lungs, 0.10 ± 0.02 in heart, 0.06 ± 0.02 in red marrow, 1.30 ± 0.50 in kidneys, 1.50 ± 0.30 in urinary bladder, and 0.06 ± 0.02 in total body, whereas in the targeted area, they increased to 5.5 ± 1.1 Gy/GBq (50% ISOROI) and 4.8 ± 1.0 Gy/GBq (30% ISOROI). Conclusion: Our preliminary results suggest that Intraoperative Avidination for Radionuclide Therapy is a simple and feasible procedure that may improve breast cancer patients' postsurgical management by shortening radiotherapy duration.
Local recurrences after breast-conserving surgery occur mostly in the quadrant harbouring primary carcinoma. The main objective of postoperative radiotherapy should be the sterilisation of residual cancer cells in the operative area while irradiation of the whole breast may be avoided. We have developed a new technique of intraoperative radiotherapy of a breast quadrant after the removal of the primary carcinoma (ELIOT). A mobile linear accelerator with a robotic arm is utilised delivering electron beams able to produce energies from 3 to 9 MeV. Different dose levels were tested from 10 to 21 Gy without important side effects. A randomized trial is currently ongoing in order to compare conventional irradiation and ELIOT. More than 400 patients have been enrolled. In addition a new approach for nipple and areola complex conservation, including ELIOT, is under investigation.
