We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an ...independent more diverse population of LNN patients from multiple institutions.
Using custom-designed DNA chips we analyzed the expression of the 76 genes in RNA of frozen tumor samples from 180 LNN patients who did not receive adjuvant systemic treatment.
In this independent validation, the 76-gene signature was highly informative in identifying patients with distant metastasis within 5 years (hazard ratio, HR, 7.41; 95% CI, 2.63 to 20.9), even when corrected for traditional prognostic factors in multivariate analysis (HR, 11.36; 95% CI, 2.67 to 48.4). The actuarial 5- and 10-year distant metastasis-free survival were 96% (95% CI, 89% to 99%) and 94% (95% CI, 83% to 98%), respectively, for the good profile group and 74% (95% CI, 64% to 81%) and 65% (53% to 74%), respectively for the poor profile group. The sensitivity for 5-yr distant metastasis-free survival was 90%, and the specificity was 50%. The positive and negative predictive values were 38% (95% CI, 29% to 47%) and 94% (95% CI, 86% to 97%), respectively. The 76-gene signature was confirmed as a strong prognostic factor in subgroups of estrogen receptor-positive patients, pre- and postmenopausal patients, and patients with tumor sizes 20 mm or smaller. The subgroup of patients with estrogen receptor-negative tumors was considered too small to perform a separate analysis.
Our data provide a strong methodologic and clinical multicenter validation of the predefined prognostic 76-gene signature in LNN breast cancer patients.
In encyclopaedic dictionaries published until 1955, the word "tumour" was defined as an "occupational disease suffered by the workers of chemical industries", thus referring to a very specific cause .......
Purpose: In an effort to additionally determine the global patterns of CpG island hypermethylation in sporadic breast cancer, we searched
for aberrant promoter methylation at 10 gene loci in 54 ...primary breast cancer and 10 breast benign lesions.
Experimental Design: Genomic DNA sodium bisulfate converted from benign and malignant tissues was used as template in methyl-specific PCR for
BRCA1 , p16 , ESR1 , GSTP1 , TR β 1 , RAR β 2 , HIC1 , APC , CCND2 , and CDH1 genes.
Results: The majority of the breast cancer (85%) showed aberrant methylation in at least 1 of the loci tested with half of them displaying
3 or more methylated genes. The highest frequency of aberrant promoter methylation was found for HIC1 (48%) followed by ESR1 (46%), and CDH1 (39%). Similar methylation frequencies were detected for breast benign lesions with the exception of the CDH1 gene ( P = 0.02). The analysis of methylation distribution indicates a statistically significant association between methylation of
the ESR1 promoter, and methylation at CDH1 , TR β 1 , GSTP1 , and CCND2 loci ( P < 0.03). Methylated status of the BRCA1 promoter was inversely correlated with methylation at the RAR β 2 locus ( P < 0.03).
Conclusions: Our results suggest a nonrandom distribution for promoter hypermethylation in sporadic breast cancer, with tumor subsets
characterized by aberrant methylation of specific cancer-related genes. These breast cancer subgroups may represent separate
biological entities with potential differences in sensitivity to therapy, occurrence of metastasis, and overall prognosis.
Abstract Cytotoxic chemotherapy may variably affect ovarian function depending on age and ovarian reserve at diagnosis, type of chemotherapy and use of tamoxifen. Ascertaining whether a premenopausal ...patient with endocrine-responsive early breast cancer and chemotherapy-induced amenorrhea has reached menopause is essential not only in order to provide accurate information on residual fertility, but also to appropriately prescribe endocrine therapy. Indeed, aromatase inhibitors are contraindicated in women with residual ovarian reserve. However, the diagnosis of menopause in patients with chemotherapy-induced amenorrhea is challenging, since clinical features, follicle-stimulating hormone and estradiol levels may be inaccurate to this aim. Recent studies demonstrated that the anti-müllerian hormone may improve the assessment of ovarian reserve residual to chemotherapy in women with early breast cancer. Herein, we review the incidence of amenorrhea and menopause induced by cytotoxic chemotherapy in women affected by early breast cancer and the suggested mechanisms that sustain these side-effects. Furthermore, it has been scrutinized the potential of new markers of ovarian reserve that may facilitate the selection of appropriate endocrine treatment for premenopausal women who develop amenorrhea following adjuvant chemotherapy for early breast cancer.
We analyzed the clinical relevance of HER-2 expression, widely investigated in breast cancer but with contradictory results, in the largest case series of node-negative breast cancer patients ...investigated to date.
The pure prognostic value of HER-2 expression was investigated in 529 patients treated with locoregional therapy alone until early relapse. Proliferative activity was evaluated as 3Hthymidine labeling index and HER-2 expression by immunohistochemistry. All biologic determinations were conducted within the context of an intra- and interlaboratory National Quality Control Program.
HER-2 expression was not related to relapse-free survival in the overall series but was a significant discriminant of prognosis in the subgroup of patients with rapidly proliferating tumors. Six-year rate of relapse was 40% for patients with highly (> or =30%) positive tumors and 26% for those with weakly HER-2-expressing tumors (P =.039).
HER-2 expression in association with proliferative activity identifies a subgroup of node-negative breast cancer patients with the worst prognosis, who are candidates for specific intensive adjuvant therapy.
The prospective applicability of new biologic tumor information to personalize adjuvant treatment of women with operable breast cancer remains to be demonstrated. The aim of the present study was to ...investigate whether patients with fast-proliferating, node-negative breast cancer could benefit from adjuvant chemotherapy with fluorouracil, epirubicin, and cyclophosphamide (FEC).
Beginning in November 1989, we analyzed the proliferative activity of primary tumors in a consecutive series of women with node-negative breast cancer to identify subgroups of patients with a worse prognosis and who were therefore suitable candidates for adjuvant systemic therapy. Proliferative activity was determined by means of the 3H-thymidine incorporation assay using an autoradiographic technique. Women with fast-proliferating breast cancer (3H-thymidine labeling index, > 2.3%) were randomized to receive either six cycles of adjuvant FEC or no adjuvant therapy until disease progression.
One-hundred twenty-five and 123 patients treated with radical surgery for pT1 to T2, N0, M0 breast cancer were randomized to the FEC and control arms, respectively. After a median follow-up of 70 months, 27 events (21.6%) were observed in the FEC arm and 39 (32.2%) in the control arm, with a significantly lower number of locoregional relapses in the FEC group. Five-year disease-free survival (DFS) was 81% in the FEC group and 69% in the control group (P <.02 by log-rank test). Cox multivariate analysis described the impact of adjuvant therapy with FEC on DFS as independent of the patients' main clinical-pathologic characteristics.
FEC adjuvant polychemotherapy seems able to significantly improve the clinical outcome of patients with fast-proliferating, node-negative breast cancer.
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