https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)17947-1.pdf

Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer.

Purpose The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor‐positive, lymph node‐negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. Methods The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy‐ treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. Results A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P .038). Patients with high-RS ( 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS ( 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, 1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit.

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2005.04.7985

Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor–Positive Breast Cancer

Breast cancer starts as a local disease, but it can metastasize to the lymph nodes and distant organs. At primary diagnosis, prognostic markers are used to assess whether the transition to systemic disease is likely to have occurred. The prevailing model of metastasis reflects this view--it suggests that metastatic capacity is a late, acquired event in tumorigenesis. Others have proposed the idea that breast cancer is intrinsically a systemic disease. New molecular technologies, such as DNA microarrays, support the idea that metastatic capacity might be an inherent feature of breast tumours. These data have important implications for prognosis prediction and our understanding of metastasis.

Breast cancer metastasis: markers and models

Background: Histologic grade in breast cancer provides clinically important prognostic information. However, 30% – 60% of tumors are classifi ed as histologic grade 2. This grade is associated with an intermediate risk of recurrence and is thus not informative for clinical decision making. We examined whether histologic grade was associated with gene expression profi les of breast cancers and whether such profi les could be used to improve histologic grading. Methods: We analyzed microarray data from 189 invasive breast carcinomas and from three published gene expression datasets from breast carcinomas. We identifi ed differentially expressed genes in a training set of 64 estrogen receptor (ER) – positive tumor samples by comparing expression profi les between histologic grade 3 tumors and histologic grade 1 tumors and used the expression of these genes to defi ne the gene expression grade index. Data from 597 independent tumors were used to evaluate the association between relapse-free survival and the gene expression grade index in a Kaplan – Meier analysis. All statistical tests were two-sided. Results: We identifi ed 97 genes in our training set that were associated with histologic grade; most of these genes were involved in cell cycle regulation and proliferation. In validation datasets, the gene expression grade index was strongly associated with histologic grade 1 and 3 status; however, among histologic grade 2 tumors, the index spanned the values for histologic grade 1 – 3 tumors. Among patients with histologic grade 2 tumors, a high gene expression grade index was associated with a higher risk of recurrence than a low gene expression grade index (hazard ratio = 3.61, 95% confi dence interval = 2.25 to 5.78; P <.001, log-rank test). Conclusions: Gene expression grade index appeared to reclassify patients with histologic grade 2 tumors into two groups with high versus low risks of recurrence. This approach may improve the accuracy of tumor grading and thus its prognostic value. [J Natl Cancer Inst 2006;98:262 – 72]

/pdf/gene-expression-profiling-in-breast-cancer-understanding-the-1izy54qkcj.pdf

Gene Expression Profiling in Breast Cancer: Understanding the Molecular Basis of Histologic Grade To Improve Prognosis

Advances in genomics, proteomics and molecular pathology have generated many candidate biomarkers with potential clinical value. Their use for cancer staging and personalization of therapy at the time of diagnosis could improve patient care. However, translation from bench to bedside outside of the research setting has proved more difficult than might have been expected. Understanding how and when biomarkers can be integrated into clinical care is crucial if we want to translate the promise into reality.

Biomarkers in cancer staging, prognosis and treatment selection.

Although distinct pathological stages of breast cancer have been described, the molecular differences among these stages are largely unknown. Here, through the combined use of laser capture microdissection and DNA microarrays, we have generated in situ gene expression profiles of the premalignant, preinvasive, and invasive stages of human breast cancer. Our data reveal extensive similarities at the transcriptome level among the distinct stages of progression and suggest that gene expression alterations conferring the potential for invasive growth are already present in the preinvasive stages. In contrast to tumor stage, different tumor grades are associated with distinct gene expression signatures. Furthermore, a subset of genes associated with high tumor grade is quantitatively correlated with the transition from preinvasive to invasive growth.

https://www.pnas.org/content/pnas/100/10/5974.full.pdf

Jessica Kessler

Papers

Gene expression profiles of human breast cancer progression