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Background: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy., Methods: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher., Results: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease., Conclusions: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

Background: Adjuvant! is a web-based program that calculates individualised 10-year survival probabilities and predicted benefit of adjuvant systemic therapy. The Adjuvant! model has not been validated in any large European series. The aim of our study was to validate Adjuvant! in Dutch patients, investigating both its calibration and discriminatory accuracy., Methods: Patients who were at least partly treated at the Netherlands Cancer Institute for breast cancer between 1987 and 1998 were included if they met the following criteria: tumour size T1 (< or =2 cm), T2 (2-5 cm), or T3 (>5 cm), invasive breast carcinoma, with information about involvement of axillary lymph nodes available, no distant metastases, primary surgery, axillary staging, and radiotherapy according to national guidelines. Clinicopathological characteristics and adjuvant treatment data were retrieved from hospital records and medical registries and were entered into the Adjuvant! (version 8.0) batch processor with blinding to outcome. Endpoints were overall survival and the proportion of patients that did not die from breast cancer (breast-cancer-specific survival [BCSS])., Findings: 5380 patients were included with median follow-up of 11.7 years (range 0.03-21.8). The 10-year observed overall survival (69.0%) and BCSS (78.6%) and Adjuvant! predicted overall survival (69.1%) and BCSS (77.8%) were not statistically different (p=0.87 and p=0.18, respectively). Moreover, differences between predicted and observed outcomes were within 2% for most relevant clinicopathological subgroups. In patients younger than 40 years, Adjuvant! overestimated overall survival by 4.2% (p=0.04) and BCSS by 4.7% (p=0.01). The concordance index, which indicates discriminatory accuracy at the individual level, was 0.71 for BCSS in the entire cohort., Interpretation: Adjuvant! accurately predicted 10-year outcomes in this large-scale Dutch validation study and is of use for adjuvant treatment decision making, although the results may be less reliable in some subgroups.

Background: Decision aids are tools that help patients make specific and deliberative choices among options. This study was a group randomized controlled trial of a novel decision aid to help patients with breast cancer make adjuvant therapy (AT) decisions., Methods: Fourteen oncology practices (n=58 physicians) were randomized to receive the decision aid or a control pamphlet. Complete data were obtained from 405 patient-oncologist pairs. Eligible patients had stage I-III disease and had completed their primary treatment. The decision aid is a simple to use computer program, titled Adjuvant!, that provides estimates of outcome with and without AT. Graphical representations of outcome are shared with patients. Consultations were audiotaped, patients interviewed, and physicians completed a self-administered survey., Results: In a multivariable model, the 54 patients (13.3%) who took no AT were more likely to have received the decision aid (p=0.02). A differential effect of the Adjuvant! Decision Guide was noted between node negative and positive patients. It was stated by 86.2% of patients that the decision aid was influential when making their treatment decision. Over 95% of patients reported that the Adjuvant Decision Guide was easy to understand and 75% of physicians believed that it helped them understand their patient's treatment preferences and 81.4% reported the information as useful for themselves., Conclusions: This study showed that a decision aid made a difference in the choice of whether or not to take AT. The decision aid allowed patients and physicians to consider the benefits of AT in an easy to understand format. Treatment decisions were more individualized for patients in the intervention than in the control group. The use of the decision aid was acceptable to both patients and physicians.

Objective: Oncology patients often seek involvement in their medical consultations. Such involvement is endorsed by most health care providers and mirrored in practice guidelines. However, oncologists exhibit great variation in how they provide patients with disease-relevant information, and many remain reluctant to do so at all. The authors examined the impact of a patient-specific decision aid on women's decisions about adjuvant therapy for breast cancer., Method: 386 women with breast cancer were randomized to receive either an informational pamphlet about adjuvant therapy (usual care) or a patient-specific, evidence-based decision aid about adjuvant therapy. The authors compared rates of adjuvant therapy between the groups controlling for age, education, marital status, race, tumor severity, and practice type of their physician (university-based or community-based)., Results: Among women with low tumor severity, only 58% (35/60) of women in the decision aid group chose adjuvant therapy, compared to 87% (33/38) of their counterparts in usual care (P<0.01)., Conclusions: This study illustrates the important impact of medical decision aids on treatment choices, particularly for patients for whom treatment has little benefit. In the case of adjuvant therapy for breast cancer, providing individualized, evidence-based risk information for shared decision making resulted in fewer women with low tumor severity choosing adjuvant treatment.

Estrogen is known to play an important role in skeletal health. Female breast cancer patients who receive treatments that reduce estrogen levels, such as aromatase inhibitors, may increase their risk of developing osteoporosis and their risk of fracture. Clinical guidelines enable the physician to assess the risk of osteoporosis by patient history and physical examination. For patients identified as being at risk, it is necessary to test bone mineral density (BMD), using the result to determine which patients require treatment. Two groups can be identified as requiring BMD assessment according to general guidelines: patients < 45 years old who become menopausal due to treatment, and breast cancer patients receiving aromatase inhibitors. Bisphosphonates appear to be the logical treatment of choice for breast cancer patients, as they do not interact with the estrogen receptor. Although not all women receiving aromatase inhibitors will require additional treatment for bone health, postmenopausal women with a history of breast cancer at risk of osteoporosis should be identified, monitored, and managed according to practice guidelines.

The human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization, are presented and contrasted in detail against the background of the published American Society of Clinical Oncology--College of American Pathologists guidelines for HER-2 testing. Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER-2 testing, are also discussed. Emerging novel HER-2 testing techniques, including mRNA-based testing by real-time polymerase chain reaction and DNA microarray methods, HER-2 receptor dimerization, phosphorylated HER-2 receptors, and HER-2 status in circulating tumor cells, are also considered. A series of biomarkers potentially associated with resistance to trastuzumab is discussed with emphasis on the phosphatase and tensin homologue deleted on chromosome ten/Akt and insulin-like growth factor receptor pathways. The efficacy results for the more recently approved small molecule HER- 1/HER-2 kinase inhibitor lapatinib are also presented along with a more limited review of markers of resistance for this agent. Additional topics in this section include combinations of both anti-HER-2 targeted therapies together as well as with novel agents including bevacizumab, everolimus, and tenespimycin. A series of novel HER-2-targeting agents is also presented, including pertuzumab, ertumaxomab, HER-2 vaccines, and recently discovered tyrosine kinase inhibitors. Biomarkers predictive of HER-2 targeted therapy toxicity are included, and the review concludes with a consideration of HER-2 status in the prediction of response to non-HER-2 targeted treatments including hormonal therapy, anthracyclines, and taxanes. [ABSTRACT FROM AUTHOR]

The article focuses on a parallel, randomised trial which assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy in postmenopausal women with endocrine-responsive, node-positive breast cancer. The patients used in the study were randomly assigned by a computer algorithm. An analysis by intention was also conducted to treat eligible patients. Findings revealed the effectiveness of chemotherapy with cyclophosphamide, doxorubicin and fluorouracil (CAF) plus tamoxifen given sequentially than adjuvant therapy.

Abstract: Background: The MINDACT (Microarray In Node-negative and 1–3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included. Methods: MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen→letrozole are offered. Results: During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7–11.8%; P <.0001). Compliance with the treatment decision was high (>92%). Conclusions: The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses. [Copyright &y& Elsevier]