Identifying research priorities in the treatment of patients with early breast cancer: from the patient perspective.

In identifying research priorities it is important to take the needs and prospective of patients with breast cancer into account.

Assessment of the prognostic and predictive utility of the Breast Cancer Index (BCI): an NCIC CTG MA.14 study.

BACKGROUND: Biomarkers that can be used to accurately assess the residual risk of disease recurrence in women with hormone receptor-positive breast cancer are clinically valuable. We evaluated the prognostic value of the Breast Cancer Index (BCI), a continuous risk index based on a combination of HOXB13:IL17BR and molecular grade index, in women with early breast cancer treated with either tamoxifen alone or tamoxifen plus octreotide in the NCIC MA.14 phase III clinical trial (ClinicalTrials.gov Identifier NCT00002864; registered 1 November 1999). METHODS: Gene expression analysis of BCI by real-time polymerase chain reaction was performed blinded to outcome on RNA extracted from archived formalin-fixed, paraffin-embedded tumor samples of 299 patients with both lymph node-negative (LN-) and lymph node-positive (LN+) disease enrolled in the MA.14 trial. Our primary objective was to determine the prognostic performance of BCI based on relapse-free survival (RFS). MA.14 patients experienced similar RFS on both treatment arms. Association of gene expression data with RFS was evaluated in univariate analysis with a stratified log-rank test statistic, depicted with a Kaplan-Meier plot and an adjusted Cox survivor plot. In the multivariate assessment, we used stratified Cox regression. The prognostic performance of an emerging, optimized linear BCI model was also assessed in a post hoc analysis. RESULTS: Of 299 samples, 292 were assessed successfully for BCI for 146 patients accrued in each MA.14 treatment arm. BCI risk groups had a significant univariate association with RFS (stratified log-rank p = 0.005, unstratified log-rank p = 0.007). Adjusted 10-year RFS in BCI low-, intermediate-, and high-risk groups was 87.5 %, 83.9 %, and 74.7 %, respectively. BCI had a significant prognostic effect [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 1.33-4.11; p = 0.004], although not a predictive effect, on RFS in stratified multivariate analysis, adjusted for pathological tumor stage (HR 2.22, 95 % CI 1.22-4.07; p = 0.01). In the post hoc multivariate analysis, higher linear BCI was associated with shorter RFS (p = 0.002). CONCLUSIONS: BCI had a strong prognostic effect on RFS in patients with early-stage breast cancer treated with tamoxifen alone or with tamoxifen and octreotide. BCI was prognostic in both LN- and LN+ patients. This retrospective study is an independent validation of the prognostic performance of BCI in a prospective trial.

Hepatitis B virus screening before adjuvant chemotherapy in patients with early-stage breast cancer: a cost-effectiveness analysis.

Most patients with hepatitis B virus (HBV) have no symptoms, and many are unaware of the infection. However, HBV can reactivate with immunosuppression; chemotherapy causes reactivation in 22 % of hepatitis B surface antigen-positive patients. HBV reactivation can be fatal. HBV reactivation can be prevented, provided that HBV is recognized prior to chemotherapy. The objective of this study is to estimate the health and economic effects of HBV screening strategies in patients receiving adjuvant chemotherapy for breast cancer. We developed a state-transition microsimulation model to examine the cost-effectiveness of three HBV screening strategies: (1) "No screening"; (2) "Screen-and-Treat to prevent reactivation" (screen-all) with either lamivudine/tenofovir (LAM/TDF) or entecavir (ETV); and (3) "Screen-and-Treat high-risk only" (screen-HR) and treat with either LAM/TDF or ETV. Model data were obtained from the published literature. We used a payer's perspective, a lifetime horizon, and a 5 % discount rate for the analysis. "Screen-all" would prevent at least 38 severe reactivations per 100,000 persons screened over the lifetime of the cohort. "Screen-all" was associated with an increase of 0.0034-0.0035 QALYs and an additional cost of C$164-C$266 per person, which translated into an incremental cost-effectiveness ratio of C$47,808/QALY-C$76,527/QALY gained compared with "No screening" depending on the antiviral therapy received. "Screen-all" was the most cost-effective strategy, while "Screen-HR" was inferior in all scenarios tested. HBV screening before adjuvant chemotherapy for breast cancer patients would prevent a significant number of reactivations, would likely be moderately cost-effective, and may extend the lives of breast cancer patients.

Assessment of osteopontin in early breast cancer: correlative study in a randomised clinical trial.

INTRODUCTION: Osteopontin (OPN) is a malignancy-associated glycoprotein that contributes functionally to tumor aggressiveness. In metastatic breast cancer, we previously demonstrated that elevated OPN in primary tumor and blood was associated with poor prognosis. METHODS: We measured OPN in plasma by ELISA, and in tumors by immunohistochemistry, in 624 (94%) and 462 (69%), respectively, of 667 postmenopausal women with hormone responsive early breast cancer treated by surgery followed by adjuvant treatment with tamoxifen +/- octreotide in a randomized trial (NCIC CTG MA.14; National Cancer Institute of Canada Clinical Trials Group Mammary.14). RESULTS: Plasma OPN was measured in 2,540 samples; 688 at baseline and 1,852 collected during follow-up. Mean baseline plasma OPN was 46 ng/ml (range 22.6 to 290) which did not differ from normal levels. Mean percentage OPN tumor cell positivity was 33.9 (95% CI: 30.2 to 37.9). There was no correlation between plasma and tumor OPN values. In multivariate analysis, neither was associated with event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), bone RFS or non-bone RFS. An exploratory analysis in patients with recurrence showed higher mean OPN plasma levels 60.7 ng/ml (23.9 to 543) in the recurrence period compared with baseline levels. CONCLUSIONS: The hypothesis that OPN tumor expression would have independent prognostic value in early breast cancer was not supported by multivariate analysis of this study population. Plasma OPN levels in women with hormone responsive early breast cancer in the MA.14 trial were not elevated and there was no evidence for prognostic value of plasma OPN in this defined group of patients. However, our finding of elevated mean OPN plasma level around the time of recurrence warrants further study. TRIAL REGISTRATION: NCT00002864, http://clinicaltrials.gov/show/NCT00002864.

Prospective study of 2-[¹8F]fluorodeoxyglucose positron emission tomography in the assessment of regional nodal spread of disease in patients with breast cancer: an Ontario clinical oncology group study.

PURPOSE: 2-[(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is potentially useful in assessing lymph nodes and detecting distant metastases in women with primary breast cancer. PATIENTS AND METHODS: Women diagnosed with operable breast cancer within 3 months underwent FDG-PET at one of five Ontario study centers followed by axillary lymph node assessment (ALNA) consisting of sentinel lymph node biopsy (SLNB) alone if sentinel lymph nodes (SLNs) were negative, SLNB with axillary lymph node dissection (ALND) if SLNB or PET was positive, or ALND alone if SLNs were not identified. RESULTS: Between January 2005 and March 2007, 325 analyzable women entered this study. Sentinel nodes were found for 312 (96%) of 325 women and were positive for tumor in 90 (29%) of 312. ALND was positive in seven additional women. Using ALNA as the gold standard, sensitivity for PET was 23.7% (95% CI, 15.9% to 33.6%), specificity was 99.6% (95% CI, 97.2% to 99.9%), positive predictive value was 95.8% (95% CI, 76.9% to 99.8%), negative predictive value was 75.4% (95% CI, 70.1% to 80.1%), and prevalence was 29.8% (95% CI, 25.0% to 35.2%). Using logistic regression, tumor size was predictive for prevalence of tumor in the axilla and for PET sensitivity. PET scan was suspicious for distant metastases in 13 patients; three (0.9%) were confirmed as metastatic disease and 10 (3.0%) were false positive. CONCLUSION: FDG-PET is not sufficiently sensitive to detect positive axillary lymph nodes, nor is it sufficiently specific to appropriately identify distant metastases. However, the very high positive predictive value (96%) suggests that PET when positive is indicative of disease in axillary nodes, which may influence surgical care.

Cost-effectiveness analysis of recurrence score-guided treatment using a 21-gene assay in early breast cancer.

PURPOSE: Most guidelines for hormone receptor (HR)-positive early breast cancer recommend addition of adjuvant chemotherapy for most women, leading to overtreatment, which causes considerable morbidity and cost. There has been recent incorporation of gene expression analysis in aiding decision making. We evaluated the cost-effectiveness of recurrence score (RS)-guided treatment using 21-gene assay as compared with treatment guided by the Adjuvant! Online program (AOL). PATIENTS AND METHODS: A Markov model was developed to compare the cost-effectiveness of treatment guided either by 21-gene assay or by AOL in a 50-year-old woman with lymph node-negative HR-positive breast cancer over a lifetime horizon. We assumed that women classified to be at high risk all received chemotherapy followed by tamoxifen and those classified to be at low risk received tamoxifen only. The model took a health care payer's perspective with results reported in 2008 Canadian dollars ($). Event rates, costs, and utilities were derived from the literature. Both costs and benefits were discounted at 5%. Outcome measures were life years gained, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs). RESULTS: For a 50-year-old woman, RS-guided treatment was associated with an incremental lifetime cost of $4,102 and a gain in 0.065 QALY, with an ICER of $63,064 per QALY compared with AOL-guided treatment. ICER increased with increasing cost of 21-gene assay and increasing age of patients. Results were most sensitive to probabilities relating to risk categorization and recurrence rate. CONCLUSIONS: The 21-gene assay appears cost-effective from a Canadian health care perspective.

Review of the clinical studies using the 21-gene assay.

PURPOSE: A major challenge in treating early-stage hormone receptor (HR)(+) breast cancer is selecting women who, after initial surgery, do not require chemotherapy. Better prognostic and predictive tests are needed. The 21-gene assay is the only widely commercially available gene signature that can be performed on formalin-fixed paraffin-embedded tissue. METHODS: We conducted a review of the literature supporting the prognostic and predictive ability of the 21-gene assay in HR(+) node-negative and node-positive breast cancer patients in chemotherapy-/endocrine-treated and untreated populations. We considered: (a) How accurate is the recurrence score (RS) as a prognostic factor for distant recurrence? (b) How accurate is the RS as a predictive factor for benefit from systemic therapy? (c) How does the RS compare with other prognostic/predictive factors such as tumor size, tumor grade, patient age, and integrated decision aids such as Adjuvant! Online? (d) How do patients and physicians view the 21-gene assay? (e) What are the cost implications of the 21-gene assay? RESULTS: The 21-gene assay: (a) provided accurate risk information; (b) predicted response to cyclophosphamide, methotrexate, and 5-fluorouracil and to cyclophosphamide, doxorubicin, and 5-fluorouracil chemotherapy; (c) added additional information to traditional biomarkers; (d) was viewed positively by both physicians and patients; and (e) fell within the cost-effectiveness values in North America. CONCLUSION: This assay may be offered to patients with node-negative HR(+) breast cancer to assist in adjuvant treatment decisions. Data are accumulating to support the use of the 21-gene assay in HR(+) node-positive patients.

Management of HER2-positive breast cancer in Asia: consensus statement from the Asian Oncology Summit 2009.

Patients with breast cancer positive for human epidermal growth-factor receptor type 2 (HER2) are an important subgroup for consideration in the Asian context. Rationally designed, anti-HER2 targeted agents that can substantially improve treatment outcomes have become commercially available, but are still too costly for some groups in developed countries and for underdeveloped and developing nations. This review discusses the available evidence for optimum management of HER2-positive early and advanced breast cancer, and how this evidence can be applied to Asian countries with different levels of health-care resources and economic development--using framework provided by the Breast Health Global Initiative. We provide a brief overview of HER2 testing and discuss management of early and advanced HER2-positive breast cancer, and formulate a consensus statement for the management of breast cancer in the context of basic, limited, enhanced, and maximum health-care resource availability.

Identification of cancer care and protocol characteristics associated with recruitment in breast cancer clinical trials.

PURPOSE: It is estimated that only 5% of patients with cancer participate in a clinical trial. Barriers to participation may relate to available protocols, physicians, and patients, but few data exist on barriers related to cancer care environments and protocol characteristics. METHODS: The primary objective was to identify characteristics of cancer care environments and clinical trial protocols associated with a low recruitment into breast cancer clinical trials. Secondary objectives were to determine yearly recruitment fraction onto clinical trials from 1997 to 2002 in Ontario, Canada, and to compare recruitment fraction among years. Questionnaires were sent to hospitals requesting characteristics of cancer care environments and to cooperative groups/pharmaceutical companies for information on protocols and the number of patients recruited per hospital/year. Poisson regression was used to estimate the recruitment fraction. RESULTS: Questionnaire completion rate varied between 69% and 100%. Recruitment fraction varied between 5.4% and 8.5% according to year. More than 30% of patients were diagnosed in hospitals with no available trials. In multivariate analysis, the following characteristics were associated with recruitment: use of placebo versus not (relative risk [RR] = 0.80; P = .05), nonmetastatic versus metastatic trial (RR = 2.80; P < .01), and for nonmetastatic trials, protocol allowing an interval of 12 weeks or longer versus less than 12 weeks (from diagnosis, surgery, or end of therapy) before enrollment (RR = 1.36; P < .01). CONCLUSION: Allowable interval of 12 weeks or longer to randomly assign patients in clinical trials could help recruitment. In our study, absence of an available clinical trial represented the largest barrier to recruitment.

Estimating per patient funding for cancer clinical trials: an Ontario based survey.

The financial implications of conducting clinical trials in oncology have not been well researched from a perspective that would facilitate the negotiation of appropriate reimbursement. A better understanding of the resources required to conduct clinical trials is central to this process. Summaries of two hypothetical clinical trials were circulated to the clinical trials departments of the nine regional cancer centres of Cancer Care Ontario (CCO), in the Province of Ontario, Canada. The centres were asked to produce itemized budgets with per patient charges detailed for each trial. Additionally, each trial was to be separately considered as if sponsored by a federally funded cooperative group, and then as if sponsored by industry. Six of the centres reported experience generating clinical trial budgets. Specific charges by the local Institutional Review or Research Ethics Boards (REB) were not included. The total of all per patient charges for the first trial ranged from 1352 dollars to 3082 dollars when considered as a cooperative group trial, and from 1700 dollars to 7217 dollars when considered as an industry sponsored trial. Similar charges for the second trial ranged from 2251 dollars to 5826 dollars and from 2251 dollars to 11,304 dollars respectively. Despite the similarities of the regional cancer centres across the province of Ontario, there were surprisingly large differences in the submitted budgets. No centre consistently produced the highest or lowest estimates. The majority of the differences appeared to be based on the range in estimates for professional support (nurse and physician), and the required radiology investigations. For centres that negotiate specific per patient funding amounts with industry, this data would suggest a need to better understand the budgeting process and its link to appropriate resource identification to ensure appropriate funding is obtained. These issues are likely not unique to oncology.

American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004.

PURPOSE: To update the 2003 American Society of Clinical Oncology technology assessment on adjuvant use of aromatase inhibitors. RECOMMENDATIONS: Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor in the adjuvant setting. Women with hormone receptor-negative tumors should not receive adjuvant endocrine therapy. The role of other biomarkers such as progesterone receptor and HER2 status in selecting optimal endocrine therapy remains controversial. Aromatase inhibitors are contraindicated in premenopausal women; there are limited data concerning their role in women with treatment-related amenorrhea. The side effect profiles of tamoxifen and aromatase inhibitors differ. The late consequences of aromatase inhibitor therapy, including osteoporosis, are not well characterized. CONCLUSION: The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.

American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002.

OBJECTIVE: To conduct an evidence-based technology assessment to determine whether the routine use of anastrozole or any of the aromatase inhibitors in the adjuvant breast cancer setting is appropriate for broad-based conventional use in clinical practice. POTENTIAL INTERVENTIONS: Anastrozole, letrozole, and exemestane. OUTCOMES: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefit. EVIDENCE: A comprehensive, formal literature review was conducted for relevant topics and is detailed in the text. Testimony was collected from invited experts and interested parties. The American Society of Clinical Oncology (ASCO)-prescribed technology assessment procedure was followed. BENEFITS/HARMS: The ASCO panel recognizes that a woman and her physician's decision regarding adjuvant hormonal therapy is complex and will depend on the importance and weight attributed to information regarding both cancer and non-cancer-related risks and benefits. CONCLUSION: The panel was influenced by the compelling, extensive, and long-term data available on tamoxifen. Overall, the panel considers the results of the Arimidex (anastrozole) or Tamoxifen Alone or in Combination (ATAC) trial and the extensive supporting data to be very promising but insufficient to change the standard practice at this time (May 2002). A 5-year course of adjuvant tamoxifen remains the standard therapy for women with hormone receptor-positive breast cancer. The panel recommends that physicians discuss the available information with patients, and, in making a decision, acknowledge that treatment approaches can change over time. Individual health care providers and their patients will need to come to their own conclusions, with careful consideration of all of the available data. (Specific questions addressed by the panel are summarized in Appendix 3.) VALIDATION: The conclusions of the panel were endorsed by the ASCO Health Services Research Committee and the ASCO Board of Directors.