William E. Barlow

Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial

Background The 21-gene Recurrence Score assay (RS) is prognostic for women with node-negative, estrogen receptor (ER)-positive breast cancer (BC) treated with tamoxifen. A low RS predicts little benefit of chemotherapy. For node-positive BC, we investigated whether RS was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher recurrence risks.BACKGROUND The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. METHODS The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. FINDINGS There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0.006; hazard ratio [HR] 2.64, 95% CI 1.33-5.27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0.97; HR 1.02, 0.54-1.93), but an improvement in disease-free survival for those with a high recurrence score (score > or =31; log-rank p=0.033; HR 0.59, 0.35-1.01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. INTERPRETATION The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. FUNDING National Cancer Institute and Genomic Health.

A Comparison of Physical Therapy, Chiropractic Manipulation, and Provision of an Educational Booklet for the Treatment of Patients with Low Back Pain

BACKGROUND AND METHODS There are few data on the relative effectiveness and costs of treatments for low back pain. We randomly assigned 321 adults with low back pain that persisted for seven days after a primary care visit to the McKenzie method of physical therapy, chiropractic manipulation, or a minimal intervention (provision of an educational booklet). Patients with sciatica were excluded. Physical therapy or chiropractic manipulation was provided for one month (the number of visits was determined by the practitioner but was limited to a maximum of nine); patients were followed for a total of two years. The bothersomeness of symptoms was measured on an 11-point scale, and the level of dysfunction was measured on the 24-point Roland Disability Scale. RESULTS After adjustment for base-line differences, the chiropractic group had less severe symptoms than the booklet group at four weeks (P=0.02), and there was a trend toward less severe symptoms in the physical therapy group (P=0.06). However, these differences were small and not significant after transformations of the data to adjust for their non-normal distribution. Differences in the extent of dysfunction among the groups were small and approached significance only at one year, with greater dysfunction in the booklet group than in the other two groups (P=0.05). For all outcomes, there were no significant differences between the physical-therapy and chiropractic groups and no significant differences among the groups in the numbers of days of reduced activity or missed work or in recurrences of back pain. About 75 percent of the subjects in the therapy groups rated their care as very good or excellent, as compared with about 30 percent of the subjects in the booklet group (P<0.001). Over a two-year period, the mean costs of care were

Analysis of Case-Cohort Designs

437 for the physical-therapy group,

Proposal for Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials: The STEEP System

429 for the chiropractic group, and

A Randomized Trial Comparing Acupuncture, Simulated Acupuncture, and Usual Care for Chronic Low Back Pain

153 for the booklet group. CONCLUSIONS For patients with low back pain, the McKenzie method of physical therapy and chiropractic manipulation had similar effects and costs, and patients receiving these treatments had only marginally better outcomes than those receiving the minimal intervention of an educational booklet. Whether the limited benefits of these treatments are worth the additional costs is open to question.

Predicting poor outcomes for back pain seen in primary care using patients' own criteria

The case-cohort design is most useful in analyzing time to failure in a large cohort in which failure is rare. Covariate information is collected from all failures and a representative sample of censored observations. Sampling is done without respect to time or disease status, and, therefore, the design is more flexible than a nested case-control design. Despite the efficiency of the methods, case-cohort designs are not often used because of perceived analytic complexity. In this article, we illustrate computation of a simple variance estimator and discuss model fitting techniques in SAS. Three different weighting methods are considered. Model fitting is demonstrated in an occupational exposure study of nickel refinery workers. The design is compared to a nested case-control design with respect to analysis and efficiency in a small simulation. In this example, case-cohort sampling from the full cohort was more efficient than using a comparable nested case-control design.

Does Utilization of Screening Mammography Explain Racial and Ethnic Differences in Breast Cancer

PURPOSE Standardized definitions of breast cancer clinical trial end points must be adopted to permit the consistent interpretation and analysis of breast cancer clinical trials and to facilitate cross-trial comparisons and meta-analyses. Standardizing terms will allow for uniformity in data collection across studies, which will optimize clinical trial utility and efficiency. A given end point term (eg, overall survival) used in a breast cancer trial should always encompass the same set of events (eg, death attributable to breast cancer, death attributable to cause other than breast cancer, death from unknown cause), and, in turn, each event within that end point should be commonly defined across end points and studies. METHODS A panel of experts in breast cancer clinical trials representing medical oncology, biostatistics, and correlative science convened to formulate standard definitions and address the confusion that nonstandard definitions of widely used end point terms for a breast cancer clinical trial can generate. We propose standard definitions for efficacy end points and events in early-stage adjuvant breast cancer clinical trials. In some cases, it is expected that the standard end points may not address a specific trial question, so that modified or customized end points would need to be prospectively defined and consistently used. CONCLUSION The use of the proposed common end point definitions will facilitate interpretation of trial outcomes. This approach may be adopted to develop standard outcome definitions for use in trials involving other cancer sites.

Circulating Tumor Cells and Response to Chemotherapy in Metastatic Breast Cancer: SWOG S0500

BACKGROUND Acupuncture is a popular complementary and alternative treatment for chronic back pain. Recent European trials suggest similar short-term benefits from real and sham acupuncture needling. This trial addresses the importance of needle placement and skin penetration in eliciting acupuncture effects for patients with chronic low back pain. METHODS A total of 638 adults with chronic mechanical low back pain were randomized to individualized acupuncture, standardized acupuncture, simulated acupuncture, or usual care. Ten treatments were provided over 7 weeks by experienced acupuncturists. The primary outcomes were back-related dysfunction (Roland-Morris Disability Questionnaire score; range, 0-23) and symptom bothersomeness (0-10 scale). Outcomes were assessed at baseline and after 8, 26, and 52 weeks. RESULTS At 8 weeks, mean dysfunction scores for the individualized, standardized, and simulated acupuncture groups improved by 4.4, 4.5, and 4.4 points, respectively, compared with 2.1 points for those receiving usual care (P < .001). Participants receiving real or simulated acupuncture were more likely than those receiving usual care to experience clinically meaningful improvements on the dysfunction scale (60% vs 39%; P < .001). Symptoms improved by 1.6 to 1.9 points in the treatment groups compared with 0.7 points in the usual care group (P < .001). After 1 year, participants in the treatment groups were more likely than those receiving usual care to experience clinically meaningful improvements in dysfunction (59% to 65% vs 50%, respectively; P = .02) but not in symptoms (P > .05). CONCLUSIONS Although acupuncture was found effective for chronic low back pain, tailoring needling sites to each patient and penetration of the skin appear to be unimportant in eliciting therapeutic benefits. These findings raise questions about acupunctures purported mechanisms of action. It remains unclear whether acupuncture or our simulated method of acupuncture provide physiologically important stimulation or represent placebo or nonspecific effects.

American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in Metastatic Breast Cancer

Study Design A prospective cohort study of patients seen in primary care for low back pain. Objectives A new measure of back pain outcomes is used to describe the status of back problems at various intervals after visits to primary care physicians and to identify subsets of patients with worse prognoses. Summary of Background Data Most previous studies of the prognosis of back pain in primary care have failed to provide clinically useful information. Methods Baseline data were collected from 219 patients making an initial visit for an episode of low back pain to a primary care clinic. A measure of how patients reported they would feel if they had their current back symptoms for the rest of their lives (“Symptoms Satisfaction”) was used to distinguish good from poor outcomes. Patient outcomes were assessed 1, 3, 7, and 52 weeks after the index visit. Results Only 67% of patients reported good outcomes after 7 weeks, and only 71% were satisfied with their condition 1 year later. After controlling for the effects of other variables measured during the initial physician visit, only younger age, depression, and pain below the knee were significant predictors of poor outcome at 7 weeks, and only pain below the knee and depression were significant predictors at 1 year. Conclusions The proportion of primary care patients with back pain who have poor outcomes appears to be higher than generally recognized. Ways of improving how primary care responds to patients with persisting pain should be investigated.

Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer

Context Breast cancer mortality rates have fallen but still differ by race and ethnicity. One explanation might be differences in mammography use. Content These investigators linked data from mammography registries to tumor registries and showed that African-American and Hispanic women have longer intervals between mammography and are more likely to have advanced-stage tumors at diagnosis and to die of breast cancer than white women. However, in women with similar screening histories, these rates were similar regardless of race or ethnicity. Implications Differences in mammography use may explain ethnic disparities in the incidence of advanced-stage breast cancer and in mortality rates. The Editors Breast cancer mortality rates in the United States began to decrease in the 1990s (1) because of increased use of screening mammography and improved breast cancer treatment (2, 3). However, these decreases have primarily benefited non-Hispanic white women, whereas the mortality rate for breast cancer in African-American women changed little (1). Although racial and ethnic differences in breast cancer mortality rates have been consistently documented (1, 4-9), reasons for the persistence of these differences have been difficult to ascertain (10). Possible explanations include differences in biological characteristics of tumors (11-13); patient characteristics, such as obesity, that may affect prognosis; mammography use (14, 15); timeliness and completeness of breast cancer diagnosis and treatment (16, 17); social factors, such as education, literacy, and cultural beliefs; and economic factors, such as income level and health insurance coverage, that might affect a patients access to and choices for breast cancer screening and treatment (18-22). Stage at diagnosis, the strongest predictor of breast cancer survival (23), is proportionally higher in all non-Asian minority groups than in white women (8). Although minority women have historically undergone less mammography than white women (14), several recent surveys have found only small differences in mammography use between white and nonwhite women (24, 25). These observations raised doubt that tumors go undiagnosed until later stages in minority women because of infrequent breast cancer screening (26). However, the 2 most widely cited surveys of mammography use are based on self-report and only inquire about recent use, not adherence over time (24, 25). We explored stage of disease at diagnosis, tumor characteristics (including size and grade), and lymph node involvement among women of different races and ethnicities whose patterns of mammography use were similar. We hypothesized that differences in tumor characteristics may result primarily from differences in mammography use and that women with similar patterns of mammography use may have similar tumor characteristics. We had sufficient sample sizes within each racial and ethnic group and obtained sufficiently detailed data regarding mammography use to permit stratification of the cohort by pattern of mammography use; this technique enabled us to compare tumor characteristics among women with similar screening histories. Methods Data Source We pooled data from facilities that participate in 7 mammography registries that form the National Cancer Institutefunded Breast Cancer Surveillance Consortium: San Francisco Mammography Registry, San Francisco, California; Group Health Cooperative, Seattle, Washington; Colorado Mammography Project, Denver, Colorado; Vermont Breast Cancer Surveillance System, Burlington, Vermont; New Hampshire Mammography Network, Lebanon, New Hampshire; Carolina Mammography Registry, Chapel Hill, North Carolina; and New Mexico Mammography Project, Albuquerque, New Mexico. The data consisted of information sent to the registries regarding all mammographic evaluations performed at these facilities, including radiology reports and breast health surveys. The surveys, which were completed by patients at each mammography examination, included questions regarding race, ethnicity, presence of breast symptoms, and previous mammography use. Breast cancer diagnoses and tumor characteristics were obtained through linkage with state tumor registries; regional Surveillance, Epidemiology, and End Results programs; and hospital-based pathology services. Previous research has shown that at least 94% of cancer cases are identified through these linkages (27). Each surveillance registry captures most mammography case reports within its respective geographic area, and mammograms in these registries include approximately 2% of mammographic examinations performed in the United States. Each registry obtains annual approval from its institutional review board to collect mammography-related information and to link with tumor registries. Participants This study included women without a history of breast cancer who were 40 years of age and older who had undergone mammography at least once for screening or diagnostic purposes between 1996 and 2002 (n= 1010515). We categorized the race and ethnicity of the participating women (the mammography registry cohort) as non-Hispanic white (n= 789997), non-Hispanic African American/black (n= 62408), Hispanic (n= 90642), Asian/Pacific Islander (n= 49867), or Native American/Native Alaskan (n= 17601). We excluded women who did not report their race or ethnicity (n= 133235 [12%]) or reported mixed or other race (n= 6003 [<1%]). Breast cancer was diagnosed in a subset of the women in the mammography registry cohort (Table 1). Table 1. General Categorization of Study Participants Characterization of Mammography Use We included all mammographic evaluations in eligible women that were performed during the study period. We characterized each mammogram that was included in the study by the time interval between that mammogram and the one most recently preceding it. We determined these intervals by using examination dates that were recorded in the database (data were available for 85% of patients) and self-reported dates that the remaining women provided at the time of their examination. The mammography screening intervals were categorized into the following groups: within 1 year (4 to 17 months); 2 years (18 to 29 months); 3 years (30 to 41 months); and 4 years or longer (>41 months). At the time of each mammogram, women completed a breast health survey and provided the date of their last mammogram. We created 2 classifications for first mammograms. Mammography was classified as a first screening if the radiologist coded the examination as screening and the woman reported no breast symptoms. The mammogram was classified as diagnostic if the radiologist coded the examination as diagnostic or if the woman reported a breast mass or nipple discharge. Women whose first mammogram was diagnostic were assigned to the never screened group. Of note, a woman could have had mammography more than once during the study period and therefore could contribute more than 1 observation to the analyses. A woman could have observations that were categorized into different mammography screening intervals. For example, a woman could have had her first mammographic evaluation in 1998 and had subsequent mammography in 1999 and 2001. Her first mammogram would have been categorized as a first screening or as diagnostic, depending on the radiologists indication for that examination and whether the patient reported symptoms. Her second mammogram would have been categorized in the 1 year group, and her third mammography would have been categorized in the 2 year group. Breast Cancer To determine breast cancer status, we tracked each participants mammogram for 365 days following the date it had been obtained or until the patient underwent her next mammographic examination (whichever came first). Consequently, each tumor was associated with a single mammogramthat obtained closest to the date of diagnosis. We characterized breast cancer as either invasive or ductal carcinoma in situ. Large tumors were defined as invasive tumors that were 15 mm or larger in diameter. We used the TNM (tumor, node, metastasis) system (which is based on the criteria of the American Joint Committee on Cancer) to classify stage at diagnosis as 0 (ductal carcinoma in situ), 1, 2, 3, or 4 (28); advanced-stage tumors were defined as invasive lesions of stage 2 or higher. High-grade tumors were defined as invasive lesions of grades 3 and 4. Lymph node status was defined as positive, negative, or unknown. Advanced disease was defined as the presence of a large, advanced-stage, high-grade tumor or lymph nodepositive tumor at the time of diagnosis. Statistical Analysis We calculated the frequency distributions of various risk factors for all women in the mammography registry cohort. Among the subset of women with breast cancer (n= 17558), we calculated the proportion of tumors that were invasive and, among invasive tumors, the proportion that were advanced-stage or high-grade tumors; we then calculated the distribution by race and ethnicity. For all women in the cohort, we evaluated whether overall and advanced cancer rates per 1000 mammograms were similar across racial and ethnic groups after we adjusted for age and registry by using Poisson regression. We then calculated whether adjusted overall and advanced cancer rates per 1000 mammograms were similar across mammography screening interval groups. Because overall and advanced cancer rates varied across racial and ethnic groups (P< 0.001) and by previous mammography use (P< 0.001), and because mammography use potentially varied by race and ethnicity, we modeled cancer rates among similarly screened women in each ethnic group. We used Poisson regression to adjust for age and registry; an interaction term between race and ethnicity and previous mammography use was included in the Poisson model to allow for possible differences in the association between ethnicity and cancer rates by mammography group