Studies of breast cancer outcomes rely on the identification of second breast cancer events (recurrences and second breast primary tumors). Cancer registries often do not capture recurrences, and chart abstraction can be infeasible or expensive. An alternative is using administrative health-care data to identify second breast cancer events; however, these algorithms must be validated against a gold standard.
We developed algorithms using data from 3152 women in an integrated health-care system who were diagnosed with stage I or II breast cancer in 1993–2006. Medical record review served as the gold standard for second breast cancer events. Administrative data used in algorithm development included procedures, diagnoses, prescription fills, and cancer registry records. We randomly divided the cohort into training and testing samples and used a classification and regression tree analysis to build algorithms for classifying women as having or not having a second breast cancer event. We created several algorithms for researchers to use based on the relative importance of sensitivity, specificity, and positive predictive value (PPV) in future studies.
The algorithm with high specificity and PPV had 89% sensitivity (95% confidence interval [CI] = 84% to 92%), 99% specificity (95% CI = 98% to 99%), and 90% PPV (95% CI = 86% to 94%); the high-sensitivity algorithm had 96% sensitivity (95% CI = 93% to 98%), 95% specificity (95% CI = 94% to 96%), and 74% PPV (95% CI = 68% to 78%).
Algorithms based on administrative data can identify second breast cancer events with high sensitivity, specificity, and PPV. The algorithms presented here promote efficient outcomes research, allowing researchers to prioritize sensitivity, specificity, or PPV in identifying second breast cancer events.
Breast density and body mass index (BMI) are correlated attributes and are both potentially modifiable risk factors for breast cancer. However, relationships between these factors and risk of molecularly-defined subtypes of breast cancer have not been established.
We used breast density and BMI data collected by the Breast Cancer Surveillance Consortium from 1,054,466 women aged 40–84 years receiving mammography, including 13,797 women subsequently diagnosed with breast cancer. Cases were classified into three groups based on expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2: 1) ER-positive (ER+, N=10,026), 2) HER2-overexpressing (ER-negative/PR-negative/HER2-positive, N=308), or triple-negative (ER-negative/PR-negative/HER2-negative, N=705). Using Cox regression, we evaluated subtype-specific associations with breast density and BMI.
Breast density was similarly positively associated with risk of all subtypes, especially among women aged 40–64 years. BMI was positively associated with risks of ER+ and triple-negative breast cancer in women aged 50–84 who were not users of hormone therapy.
Breast density is positively associated with breast cancer risk, regardless of disease subtype. Associations with BMI appear to vary more by breast cancer subtype. Additional studies are needed to confirm and further characterize risk factors for HER2-overexpressing and triple-negative breast cancer.
breast cancer; triple-negative; breast density; body mass index; estrogen receptor; progesterone receptor; HER2
A simple oral combination of capecitabine and cyclophosphamide for the treatment of patients with metastatic breast cancer was evaluated. The addition of cyclophosphamide did not result in outcomes superior to those seen with capecitabine alone.
After completing this course, the reader will be able to:
Compare outcomes in patients treated with capecitabine plus CPA with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone.Identify patients for whom single-agent capecitabine is recommended.
This article is available for continuing medical education credit at CME.TheOncologist.com
Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC.
The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor–positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1–14, and capecitabine, 1,500 mg twice daily on days 8–21, in 21-day cycles.
In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7–8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1–22.0 months). The RR was 36% (95% CI, 26%–48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%–48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths.
PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.
Metastatic breast cancer; Capecitabine; Cyclophosphamide; Oral therapy
We assessed SNPS in the Fanconi Anemia (FA)/BRCA pathway in women being was taxanes for breast cancer in an effort to find a prognostic biomarker for neurological toxicities, which while improve survival remain a debilitating outcome.
Patients and Methods
We used data and samples (n=888) from SWOG0221, a phase III adjuvant trial of 4 dose/schedules of cyclophosphamide (C), doxorubicin (A) and paclitaxel (T) for high risk breast cancer. The relationship of SNPs in the (FA)/BRCA pathway with risk grade 3/4 neurotoxicities. In a separate cohort we measured the correlation of significant SNPs in this pathway with corresponding gene expression.
No associations between SNPs in BRCA1 and taxane-induced neuropathy was found. For FANCD2, significant associations between 4 (out of 20) SNPs and neurological toxicities, with risk estimates approaching 2. Two FANCD2 haplotypes were also found to be significantly associated with neurological toxicity, increasing the odds in the overall population 1.8 (95% confidence interval (CI) 1.3–2.5) and 1.7 (95% CI, 1.2–2.4) fold. Although numbers were small, there appeared to be a specific African-American haplotype that was associated with an almost 3-fold increase in risk of neurological toxicity. Expression analyses revealed that significant FANCD2 SNPs were associated with FANCD2 expression levels (p=0.03)
SNPs in FANCD2, were associated with a 70 to 80% increase in the odds of grade 3/4 neurological toxicities and increased expression of the gene. If replicated, women with these genotypes should be closely monitored for toxicities, and could be targeted for preventive measures or alternative therapeutic approaches.
SWOG trial S0102 showed significant activity of the combination of docetaxel and vinorelbine in HER2-negative metastatic breast cancer (MBC). For HER2-positive patients, additional benefit may occur with the addition of trastuzumab due to its synergy with docetaxel and vinorelbine.
Patients with HER2-positive MBC, but without prior chemotherapy for MBC or adjuvant taxane, were eligible. Docetaxel (60 mg/m2) was given intravenously on Day 1, vinorelbine (27.5 mg/m2) intravenously on Days 8 and 15, and filgrastim (5 μg/kg) on Days 2–21 of a 21-day cycle. Additionally, patients received weekly infusions of trastuzumab (2 mg/kg) after an initial bolus of 4 mg/kg. The primary outcome was one-year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate, and toxicity. Due to slow accrual (February 2003-December 2006), enrollment was stopped after 76 of 90 planned patients.
There have been 32 deaths and 51 progressions among the 74 eligible patients who received treatment. The estimated 1-year OS was 93% (95% CI 84%–97%) with a median of 48 months. One-year PFS was 70% (95% CI 58–79%) with a median of 20 months. Response rate for measurable disease was 84%. No deaths were attributed to treatment. Grade 4 toxicities were reported for 19% with neutropenia the most common (15%). The most common grade 3 toxicities (33%) were leucopenia (14%) and fatigue (10%).
The combination of trastuzumab, docetaxel, and vinorelbine is effective as first-line chemotherapy in HER2-positive MBC with minimal toxicity. One-year survival estimates are among the highest reported in this population.
Docetaxel; vinorelbine; trastuzumab; HER2-positive metastatic breast cancer
Imatinib mesylate is a potent inhibitor of the Bcr-Abl, c-kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases. Based on variable expression of c-kit and PDGFR in breast cancer, and on in vitro data supporting synergy between imatinib and capecitabine, the Southwest Oncology Group conducted a phase II trial of the combination in metastatic breast cancer.
Patients and Methods
Eligible patients had progressive, measurable metastatic breast cancer and received up to two prior chemotherapy regimens for metastatic disease. Prior 5-fluorouracil or capecitabine for metastatic disease was not allowed. Patients were accrued on a 2-stage design and received imatinib mesylate 400 mg by mouth daily and capecitabine at 1000 mg/m2 by mouth twice daily for 14 days of a 21-day cycle. The primary endpoint was the confirmed response rate (RR). Tumors were evaluated for c-kit, PDGFRβ, and hormone receptor expression.
Nineteen fully evaluable patients were enrolled with a confirmed RR of 11% (95% CI 1–33%). Eleven percent had unconfirmed partial responses and 42% had stable disease. The trial did not accrue to the second stage. The estimated 6-month progression-free survival was 16% (95% CI 0–32%) and the median overall survival was 14 months (95% CI 7–15). The combination was well tolerated. Of 8 available tumor samples, 2 stained for c-kit and all had stromal staining for PDGFRβ.
In unselected patients, the combination of imatinib mesylate and capecitabine was well tolerated but did not result in improved response rates compared to that reported with capecitabine alone.
breast cancer; imatinib mesylate; capecitabine
Computer-aided detection (CAD) is applied during screening mammography for millions of US women annually, although it is uncertain whether CAD improves breast cancer detection when used by community radiologists.
We investigated the association between CAD use during film-screen screening mammography and specificity, sensitivity, positive predictive value, cancer detection rates, and prognostic characteristics of breast cancers (stage, size, and node involvement). Records from 684 956 women who received more than 1.6 million film-screen mammograms at Breast Cancer Surveillance Consortium facilities in seven states in the United States from 1998 to 2006 were analyzed. We used random-effects logistic regression to estimate associations between CAD and specificity (true-negative examinations among women without breast cancer), sensitivity (true-positive examinations among women with breast cancer diagnosed within 1 year of mammography), and positive predictive value (breast cancer diagnosed after positive mammograms) while adjusting for mammography registry, patient age, time since previous mammography, breast density, use of hormone replacement therapy, and year of examination (1998–2002 vs 2003–2006). All statistical tests were two-sided.
Of 90 total facilities, 25 (27.8%) adopted CAD and used it for an average of 27.5 study months. In adjusted analyses, CAD use was associated with statistically significantly lower specificity (OR = 0.87, 95% confidence interval [CI] = 0.85 to 0.89, P < .001) and positive predictive value (OR = 0.89, 95% CI = 0.80 to 0.99, P = .03). A non-statistically significant increase in overall sensitivity with CAD (OR = 1.06, 95% CI = 0.84 to 1.33, P = .62) was attributed to increased sensitivity for ductal carcinoma in situ (OR = 1.55, 95% CI = 0.83 to 2.91; P = .17), although sensitivity for invasive cancer was similar with or without CAD (OR = 0.96, 95% CI = 0.75 to 1.24; P = .77). CAD was not associated with higher breast cancer detection rates or more favorable stage, size, or lymph node status of invasive breast cancer.
CAD use during film-screen screening mammography in the United States is associated with decreased specificity but not with improvement in the detection rate or prognostic characteristics of invasive breast cancer.
Methods to estimate the direct medical costs of cancer care have evolved into several commonly used methods.
We describe the different estimation techniques briefly to contrast these approaches and provide a framewok for other papers in this monograph.
Measures and results
One can estimate costs for all individuals with a specific cancer in a fixed calendar period (prevalent costs) or describe costs starting at the point of diagnosis and estimate immediate and long-term costs (incident costs). A variant of the incidence approach is to divide cancer care into initial, continuing, and terminal care phases and apply these phase specific cost estimates to survival probabilities. The additional burden due to cancer may be computed using cancer services (attributable costs) or by subtracting costs of healthy matched individuals (net costs).
The strengths and weaknesses of these approaches are illustrated to show that the most appropriate choice will depend on whether the goal is to plan for health care costs, set public policy, or assess impact of potential interventions.
About one-third of adults with diabetes have severe oral complications. However, limited previous research has investigated dental care utilization associated with diabetes. This project had two purposes: to develop a methodology to estimate dental care utilization using claims data and to use this methodology to compare utilization of dental care between adults with and without diabetes.
Data included secondary enrollment and demographic data from Washington Dental Service (WDS) and Group Health Cooperative (GH), clinical data from GH, and dental-utilization data from WDS claims during 2002–2006. Dental and medical records from WDS and GH were linked for enrolees continuously and dually insured during the study. We employed hurdle models in a quasi-experimental setting to assess differences between adults with and without diabetes in 5-year cumulative utilization of dental services. Propensity score matching adjusted for differences in baseline covariates between the two groups.
We found that adults with diabetes had lower odds of visiting a dentist (OR = 0.74, p < 0.001). Among those with a dental visit, diabetes patients had lower odds of receiving prophylaxes (OR = 0.77), fillings (OR = 0.80) and crowns (OR = 0.84) (p < 0.005 for all) and higher odds of receiving periodontal maintenance (OR = 1.24), non-surgical periodontal procedures (OR = 1.30), extractions (OR = 1.38) and removable prosthetics (OR = 1.36) (p < 0.001 for all).
Patients with diabetes are less likely to use dental services. Those who do are less likely to use preventive care and more likely to receive periodontal care and tooth-extractions. Future research should address the possible effectiveness of additional prevention in reducing subsequent severe oral disease in patients with diabetes.
Triple-negative breast cancer accounts for less than 20% of breast cancers overall, but is the predominant subtype among carriers of mutations in BRCA1. However, few studies have assessed the association between breast cancer family history and risk of triple-negative breast cancer. We examined the relationship between having a family history of breast cancer in first-degree relatives and risk of triple-negative breast cancer, and risk of two other breast cancer subtypes defined by tumor marker expression.
We evaluated data collected by the Breast Cancer Surveillance Consortium from 2,599,946 mammograms on 1,054,466 women, among whom 15% reported a first-degree family history of breast cancer. Using Cox regression in this cohort we evaluated subtype-specific associations between family history and risk of triple-negative (N=705), estrogen receptor-positive (ER+, N=10,026), and hormone receptor-negative / HER2-expressing (ER-/PR-/HER2+, N=308) breast cancer among women aged 40-84 years.
First-degree family history was similarly and significantly associated with an increased risk of all subtypes [hazard ratio (HR)=1.73, 95% confidence interval (CI): 1.43-2.09, HR=1.62, 95% CI: 1.54-1.70, and HR=1.56, 95% CI: 1.15-2.13, for triple-negative, ER+, and ER-/PR-/HER2+, respectively]. Risk of all subtypes was most pronounced among women with at least two affected first-degree relatives (versus women with no affected first-degree relatives, HRtriple-negative=2.66, 95% CI: 1.66-4.27, HRER+=2.05, 95% CI: 1.79-2.36, HRER-/PR-/HER2+=2.25, 95% CI: 0.99-5.08).
Having a first-degree family history of breast cancer was associated with an increased risk of triple-negative breast cancer with a magnitude of association similar to that for the predominant ER+ subtype and ER-/PR-/HER2+ breast cancer.
family history; breast cancer; triple-negative; estrogen receptor; progesterone receptor; HER2
Patients with inflammatory breast cancer (IBC) or locally advanced breast cancer (LABC) were randomly assigned to 21-day doxorubicin and cyclophosphamide administered for five cycles (standard arm) versus weekly doxorubicin and daily oral cyclophosphamide administered with granulocyte colony-stimulating factor support for 15 weeks (continuous arm). All patients had subsequent weekly paclitaxel for 12 weeks before surgery.
Patients and Methods
Patients (n = 372) were randomly assigned to the standard arm (n = 186) or the continuous arm (n = 186) stratified by disease type (LABC, n = 256; IBC, n = 116). The primary outcome was microscopic pathologic complete response (pCR) at surgery. Secondary outcomes included disease-free survival, overall survival, and toxicity.
More patients in the standard arm had grade 3 to 4 leukopenia and neutropenia, but there were more instances of stomatitis/pharyngitis and hand-foot skin reaction in the continuous arm. Assessed among 356 eligible patients, pCR was not different between the treatment groups stratified by disease type (P = .42). In subset analysis, higher pCR rates were observed in the continuous arm versus the standard arm only for stage IIIB disease (P = .0057) and in IBC (P = .06). Comparison of overall survival and disease-free survival showed no difference between treatment groups (P = .37 and P = .87, respectively).
No significant clinical benefit was seen for the investigational arm in this trial overall.
Breast cancer subtypes defined by estrogen-receptor (ER), progesterone-receptor (PR), and HER2 expression are biologically distinct and, thus, may have distinct etiologies. In particular, it is plausible that risk factors operating through hormonal mechanisms are differentially related to risk of such tumor subtypes. Using data from the Breast Cancer Surveillance Consortium, we explored associations between reproductive history and three breast cancer subtypes. Data on parity and age at first birth were collected from 743,623 women, 10,896 of whom were subsequently diagnosed with breast cancer. Cases were classified into three subtypes based on tumor maker expression: 1) ER-positive (ER+, N=8,203), 2) ER-negative / PR-negative / HER2-positive (ER-/PR-/HER2+, N=288), or 3) ER, PR, and HER2-negative (triple-negative, N=645). Associations with reproductive history, evaluated using Cox regression, differed significantly across tumor subtypes. Nulliparity was most strongly associated with risk of ER+ breast cancer [hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.23–1.39]; late age at first birth was most strongly associated with risk of ER-/PR-/HER2+ disease (HR=1.83, 95% CI: 1.31–2.56). Neither parity nor age at first birth was associated with triple-negative breast cancer. In contrast to ER+ and ER-/PR-/HER2+ subtypes, reproductive history does not appear to be a risk factor for triple-negative breast cancer.
breast cancer; parity; age at first birth; triple-negative
Markers for treatment selection are being developed in many areas of medicine. Technological advances are rapidly producing an abundance of candidates for study. Clinicians hope to use these markers to identify which individuals will benefit from a given treatment, with the goal of maximizing good outcomes and minimizing side effects, treatment burden, and medical costs.
It is essential that we have appropriate methods for evaluating treatment selection markers, in order to make informed decisions regarding marker advancement and, ultimately, clinical application. However, existing statistical methods for evaluating treatment selection markers are largely inadequate. This paper proposes several novel statistical measures of marker performance aimed at addressing key questions in marker evaluation: 1) Does the marker help patients choose amongst treatment options?; 2) How should treatment decisions be made based on a continuous marker measurement?; 3) What is the impact on the population of using the marker to select treatment?; and 4) What proportion of patients will have different treatment recommendations following marker measurement? The proposed approach is contrasted with existing methods for marker evaluation, including assessing a marker’s prognostic value, evaluating treatment effects in a subset of the population who are marker-positive, and testing for a statistical interaction between marker value and treatment. The approach is illustrated in the context of choosing adjuvant chemotherapy treatment for women with estrogen-receptor positive and node-positive breast cancer. The results have important implications for the design of marker evaluation studies, and can serve as the basis for further development of standards for assessing treatment selection markers.
To develop a self-assessed melanoma risk score to identify high-risk persons for screening
We used data from a 1997 melanoma case-control study from Washington State, USA, where 386 cases with invasive cutaneous melanoma and 727 controls were interviewed by telephone. A logistic regression prediction model was developed on 75% of the data and validated in the remaining 25% by calculating the area under the receiver operating characteristic curve (AUC), a measure of predictive accuracy from 0.5–1 (higher scores indicating better prediction). A risk score was calculated for each individual, and sensitivities for various risk cutoffs were calculated.
The final model included sex, age, hair color, density of freckles, number of severe sunburns in childhood and adolescence, number of raised moles on the arms, and history of non-melanoma skin cancer. The area under the receiver operating characteristic curve(AUC) was 0.70 (95% CI: 0.64, 0.77). The top 15% risk group included 50% of melanomas (sensitivity 50%).
This self-assessed score could be used as part of a comprehensive melanoma screening and public education program to identify high-risk individuals in the general population. This study suggests it may be possible to capture a large proportion of melanomas by screening a small high-risk group. Further study is needed to determine the costs, feasibility, and risks of this approach.
Melanoma; Risk; Prediction; Screening
There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a Southwest Oncology Group trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematological toxicity and disease-free survival (DFS).
Germline DNA was available from 458 women who were at high risk of relapse and randomized to CAF vs CMF ± tamoxifen and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematological toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6, CYP3A4, GSTA1, and GSTP1 were estimated by logistic regression and Cox proportional hazard regression.
Compared to women with AA genotypes, those with at least one GSTP1 variant G allele had reduced risk of grade 3 and 4 neutropenia (OR=0.63, 95% CI=0.41–0.97) and leucopenia (OR=0.59, 95% CI=0.39–0.89). No other associations between SNPs and toxicity or survival were found in the treated or untreated group.
Known genetic variants in genes involved in CP pharmacokinetics may not have major effects on DFS in breast cancer patients. The lower risk of developing high grade hematological toxicity among women with variant GSTP1 alleles suggests that genetic markers in combination with clinical factors may be useful in defining a subgroup of women who are less susceptible to adverse hematological toxicities with CP-containing therapies.
cyclophosphamide; GSTP1; disease-free survival; toxicity; breast cancer
To examine whether there are any characteristics of women or their initial tumors that might be useful for tailoring surveillance recommendations to optimize outcomes. We followed 17,286 women for up to 5 years after an initial diagnosis of ductal carcinoma in situ (DCIS) or early stage (I/II) invasive breast cancer diagnosed between 1996 and 2006. We calculated rates per 1,000 women years of recurrences and second breast primaries relative to demographics, risk factors, and characteristics of initial diagnosis: stage, treatment, mode of initial diagnosis. Nearly 4% had a second breast cancer event (314 recurrences and 344 second breast primaries). Women who used adjuvant hormonal therapy or were ≥80 years had the lowest rates of second events. Factors associated with higher recurrence and second primary rates included: initial DCIS or stage IIB, estrogen/progesterone receptor-negative, younger women (<50 years). Women with a family history or greater breast density had higher second primary rates, and women who received breast conserving surgery without radiation had higher recurrence rates. Roughly one-third of recurrences (37.6%) and second primaries (36.3%) were not screen-detected. Initial mode of diagnosis was a predictor of second events after adjusting for age, stage, primary treatment, and breast density. A recent negative mammogram should not falsely reassure physicians or women with new breast symptoms or changes because one-third of second cancers were interval cancers. This study does not provide any evidence in support of changing surveillance intervals for different subgroups.
Carcinoma; Ductal; Breast; Recurrence; Neoplasm recurrence; Local; Neoplasms; Second primary; Ultrasonography; Mammary; Diagnostic imaging; Breast neoplasms; Mammography
Computer-aided detection identifies suspicious findings on mammograms to assist radiologists. Since the Food and Drug Administration approved the technology in 1998, it has been disseminated into practice, but its effect on the accuracy of interpretation is unclear.
We determined the association between the use of computer-aided detection at mammography facilities and the performance of screening mammography from 1998 through 2002 at 43 facilities in three states. We had complete data for 222,135 women (a total of 429,345 mammograms), including 2351 women who received a diagnosis of breast cancer within 1 year after screening. We calculated the specificity, sensitivity, and positive predictive value of screening mammography with and without computer-aided detection, as well as the rates of biopsy and breast-cancer detection and the overall accuracy, measured as the area under the receiver-operating-characteristic (ROC) curve.
Seven facilities (16%) implemented computer-aided detection during the study period. Diagnostic specificity decreased from 90.2% before implementation to 87.2% after implementation (P<0.001), the positive predictive value decreased from 4.1% to 3.2% (P = 0.01), and the rate of biopsy increased by 19.7% (P<0.001). The increase in sensitivity from 80.4% before implementation of computer-aided detection to 84.0% after implementation was not significant (P = 0.32). The change in the cancer-detection rate (including invasive breast cancers and ductal carcinomas in situ) was not significant (4.15 cases per 1000 screening mammograms before implementation and 4.20 cases after implementation, P = 0.90). Analyses of data from all 43 facilities showed that the use of computer-aided detection was associated with significantly lower overall accuracy than was nonuse (area under the ROC curve, 0.871 vs. 0.919; P = 0.005).
The use of computer-aided detection is associated with reduced accuracy of interpretation of screening mammograms. The increased rate of biopsy with the use of computer-aided detection is not clearly associated with improved detection of invasive breast cancer.
Compare GHb among people with diabetes who have and have not received periodontal care.
RESEARCH DESIGN AND METHODS
This cross-sectional study linked 5 years of electronic medical record and dental insurance data for dually insured patients with diabetes, ages 40–70 years (n = 5,103). We assessed the association between annual mean GHb (%) and periodontal care (a proxy for periodontitis) defined using claim codes. Among patients who received periodontal care, we assessed the association between GHb and periodontal treatment intensity. We determined associations using linear regression adjusted for potential confounders and tested for effect modification by age, sex, insulin use, diabetes severity, BMI, and smoking.
Mean GHb was 7.66%; 38% of participants received periodontal care during the 5 years. After multivariate adjustment, patients who received periodontal care had a GHb level 0.08 percentage points higher than patients who did not (P = 0.02). In stratified analyses, the association was present for women (0.18 percentage points higher GHb with periodontal care, P < 0.001) but not significant for men (0.008 percentage points lower, P = 0.86). In patients who received periodontal care, those with one, and with two or more, surgical treatments had GHb 0.25 (P = 0.04) and 0.36 (P = 0.002) percentage points lower, respectively, than patients without periodontal surgeries.
This population-based cross-sectional study showed small associations between periodontal care (a proxy for periodontitis) and higher GHb. Well-controlled longitudinal studies or clinical trials are needed to evaluate causality and temporal trends. Sub-analyses suggest that further investigation of this association among women, and by intensity of periodontal treatment, may be of interest.
Obesity is increasing among American women, especially as they age. The influence of obesity on the accuracy of screening mammography has not been studied extensively.
We analyzed 100622 screening mammography examinations performed on members of a nonprofit health plan. The relationship between body mass index (weight in kilograms divided by the square of height in meters) and measures of screening accuracy was assessed. Body mass index was categorized as underweight or normal weight (<25), overweight (25–29), obesity class I (30–34), and obesity classes II to III (≥35).
Compared with underweight or normal weight women, overweight and obese women were more likely to be recalled for additional tests after adjusting for important covariates, including age and breast density (overweight odds ratio [OR], 1.17; 95% confidence interval [CI], 1.11–1.23); obesity class I OR, 1.27; 95% CI, 1.19–1.35; obesity classes II–III OR, 1.31; 95% CI, 1.22–1.41). As body mass index increased, women were more likely to have lower specificity (overweight OR, 0.86; 95% CI, 0.81–0.90; obesity class I OR, 0.79; 95% CI, 0.74–0.84; and obesity classes II–III OR, 0.77; 95% CI, 0.71–0.82). No statistically significant differences were noted in sensitivity. Adjusted receiver operating characteristic analysis showed statistically significant improvement in the area under the curve (AUC) for underweight or normal weight women (AUC=0.941) vs overweight women (AUC=0.916, P=.02) and underweight or normal weight women vs obesity classes II and III women (AUC=0.904, P=.02).
Obese women had more than a 20% increased risk of having false-positive mammography results compared with underweight and normal weight women, although sensitivity was unchanged. Achieving a normal weight may improve screening mammography performance.
To assess the relationship between radiologists’ perception of and experience with medical malpractice and their patient-recall rates in actual community-based clinical settings.
MATERIALS AND METHODS
All study activities were approved by the institutional review boards of the involved institutions, and patient and radiologist informed consent was obtained where necessary. This study was performed in three regions of the United States (Washington, Colorado, and New Hampshire). Radiologists who routinely interpret mammograms completed a mailed survey that included questions on demographic data, practice environment, and medical malpractice. Survey responses were linked to interpretive performance for all screening mammography examinations performed between January 1, 1996, and December 31, 2001. The odds of recall were modeled by using logistic regression analysis based on generalized estimating equations that adjust for study region.
Of 181 eligible radiologists, 139 (76.8%) returned the survey with full consent. The analysis included 124 radiologists who had interpreted a total of 557 143 screening mammograms. Approximately half (64 of 122 [52.4%]) of the radiologists reported a prior malpractice claim, with 18 (14.8%) reporting mammography-related claims. The majority (n = 51 [81.0%]) of the 63 radiologists who responded to a question regarding the degree of stress caused by a medical malpractice claim described the experience as very or extremely stressful. More than three of every four radiologists (ie, 94 [76.4%] of 123) expressed concern about the impact medical malpractice has on mammography practice, with over half (72 [58.5%] of 123) indicating that their concern moderately to greatly increased the number of their recommendations for breast biopsies. Radiologists’ estimates of their future malpractice risk were substantially higher than the actual historical risk. Almost one of every three radiologists (43 of 122 [35.3%]) had considered withdrawing from mammogram interpretation because of malpractice concerns. No significant association was found between recall rates and radiologists’ experiences or perceptions of medical malpractice.
U.S. radiologists are extremely concerned about medical malpractice and report that this concern affects their recall rates and biopsy recommendations. However, medical malpractice experience and concerns were not associated with recall or false-positive rates. Heightened concern of almost all radiologists may be a key reason that recall rates are higher in the United States than in other countries, but this hypothesis requires further study.
Radiologists differ in their ability to interpret screening mammograms accurately. We investigated the relationship of radiologist characteristics to actual performance from 1996 to 2001.
Screening mammograms (n = 469 512) interpreted by 124 radiologists were linked to cancer outcome data. The radiologists completed a survey that included questions on demographics, malpractice concerns, years of experience interpreting mammograms, and the number of mammograms read annually. We used receiver operating characteristics (ROC) analysis to analyze variables associated with sensitivity, specificity, and the combination of the two, adjusting for patient variables that affect performance. All P values are two-sided.
Within 1 year of the mammogram, 2402 breast cancers were identified. Relative to low annual interpretive volume (≤1000 mammograms), greater interpretive volume was associated with higher sensitivity (P = .001; odds ratio [OR] for moderate volume [1001–2000] = 1.68, 95% CI = 1.18 to 2.39; OR for high volume [>2000] = 1.89, 95% CI = 1.36 to 2.63). Specificity decreased with volume (OR for 1001–2000 = 0.65, 95% CI = 0.52 to 0.83; OR for more than 2000 = 0.76, 95% CI = 0.60 to 0.96), compared with 1000 or less (P = .002). Greater number of years of experience interpreting mammograms was associated with lower sensitivity (P = .001), but higher specificity (P = .003). ROC analysis using the ordinal BI-RADS interpretation showed an association between accuracy and both previous mammographic history (P = .012) and breast density (P<.001). No association was observed between accuracy and years interpreting mammograms (P = .34) or mammography volume (P = .94), after adjusting for variables that affect the threshold for calling a mammogram positive.
We found no evidence that greater volume or experience at interpreting mammograms is associated with better performance. However, they may affect sensitivity and specificity, possibly by determining the threshold for calling a mammogram positive. Increasing volume requirements is unlikely to improve overall mammography performance.
To evaluate the current (2001–2002) capacity of community-based mammography facilities to deliver screening and diagnostic services in the United States.
MATERIALS AND METHODS
Institutional review board approvals and patient consent were obtained. A mailed survey was sent to 53 eligible mammography facilities in three states (Washington, New Hampshire, and Colorado). Survey questions assessed equipment and staffing availability, as well as appointment waiting times for screening and diagnostic mammography services. Criterion-related content and construct validity were obtained first by means of a national advisory committee of academic, scientific, and clinical colleagues in mammography that reviewed literature on existing surveys and second by pilot testing a series of draft surveys among community mammography facilities not inclusive of the study facilities. The final survey results were independently double entered into a relational database with programmed data checks. The data were sent encrypted by means of file transfer protocol to a central analytical center at Group Health Cooperative. A two-sided P value with α = .05 was considered to show statistical significance in all analyses.
Forty-five of 53 eligible mammography facilities (85%) returned the survey. Shortages of radiologists relative to the mammographic volume were found in 44% of mammography facilities overall, with shortages of radiologists higher in not-for-profit versus for-profit facilities (60% vs 28% reported). Shortages of Mammography Quality Standards Act–qualified technologists were reported by 20% of facilities, with 46% reporting some level of difficulty in maintaining qualified technologists. Waiting times for diagnostic mammography ranged from less than 1 week to 4 weeks, with 85% performed within 1 week. Waiting times for screening mammography ranged from less than 1 week to 8 weeks, with 59% performed between 1 week and 4 weeks. Waiting times for both diagnostic and screening services were two to three times higher in high-volume compared with low-volume facilities.
Survey results show shortages of radiologists and certified mammography technologists.
To determine radiologists’ reactions to uncertainty when interpreting mammography and the extent to which radiologist uncertainty explains variability in interpretive performance.
The authors used a mailed survey to assess demographic and clinical characteristics of radiologists and reactions to uncertainty associated with practice. Responses were linked to radiologists’ actual interpretive performance data obtained from 3 regionally located mammography registries.
More than 180 radiologists were eligible to participate, and 139 consented for a response rate of 76.8%. Radiologist gender, more years interpreting, and higher volume were associated with lower uncertainty scores. Positive predictive value, recall rates, and specificity were more affected by reactions to uncertainty than sensitivity or negative predictive value; however, none of these relationships was statistically significant.
Certain practice factors, such as gender and years of interpretive experience, affect uncertainty scores. Radiologists’ reactions to uncertainty do not appear to affect interpretive performance.
medical decision making; physician uncertainty; medical malpractice; mammography interpretation
Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone receptor-positive breast cancer. The benefit of adding chemotherapy and optimal timing of tamoxifen with chemotherapy are unknown.
We conducted a parallel randomized phase III trial in postmenopausal women with hormone receptor-positive, node-positive breast cancer to test whether disease-free survival (DFS) with cyclophosphamide, doxorubicin (AdriamycinR), and 5-fluorouracil (CAF) plus 5 years of tamoxifen was longer than with tamoxifen alone; and whether DFS with CAF followed by tamoxifen (CAF-T) was better than CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes. Randomization was a 2:3:3 (T:CAF-T:CAFT) unblinded allocation and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00929591.
Of 1558 women randomized, 1477 (95%) were eligible (tamoxifen, 361; CAF-T, 566; CAFT, 550). The combined CAF groups were superior to tamoxifen for the primary outcome of DFS (P=0.002), with adjusted Cox regression hazard ratio (HR) =0.76 (95% CI 0.64,0.91). CAF-T was marginally better than CAFT for DFS (P=0.055) with adjusted HR 0.84 (0.70,1.01). Ten-year DFS for CAF-T, CAFT, and T were 60%, 53%, and 48%, respectively. The planned secondary outcome, overall survival, showed a similar pattern of results, with combined CAF groups seem superior to tamoxifen [p=0.043, adjusted HR 0.83 (0.68,1.01)]. Neutropenia, stomatitis, thromboembolism, congestive heart failure and leukemia were more frequent with CAF than tamoxifen alone.
Chemotherapy with CAF plus tamoxifen resulted in longer survival over tamoxifen in endocrine-responsive, node-positive breast cancer, with greater benefit when tamoxifen followed CAF.
National Cancer Institute (NIH-USA).
To understand mammographers’ perception of individual women’s breast cancer risk.
Materials and Methods
Radiologists interpreting screening mammography examinations completed a mailed survey consisting of questions pertaining to demographic and clinical practice characteristics, as well as 2 vignettes describing different risk profiles of women. Respondents were asked to estimate the probability of a breast cancer diagnosis in the next 5 years for each vignette. Vignette responses were plotted against mean recall rates in actual clinical practice.
The survey was returned by 77% of eligible radiologists. Ninety-three percent of radiologists overestimated risk in the vignette involving a 70-year-old woman; 96% overestimated risk in the vignette involving a 41-year-old woman. Radiologists who more accurately estimated breast cancer risk were younger, worked full-time, were affiliated with an academic medical center, had fellowship training, had fewer than 10 years experience interpreting mammograms, and worked more than 40% of the time in breast imaging. However, only age was statistically significant. No association was found between radiologists’ risk estimate and their recall rate.
U.S. radiologists have a heightened perception of breast cancer risk.
perception; risk; pretest probability