Erin J. Aiello Bowles, MPH

Human epidermal growth factor receptor 2 (HER2) expression is amplified in about 20% of breast cancer tumors, and evaluation of HER2 status should influence therapy selection. A critical gap in our knowledge is the real-world implementation of HER2 testing and its impact on treatment decisions for women diagnosed with breast cancer.

To assess use of HER2 testing, to describe characteristics of patients who do or do not receive HER2 testing, to describe which HER2 tests were used (fluorescence in situ hybridization or immunohistochemistry), and to evaluate trastuzumab use as a function of HER2 results.

The population included 6460 women diagnosed with invasive breast cancer between 1999 and 2007 at 8 geographically distributed Cancer Research Network healthcare delivery systems in the United States.

Electronic records were used to identify patient and tumor characteristics and treatment with trastuzumab. Chart abstraction was performed for 400 women (50 per site) to identify receipt of HER2 testing and results.

More than 90% of study participants received HER2 testing. Everyone who received trastuzumab had a HER2 test, and nearly all (>95%) who received trastuzumab had a positive HER2 test result recorded in their medical chart. Most (77%) eligible patients with a positive HER2 test result diagnosed after 2005 received trastuzumab. This study expands upon previous work in individual health plans.

HER2 status has been successfully incorporated into medical practice to guide treatment decisions for breast cancer patients in diverse integrated healthcare delivery settings.

We evaluated real-world implementation of human epidermal growth factor receptor 2 (HER2) testing and its impact on treatment decisions for women diagnosed with breast cancer between 1999 and 2007 at 8 US integrated delivery systems. There was consistent success in implementation of HER2-guided treatment decisions for breast cancer patients in these settings.

More than 90% of study participants received HER2 testing.

Everyone who received trastuzumab had a HER2 test, and more than 95% of these women had a positive HER2 test result.

Most (77%) eligible patients with a positive HER2 test result diagnosed after 2005 received trastuzumab.

In 2011, about 230,000 women in the United States were newly diagnosed with invasive breast cancer.

About 40,000 of these women are expected to die of this disease. Recent advances in medicine utilizing genetic-based technologies better predict cancer recurrence or response to various treatments and present an important opportunity for patients and their physicians to individualize therapy. However, there are limited reports in the literature about how such technologies are being incorporated into clinical practice and whether they are being used appropriately.

 As genetic-based technologies proliferate, understanding how and when these applications should be used in clinical practice becomes increasingly important.

One such genetic technology targets human epidermal growth factor receptor 2 (HER2). HER2 is a gene that influences cell growth, division, and repair. A normal cell has 2 copies of HER2. About 18% to 20% of breast cancers have HER2 gene amplification (more than 2 copies of this gene).

 HER2 amplification is associated with rapid tumor proliferation, shorter disease-free survival, and poorer overall survival.

The drug trastuzumab (Herceptin, Genentech Inc, San Francisco, California) is indicated for individuals with breast cancer that either overexpresses the HER2 protein or amplifies the HER2 gene to prevent the growth of HER2-positive cancer cells.

 It was approved by the US Food and Drug Administration (FDA) for use in the treatment of metastatic breast cancer in 1998 based on the findings from 2 clinical trials, which showed improvement in the median time to progression of 3 to 5 months, and an increase in the overall response rate of 10% to 30%.

 Despite the fact that trastuzumab is also well established as a highly efficacious (adjuvant) antineoplastic agent for HER2-positive breast cancer, it is expensive ($44,000-$65,000 per year

) and may have serious cardiotoxic effects.

 Because of these factors, selecting patients for whom trastuzumab treatment is appropriate remains vital. Trastuzumab treatment should be cautiously used for patients with preexisting cardiac dysfunction or deteriorating cardiac function even if they have a positive HER2 test result, especially older women with prior cardiac history or prior cardiotoxic therapies.

Two types of tests are FDA approvedto select patients for treatment with trastuzumab. The first test is a based on immunohistochemistry (IHC) (eg, Dako HercepTest, Ventana PATHWAY), which measures membrane expression of HER2 receptor protein. The second type of test (eg, Vysis PathVysion, Ventana INFORM HER2 probe) is based on the fluorescence in situ hybridization (FISH) technology to measure the underlying gene amplification in tumor cells. In this approach, fluorescent probes are used to quantify the number of HER2 gene copies in a tumor cell. If there are 2 or more copies of the HER2 gene per chromosome 17, then a gene amplification has occurred, and the breast cancer is considered HER2 positive.

The American Society of Clinical Oncology and College of American Pathologists HER2 testing guidelines currently recommend initial testing by IHC testing and reflex testing of equivocal result (2+) by FISH testing.

 Although some reports have suggested that the FISH technology more accurately predicts response to trastuzumab than IHC technology,

 a recent summary report indicates that both technologies perform equally well if carefully validated testing is performed.

 Cost may also be a factor in the selection of test modality, because the FISH test is generally more expensive to perform than the IHC test. For both testing methods, underlying quantitative measures can be translated into a dichotomous positive/negative finding. Both tests are considered equivocal when the quantitative measures are near the threshold for a positive result. Retesting might resolve these equivocal findings.

 Increased error rates and inconsistent results are also introduced by decentralized testing, particularly for centers with a low volume of testing. Thus, Wolff and colleagues

 recommend a quality assurance program for HER2 testing, and suggest various accreditation, proficiency, and competency measures for laboratories conducting HER2 testing.

Trastuzumab was initially approved by the FDA in 1998 for use in breast cancer patients with metastatic cancer. In November 2006, the FDA approved the use of trastuzumab in the adjuvant setting for women with lymph node—positive and HER2-positive breast cancer, following several major trials.

 Professional organizations, including a joint guideline from the American Society of Clinical Oncologists and College of American Pathologists, currently recommend that HER2 testing should be performed for all invasive breast cancers regardless of lymph node disease status.

The National Comprehensive Cancer Network has also issued physician practice guidelines endorsing HER2 testing.

 Despite these evidence-based practice guidelines, there are few reports on how HER2 testing has been utilized in realworld settings. In particular, Phillips and colleagues

 highlighted the fact that little is known about how many patients are tested for HER2, which testing methods are used, whether patients are retested to confirm indeterminate results, and how many patients with negative or equivocal results receive trastuzumab. Additionally, it is not clear how trastuzumab is utilized across important subgroups such as patient age, race, and cancer stage.

To answer these questions, we conducted a large, multiinstitutional study in 8 Cancer Research Network (CRN) integrated healthcare delivery systems across the United States. The organizations participating in this study provide a unique resource to address this research question by providing access to longitudinal and comprehensive electronic medical record data for populations totaling more than 6 million covered lives. We describe the real-world implementation of HER2 testing and trastuzumab prescribing in this setting.

The study population included 6460 women who were diagnosed with an invasive breast cancer that was 2+ cm in size or who had positive nodes at diagnosis from January 1, 1999, to December 31, 2007, and who were enrolled at one of the 8 participating CRN study sites for at least 12 months prior to diagnosis. These tumor size and lymph node status criteria were used to restrict the population to women similar to those in the adjuvant trastuzumab clinical trials. Subjects were followed for up to 12 months following diagnosis. Follow-up periods of less than 12 months were due to death or disenrollment during that period. The 8 participating study sites are geographically distributed within the United States and represent diverse populations: Group Health Cooperative (Washington), Kaiser Permanente Northwest (Oregon and Washington), Kaiser Permanente Northern California, Kaiser Permanente Colorado, Kaiser Permanente Georgia, Marshfield Clinic (Wisconsin), Henry Ford Health System (Michigan), and Harvard Pilgrim Health Care Institute with clinical data from Harvard Vanguard Medical Associates (Massachusetts). The study population included all eligible subjects at each site except for Kaiser Permanente Northern California, which contributed data on a 10% random sample of their eligible population.

A subset of 400 cases (50 from each site) was sampled from the original cohort for detailed chart review using stratified sampling (

) to ensure adequate numbers of subjects with chemotherapy exposure and the outcome of heart failure. Weights were used for some analyses, and were calculated as 1 over the probability of being sampled (ie, 1/(1/N), where N is the number of subjects in that stratum; N 

1, since at minimum the sampled subject belongs to the stratum). The primary purpose of the chart review was to validate electronic administrative data for chemotherapy exposure to anthracyclines or trastuzumab and the outcome of heart failure, as measured by clinical criteria and measurement of left ventricular ejection fraction, which was previously reported in a separate publication.

 However, the availability of data on HER2 genetic testing from the chart abstraction allowed us to conduct this secondary analysis. This study was approved by the institutional review boards (IRBs) at Group Health Cooperative, Marshfield Clinic Research Foundation, and Henry Ford Health System, and did not require written informed consent. The IRBs for the remaining sites ceded authority to the Group Health Cooperative IRB. A small number of health system members at each site have elected not to participate in anonymous or unconsented research protocols, and these subjects were excluded from this research study.

All genetic test results used in this study are from testing that occurred as part of routine medical care at each of the 8 participating sites. The laboratory performing the testing varied by site; however, the interpretation was similar. IHC testing for HER2 was classified as negative (0 or 1+), equivocal (2+), or positive (3+), except at Henry Ford Health System where 2+ was considered positive. FISH testing for HER2 was classified as negative (HER2/CEP 17 ratio <1.8), equivocal (HER2/CEP 17 ratio between 1.8 and 2.2), or positive (HER2/CEP 17 ratio >2.2). At Kaiser Permanente Northern California, the cutoff for FISH positive was a HER2/CEP 17 ratio of >2.0 for all but the last year of this study, following the American Society of Clinical Oncology and College of American Pathologists recommendation to change the cut point to 2.2 in January 2007.

We identified the internal practice guidelines for HER2 testing at each site. Since 2000, guidelines for all sites specify that all new invasive breast cancer patients are automatically ordered a HER2 test using IHC testing. Reflex testing is performed using FISH to clarify or confirm equivocal IHC findings (at all sites) plus additional subsets including all positive IHC findings at 2 sites, cases at the discretion of the treating oncologist at 2 other sites, or cases with an IHC test result of 1+ or more positive at 1 additional site. At 1 site, the protocol was changed in October 2007 to initially test all invasive tumors for HER2 by FISH.

We used stratified sampling to ensure adequate representation of the chemotherapy exposures and outcomes in the chart-reviewed sample (eAppendix). Identification of prevalent heart failure at the time of diagnosis (a possible contraindication for trastuzumab use) was also obtained exclusively from chart abstraction. The method used to define heart failure is described elsewhere.

 We used standardized abstraction forms and abstractor training protocols to ensure uniform data recording across sites and abstractors. The lead project manager rereviewed 10% of charts from each CRN site for inconsistencies, inaccuracies, and missing data, and questions were referred back to the originating site for clarification. During chart review, both qualitative and quantitative descriptions of HER2 results were collected from the medical record. Any apparent discrepancies were resolved by rereview at the originating site.

Each CRN site maintains electronic health record information on its member population including membership, diagnoses, pharmacy data, and a tumor registry. From these records, we extracted electronic data on patient characteristics (age at diagnosis, sex, race, ethnicity, year of diagnosis), tumor characteristics (stage, lymph node involvement, tumor size), and chemotherapy treatment. The Charlson Comorbidity Index is a quantitative variable that was computed using diagnosis codes as previously described anchored at the date of diagnosis.

Patients were classified as receiving trastuzumab using a dichotomous indicator variable if any of the following national drug codes were in the pharmacy records after their date of diagnosis: 50242013460, 50242013468, 50242005656, or 63552047001, or if procedure code J9355 was in the procedures database. This definition was validated against data from chart abstraction and demonstrated to have high predictive value.

Lymph node status was a dichotomous indicator variable defined as positive (1 or more positive nodes) or negative. Tumor size was a quantitative trait defined as the size of the largest qualifying tumor (a small number of patients had more than 1 primary tumor during the study period). We defined invasive breast cancer using Surveillance Epidemiology and End Results (SEER) staging criteria

 as patients diagnosed with localized, regional, or distant metastatic breast cancer. The primary dependent variable was receipt of HER2 testing, which was treated as a dichotomous indicator variable. Data on receipt of HER2 testing and the test result (categorical variable) were obtained exclusively from chart abstraction of the medical record.

All analyses, including descriptive statistics, summaries, and multivariate linear regression, were produced using R (version 2.11.1; R Foundation for Statistical Computing, www.r-project.org) and SAS version 9.2 (SAS Institute Inc, Cary, North Carolina). We used a Bonferroni correction to adjust the simultaneous confidence intervals. The multivariate model used a generalized linear model with receipt of HER2 testing as the dependent variable and the following independent variables: diagnosis year, race, lymph node status, SEER stage, site, age, presence of heart failure, and Charlson Comorbidity Index.

Of the entire cohort of 6460 women, 7.5% (n = 483) received trastuzumab. Trastuzumab use varied by year of diagnosis and stage of disease. Although the 

 of subjects who received trastuzumab was highest among women with distant stage breast cancer (

), women with distantstage breast cancer represented the smallest 

 who received trastuzumab in every year (

), because most women are diagnosed at an earlier stage of disease. The proportion of subjects who received trastuzumab increased for all stages of disease after 2004 when professional guidelines changed (Figure 1). The proportion of women in the chart review population who received trastuzumab was 18% (72/400), which is higher than the proportion of women who received trastuzumab in the entire study population, because we intentionally overselected trastuzumab recipients for review. However, after adjustment using the weights described above, 6.4% of the chart review population received trastuzumab.

All of the sites performed IHC testing in-house, and most sites used the HercepTest kit (Dako, Carpenteria, California). All except 1 site used a reference laboratory to perform FISH testing, and all sites used the Vysis PathVysion test (Abbott Molecular, Abbott Park, Illinois). Among the 400 subjects in the chart review population, 367 had tumors tested by IHC and 94 had tumors tested by FISH. Only 30 women (7.5%) received neither test.

Consistent with practice guidelines at the 8 sites, nearly everyone who was tested received IHC testing, with only 4 women receiving FISH testing alone. FISH testing occurred more frequently in the latter years of the study, possibly reflecting a phasing in of FISH testing during this time frame. Of those who received both tests, 74% had a positive or borderline IHC test result, whereas the majority of patients (69%) who received IHC testing alone had a negative HER2 result. A substantial proportion (40%) of subjects with a borderline IHC test result had no evidence of receiving FISH testing, contrary to most site practice guidelines. Among 17 patients with a borderline IHC test result, 3 received trastuzumab. There was also large variation among sites in the proportion of subjects with a borderline IHC test who did not receive FISH testing (range 0%-63%; 

Of those who did not receive either test, 50% (n = 14) were diagnosed in 1999, around the time that testing was initiated at most of the sites (

). Excluding the 28 patients diagnosed in 1999, 96% (356/372) of patients received some form of HER2 testing. The remaining 16 patients who were not tested were more likely to be older than 70 years (

 = .026), to have distant-stage disease (

 = .0032), to have negative lymph nodes (

 = .013), or to have been diagnosed in 2005. We also detected differences in the proportion who did not receive testing across sites ranging from 0% to 14% (

 = .0003), although about one-third of the women had missing data for race/ethnicity.

Trastuzumab Use as a Function of HER2 Status

As expected based on the sampling criteria, a higher proportion (32% [119/373]) of women in the chart review sample who received HER2 testing were HER2 positive compared with population estimates.

Trastuzumab was primarily used by patients with a HER2- positive test result (

). None of the patients in this sample who were not tested for HER2 status used trastuzumab. Of patients with only a HER2-negative or borderline result, 1.6% (4/255) used trastuzumab, and 35% (9/26) of patients with HER2 discordant results used trastuzumab. In these 9 discordant cases, 7 patients had positive FISH tests and 2 had a positive IHC test. Of the 17 who did not receive trastuzumab, 10 had positive FISH tests and 7 had positive IHC tests. Overall, 64% (61/96) of patients with HER2-positive results received trastuzumab; however, this use was dependent on year of diagnosis and stage of disease. In 1999-2005 (when trastuzumab was primarily recommended for patients with distant metastatic disease) only 52% of HER2-positive patients used trastuzumab, whereas in 2006-2007 (by which time recommendations had been adopted for use of trastuzumab in all cases of invasive cancer), 84% of HER2-positive patients used trastuzumab.

Some subjects with positive HER2 status did not receive trastuzumab. Of the 6 subjects with localized or regional disease who were diagnosed after 2005 and who did not receive trastuzumab, one had heart failure at diagnosis. For the remainder, a rationale was not readily apparent based on our assessment of the comorbidity index, age at diagnosis, or other patient characteristics. In addition, 2 subjects with distant metastatic disease who were HER2 positive did not receive trastuzumab. One of these patients had heart failure at diagnosis, while the other case could not be readily explained based on patient characteristics in our data set. Other factors such as patient preference, physician opinion, unrecorded negative or borderline HER2 test results, or treatment outside of the reporting sites could explain these observations.

Articles

Evaluation of real-world implementation of HER2 testing showed that uptake was high (>90%) and trastuzumab treatment was targeted to patients with positive HER2 status.

Utilization of HER2 Genetic Testing in a Multi-Institutional Observational Study

To evaluate woman-level characteristics associated with timing of follow-up after abnormal mammograms in an integrated healthcare system with an active breast health program.

 The study included women aged 40-84 years who had an abnormal mammogram (20,060 screening and 3184 diagnostic) recommended for follow-up. We compared characteristics of women who received any follow-up evaluation within <7, 8 to 14, 15 to 21, and 22 to 180 days. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariate ordinal logistic regression.

 The proportion of women seeking care within 7 days was 23% for screening and 69% for diagnostic mammograms. Characteristics associated with later follow-up (>8 days vs <7 days) after an abnormal screening mammogram included being older (OR = 1.15; 95% CI, 1.04-1.26 [age 70-79 years]; OR = 1.31; 95% CI, 1.14-1.51 [age 80 years]), Asian (OR = 1.18; 95% CI, 1.04-1.33), or having a college degree (OR = 1.10; 95% CI, 1.01-1.19). Characteristics associated with earlier follow-up included family history of breast cancer (OR = 0.93; 95% CI, 0.88-0.98), symptoms at time of mammogram (OR = 0.79; 95% CI, 0.70-0.88), or extremely dense breasts (OR = 0.82; 95% CI, 0.69-0.96). For diagnostic mammograms, symptoms at time of mammogram (OR = 0.47; 95% CI, 0.39-0.56) and being obese (OR = 0.79; 95% CI, 0.65-0.98) were associated with earlier follow-up.

 Several woman-level characteristics were associated with timely follow-up after an abnormal screening exam, but only presence of symptoms and being obese was associated with timely follow-up after an abnormal diagnostic exam.

	Within an integrated healthcare system with an active breast health program to facilitate care after an abnormal mammogram, there remains woman-level characteristics associated with timely follow-up.

		Presence of symptoms was associated with timely follow-up after both abnormal screening and diagnostic mammogram.

		Women who were older, Asian, or more educated were less likely to return earlier after an abnormal screening mammogram. Efforts to understand and reduce barriers might be important in these groups of women.

	Approximately 75% of US women report having at least 1 screening mammogram to detect breast cancer.

 Abnormal mammograms, which require additional imaging or surgical follow-up, occur at a rate of almost 10% and 8% of screening and diagnostic exams, respectively.

 There are currently no published national data available for mammography facilities and practices benchmarks for the appropriate timing for receipt of follow-up evaluation after an abnormal mammogram.

	A delay in follow-up can be attributed to characteristics of the woman (ie, not making an appointment), the provider (ie, not communicating the importance of follow-up), or the healthcare system (ie, insufficient scheduling space for prompt return). Failure of 1 or all of these systems results in delayed follow-up by the patient, which may contribute to a delayed diagnosis of breast cancer, later stage disease,

 Woman-level characteristics associated with a delay or lack of follow-up after an abnormal mammogram include being older,

	Evaluating the follow-up of breast health within an HMO setting provides opportunities to monitor women after an abnormal mammographic exam when access to appropriate follow-up care should be equitable. Two prior studies have evaluated follow-up after an abnormal mammogram within an HMO setting,

 but neither study had an active program for breast health, which would identify and schedule care for women with abnormal mammograms. In our study, we investigated woman-level characteristics associated with  follow-up after an abnormal mammography examination in women enrolled in a health plan with an active breast health program.

	Women aged 40 to 84 years who received a mammogram between 1996 and 2003 in Group Health, an integrated delivery system in the Puget Sound region of Washington State, and were enrolled for at least 12 months were eligible for this study. All women had access to free mammography through the health plan, including screening and diagnostic exams. This analysis is restricted to women with an abnormal result from mammography defined as a Breast Imaging Reporting and Data System (BI-RADS)

 assessment of 0 (incomplete), 4 (suspicious abnormality), or 5 (highly suspicious of malignancy). We specifically excluded women recommended for 6-month short-interval follow-up (BI-RADS 3) because we were interested in abnormal exams that required immediate attention. Further, we restricted the sample to women who were recommended to receive additional follow-up with 1 of 4 procedures: (1) biopsy, (2) fine needle aspiration, (3) surgical evaluation, or (4) ultrasound. Women had to be continuously enrolled for 12 months after the abnormal mammogram to ensure adequate information on follow-up. We identified 25,272 and 5074 abnormal screening or diagnostic mammograms, respectively.

 Breast Cancer Screening Program at Group Health

	Since 1985, the Breast Cancer Screening Program at Group Health has sent reminder letters to women to encourage participation in mammography screening.

 To date, the program has mailed more than 500,000 letters. Breast clinic nurses were responsible for much of the follow-up after a mammogram. For 

, the radiologist interpreted the image the next working day after the mammogram. The breast clinic nurses called the patient within 24 to 48 hours after the report was issued with the patient’s result. If a patient had an abnormal result, the breast clinic nurse attempted to schedule the next available appointment for the patient. For 

, the radiologist interpreted the image the same day and reported the result of the mammogram to the woman. A patient with an abnormal diagnostic mammogram would have scheduled the next available follow-up appointment recommended by the radiologist with the breast clinic nurse. Among nonresponders for either screening or diagnostic mammograms, the breast clinic nurse would call the patient to schedule the follow-up appointment.

	At the time of the mammography visit, women completed a self-administered questionnaire,

 which collected information on age, reproductive risk factors, breast screening, medical history, and concerns regarding women’s breasts at the time of the exam. Women completed the questionnaire before knowing the results of their mammogram. The  uestionnaire served as the data source for woman-level characteristics under evaluation.

	Information about follow-up procedures was available through electronic administrative data including pathology, radiology, utilization, and claims databases. Time to follow-up care was calculated from the date of the mammogram until the first date of follow-up care with any of the 4 procedures. Women might have received a procedure that was different from the one recommended, but was still 1 of the 4 procedures of interest. We categorized women according to receipt of follow-up care within <7, 8 to 14, 15 to 21, and 22 to 180 calendar days, based on ability to seek follow-up care within sequential weeks up to 4 weeks.

	This study was approved by the institutional review board at Group Health Research Institute.

	Woman-level characteristics of interest for this analysis included the following risk factors: age, race, body mass index (kg/m2), education, family history of breast cancer in first- or second-degree relatives, self-reported symptoms at the time of mammography, biopsy history prior to the mammography examination, radiologists’ interpretation of mammographic breast density,

 and use of postmenopausal hormone therapy. Women with missing data for any of the risk factors or without follow-up within 180 days were excluded from the  analysis. The final sample size included 20,060 screening and 3184 diagnostic mammograms. Descriptive summary statistics were calculated for each variable by interval of follow-up time.

	We used a multivariate ordinal logistic regression model (ologit) for ordered outcome variables to compare differences in the follow-up timing intervals.

An ordinal logistic model is a model for multinomial data that generalizes the logistic regression model. The model allows the consideration of differences in “early” versus “later” follow-up at each of the 3 thresholds of the outcome. The interpretation of the odds ratio is the comparison of early versus late defined in our analysis as <7 days versus >8 days. All analyses included all potential risk factors and used robust methods to account for clustering for multiple records per woman. Tests for trends were evaluated by entering the ordinal term representing  the categorical variable into the ordinal model. We evaluated the contribution of each variable using a likelihood ratio test, comparing the full model with the reduced model. All hypothesis tests were 2-sided and assumed a type I error rate of alpha = .05.

	All analyses were conducted in Stata/MP 11.0 (Stata-Corp, College Station, TX).

	For women who had an abnormal screening mammogram, the median time from receipt of the exam to followup was 13 days. The proportion of women receiving care within <7, 8 to 14, 15 to 21, and 22 to 180 days was 23.3%, 36.3%, 22.0%, and 18.3%, respectively, among women with abnormal screening mammogram (

). For women who had an abnormal diagnostic mammogram, the median time to further follow-up was 5 days. Further, the proportion of women receiving care within 7, 8 to 14, 15 to 21, and >22 days was 69.1%, 10.6%, 7.0%, and 13.2%, respectively (

	Among women with an abnormal screening mammogram, those more likely to receive follow-up care after 7 days were older (70-79 and >80 years) (P-trend <.001), Asian or Pacific Islander, and college graduates (P-trend = .006). The woman-level factors associated with being more likely to receive follow-up care within 7 days included reporting symptoms at the time of the exam, having a positive family history of breast cancer, and having extremely dense breasts (P-trend = .001) (Table 1).

	Among women with an abnormal diagnostic mammogram, few woman-level characteristics were associated with earlier or later follow-up. Older women had later follow-up than younger women, though the results were not statistically significant at all levels. Women with higher body mass index P-trend = .026) and symptoms at the time of the mammogram were more likely to have follow-up care earlier rather than later.

	This is the largest study to date to investigate the timing of follow-up after an abnormal mammogram. Unique features of this analysis include the available data from an integrated healthcare system and active surveillance by nurses to encourage and assist patients in returning to evaluate the abnormality noted on the mammogram. Further, we had sufficient data to investigate follow-up for both screening and diagnostic mammograms.

	We confirmed that women of older age were more likely to seek care later rather than earlier for both screening and diagnostic mammograms.

 We also detected that having symptoms at the time of the mammogram was associated with earlier follow-up for both screening and diagnostic exams. Our finding is supported by Caplan and colleagues, who determined that women with breast symptoms were diagnosed with breast cancer 6 days earlier than women without breast symptoms.

	In this study, we found that women of Asian/Pacific Islander descent were more likely than white women to delay follow-up care after an abnormal screening mammogram. Karliner and colleagues reported that Asian women did not fully understand their physicians’ reports of their mammograms, particularly Chinese-speaking women.

 It is unclear whether language barriers were responsible for the longer delay in seeking care among Asian/Pacific Islander women in our study, but language interpreters or written materials might help reduce delay in other programs.

	Women with extremely dense breasts were more likely to seek follow-up care quickly compared with women with less dense breasts. Prior studies have not reported on breast density and delay in follow-up care. The sensitivity of mammography in women with extremely dense breasts is only 30% compared with 80% in women with fatty breasts.

 These women are also likely to have an increased risk of interval cancers,

 which likely results in their prompt follow-up.

	In our study, fewer than 1% and 4% of women with abnormal screening and diagnostic mammograms, respectively, did not receive any follow-up within 180 days (data not shown). Other studies have reported lack of follow-up in women after abnormal exams at rates between 8% and 28%.

 The difference in rates of follow-up is likely due to the ability of women to receive additional medical services within our health system at no financial burden and with the assistance of specially trained nurses working in the breast program. The use of computer monitoring to follow up with women postmammography reduces the delays in seeking care.

 Group Health’s Breast Cancer Screening Program implemented active follow-up of women with breast clinic nurses and now uses the electronic medical record to help track women.

	This study was conducted in a well-characterized defined population of women who receive healthcare through an integrated delivery system. There was thorough assessment and follow-up of mammography screening because of the Breast Cancer Screening Program at Group Health. We might have missed some clinical care that occurred at outside facilities that was not submitted for a claim. However, this is unlikely for women with their primary insurance at the health plan, because filing a claim would enable payment for outside services and women would be motivated to do so.

	Clinical guidelines for promptness in obtaining an evaluation after an abnormality is noted on mammography examination are not well established. An assessment of the National Initiative on Cancer Care Quality in the United States suggests that 90% of patients should be seen within 3 weeks of an abnormal screening mammogram for a diagnostic mammogram, within 14 days from needing an open biopsy to cancer diagnosis, and within 5 working days from breast cancer diagnosis to an appointment with the treating physician.

 While we cannot make a direct comparison to the National Initiative for Cancer Care Quality, we can report that 82% of women received the recommended follow-up care within 3 weeks of their abnormal screening mammogram. Further, 69% of women with abnormal diagnostic mammograms received recommended follow-up care within 7 days. In 2004, the National Quality Measures for Breast Centers identified 2 measures of timely follow-up: imaging timeliness of care (ie, time between screening mammogram, diagnostic mammogram, needle biopsy, surgery) and surgical timeliness (ie, time between diagnostic mammogram, open surgical biopsy/excision, initial breast cancer surgery).

 There are characteristics that influence women’s timeliness to follow-up that future interventions may address to reduce delays in breast cancer diagnosis.

 From Group Health Research Institute (KJW, EJAB, SH, DSMB), Seattle, WA; and Department of General Internal Medicine (JGE), University of Washington, Seattle, WA.

 This research was supported by the National Cancer Institute (Dr Buist, Principal Investigator, U01CA63731; and Dr Elmore, Principal Investigator, K05CA104699).

 The authors (KJW, EJAB, SH, JGE, DSMB) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Woman-level characteristics such as breast symptoms at mammography are associated with earlier follow-up within an integrated health system with an active breast health plan.

Erin J. Aiello Bowles, MPH

Articles

Utilization of HER2 Genetic Testing in a Multi-Institutional Observational Study

Timing of Follow-up After Abnormal Screening and Diagnostic Mammograms