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

Abstract

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.

Objective

Study aims were 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 [FISH] or immunohistochemistry [IHC]), and to evaluate trastuzumab use as a function of HER2 results.

Study Design

The population included 6,460 women diagnosed with invasive breast cancer between 1999 and 2007 at eight geographically distributed Cancer Research Network health care delivery systems in the United States.

Methods

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

Results

Over 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 cases with a positive HER2 test result diagnosed after 2005 received trastuzumab. This study expands upon previous work in individual health plans.

Conclusions

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

Introduction

In 2011, about 230,000 women in the US will be newly diagnosed with invasive breast cancer.¹ 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 presenting 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.^2,3 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 two copies of HER2. About 18-20% of breast cancers have HER2 gene amplification (more than two copies of this gene).^4-6 HER2 amplification is associated with rapid tumor proliferation, shorter disease-free survival, and poorer overall survival. ^7-9 The drug trastuzumab (Herceptin®, Genentech Inc., San Francisco, CA) 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.^10-14 It was approved by the FDA for use in the treatment of metastatic breast cancer in 1998 based on the findings from two clinical trials, which showed improvement in the median time to progression of three to five months, and an increase in the overall response rate between 10% to 30%.¹⁵ 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 ^16,17) and may have serious cardiotoxic effects.¹⁸ Because of this, selecting patients for whom trastuzumab treatment is appropriate remains vital. Trastuzumab treatment should be cautiously used for patients with pre-existing cardiac dysfunction or deteriorating cardiac function even if they have a positive HER2 test result, especially in older women with prior cardiac history or prior cardiotoxic therapies.

Two types of tests are FDA approved to select patients for treatment with trastuzumab. The first test is an immunohistochemistry (IHC)-based test (e.g., DAKO HercepTest; Ventana Pathway), which measures membrane expression of HER2 receptor protein. The second type of test (e.g., 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 two 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 (ASCO/CAP) HER2 testing guidelines currently recommend initial testing by IHC testing and reflex testing of equivocal result (2+) by FISH testing.¹⁹ Although some reports have suggested that the FISH technology more accurately predicts response to trastuzumab than IHC technology,²⁰ a recent summary report indicates that both technologies perform equally well if carefully validated testing is performed.¹⁹ Cost may also be a factor in the selection of test modality, where 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. Re-testing might resolve these equivocal findings.¹⁹ Increased error rates and inconsistent results are also introduced by decentralized testing, particularly for centers with a low volume of testing. Thus, Wolff and colleagues¹⁹ 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 U.S. Food and Drug Administration (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.^11-13 Professional organizations, including a joint guideline from the American Society of Clinical Oncologists (ASCO) and College of American Pathologists (CAP), currently recommend that HER2 testing should be performed for all invasive breast cancers regardless of lymph node disease status.¹⁹ The National Comprehensive Cancer Network (NCCN) has also issued physician practice guidelines endorsing HER2 testing.^21-24

Despite these evidence-based practice guidelines, there are few reports on how HER2 testing has been utilized in real world settings. In particular, Phillips and colleagues (2008)³ highlighted the fact that little is known about how many patients are tested for HER2, which testing methods are used, whether patients are re-tested 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, multi-institutional study in eight Cancer Research Network (CRN) integrated health care delivery systems across the US. 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.

Methods

Study Population

The study population included 6,460 women diagnosed with an invasive breast cancer that was either 20 mm or larger, or had positive nodes at diagnosis from January 1, 1999 to December 31, 2007 who were enrolled at one of the eight participating Cancer Research Network (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 eight participating study sites are geographically distributed within the United States and represent diverse populations including Group Health Cooperative (Washington) [GHC], Kaiser Permanente Northwest (Oregon and Washington) [KPNW], Kaiser Permanente Northern California [KPNC], Kaiser Permanente Colorado [KPCO], Kaiser Permanente Georgia [KPG], Marshfield Clinic (Wisconsin) [MCRF], Henry Ford Health System (Michigan) [HFHS], and Harvard Pilgrim Health Care Institute [HPHC] with clinical data from Harvard Vanguard Medical Associates (Massachusetts). The study population included all eligible subjects at each site except KPNC, 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 [Supplemental Table 1] 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 one over the probability of being sampled (i.e., 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 (LVEF), which was previously reported in a separate publication.²⁵ 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 (IRB) 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.

HER2 Genetic Testing

All genetic test results used in this study are from testing that occurred as part of routine medical care at each of the eight 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 HFHS 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 KPNC, 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 ASCO/CAP recommendation to change the cut point to 2.2 in January 2007.¹⁹

We identified the internal practice guidelines for HER2 testing as 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 two sites, or cases at the discretion of the treating oncologist at two other sites, or cases with an IHC test result of 1+ or more positive at one additional site. At one site, the protocol was changed in October, 2007 to initially test all invasive tumors for HER2 by FISH.

Chart Abstraction

We used stratified sampling to ensure adequate representation of the chemotherapy exposures and outcomes in the chart reviewed sample (Supplemental Table 1). Identification of prevalent heart failure at the time of diagnosis (a possible contraindication for trastuzumab use) was also obtained exclusively from chart abstraction, and the method used to define heart failure is described elsewhere.²⁶ We used standardized abstraction forms and abstractor training protocols to ensure uniform data recording across sites and abstractors. Ten percent of charts from each CRN site were re-reviewed centrally by the lead project manager 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 re-review at the originating site.

Variable Definitions

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, gender, race, ethnicity, year of diagnosis), tumor characteristics (stage, lymph node involvement, tumor size), and chemotherapy treatment. Charlson co-morbidity index is a quantitative variable that was computed using diagnosis codes as previously described anchored at the date of diagnosis.²⁷ Patients were classified as receiving trastuzumab using a dichotomous indicator variable if any of the following national drug codes (NDCs) were in the pharmacy records after their date of diagnosis: 50242013460, 50242013468, 50242005656, 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.²⁸ Lymph-node status was a dichotomous indicator variable defined as positive (one 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 one primary tumor during the study period). We defined invasive breast cancer using SEER staging criteria²⁹ 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.

Statistical Methods

All analyses, including descriptive statistics and 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). 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 co-morbidity index.

Results

Trastuzumab Treatment

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 proportion of subjects who received trastuzumab is highest among women with distant stage breast cancer (Figure 1), women with distant stage breast cancer represented the smallest number of cases who receive trastuzumab in every year (Figure 2), 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.

Figure 1.

A) Proportion of invasive breast cancer patients who receive trastuzumab.Colored lines indicate the average proportion from 1999 to 2004 and from 2005 to 2007, separately, for patients with localized (blue), regional (red), and distant (purple) disease. B) Number of invasive breast cancer patients who receive trastuzumab. Colored lines indicate a fitted trend line using polynomial regression for subjects with localized (blue), regional (red), and distant (purple) disease. For both figures, black lines indicate the observed proportions each year for subjects with localized (circle), regional (square), and distant (triangle) disease. This data on 6,460 subjects does not account for HER2 status, since HER2 status was not collected in a readily available electronic format for the majority of subjects.

Figure 2. Number of patients who received IHC and FISH testing by diagnosis year.

HER2 Testing Patterns

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

Consistent with practice guidelines at the eight 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. Three of 17 of these patients received trastuzumab. There was also large variation among sites in the proportion of subjects with a borderline IHC test that did not receive FISH testing (range 0%-63%) [p=0.0043].

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 [Table 1]. 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 (over 70) [p=0.026], to have distant stage disease [p=0.0032], to have negative lymph nodes [p=.013], or to be diagnosed in 2005. We also detected differences in the proportion who did not receive testing across sites ranging from 0% to 14% [p=0.038], and across race/ethnicity [p=0.0003], although about one-third of the women had missing data for race/ethnicity.

Table 1. Impact of patient characteristics on the percentage of patients who do not receive HER2 testing.

Grey shaded areas represent the Bonnferroni adjusted 95% confidence interval around the average (black bar) from multivariate analysis.

Pvalues are the Bonnferroni adjusted pvalues from a linear regression model, using HER2 testing status as a dichotomous independent variable, and the dependent variables categorized as described above.

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 [Table 2]. 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. For these nine discordant cases, seven had positive FISH tests and two had a positive IHC test. Of the seventeen that did not receive trastuzumab, ten had positive FISH tests and seven had positive IHC tests. Overall, 64% (61/96) of patients with HER2 positive results used trastuzumab; however, this 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 for all invasive cancer), 84% of HER2 positive patients used trastuzumab.

Table 2. Trastuzumab use by disease stage and HER2 status.

	Diagnosis year between 1999 and 2005
SEER Stage	HER2 Positive1	HER2 Discordant2	HER2 Negative or Borderline3	HER2 Missing4
Distant	2/45	-	1/9	0/4
Regional	26/50	5/11	2/88	0/6
Localized	5/9	1/6	0/89	0/20
Total	33/63 (52%)	6/17 (35%)	3/186 (2%)	0/30 (0%)
	Diagnosis year between 2006 and 20076
SEER Stage	HER2 Positive	HER2 Discordant	HER2 Negative or Borderline	HER2 Missing
Distant	-	-	0/2	-
Regional	19/22	2/4	0/32	-
Localized	9/11	1/5	1/28	-
Total	28/33 (84%)	3/9 (33%)	1/62 (2%)	-
Overall Total	96	26	248	30

¹The category “HER2 Positive” refers to patients with a HER2 positive result for either IHC or FISH or Both, and who did not have a HER2 negative result.

²The category “HER2 Discordant” refers to patients with a HER2 positive result for IHC and a HER2 negative result for FISH or vice versa.

³The category “HER2 Negative or Borderline” refers to patients who received IHC and/or FISH testing, but whose results were only negative and/or borderline.

⁴The category “HER2 Missing” refers to patients who did not receive HER2 testing for IHC and FISH (n=30) or who did receive testing, but the test failed (n=3).

⁵The numerator is the number of patients in this category who received trastuzumab, and the denominator is the total number of patients in this category, where the category is defined by SEER stage, diagnosis date, and HER2 status. Reported counts are unweighted, descriptive observations of the chart review sample (n=400).

⁶Data for patients diagnosed between 2006 and 2007 are presented separately because the professional recommendations for trastuzumab treatment changed after 2005 to include women with regional or localized stage of disease in addition to those with distant metastatic cancer.

Some subjects with positive HER2 status did not receive trastuzumab. Of the six subjects with localized or regional disease who were diagnosed after 2005 and who did not receive trastuzumab, one had heart failure (HF) 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, there were two subjects with distant metastatic disease who were HER2 positive but did not receive trastuzumab. One of these cases had HF at diagnosis, while the other case could not be readily explained based on patient characteristics in our dataset. 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.

Discussion

Selection of patients for treatment with trastuzumab based on HER2 status is one of the first examples of targeted therapy in oncology. In this study, over 90% of eligible breast cancer patients received HER2 testing during the study period from 1999 to 2007. Trastuzumab use increased for all stages of breast cancer, and most women who receive trastuzumab have regional or localized disease. In the majority of cases, trastuzumab is appropriately used based on HER2 status. Everyone (100%) 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 (84%) eligible cases with a positive HER2 test result diagnosed after 2005 received trastuzumab, and the majority of patients with a positive HER2 test result prior to 2005 also received trastuzumab (52%).

Our findings are consistent with several previous studies that have reported similar results from individual health plans in the US and the UK [Table 3]. Because the studies span different time frames, we can observe a general improvement in the proportion of women who receive HER2 testing over time (from 52% in 1999-2000 to 84% in 2006-2007). This steady increase closely aligns with the timeline of professional recommendations for trastuzumab use and HER2 testing, which have broadened the eligible population for this testing and treatment. In our study population, there was a larger proportion of patients who did not receive testing in 1999 and in 2005. Although the reduced proportion in 1999 makes sense, because this was during the time frame immediately after the recommendation for HER2 testing became available, there is no immediately apparent reason for the reduced proportion in 2005. In general, a high percentage of women who are HER2 positive receive treatment with trastuzumab.

Table 3. Published Reports from Individual Health Plans.

Reference	Reporting Site	Diagnosis Years	No. Women with Invasive Breast Cancer	No. (%) women not evaluated for HER2	% HER2 positive1	No. (%) women who received trastuzumab without a documented positive HER2 result	No. (%) HER2 positive women who received trastuzumab
Stark (2004) 27	Henry Ford Health System	1999-2000	451	212 (48%)	Not reported	Not reported	Not reported
Onitilo (2009) 28	Marshfield Clinic	1998-2005	1767	612 (35%)2	201 (18%)	Not reported	Not reported
Barron (2009) 29	Three commercial health plans	2005-mid 2006	322	6 (2%)	72 (21%)	1/52 (2%)	39/45 (87%) stage II or higher
Webster (2010) 30	SW Wales Cancer Network (UK)	2006-2007	453	61 (13.5%)	47 (10%)	Not reported	34/47 (72.3%)
Webster (2010) 30	SW Wales Cancer Network (UK) – Cardiff & Vale only	2005-2008	121	Not reported	121 (100%)3	Not reported	93/121 (76.8%)
Coulson (2010) 31	North Trent Cancer Network (UK)	Sept. 2007 – Aug. 2008	13194	Not reported	199 (15%)	Not reported	133/199 (67%)
Haas (2011)32	Aetna	July 2006 – June 2007	775	24 (3.1%)	137 (18%)	25/104 (24%)	79/137 (57.7%) stage I, II, or III
Goddard (2011)33	Kaiser Permanente Northwest	1998-2007	3054	579 (19%)	496 (14%)	26/134 (19%)	19/32 (60%) distant metastatic 28/41 (68%) regional (after 2005) 35/79 (44%) localized (after 2005)

¹of those evaluated for HER2 status.

²women were not tested for ER/PR or HER2. The data for HER2 alone were not reported separately.

³Selected for the study on these criteria.

⁴metastatic breast cancer cases were excluded

We found that practice guidelines were not followed for 40% of subjects with a HER2 borderline test result in that FISH testing was not offered to these patients to clarify HER2 status. We also found variation across CRN sites with up to 14% of subjects who did not receive HER2 testing, as well as variation based on patient characteristics. This practice variation is unlikely to be explained by financial barriers, since all of the delivery organizations involved with this study have coverage policies for this testing and treatment.

There are several important limitations in the study design. First, our study was limited to women with lymph node positive disease or 2+ cm tumors, Second, subjects were not randomly selected for chart review, but were selected based on HF status and trastuzumab use. Therefore our estimates of proportion may not represent the true estimate in the general breast cancer patient population. We attempted to compensate for this by presenting weighted estimates whenever possible. Third, a small proportion of HER2 tests may have been received outside of our delivery systems. These tests could be missed if the test result was not recorded in the patient's medical record. This type of error will lead to an underestimate of the rate of utilization.

Patients who used trastuzumab were over-represented in the sample, which likely biases some estimates presented in this manuscript. We have attempted to adjust for this bias by presenting weighted estimates, where appropriate. However, not all categories of HER2 status were well represented in the chart review sample, which limits our ability to completely account for this limitation. The chart review sample also differs from the overall cohort because they are older (52% vs. 36% are over 65 years), but other patient characteristics are similar, as previously described.²⁸ Nevertheless, our findings are broadly consistent with previous work on similar questions, and represent the largest number of health care delivery organizations in the US that have been examined to date. Second, because of the very large number of patients in this study (over 6,000), and the fact that HER2 status was not the primary research question for this study, our analysis is necessarily restricted to limited data that was available through electronic sources or abstracted from a limited chart review. Thus, we were not able to address some questions, such as the reasons for not receiving trastuzumab among HER2 positive patients. The result is not generalizable to patients with smaller and node negative tumors.

We demonstrate rapid dissemination and implementation of HER2 testing and treatment programs across a large number of practice settings with strong concordance with professional recommendations. However, our findings also highlight unexplained practice variation, which can inform future methods of care delivery to reduce barriers to receipt of HER2 testing.

Take Away points.

We evaluated the real-world implementation of HER2 testing and its impact on treatment decisions for women diagnosed with breast cancer between 1999 and 2007 at eight integrated delivery systems in the United States.

• Over 90% of study participants received HER2 testing.

• Everyone who received trastuzumab had a HER2 test, and nearly all of these women (>95%) had a positive HER2 test result.

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

This study shows consistent success in the implementation of HER2-guided treatment decisions for breast cancer patients in these settings.