Three SEER registries (Los Angeles, Louisiana, and Seattle-Puget Sound) participated in this feasibility study focused on invasive first primary breast cancer patients diagnosed between June and December 2007. At each registry facilities diagnosing breast cancer cases were divided into tertiles of facility size (large, medium and small) based on the number of new cancer cases submitted to each registry in the last complete year of ascertainment. Numbers of cancer cases seen at large, medium and small facilities may differ by registry. Facilities were selected at random from each tertile. A target number of patients for each registry was set at 30 from each of 4 large facilities, 30 from each of 4 medium facilities, and 10 from each of 5 small facilities for a total of 290 cases. A run-in phase was established to test data collection procedures. The accrual goal for the run-in period was 50 cases from each registry, with 20 from a total of at least 3 large, 20 from a total of at least 3 medium and 10 from at least 3 small facilities. After the run-in period, the Los Angeles registry experienced a drastic change in resources necessitating modification of some registry processes. The registry ceased further study participation during this transition period.
Certified tumor registrars from the registry’s staff utilized a standard data collection form to extract the HER2 data from pathology reports and medical records. These forms, which included a generated number for patient identification, were submitted to the SEER Program at the NCI. Data were collected on the type of HER2 test performed (i.e. immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and/or other/unknown), quantitative results of test(s) performed, interpretation of test(s) performed, and the source of data for each data item (i.e. pathology report, addendum to pathology report, lab report in chart, other electronic data, other). In addition, the type of FISH test performed (ratio or copy number) and the cut point of the FISH test for positivity was obtained.
We defined HER2 positivity based on current clinical practice for interpreting the results of IHC and/or FISH testing, the two most commonly used approaches for evaluating HER2 status. FISH is generally considered the ‘gold-standard’ assay and is less susceptible to adverse effects of tissue handling than IHC. However, FISH is also more expensive and time-consuming, and requires equipment and training that may not be available in all clinical settings. FISH testing can be reported in two ways: as a ratio of HER2 gene copy number to an internal control probe; or as the number of gene copies per nucleus when an internal probe is not used. CEP17, a centromeric probe for chromosome 17, on which the HER2 gene is located, is used as an internal control. ASCO/CAP guidelines (1
) suggest a FISH test be deemed negative for a ratio of <1.8 or HER2 gene copy number <4.0, positive for a ratio >2.2 or a copy number >6.0, and equivocal for a ratio between 1.8 and 2.2 or a copy number of 4.0 to 6.0. This is estimated to result in an equivocal group of not more than 3%. Because studies have documented close to 95% concordance between IHC scores of 0/1+ and FISH non-amplification (i.e., HER2−) and greater than 90% concordance between IHC scores of 3+ and FISH amplification (i.e., HER2+) (6
), a common clinical protocol calls for the use of FISH testing only when IHC results are equivocal (i.e., 2+). Previous studies have shown that approximately 17–23% of breast tumors scored as 2+ by IHC are classified as positive by FISH (6
). Thus, HER2 testing in individual cases may be performed by IHC alone, FISH alone, or a combination of IHC and FISH. In this study HER2 status was derived by giving priority to FISH results over IHC, and to IHC results over a test of unknown type. Cases with a 2+ IHC result and no FISH testing were categorized as equivocal.
Information regarding patient age at diagnosis, race/ethnicity, tumor stage and grade were obtained from registries as available. Data were collected for this study much closer to date of diagnosis than is standard for the SEER Program; thus items, such as race and ethnicity, that would be complete when the case is officially reported to SEER, may not have been complete at the time of this study. Deidentified data from all three registries was combined in a database for analysis using the SAS statistical package. Percents of cases with HER2 related data items were calculated by various characteristics and statistical associations determined by chi square tests.