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    • We acknowledge some important limitations

    2022-08-22

    We acknowledge some important limitations to the study. Given that SEER is a national database of abstracted clinical information, there is selection bias as to which patients underwent RS testing. As clinicians are selecting which patients to test, the RS distributions may not reflect the true distributions in HER2+ patients. This may in part explain why the RS distributions are similar to those patients with HER2− breast cancer, as we would expect that the more aggressive tumor biology in HER2+ patients would lead to increased high-risk scores. Further, because SEER only began recording HER2 status in 2010, our study is limited from that date onward. With this short time period, we are unable to determine the implications of RS stratification and chemotherapy use on survival in this cohort. Further, HER2 information is collected as a dichotomous variable from several different data items in SEER, including results of immunohistochemistry, fluorescence in situ hybridization, and ‘unknown’ or ‘other’ test results. We are unable to parse out the variation in receptor fdps among those who are positive. Additionally, we are unable to obtain data on the use of HER2-directed therapy from the SEER database, and therefore cannot draw any conclusions on if RS testing in this population is impacting use of trastuzumab. Despite these limitations, this study is the first population-based study to evaluate the use of RS testing among patients with HER2+ breast cancer. We found that 5% of patients with HER2+ breast cancer in the United States underwent RS testing. Among those tested, the distributions of scores appear similar to those with HER2− disease, and clinicians appear to be forgoing chemotherapy administration more frequently in patients with low or intermediate scores. Further studies on RS testing in patients with HER2+ breast cancer are necessary to determine the validity of the test in this population, characterize long-term outcomes, and help clinicians identify additional patients who may be able to forgo chemotherapy administration without decrements to long-term outcomes.
    Disclosure
    Acknowledgments The authors would like to acknowledge Stephanie Lundgren and the Department of Surgical Oncology for their assistance with this manuscript. This project was in part funded by the Institute for Basic and Applied Research in Surgery and the VFW fund of the University of Minnesota.
    Introduction Human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in approximately 12–20% of invasive breast carcinomas and patients with HER2 positive breast cancers are considered eligible for treatment with HER2-targeted therapies [1,2]. Numerous studies have shown that HER2 is an important prognostic factor of breast cancer [[3], [4], [5]]. Herceptin, a humanized monoclonal antibody targeting HER2, has long been shown to significantly improve disease-free survival and progression-free survival in breast cancer patients [[6], [7], [8], [9]]. In recent years, other HER2-targeting drugs such as lapatinib, pertuzumab, and T-DM1 have been approved for breast cancer treatment and also have shown survival benefits [[10], [11], [12]]. Accurate HER2 testing is essential to identify right patients that can benefit from these treatments and reduce unnecessary costs and side effects. Currently, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are two assays approved by the FDA for HER2 testing. IHC is usually used as an initial testing assay, followed by FISH for samples with equivocal or discordant results [13,14]. In 2007, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) published guidelines on HER2 testing for breast cancer to improve the accuracy of HER2 testing for invasive breast cancer, which were then updated in 2013 [13,15]. According to the 2013 ASCO/CAP guideline recommendations, cases with HER2/chromosome enumeration probe 17(CEP17) ratio ≥2.0, or cases with HER2/CEP17 ratio <2.0 and the average number of HER2 signals ≥6 were classified as positive; and cases with HER2/CEP17 ratio <2.0 and the average number of HER2 signals per cell ≥4 and <6 were classified as equivocal when using a dual-probe FISH assay. Recently, the guidelines were once again updated. The 2018 ASCO/CAP guidelines clearly defined HER2 FISH results of five groups: group1 to group 5 [16]. For cases of group 2–4, the HER2 status diagnosis should base on the combined interpretation of FISH and IHC assays. If the HER2 IHC result is 2+, the FISH result should be recounted by another observer.