HER2 Testing in Breast Cancer American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update

HER2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. Accurate determination of HER2 status of the tumor is therefore essential for patients with invasive breast cancer, to ensure that those most likely to benefit are offered a HER2-targeted therapy and those who are unlikely to benefit can avoid toxicities as well as financial burden associated with those drugs.
Laboratory testing for HER2 status in patients with breast cancer in the US is performed according to guidelines developed by an Expert panel of members of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). The ASCO/CAP guidelines were first published in 2007 and were updated in 2013. The Expert panel in 2018 developed and issued a focused update of the clinical practice guideline on HER2 testing in breast cancer. This new information made available since the previous update in 2013 addresses uncommon clinical scenarios and improves clarity, particularly for infrequent HER2 test results that are of uncertain biologic or clinical significance. There are currently two approved methods for determining HER2 status in breast cancer: ImmunoHistoChemistry (IHC) and In Situ Hybridization (ISH). This new guideline enables the Health Care Provider, how to best evaluate some of the less common patterns in HER2 results emerging from ISH. 
Guideline Questions
1) What is the most appropriate definition for ImmunoHistoChemistry (IHC) 2+ (IHC equivocal)?
2) Must Human Epidermal growth factor Receptor 2 (HER2) testing be repeated on a surgical specimen if the initially tested core biopsy is negative?
3) What is the optimal algorithm for less common patterns observed when performing dual-probe In Situ Hybridization (ISH) HER2 testing in breast cancer?
Updated Recommendations
1) Immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in more than 10% of tumor cells.
2) If the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not “must”) be ordered on the excision specimen based on some criteria (such as tumor grade 3).
3)The HER2 testing algorithm now includes more rigorous interpretation criteria of the less common patterns that can be seen in about 5% of all cases when HER2 status in breast cancer is evaluated using a dual-probe ISH assay. These scenarios are described as ISH group 2 (HER2/Chromosome Enumeration Probe 17 [CEP17] ratio of 2.0 or more; average HER2 copy number less than 4.0 signals per cell), ISH group 3 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 6.0 or more signals per cell), and ISH group 4 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 4.0 or more and less than 6.0 signals per cell). These cases, described as ISH groups 2-4, should now be assessed using a diagnostic approach that includes a concomitant review of the IHC (ImmunoHistoChemistry) test, which will help the pathologist make a final determination of the tumor specimen as HER2 positive or negative.
4)The Expert Panel also preferentially recommends the use of dual-probe instead of single-probe ISH assays, but it recognizes that several single-probe ISH assays have regulatory approval in many parts of the world. 
Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Wolff AC, Hammond EH, Allison KH, et al. J Clin Oncol 2018; 36:2105-2122.