Version May 2024
INTRODUCTION — Breast cancer is a heterogeneous, phenotypically diverse disease composed of several biologic subtypes that have distinct behavior. Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2) oncogene is present in approximately 15 percent of primary invasive breast cancers [1]. Women with both early-stage and metastatic breast cancer that meet criteria for HER2 positivity are treated with regimens including HER2-directed therapy.
Here we will review the definition of HER2 positivity, and the approach to HER2 discordance. Management of those with HER2-positive disease in the neoadjuvant, adjuvant, and metastatic settings, as well as treatment protocols for HER2-positive breast cancer, are discussed elsewhere:
●(See "Neoadjuvant therapy for patients with HER2-positive breast cancer".)
●(See "Adjuvant systemic therapy for HER2-positive breast cancer".)
●(See "Systemic treatment for HER2-positive metastatic breast cancer".)
●(See "Treatment protocols for breast cancer", section on 'Regimens for HER2-positive breast cancer'.)
THE HER2 ONCOGENE — The HER2 oncogene encodes for a 185 KD transmembrane glycoprotein receptor with intracellular tyrosine kinase activity [1]. The HER2 receptor belongs to the epidermal growth factor receptor (EGFR) family of receptors, which are critical in the activation of subcellular signal transduction pathways controlling epithelial cell growth and differentiation [2,3] and possibly angiogenesis [4,5]. HER2, the epidermal growth factor receptor 2, was previously called HER2/neu, or ERBB-2.
Clinical utility of HER2 testing — Because HER2 status is a predictive factor in breast cancer, we recommend routine testing of HER2 expression on newly diagnosed, invasive, and metastatic breast cancers, in accordance with several guideline bodies [6-10]. High levels of HER2 expression identify those women who benefit from treatment with agents that target HER2.
HER2 overexpression was associated with high rates of disease recurrence and death in the absence of adjuvant systemic therapy. However, the value of this prognostic information in clinical practice is questionable, particularly with the earlier use of HER2-directed agents in the neoadjuvant and adjuvant setting.
For women with hormone receptor-positive breast cancer, HER2 gene expression is an important component of the 21-gene recurrence score assay. (See "Prognostic and predictive factors in early, non-metastatic breast cancer".)
TESTING FOR HER2 EXPRESSION — There are many ways to measure the activity of the HER2 oncogene; the best method, both in terms of the type of assay used and the optimal way to perform each type of assay, is controversial. The assays used clinically are below:
●Overexpression of the HER2 protein product – Western blotting, enzyme-linked immunosorbent assay (ELISA), or immunohistochemistry (IHC).
●HER2 gene amplification by in situ hybridization (ISH) – Fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), silver-enhanced in situ hybridization (SISH), or differential polymerase chain reaction (PCR).
IHC and ISH — The majority of patients who test positive for HER2 should receive HER2-directed therapy.
We agree with the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for HER2 testing, which are summarized in the table (table 1) [8,10].
In general, we obtain immunohistochemistry (IHC) in cases of newly diagnosed, invasive breast cancer or recurrence, and obtain in situ hybridization (ISH) for IHC 2+. The interpretation of IHC and FISH testing of breast tumors is discussed below.
●HER2 testing should be performed on the invasive component using a validated IHC or ISH assay.
●IHC staining is defined as:
•IHC 3+ if there is complete and intense circumferential membrane staining within >10 percent of tumor cells. All IHC 3+ tumors are considered HER2 positive. (See "Adjuvant systemic therapy for HER2-positive breast cancer".)
•IHC 2+ if there is incomplete and/or weak/moderate, circumferential membrane staining within >10 percent of tumor cells. All IHC 2+ tumors are reported as HER2 equivocal.
•IHC 1+ if there is faint or barely perceptible, incomplete membrane staining within >10 percent of tumor cells. All IHC 1+ tumors are reported as HER2 negative.
•IHC 0 if (1) no staining is observed, or (2) there is faint or barely perceptible, incomplete membrane staining within <10 percent of tumor cells. All IHC 0 tumors are reported as HER2 negative.
•Equivocal HER2 testing should trigger reflex HER2 testing using ISH on the same specimen or a new test (using a different specimen with either IHC or ISH). Alternative genomic tests are not recommended for routine use, as they have not been clinically validated.
●Results from ISH are defined as the ratio of gene amplification of HER2 and the chromosome 17 enumeration probe (CEP17). Results are reported as:
•ISH positive if the HER2/CEP17 ratio is ≥2.0, and the HER2 copy number signals/cell is ≥4.
•Definitive diagnosis will be rendered pending further workup in the following instances (table 2) [11]:
1) If the HER2/CEP17 ratio is ≥2.0 and an average HER2 copy number is <4.0 signals/cell.
2) If the HER2/CEP17 ratio is <2.0 and the average HER2 copy number is ≥6.0 signals/cell.
3) If the HER2/CEP17 ratio is <2.0 and an average HER2 copy number is between ≥4.0 and <6.0 signals/cell.
•ISH negative if the HER2/CEP17 ratio is <2.0 and average HER2 copy number is <4.0 signals/cell.
●Specimens should be processed quickly (time to fixation within one hour) using 10 percent neutral buffered formalin for 6 to 72 hours. Reporting should incorporate these times.
Situations in which to retest — The ASCO/CAP update suggests repeat testing of patients with newly diagnosed breast cancer if histopathologic features are present suggesting HER2 discordance [8,10].
In summary, repeat HER2 testing should be performed if:
●The initial test was HER2-positive in a histologic grade 1 carcinoma of the following types:
•Infiltrating ductal or lobular carcinoma, hormone receptor-positive.
•Any of the following histologies, all of which at least 90 percent pure: mucinous, cribriform, tubular, or adenoid cystic.
The 2018 ASCO/CAP update notes that repeat HER2 testing may be performed in the following instances:
●The test was HER2-negative in a tumor exhibiting any of the following:
•Grade 3 differentiation.
•The invasive component was small (if initial testing was performed on biopsy material).
•Carcinoma at definitive resection contains a high-grade carcinoma morphologically distinct from that in the original biopsy.
●The core biopsy result was equivocal by both IHC and ISH.
●There is doubt about the specimen handling, or testing error is suspected.
●The 2013 ASCO/CAP guidelines recommend that HER2 status be reanalyzed on a repeat biopsy sample in patients who present with recurrent or metastatic breast cancer [8], given that the level of discordance in HER2 status in paired primary and metastatic breast cancers ranges between 2 and 25 percent [12-15]. A substantial proportion of women with HER2-negative primary tumors acquired protein overexpression when their tumors recurred [15-18].
No indication for assessment of circulating HER2 ECD — The clinical utility of assessing or following circulating HER2 protein extracellular domain (c-ECD) levels during HER2-directed therapy is not established. The ASCO expert panel on tumor markers in breast cancer recommended against the use of serum c-ECD in any clinical setting [19].
Multiple studies have addressed whether circulating HER2 c-ECD predicts response to HER2-directed treatment, with conflicting results [20-23]. For example, in a pooled analysis of seven trials of first-line trastuzumab with or without chemotherapy, patients with a 20 percent or greater decline in c-ECD levels over baseline had significantly higher response rates to trastuzumab (57 versus 28 percent) as well as significantly longer time to progression and overall survival compared with those with a lesser degree of decline [23,24]. However, a separate review of 63 studies concluded that concentrations of HER2 ECD are not consistently related to patient outcomes [25].
Other researchers have studied the relationship between pretreatment serum levels of circulating HER2 ECD and response to hormone therapy in women with metastatic breast cancer [26-32]. However, results are inconclusive, and serum levels of circulating HER2 ECD should not guide choice of any therapy.
Differences between the 2013 and 2018 ASCO/CAP guidelines — Compared with the 2013 guideline, the 2018 guideline revised the approach to less common clinical scenarios observed when using a dual-probe ISH assay, specifically the following:
●If the HER2/CEP17 ratio is ≥2.0 and an average HER2 copy number is <4.0 signals/cell. (This previously was considered HER2-positive disease, per 2013 guidelines.)
●If the HER2/CEP17 ratio is <2.0 and the average HER2 copy number is ≥6.0 signals/cell. (This previously was considered HER2-positive disease, per 2013 guidelines.)
●If the HER2/CEP17 ratio is <2.0 and an average HER2 copy number is between ≥4.0 and <6.0 signals/cell.
In each of these situations, further workup is necessary. The approach to these less common scenarios is described in the table (table 2). Alternative genomic tests are not recommended for routine use, as they have not been clinically validated.
HER2 STATUS AND PREDICTING TREATMENT RESPONSE — The only HER2 test results that are known to predict benefit from trastuzumab are immunohistochemistry (IHC) 3+ score or fluorescence in situ hybridization (FISH) ≥2 ratio [33]. The other "equivocal" findings on FISH (eg, single copy >6, etc.) are of unknown value in predicting benefit from trastuzumab.
Fam-trastuzumab deruxtecan is available for patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/ISH-negative) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. This is discussed elsewhere. (See "Overview of the approach to metastatic breast cancer", section on 'HER2-low tumors'.)
However, we also note that the interobserver pathologist reproducibility of classifying lesions as "1+" versus "0" is poor and is likely inadequate to accurately predict benefit from a chemotherapeutic agent; further data are needed.
Those with non-HER2-overexpressing breast cancers experience no benefit from adjuvant trastuzumab. In a randomized trial of 3270 women with invasive breast cancer and IHC score of 1+ or 2+ with FISH <2 (or, if ratio was not performed, HER2 gene copy number <4), the addition of trastuzumab to chemotherapy did not improve disease-free or overall survival [33].
In addition to predicting benefit from HER2-directed treatment, innumerable studies have examined HER2 expression as a predictor of benefit for other treatments for local and advanced breast cancer, including chemotherapy and endocrine therapy. However, the vast majority of these studies were done before the development of effective, anti-HER2 targeted drugs for early- (trastuzumab) and late-stage (trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) breast cancer. The importance of HER2 status for predicting use of non-HER2 therapies in the era of effective anti-HER2 treatments is less clear.
●Relevant discussion addressing the optimal chemotherapy regimen for those with early and metastatic HER2-positive tumors is discussed elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Choice of chemotherapy' and "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Standard regimens' and "Systemic treatment for HER2-positive metastatic breast cancer".)
●Although several trials have concluded that patients with HER2-overexpressing tumors are relatively resistant to adjuvant hormone therapy [34-39], a similar number have failed to demonstrate such a relationship [11,40-44], and others even suggest a positive influence of HER2 overexpression on treatment response. As such, guidelines from an expert panel on tumor markers in breast cancer convened by the American Society of Clinical Oncology (ASCO) recommended that HER2 status not be used to withhold endocrine therapy for a patient with a hormone receptor-positive breast cancer, nor to select one specific type of endocrine therapy over another [19]. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Neoadjuvant endocrine therapy' and "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Special considerations for hormone receptor-positive disease'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Treatment of early HER2-positive breast cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Introduction – Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2) oncogene is present in approximately 15 percent of primary invasive breast cancers. (See 'Introduction' above.)
●Rationale for HER2 testing – We recommend routine testing of HER2 expression on newly diagnosed, invasive, and metastatic breast cancers. High levels of HER2 expression identify those women who benefit from treatment with agents that target HER2. (See 'Clinical utility of HER2 testing' above.)
●Guidelines for HER2 testing – Guidelines for HER2 testing from a joint consensus panel of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) are provided (table 1). Although HER2 status is typically initially assessed by immunohistochemistry (IHC), we recommend confirmatory fluorescence in situ hybridization (FISH) testing for patients whose tumors are 2+ by IHC. (See 'Testing for HER2 expression' above.)
●Treatment implications – For patients with high levels of HER2 overexpression (IHC 3+; or HER2/CEP17 ratio on FISH ≥2.0 with average HER2 copy number on FISH ≥4.0 signals/cell), we recommend administration of HER2-directed treatment in the adjuvant and/or metastatic setting (Grade 1A). (See 'Testing for HER2 expression' above.)
●When to retest – Given the possibility of discordant HER2 expression from the primary and metastases, HER2 status should be reanalyzed in biopsies obtained from newly recurrent metastases, particularly if the primary tumor was negative or only weakly positive. (See 'Situations in which to retest' above.)
●Anti-HER2 therapy with chemotherapy – Relevant discussion addressing the optimal chemotherapy regimen for those with early and metastatic HER2-positive tumors is discussed elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Choice of chemotherapy' and "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Standard regimens' and "Systemic treatment for HER2-positive metastatic breast cancer".)
●Role of HER2 status in hormone receptor-positive cancers – HER2 status should not be used to withhold endocrine therapy for a patient with a hormone receptor-positive breast cancer, nor to select one specific type of endocrine therapy over another. (See 'HER2 status and predicting treatment response' above and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Neoadjuvant endocrine therapy' and "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Special considerations for hormone receptor-positive disease'.)
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