Implications of Accurately Determining HER2 Status

Laboratory assays for the HER2 gene and protein in tumor tissue are used to determine the HER2 status of patients with breast cancer (positive if either HER2 gene amplification or HER protein overexpression is present; negative if neither is present). As outlined in guideline recommendations for HER2 testing in breast cancer from the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP; Wolff, Hammond, Schwartz, et al., 2007a), and in a report from a task force of the National Comprehensive Cancer Network (NCCN; Carlson, Moench, Hammond, et al., 2006), information regarding a patient's HER2 status can contribute to treatment and other patient management decisions in several ways. HER2 overexpression has been associated with clinical outcomes in patients with breast cancer (Press, Pike, Chazin, et al., 1993; Press, Bernstein, Thomas, et al., 1997; Yamauchi, Stearns, Hayes, 2001). Because HER2 positivity is associated with a worse prognosis in patients with newly diagnosed breast cancer who do not receive systemic adjuvant chemotherapy, HER2 status may be incorporated along with other prognostic factors into decision making regarding such therapy (Wolff, Hammond, Schwartz, et al., 2007a; Carlson Moench, Hammond, et al., 2006).

HER2 positivity also appears to be associated with relative, but not absolute, resistance to certain endocrine therapies (e.g., tamoxifen; less so for aromatase inhibitors) and lower benefit from nonanthracycline, nontaxane-containing chemotherapy regimens (Konecny, Pauletti, Pegram, et al., 2003; Ellis, Coop, Singh, et al., 2001; Menard, Valagussa, Pilotti, et al., 2001). HER2 status is also used to determine whether a patient is eligible to receive biologic therapy specifically targeted to HER2 activity, e.g., trastuzumab (Herceptin®, Genentech, San Francisco, CA) or lapatinib (Tykerb®, GlaxoSmithKline, Research Triangle Park, NC).

Additionally, therapies have been developed that specifically target the HER2 protein (Dinh, de Azambuja, Piccart-Gebhart, et al., 2007; Pal and Pegram, 2007; Viani, Afonso, Stefano, et al., 2007; Lin and Rugo, 2007). Evidence from multiple randomized trials demonstrates that trastuzumab, a therapeutic monoclonal antibody that targets HER2, decreases the risk of recurrence and mortality when added to adjuvant chemotherapy regimens for resected HER2-positive breast cancer. A recent meta-analysis (five trials; pooled N=9,117) reported an odds ratio (OR) for mortality with versus without trastuzumab of 0.52 (95 percent CI: 0.44–0.62; p<0.00001), while OR for recurrence was 0.53 (95 percent CI: 0.46–0.60; p<.00001) (Viani, Alfonso, Stefano et al. 2007). In patients with metastatic HER2-positive breast cancer, trastuzumab alone or with chemotherapy increases time to disease progression and improves survival. Thus, there is increased emphasis on accurately determining the HER2 status of patients with newly diagnosed or recurrent breast cancer.

There are several assays available to measure or detect HER2 in tissue specimens: immunohistochemistry (IHC) assays measure overexpressed protein coded for by the HER2 gene, and in-situ hybridization techniques that rely on fluorescence (FISH), chromogenic (CISH), or silver-enhanced (SISH) assays, measure gene amplification (Table 2). Additionally, these and other methods (e.g., mRNA assays) can detect or measure HER2 in circulating tumor cells (Meng, Tripathy, Shete, et al., 2004; Apostolaki, Perraki, Pallis, et al., 2007). There is also a serum-based enzyme-linked immunosorbent assay (ELISA; Immuno 1®/ADVIA Centaur®, Bayer) that measures circulating levels of extracellular domain of HER2 (Carlson, Moench, Hammond, et al., 2006; Harris, Fritsche, Mennel, et al., 2007); however, the tissue-based assays are most commonly used to establish a patient's tumor HER2 status.

Table 2

HER2 assays used in tissue specimens and serum: clinical trials, clinical practice, and under development (adapted with permission from the American Society of Clinical Oncology; Wolff, Hammond, Schwartz, et al., 2007a and including information from Carlson, (more...)

Key Questions for this Systematic Review

This systematic review will address five key questions regarding HER2 testing to manage patients with breast cancer or other solid tumors:

1.

What is the evidence on concordance and discrepancy rates for methods (e.g., FISH, IHC, etc.) used to analyze HER2 status in breast tumor tissue?

2.

For patients who are not unequivocally HER2 positive, what is the evidence on outcomes of treatment targeting the HER2 molecule (trastuzumab, etc.), or on differences in outcomes of a common chemotherapy or hormonal therapy regimen with versus without additional treatment targeting the HER2 molecule, in:

a)

Breast cancer patients characterized by discrepant HER2 results from different tissue assay methods performed adequately; and

b)

For those with HER2-negative breast cancer?

3.

For breast cancer patients, what is the evidence on clinical benefits and harms of using HER2 assay results to guide selection of:

a)

Chemotherapy regimen; or

b)

Hormonal therapy?

4.

What is the evidence that monitoring serum or plasma concentrations of HER2 extracellular domain in patients with HER2-positive breast cancer predicts response to therapy, or detects tumor progression or recurrence, and if so, what is the evidence that decisions based on serum or plasma HER2 assay results improve patient management and outcomes?

5.

In patients with ovarian, lung, prostate, or head and neck cancers, what is the evidence that:

a)

Testing tumor tissue for HER2; or

b)

Monitoring serum or plasma concentrations of HER2;

either predicts response to therapy, or detects tumor progression or recurrence; and if so, what is the evidence that decisions based on HER2 assay results improve patient management and outcomes?

The first Key Question will be dealt with via a narrative review of the recent ASCO/CAP guidelines and evidence published subsequently.