Editor’s Note Getting it Right

CASE 1: (Adapted from “Meet the Professor” session, Miami Breast Cancer Conference, February 28, 2003) A 54-year-old woman presented with a 2.1-cm, infiltrating, ductal carcinoma of the right breast and two positive axillary lymph nodes. Assays for estrogen and progesterone receptor status were interpreted as strongly positive (greater than 60 percent of the cells staining positively). The tumor’s HER2 status was assessed by immunohistochemistry (IHC) and scored 3+. The patient was believed to be a candidate for BCIRG-006, an adjuvant trial evaluating chemotherapy with or without trastuzumab. Central reference laboratory testing demonstrated that the tumor’s HER2 status by fluorescence in situ hybridization (FISH) was negative and by repeat IHC was 2+. Subsequently, the patient was treated off protocol with an aromatase inhibitor and chemotherapy.

CASE 2: (Adapted from “Meet the Professor” session, American Society of Breast Disease Meeting, April 13, 2003) A 65-year-old woman presented with rapidly progressing liver, lung and bone metastases two years after receiving adjuvant doxorubicin/cyclophosphamide for an estrogen receptor-negative breast cancer. The tumor’s HER2 status at the time of diagnosis assessed by IHC revealed a score of 1+. At the time of recurrence, a supraclavicular node was biopsied and assessed for HER2 status by FISH, which revealed HER2 gene amplification. The patient was treated with trastuzumab and paclitaxel, with significant reduction in tumor volume (partial response) and complete symptom relief. After six cycles, paclitaxel was discontinued. The patient’s cancer remains in partial remission on trastuzumab 18 months later.

These two cases provide examples of daily clinical scenarios in which HER2 testing can have an enormous impact on current and future breast cancer care. Four major cooperative group adjuvant trastuzumab trials (Table 1) are currently accruing patients, and many researchers are cautiously optimistic that these studies will be the first adjuvant trials in which a biologic approach may be beneficial. This crucial “proof of principle” is entirely dependent on accurately testing patients for the therapeutic target. As recounted on the enclosed audio program by Dr Edith Perez, the principal investigator of one of these groundbreaking studies, investigators have invested a great deal of effort to ensure that only women with truly HER2-positive tumors are enrolled.

The initial false-positive HER2 result in Case 1 illustrates a more immediate lesson for current clinical practice. Since trastuzumab is utilized selectively in the metastatic setting, it is important to ensure that women with HER2-positive tumors are accurately identified and that women with HER2-negative tumors are not exposed to the expense and potential toxicity of an inappropriate therapy. Case 2 is a striking example of the potential human impact of imprecise HER2 testing. This woman may have been denied the prolonged clinical remission of her otherwise rapidly-progressing metastatic disease, had her treating physician not had the foresight to send her tissue for a confirmatory FISH test.

This CME monograph is intended to provide medical oncologists and pathologists a concise review of currently published medical journal articles and abstracts related to this critical issue. The audio program provides commentary from four research leaders who assisted in selecting these journal articles and abstracts, and their remarks focus on how these publications relate to clinical practice. Drs Perez, Thor, Pegram and Press note that there are a number of important analogies between HER2 and estrogen receptor testing, for which there have been longstanding efforts to implement quality control in terms of performance and interpretation. Most importantly, clinicians utilize these assays to determine whether to administer highly targeted, relatively nontoxic therapies that offer an excellent risk-to-benefit ratio in selected patients.

Undoubtedly, the articles selected for this monograph will be replaced by newer reports that will shed additional light on this critical topic. As noted by Dr Thor, until HER2 testing is more refined, the most valuable clinical asset for both pathologists and oncologists is the awareness that our current methodology is far from perfect.

Neil Love, MD