Testing for Discordance at Metastatic Relapse: Does It Matter?

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In the articles that accompany this editorial, two studies are reported that challenge the belief that a biopsy at the time of metastatic breast cancer relapse is not routinely required, because it provides no further information in regard to the optimal treatment of an individual patient’s tumor. Amir et al 1 report on a prospective trial assessing the clinical impact of tissue confirmation of metastatic disease in patients with breast cancer, and Niikura et al 2 describe rates of discordance and survival in a large single-institution cohort of patients with human epidermal growth factor 2 (HER2) positive primary breast cancer who had a metastatic tumor biopsy result available. Both of these studies are important for solidifying the results of numerous retrospective studies that have consistently demonstrated a discordant rate for either the estrogen receptor (ER) or HER2 receptor between the primary tumor and metastatic lesion. Although it is rational to attempt a biopsy for confirmation of metastatic disease for prognostic purposes, perhaps more contentious are the potential reasons behind, and the resultant clinical consequences of, an apparent discordant result. In the pragmatic and well-designed prospective cohort study by Amir et al, 1 patients presenting with evidence suggestive of metastatic disease or who were experiencing progression while receiving a palliative systemic treatment were enrolled. Strengths of the study were that the primary end point of the study was the proportion of patients in whom the biopsy result led to a change in systemic management, with secondary end points including patient-reported outcomes related to patient satisfaction. Neither of these important end points can be properly measured by means of retrospective study. The main conclusion of the study was the finding of discordance in either ER or HER2 in 16% and 10% of patients, respectively. In 14% of all patients enrolled, the biopsy result led to a reported change in management, with 88% of all participants stating they would recommend the biopsy procedure to other patients. In the retrospective study from the MD Anderson Cancer Centre (MDACC), 182 patients with HER2-positive primary breast cancers were identified, of whom 24% (n 43) were found to have an HER2-negative metastatic lesion on review. 2 Furthermore, the investigators demonstrated that the patients with a discordant HER2 result (HER2-positive primary disease but HER2-negative metastases) had worse survival than the patients with a concordant HER2 result (hazard ratio, 0.43; P .003). Strengths of this study were the relatively large cohort of HER2-positive primary breast cancers identified, the attempted central review of HER2 results (for those patients who were originally assessed at other institutions), and correlation of treatments and outcome between discordant and concordant subgroups. A discordant rate of approximately 25% in either ER or HER2 is well within the range seen in several recent larger retrospectives studies as well as one prospective study (BRITS [Breast Recurrence in Tissues Study]). 3-9 This range of discordance, between 20% and 30%, has been repeatedly demonstrated in these studies despite differences in methodology of assessment for the biomarkers between the primary and relapsed lesions, inclusion of both local and regional relapses with the distant tumors, and heterogeneity in patient populations. Despite