NEW BIOPSY FOR METASTATIC BREAST CANCER SHOULD BECOME ROUTINE

Therapeutic decisions in this setting are based on the features of the tumor at initial diagnosis

Currently acquisition of tissue from presumed metastatic deposits in breast cancer is not routine and the current default position for therapeutic decision making is based on the histopathology of the primary tumor; acquisition of tissue from presumed metastatic deposits is generally only carried out if there is diagnostic uncertainty. A group of authors of the Department of Surgery and Cancer, Imperial College London, UK led by Dr Carlo Palmieri discuss in the February issue of Nature Reviews Clinical Oncology why should we biopsy a new metastatic deposit.

Firstly, a biopsy of a suspected metastatic deposit is diagnostic. Misdiagnosis of recurrent breast cancer in women with a previous history of breast cancer can occur despite the best efforts of those involved.

Secondly, emerging evidence from studies that have paired samples of the primary tumor and secondary deposits suggests that tumor receptor status may change dynamically during the natural history of an individual patient's disease. Changes in receptor expression may occur spontaneously or in response to the selective pressures imposed by treatment. Predominantly retrospective analysis of primary and secondary samples has demonstrated discordance rates of 15–40% for ER/PgR and 7–26% for HER2 amplification, respectively. These studies can be criticized for relying on pathology reports, the use of older pathological techniques, different staining techniques used to assess the primary and the secondary tumors, or due to heterogeneous groupings, which include those with local recurrences. In addition, there are inherent selection biases in such studies. Changes in receptor status are also supported by data from measuring serum HER2 and circulating tumor cells, in which 25–37% of patients converted to a positive HER2 phenotype.

Changes in expression of endocrine receptors and HER2 occur with clear implications for the management of these patients. Furthermore, for ER expression, evidence exists that there is variability in the rate of discordance based on the site of recurrence and the response to initial endocrine therapy. Loss of ER is associated with distant metastasis compared with loco-regional recurrence, as well as de novo endocrine resistance. Considering this background, the development of metastatic disease and early failure of therapy would seem to be indicators for a biopsy. A number of prospective studies are underway that aim to build upon these observations; these include identifying changes in expression of ER, PgR and HER2 between the primary and recurrence (the BReast Recurrence In Tissues Study), and evaluating the changes in molecular biomarkers in HER2-positive metastatic breast cancer during trastuzumab therapy (SHERsig study).

Thirdly, biopsy of recurrent disease can have clinical implications and impact on survival. A study of 50 endocrine naive patients found that loss of ER in the secondary tumor was a significant predictor of poor response to endocrine therapy. Acquisition of metastatic tissue resulted in a change of management plan, with 8% of those with confirmed metastatic disease having their treatment changed. Patients with concordant ER/PgR had significantly better post-recurrence survival than discordant cases who had unfavorable survival similar to that observed in patients with triple-negative breast cancer.

While primary and secondary tumors are similar at the transcriptome level, differences in the metastatic deposit have been noted with upregulation of genes involved in DNA replication and signal transduction. Furthermore, there is evidence that differences in the tumor background can influence responsiveness to therapeutic interventions; for example, the association between PTEN loss and responsiveness to trastuzumab. Therefore, acquisition of metastatic tissue is required to assess molecular differences not only at the receptor level but at the functional pathway level with an integrated genomic-proteomic approach central to such research. Target driven therapeutic interventions may then be developed that are both metastatic breast cancer specific but also metastatic site specific.

Acquisition of metastatic tissue is required to establish metastatic bio banks, which will enable tissue specific, treatment specific, pathway specific and platform-specific research questions to be answered. Issues that may prevent clinicians proposing or undertaking a biopsy in the metastatic setting include lack of resources, technical difficulties in obtaining metastatic tissue or a reluctance to undertake an invasive procedure in a patient who has advanced disease. Future trials for metastatic breast cancer should incorporate re-biopsy of the most easily accessible tissue. With resources for targeted agents already limited, pathological analysis of metastatic tissue makes economic as well as clinical sense and has the additional advantage of obtaining tissue to facilitate translational research.