However, despite significant research efforts over the past 20 years, with literally hundreds of thousands of research publications relating to prognostic and predictive markers of response, relatively few predictive or pharmacodiagnostic assays are internationally accepted as of value in patient management and treatment selection. For example, in breast cancer only two pharma-codiagnostic tests are currently linked to targeted therapy: tumour expression of oestrogen receptor (ER), and HER2, linked to tamoxifen and Herceptin treatment, respectively. This contrasts with clear evidence that breast cancer represents a spectrum of different molecular disease types, each of which has the potential to respond to different therapeutic approaches. There is currently an urgent need to develop appropriate tests to stratify patients for targeted therapy to ensure that these novel agents are given to patients who are most likely to respond. By focusing on the potential for novel pharmacodiagnostic tests in breast cancer, the authors highlight the key steps in meeting the challenge of successfully developing and implementing novel pharmacodiagnostics in the clinical setting.

Current Pharmaco diagnostic Tests
During the last 50 years clinicians have relied predominantly on the anatomic and morphologic classification of tumours to predict outcome (prognosis). Stratification of breast cancer patients, using indices such as the Nottingham prognostic index and adjuvant online provide support for decisions relating to treatment. However, these indices do not directly take into account the molecular changes that occur within tumours. The first use of pharmacodiagnostics in breast cancer occurred in the 1960s and 70s with the discovery that the response of post-menopausal women to endocrine-based therapy (most often tamoxifen) was limited to ER-positive breast cancers. The synergy between pharmacodiagnostics and patient benefit from a linked targeted therapy was, however, almost forgotten prior to the introduction of Herceptin in the late 1990s. Herceptin targets HER2 and pharmacodiagnostic profiling of tumours was essential for patient stratification since only patients whose tumours have HER2 overexpression and/or gene amplification respond to Herceptin treatment.

The recent implementation of Herceptin and its linked pharmacodiagnostic test into clinical practice challenged the ‘one-size-fits-all’ treatment strategy that has existed among researchers and clinical oncologists for many years. The focus of the majority of clinical trials is to treat all breast cancer patients with the same drug without taking into account molecular differences that may select for response to such agents. This one-size-fits-all strategy ignores the possibility that the patients responding to novel treatments (reflected by an apparent overall improvement in outcome) may present with tumours with a different molecular profile to those responding to the previously accepted treatment and may therefore represent a different group of patients altogether. While this is unlikely to be the case in all instances, there is a clear risk that such a strategy has improved treatment for one group of patients at the cost of reducing treatment efficacy for others.