Thursday, March 04, 2010

Avandia's MammaScreen - Answering the question of how to treat small tumours in breast cancer patients

As reported in our recent feature "Breast Cancer - Targeted Therapies, New Cytotoxics and Vaccines" the incidence of breast cancer in the seven major markets is close to 0.5 million, while over 100,000 women will die from the disease. Despite advances in treatment over the past decade, significant unmet needs remain. This level of demand and the large patient potential makes breast cancer a relatively attractive indication for drug developers. Collectively, late-phase pipeline candidates are forecast to achieve $2,230m in sales in 2017 in the seven major pharmaceutical markets.

There are over 100 drugs in clinical development for breast cancer. These are primarily targeted therapies and cytotoxics. Unlike cervical cancer (see our earlier editorial Advaxis lights up the future for cervical cancer ) therapeutic vaccines account for just a small part of clinical development . Importantly, the majority of clinical trials of drugs in late-phase development for breast cancer are in the metastatic setting. This reflects the higher level of unmet need, lower bar to market entry and shorter trial completion time as compared with the adjuvant or neoadjuvant treatment setting.

In addition to developing improved treatments, better diagnostic and prognostic tools are equally required. For example, primary tumor size, in addition to axillary lymph node status, is considered to be one of the most important prognostic factors in breast cancer, with small tumor size being an indicator of good prognosis. However, even small tumors can metastasize. Predicting which patients with small tumors will metastasize represents an unmet need that will likely be addressed by advances in the field of molecular diagnostics.

Another of our featured reports "Molecular Diagnostics in Cancer Testing" describes this rapidly-advancing area. New technologies and applications are being continually added. The technologies that come under the umbrella of molecular diagnostics include first-generation amplification, DNA probes, fluorescent in-situ hybridization (FISH), second-generation biochips and microfluidics, next-generation signal detection, biosensors and molecular labels, and gene expression profiling using microarrays.

Together the global in vitro diagnostics market generated sales of over $40bn in 2008. The market will generate nearly $60bn in 2014. One diagnostic tool described in"Molecular Diagnostics in Cancer Testing" is Agendia's MammaPrint. This prognostic tool was cleared by the FDA in 2007 to predict breast cancer recurrence.

Specifically MammaPrint provides a unique 70-gene signature to identify which early-stage breast cancer patients are at risk of distant recurrence following surgery, independent of Estrogen Receptor status and any prior treatment. Unlike previous generation genomic tests, MammaPrint interrogates all of the critical molecular pathways involved in the breast cancer metastatic cascade. It analyzes 70 critical genes that comprise a definitive gene expression signature and stratifies patients into two distinct groups — low risk or high risk of distant recurrence.

Breast cancers are staged according to the absence (N0) or presence (N1-3) of nodal involvement and the size of tumor. MammaPrint has previously demonstrated prognostic power according to nodal involvement. Today's featured journal article from the Annals of Surgical Oncology report on the prognostic ability of the MammaPrint signature specifically in patients with small invasive tumours. This is particularly important given that the number of patients presenting with such tumors is expanding in parallel with breast cancer screening programs and increased awareness

The study reported by Mook et al took a retrospective look at 964 breast cancer patients, 14% of whom had a pT1ab tumor (primary; 0-1cm), 86% had a pT1c tumor (1-2cm). The majority of patients were node negative. During follow-up 154 patients developed distant metastases. The probability of metastasis-free survival at 10 years was 90% and 86% for pT1ab and pTc patients classified as low risk compared to 76% and 72% classified as high risk. Simply put, the chance of metastasis-free survival at 10 years was increase 2.5-3.5-fold in the low risk group.

Among the 964 patients 57% received no adjuvant systemic therapy while almost all of the others received endocrine- and/or chemotherapy. The prognostic ability of MammaPrint was similar irrespective of therapy.

So what do these data mean? Mammograms have come under significant criticism over the past few years for a number of reasons. Firstly, false-positive results from mammograms expose women to unnecessary biopsies. Secondly, there is the issue of how to medically manage women who have been diagnosed with breast cancer following screening. The issue is particularly troublesome in those individuals with small tumours as treatment guidelines are vague for T1 stage disease. The present study demonstrates the significant benefit of MammaPrint; specifically it can identify those women who are at high risk and may require more aggressive adjuvant chemotherapy and likewise those at lower risk who may gain protection from endocrine therapy without suffering the adverse events of chemotherapy. Mammograms are undeniably useful; we hope that MammaPrint will address some of the criticism screening has attracted and contribute to the overall advance of breast cancer management.

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