Abstract ES1-2: The Practical Use of Molecular Profiling: The View of a Medical Oncologist

Adjuvant therapy changed the natural of early stage breast cancer. Starting in the 1970s, randomized trials have shown a survival benefit from adjuvant chemotherapy in operable, node-pos disease. Since 1985, the Oxford Overview led the rapid adoption of adjuvant chemotherapy (for ER-neg disease) and tamoxifen (for ER-pos disease), and this trend accelerated after the 1988 NCI Clinical Alert on adjuvant chemotherapy in node-neg disease. However, this was not without controversy. In 1990, an NIH Consensus Development Conference concluded that “… some degree of improvement (from adjuvant therapy) may be so small that they are outweighed by the disadvantages of therapy.” Soon, adjuvant chemotherapy also became a standard in ER-pos, node-neg disease. Starting in the mid 1990s, data began to suggest that not all patients with ER-pos disease benefitted from chemotherapy. Decision algorithms based on routine clinicopathologic factors (eg, TNM, grade, ER, and HER2) proved quite useful for decision-making for the average patient. But by the early 2000s, new molecular tools to stratify recurrence risk (prognosis) and likelihood of benefit from chemotherapy (prediction) became available in clinical practice to further individualize clinical decisions. Prospective-retrospective studies tested the prognostic/predictive utility of Oncotype DX. Soon, it became clear that it and routine clinicopathologic parameters offered independent prognostic utility in ER-pos disease. The TailoRx (node-neg) and RxPONDER (node-pos) trials are now prospectively testing Oncotype DX to guide the decision to add chemotherapy to endocrine therapy in patients with a lower/intermediate recurrence score. Mammaprint became the first FDA-cleared IVDMIA assay, and the MINDACT study directly addresses this predictive utility question by having randomized patients with a discordant result (compared to Adjuvant! Online) also receive chemotherapy or not. Patients with HER2-pos disease are offered HER2-directed therapy plus chemotherapy. Consequently, a clinical decision gap exists in triple-neg disease (TNBC), which affects 50,000 women just in the US each year. Decision algorithms for them are exclusively based on clinicopathological factors like TNM, grade, and HER2, as molecular assays like Oncotype DX and MammaPrint have no role in this setting. New molecular assays based on DNA methylation, immune markers, or other gene expression signatures are under development. In the meantime, adjuvant chemotherapy is routinely offered to all TNBC patients with at least T1b tumors, despite the fact that most patients with ER-neg, node-neg disease remain disease-free long-term when treated with just locoregional therapy. Various studies examined clinical decisions based on standard clinicopathologic parameters alone or with knowledge of molecular assay results. However, data beyond costs of care are needed to assess their independent and complementary role to improve the most important clinical outcome to patients (i.e., survival). Until then, access to accurate routine clinicopathologic markers for all patients worldwide remains critical to ensure the most optimal outcome to all patients in high and low income countries. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES1-2.