Benefit of the 70-gene profile for widely used guidelines: an answer to increased selection for adjuvant chemotherapy in breast cancer

Introduction: Risk assessment for breast cancer patients differs substantially among treatment guidelines. The NCCN, St.Gallen, Adjuvant!Online, and Dutch 2008 guidelines are less restrictive in comparison to the 2004 Dutch guidelines and Nottingham Prognostic Index, when selecting patients for adjuvant systemic treatment. The Dutch Institute for Healthcare Improvement (CBO) has introduced slight changes in the concept 2008 guidelines. Adjuvant systemic treatment is only advised when the absolute 10-years survival benefit is 5% or more. The new recommendations for adjuvant systemic treatment are based on survival tables used in the Adjuvant! software. The changes affect only node-negative patients aged >35 years: since 2008 patients with G2/G3 tumors >1cm or every tumor >2cm are advised to undergo adjuvant systemic therapy, while in 2004 this was the case for tumors G3>1cm, G2>2cm or every tumor >3cm.

Patients and Methods: Risk was assessed for 427 lymph-node negative (LNN) patients in the prospective RASTER-study (Bueno-de-Mesquita, 2007) and 151 LNN patients in the NEJM- series (van de Vijver, 2002). Clinical risk was calculated using the 2004 and 2008 Dutch guidelines. Genetic risk was assigned according to the result of the Amsterdam 70-gene signature. Survival analyses were done according to the univariate Kaplan-Meier-method.

Results: Instead of 57% in 2004, in 2008 only 24% of patients were assigned to clinical low risk in the RASTER study, and 141 patients (33%) changed from low to high risk (p<0.001). The rate of discordant findings between clinical assessment and 70- gene signature increased from 30% in 2004 to 41% in 2008 (p<0.001, table 1). Similar results were obtained for the 151 patients of the NEJM-series (30% and 35% discordance for the 2004 and 2008 CBO guidelines, respectively). At 10 years follow-up, differences between the high and low risk categories according to the 2004, 2008 guidelines and the 70-gene profile, were best predicted by the latter: distant-disease-free survival (DDFS) log-rank p=0.002, p=0.11 and p<0.001 respectively.

Discussion: As adjuvant systemic treatments become more effective, guidelines become less restrictive, resulting in more patients being selected for adjuvant therapy. Since newer treatment guidelines do not better predict survival, the magnitude of the 70- gene profiles benefit, which is defined as proportion of patients in whom over- and undertreatment can be avoided, depends on present guidelines for risk assessment and shows a remarkable increase.