Abstract AL-2: William L. McGuire memorial lecture – Local therapy in the molecular era: Relevant or relic?

Surgery has always been driven by disease burden; initially, to determine operability, and recently, to select patients for BCT. Systemic therapy also initially relied on disease burden (axillary nodes, tumor size), but gene profiles and molecular targets now predominate in selecting systemic therapy. Reliance on disease burden as a determinant of the intensity of local therapy is problematic as advanced imaging modalities and molecular pathology allow detection of increasingly smaller tumors. The application of management strategies proven beneficial for macroscopic tumor to subclinical disease has the potential for overtreatment as evidenced by increased mastectomy rates in patients undergoing preoperative MRI, and use of ALND and chemotherapy for sentinel node micrometastases. It is an appropriate time to ask how recognition of molecular subtypes and improvements in systemic therapy can be leveraged to improve local therapy outcomes and decrease the burden of therapy. Recognition that systemic therapy results in a major decrease in the rate of IBTR was the major impetus for SSO and ASTRO to commission a systemic review on margins for BCT in stage I and II breast cancer as the evidence base for a consensus conference. We concluded that evidence that margins more widely clear than no ink on tumor significantly improve local control was lacking and the routine practice of obtaining more widely clear margins is not indicated. Adoption of this approach has the potential to spare many women unnecessary surgery. The morbidity of ALND can also be avoided in many patients. The ACOSOG Z0011 trial showed no benefit to ALND for patients with 1 or 2 sentinel node metastases receiving WBRT and systemic therapy. There were many criticisms of this study, but 3 other prospective randomized trials (NSABP B04, NSABP B32, IBCSG 2013) demonstrate that residual axillary nodal disease does not translate to regional recurrence or a decrease in survival in a 1:1 ratio, and that systemic therapy greatly reduces the incidence of regional recurrence. In a prospective study of the applicability of Z0011 findings to an unselected population of women meeting study eligibility criteria, we found that only 16% of 287 consecutive patients had metastases in ≥3 sentinel nodes or matted nodes identified intraoperatively, sparing 84% ALND. These examples represent initial steps in reducing the morbidity of local therapy. Moving forward, it is appropriate to ask whether patients with favorable molecular profiles (luminal A), require the same local therapy as those with other molecular subtypes. More controversially, the success of HER2 blockade in improving survival raises the question of whether effective targeted therapy could allow a reduction in local therapy intensity. A major barrier to progress is the belief of many clinicians and patients that bigger surgery is better surgery. The full realization of multidisciplinary care will occur when improvements in outcomes with one modality result in studies examining the elimination of other treatments which may no longer be beneficial to patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr AL-2.