Personalized Radiation Oncology for Breast Cancer: The New Frontier

Radiation therapy (RT) to the breast after breast-conserving surgery (BCS) is considered a standard of care for most women with early-stage invasive breast cancer. Adjuvant RT has repeatedly been shown to decrease the risk of an in-breast recurrence. Although no single study has shown a survival benefit to the addition of RT, a meta-analysis of randomized studies including 10,801 patients showed a 10-year reduction in any first recurrence from 35% to 19.3% with radiation (P .001), which translated to a 3.8% absolute improvement in breast cancer–specific survival at 15 years (25.2% to 21.4%; P .001). However, the survival benefit was not uniform across all risk groups. When stratified by absolute difference in 10-year risk of recurrence, patients who experienced an improvement greater than 20% with RT had a corresponding 7.8% difference in 15-year breast cancer mortality. However, for patients with an absolute improvement less than 10%, the breast cancer mortality benefit was only 0.1% (absolute mortality reduction trend P .03). Moreover, RT is inconvenient, has some toxicity, and adds costs to the health care system. Identifying a group of patients with sufficiently low risk of recurrence, such that RT has no meaningful impact on survival and can therefore be reasonably omitted, has therefore been the goal of multiple randomized and single-arm studies. Patients in these early trials were selected largely by anatomic features of their pathology rather than by characterization of the tumor’s biology. The Harvard hospitals initiated a prospective trial of lumpectomy alone in putatively favorable T1N0 cancers with wide surgical margins in 1986 in an attempt to identify a favorable subgroup of patients in whom RT could be avoided. Estrogen receptor (ER) status was unknown in 50% of those patients. The study was closed prematurely when stopping rules were met as a result of a 23% crude local recurrence (LR) rate at a median of 86 months of followup. A randomized trial of 264 women from Finland also attempted to identify a group of women with a low rate of LR without RT. Despite widely negative surgical margins, the rate of LR was significantly lower with adjuvant RT than with BCS alone (P .0013). The National Survival Adjuvant Breast and Bowel Project B-21 trial (NSABP B-21) asked a similar question for women with tumors smaller than 1.0 cm. One thousand nine women were randomly assigned to receive tamoxifen, RT, or both. LR was significantly higher in women not receiving radiation, with an 8-year cumulative incidence of LR of 16.5% with tamoxifen alone, 9.3% with RT alone, and 2.8% with tamoxifen and RT. Even in this series of women with small but otherwise unselected tumors, there was still a benefit with RT. More recently Cancer and Leukemia Group B trial 9343 (CALGB 9343) also found a reduction in LR with RT in women older than age 70 years with T1N0 (clinically or pathologically) ER-positive early-stage disease, although the benefit to RT was quite modest in this elderly population. During the past 15 years, there has been increased awareness that early-stage breast cancer represents a heterogeneous group of diseases defined by unique molecular subtypes. Given the wide availability of immunohistochemistry techniques, ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as well as markers of proliferation and grade have typically been used to approximate these molecular subtypes. However, attention has largely focused on subtype and the risk of distant disease. More recently, the impact of subtype on LR has also been appreciated. Arvold et al examined the risk of LR in 1,434 patients who underwent BCS and RT; 91% also received systemic therapy. The authors found a 5-year cumulative risk of LR of 2.1% (95% CI, 1.4% to 3.0%) for the group as a whole. This compares favorably with rates seen in the largely older studies, likely because of the increased use of effective systemic therapy. However, when specifically looking at a subset of 905 patients with luminal A disease—approximated by ERor PR-positive, HER2negative status and low or intermediate grade—the risk of LR was only 0.8% (95% CI, 0.4% to 1.8%). Several other series in the breast conservation and mastectomy settings as well as a meta-analysis including more than 12,000 patients have corroborated these findings. Other efforts to group patients on the basis of the biologic character of their tumors have focused on gene expression profiling. Although initial research focused on predicting the risk of distant recurrence, improved tumor characterization may also help inform the risk of LR as well. Mamounas et al looked at the risk of LR in patients with node-negative disease from NSABP B-14 and B-20 by using the OncotypeDX (Genomic Health, Redwood City, CA) recurrence score (RS). RS was significantly associated with LR across all systemic therapy treatment groups and, after multivariable analysis, independently predicted for LR. In patients with node-positive disease treated on NSABP B-28, RS was also highly predictive of LR (P .001). After multivariable analysis, RS was more closely associated with LR (hazard ratio [HR], 2.86) than with other traditional factors, including the number of involved nodes ( 4 v 1-3; HR, 2.08) or tumor size (HR, 1.26). It is conceivable that a gene panel designed specifically to look at the risk of LR may yield an even more accurate risk assessment. Nonetheless, the possibility of a biologic indicator JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 18 JUNE 2