Prognostic Factors for Local Control After Breast Conservation: Does Margin Status Still Matter?

In this issue of Journal of Clinical Oncology, Jones et al report on the results of a subgroup analysis of pathologic and clinical characteristics for patients enrolled onto the European Organisation for Research and Treatment of Cancer (EORTC) 22881/10882 boost trial, which compared boost to no boost in breast cancer patients receiving radiation for breast conservation. This analysis is important for a number of reasons. Despite being a subgroup analysis, the large number of patients, length of follow-up, and central pathology review give the data credence. In addition, this article not only tells us which patients may be at greater risk for local recurrence, but also informs us that the dose of radiation we deliver can affect outcomes for some of these patients. Radiation therapy is considered an established, standard component of breast-conserving therapy. Conventional radiation includes treatment to the whole breast in 1.8to 2.0-Gy fractions to a total dose of 45 to 50.4 Gy. Because the majority of local recurrences occur within or in close proximity to the lumpectomy cavity, it was hypothesized that an additional radiation dose to the lumpectomy site, often referred to as a boost, would decrease the risk of local recurrence. The EORTC 22881/10882 boost versus no boost trial assessed the efficacy of delivering an extra dose of 16 Gy to the tumor bed. The initial publication showed a decrease in local recurrence with a boost, but this benefit was driven largely by the inclusion of younger patients in the study. With time, this benefit was also seen for older patients, and at 10 years, the boost was found to significantly decrease local recurrence from 10.2% for no boost to 6.2% with a boost for the cohort as a whole. The current analysis published in this issue found that characteristics significantly impacting local recurrence include grade of tumor (high v low/intermediate) and age of patient ( 50 v 50 years), with younger patients with high-grade tumors having the highest local recurrence rates. For both subsets of patients, delivering an additional dose of 16 Gy to the tumor bed substantially decreased the risk of local recurrence (from 18.9% to 8.6% for patients with high-grade tumors and from 19.4% to 11.4% for patients 50 years old). These numbers are quite compelling, and radiation oncologists not routinely delivering a boost for these subsets of patients should strongly consider changing their practice. These findings also underscore the importance of investigating the use of additional prognostic factors to determine local radiation dose and, perhaps, even volume. Over the past decade, clinical and pathologic information, aside from staging for breast cancer, has become increasingly valued for determining systemic treatment. This has been investigated less by radiation oncologists but should be examined further to determine whether tailored radiation doses or volumes based on molecular profiles or biologic subtypes will be of benefit. Although radiation oncologists could potentially take into consideration receptor status and genomic profiles, there are no established guidelines to alter recommendations for local therapy. The findings of improved local control with additional radiation to the tumor bed for younger patients and high-grade tumors should encourage investigators to evaluate on clinical trials the use of more aggressive local therapy for poor pathologic and biologic subtypes, as well as clinical prognostic factors. One surprising finding in the study by Jones et al was the lack of margin status as a prognostic or predictive factor. As the authors indicate, there are overwhelming data in the literature indicating surgical margins as one of the most important factors for local control. As a part of this trial, the EORTC randomly assigned patients with known involved margins to an additional boost of 10 or 26 Gy. These results are published elsewhere, but to summarize, it was found that the additional boost dose showed a nonsignificant trend toward improved local control. The EORTC did compare the cohort with positive margins with patients on the trial with microscopically negative margins and demonstrated that patients with incomplete resection had almost double the rate of local recurrence compared with patients with a complete resection (15% v 8% at 10 years, respectively). These results suggest that having a positive margin is an adverse prognostic factor. One reason for the absence of effect of margin status for local control in the current publication could be the small number of patients with close or positive margins. There were only a few patients thought to have negative margins but found to have positive margins on central review (only 3.4% of patients had margins positive for invasive disease). Another notable aspect is that close or positive margins were compared with negative margins. Although some studies have grouped patients in this manner, others compare positive margins with close or negative margins. There is a general consensus that positive margins result in increased rates of local recurrence, but there is great debate over how large this margin should be, and a universal definition of a negative margin has not yet been established (eg, 1, 2, or 3 mm, and so on). Therefore, the manner in which these patients were grouped may have decreased the impact of margin status as a prognostic factor. The benefit of a boost for patients with a close or JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 30 OCTOBER 2