Local Therapy Matters

As breast cancer remains the most commonly diagnosed cancer among women in the United States, there has been a decline in breast cancer–related mortality for the past 2 decades; this is likely related to diagnosis at an earlier stage and the availability of more effective treatment regimens.

Historically, breast cancer was thought to be primarily a local disease. As the “systemic” view began to emerge, the multidisciplinary setting has become an increasingly important venue for making substantial improvements in the survival of patients with clinically localized cancer. The authors reference a landmark study by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which was the first to demonstrate a link between locoregional treatment and long-term survival benefit in women with breast cancer. The authors also offer a refined definition of the survival benefit from improved local therapy across molecular subtypes of breast cancer.

Local Control With Radiation Therapy: Level I Evidence

All of the available prospective randomized trials and large clinical databases support equivalent long-term (with up to 20 years of follow-up data) disease-free, distant disease-free, and overall survival for breast conservation (breast-conserving surgery [BCS] + radiation therapy [RT]) when compared to mastectomy for primary breast carcinoma. Although this was evidence to prove breast cancer as a “systemic” disease there were an inadequate number of events or deaths to detect a statistically small, but clinically significant difference in survival. There is evidence from randomized clinical trials studying adjuvant radiotherapy in the postmastectomy setting that has shown not only decreased local recurrences but also an improvement in overall survival.[1]

Characterizing Survival Benefit With Optimal Local Control

The authors emphasize the EBCTCG data that provide a link between the absolute magnitude of the reduction in local recurrence at 5 years and the absolute 15-year survival improvement.[2] These data formed the basis of the “4:1 ratio”; ie, for every four local recurrences prevented at 5 years, one death is prevented at 15 years. It is important to note that factors related to overall survival benefit may become statistically more significant with increasing maturity as the early reports by EBCTCG in 1987, 1990, 1995, and 2000 did not reveal such impressive survival improvements.[3]

Traditionally, survival benefit in patients with metastatic cancer of any origin, as in colorectal cancer, has primarily been associated with systemic therapy.[4] Historically, local therapy of the primary tumor in metastatic patients has been reserved for palliation of symptoms. However, several studies have shown that carefully selected patients with de novo metastatic disease who undergo resection of the primary tumor survive approximately 40% to 50% longer.[5] A recent analysis by Le Scodan et al demonstrated a survival improvement associated with aggressive local-regional radiation therapy in patients with metastatic disease.[6] Of 581 patients presenting with metastatic disease at diagnosis, correcting for other confounding factors, there was a statistically significant survival advantage to aggressive local-regional treatment (a majority treated with exclusive local-regional radiation), compared to those who did not receive local-regional treatment (hazard ratio = 0.70; 95% confidence interval = 0.58–0.85; P = .0002). In light of these types of data, there is a need to prospectively examine the role of locoregional therapy in the form of surgery and/or radiation, compared to systemic therapy alone for metastatic patients.

Can We Personalize Survival Benefit?

The authors should be commended for attempting to personalize the 4:1 ratio that has been adopted by the radiation oncologist. Modern medicine has allowed us to understand the biologic heterogeneity of breast cancer and to optimize individualized cancer care. As the authors depicted in the re-analysis of the Danish PMRT (postmastectomy radiation therapy) trials,[1] the “poor” risk group of patients experienced the largest reduction in local recurrence, but mortality remained unchanged despite more aggressive local treatment. Therefore, when using classical prognostic indicators such as nodal status, tumor grade, hormonal status, and tumor size, we may be able to offer a survival benefit with PMRT for those patients with at least a moderate risk for local recurrence but a low risk for distant failure.

The authors found an interesting relationship in the ratio of benefit of 5-year local recurrence to 15-year mortality reduction in the Danish PMRT trials when examining subsets of biologically “distinct” cancers. In the Danish trials, it is clear that the 4:1 ratio set forth by the EBCTCG meta-analysis is much improved in subset analysis. Interestingly, it is not the HER2 or basal group of tumors, but rather the luminal B subset that experienced the highest rate of 5-year local relapse (36%) despite optimal local therapy. Naturally it would be this group of patients that would have the greatest magnitude of mortality benefit (ratio = 1.5:1), but it was still the basal subtype that had a closer to 1:1 ratio of benefit. It may be that this benefit is even quite larger, given modern clinical trials employing newer agents and more active, selective chemotherapy agents tailored to breast cancer subtypes. As pointed out by Drs. Winkfield and Harris, the subtyping of breast cancers by ER, PR, HER2/neu, and other novel molecular markers and molecular profiling may have significant impact on local control and the differential potential benefits of local-regional treatment in patients undergoing BCS plus RT as well.[7-10]

Concluding Thoughts

As several prospective datasets and large-scale retrospective analyses continue to mature, we will likely see the survival benefit once thought to accompany locoregional treatment of breast cancer. The landmark meta-analysis by the EBCTCG demonstrated a simplified relationship between aggressive local therapy and survival. The refinements to the 4:1 ratio in subset analyses demonstrate an even more impressive survival advantage in the postmastectomy setting as well as in biologically more aggressive subtypes of breast cancer.

Of course 15-year mortality is largely based on competing risks of local and distant failures. A more complete understanding of the heterogeneity of breast cancer and the molecular drivers responsible for each of the subgroups may provide additional therapeutic and prognostic information to help guide individualized breast cancer therapy.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Nielsen HM, Overgaard M, Grau C, et al: Study of failure pattern among high-risk breast cancer patients with or without postmastectomy radiotherapy in addition to adjuvant systemic therapy: Long-term results from the Danish Breast Cancer Cooperative Group DBCG 82 b and c randomized studies. J Clin Oncol 24:2268-2275, 2006
2. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-106, 2005
3. Vinh-Hung V, Verschraegen C, Promish DI, et al: Ratios of involved nodes in early breast cancer. Breast Cancer Res 6:R680-R688, 2004.
4. Glick JH, Fowble BL, Haller DG, et al: Integration of full-dose adjuvant chemotherapy with definitive radiotherapy for primary breast cancer: Four-year update. NCI Monogr 297-301, 1988.
5. Khan SA: Does resection of an intact breast primary improve survival in metastatic breast cancer? Oncology (Williston Park) 21:924-942 (incl discussion), 2007.
6. Le Scodan R, Stevens D, Brain E, et al: Breast cancer with synchronous metastases: Survival impact of exclusive locoregional radiotherapy. J Clin Oncol 27:1375-1381, 2009.
7. Haffty BG, Brown F, Carter D, et al: Evaluation of HER-2 neu oncoprotein expression as a prognostic indicator of local recurrence in conservatively treated breast cancer: A case-control study. Int J Radiat Oncol Biol Phys 35:751-757, 1996.
8. Haffty BG, Yang Q, Reiss M, et al: Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24:5652-5657, 2006.
9. Nguyen PL, Taghian AG, Katz MS, et al: Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 26:2373-2378, 2008.
10. Nuyten DS, Kreike B, Hart AA, et al: Predicting a local recurrence after breast-conserving therapy by gene expression profiling. Breast Cancer Res 8:R62, 2006.