Originally published as JCO Early Release 10.1200/JCO.2009.23.6679 on August 31 2009

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

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

In this issue of Journal of Clinical Oncology, Jones et al¹ 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.^2,3 Conventional radiation includes treatment to the whole breast in 1.8- to 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.⁴ 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.^5,6 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.¹ 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.^7,8 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 al¹ 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.^9–17 As a part of this trial, the EORTC randomly assigned patients with known involved margins to an additional boost of 10 or 26 Gy.¹⁸ 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).¹⁸ 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).¹⁹ 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 positive margin is unclear; some studies have found a benefit, whereas others have not.^10,13,15,18

Another important aspect is that few patients on this trial received systemic therapy, either hormonal therapy or chemotherapy. At present, the vast majority of women with invasive cancer do receive some form of systemic treatment. This would likely improve outcomes, including local control, but would have an unknown effect on the difference in outcomes between patients receiving and not receiving a boost.

In summary, the EORTC group has provided some interesting predictive and prognostic factors worthy of future research. Although this subgroup analysis did not find margins to be a prognostic factor for local recurrence, numerous studies have found it be one of the strongest prognostic factors. Surgical re-excision for positive margins should continue to be routinely performed. Although we should recognize the prognostic factors this study brings attention to, we must realize that it does not give us reason to ignore the importance of margin status, which is a well-established prognostic factor for local control.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Shannon MacDonald, Alphonse G. Taghian

Manuscript writing: Shannon MacDonald, Alphonse G. Taghian

Final approval of manuscript: Shannon MacDonald, Alphonse G. Taghian

NOTES

See accompanying article on page 4939

REFERENCES

1. Jones HA, Antonini N, Hart AAM, et al: Impact of pathological characteristics on local relapse after breast-conserving therapy: A subgroup analysis of the EORTC Boost Versus No Boost Trial. J Clin Oncol 27:4940–4948, 2009.

2. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233–1241, 2002.[Abstract/Free Full Text]

3. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227–1232, 2002.[Abstract/Free Full Text]

4. Bartelink H, Horiot JC, Poortmans P, et al: Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 345:1378–1387, 2001.[Abstract/Free Full Text]

5. Bartelink H, Horiot JC, Poortmans PM, et al: Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 25:3259–3265, 2007.[Abstract/Free Full Text]

6. Poortmans P, Bartelink H, Horiot JC, et al: The influence of the boost technique on local control in breast conserving treatment in the EORTC ‘boost versus no boost’ randomised trial. Radiother Oncol 72:25–33, 2004.[CrossRef][Medline]

7. 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.[Abstract/Free Full Text]

8. Kyndi M, Sorensen FB, Knudsen H, et al: Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group. J Clin Oncol 26:1419–1426, 2008.[Abstract/Free Full Text]

9. Jobsen JJ, van der Palen J, Ong F, et al: The value of a positive margin for invasive carcinoma in breast-conservative treatment in relation to local recurrence is limited to young women only. Int J Radiat Oncol Biol Phys 57:724–731, 2003.[CrossRef][Medline]

10. Romestaing P, Lehingue Y, Carrie C, et al: Role of a 10-Gy boost in the conservative treatment of early breast cancer: Results of a randomized clinical trial in Lyon, France. J Clin Oncol 15:963–968, 1997.[Abstract/Free Full Text]

11. Anscher MS, Jones P, Prosnitz LR, et al: Local failure and margin status in early-stage breast carcinoma treated with conservation surgery and radiation therapy. Ann Surg 218:22–28, 1993.[Medline]

12. Mansfield CM, Komarnicky LT, Schwartz GF, et al: Ten-year results in 1070 patients with stages I and II breast cancer treated by conservative surgery and radiation therapy. Cancer 75:2328–2336, 1995.[CrossRef][Medline]

13. Smitt MC, Nowels KW, Zdeblick MJ, et al: The importance of the lumpectomy surgical margin status in long-term results of breast conservation. Cancer 76:259–267, 1995.[CrossRef][Medline]

14. DiBiase SJ, Komarnicky LT, Schwartz GF, et al: The number of positive margins influences the outcome of women treated with breast preservation for early stage breast carcinoma. Cancer 82:2212–2220, 1998.[CrossRef][Medline]

15. Wazer DE, Schmidt-Ullrich RK, Ruthazer R, et al: Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed. Int J Radiat Oncol Biol Phys 40:851–858, 1998.[CrossRef][Medline]

16. Park CC, Mitsumori M, Nixon A, et al: Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: Influence of margin status and systemic therapy on local recurrence. J Clin Oncol 18:1668–1675, 2000.[Abstract/Free Full Text]

17. Kreike B, Hart AA, van de Velde T, et al: Continuing risk of ipsilateral breast relapse after breast-conserving therapy at long-term follow-up. Int J Radiat Oncol Biol Phys 71:1014–1021, 2008.[Medline]

18. Poortmans PM, Collette L, Horiot JC, et al: Impact of the boost dose of 10 Gy versus 26 Gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10-year results of the randomised EORTC boost trial. Radiother Oncol 90:80–85, 2009.[CrossRef][Medline]

19. Taghian A, Mohiuddin M, Jagsi R, et al: Current perceptions regarding surgical margin status after breast-conserving therapy: Results of a survey. Ann Surg 241:629–639, 2005.[CrossRef][Medline]

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