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Ipsilateral Breast Tumor Recurrence After Lumpectomy: Is It Time to Take the Bull by the Horns?

Northeastern Ohio Universities College of Medicine, Rootstown, OH, Aultman Cancer Center, Canton, OH

THE INCREASING use of lumpectomy as the preferred surgical procedure for operable breast cancer has resulted in a corresponding increase in the number of ipsilateral breast tumor recurrences (IBTR) despite a reduction in the rates of IBTR that has occurred as a result of improvements in surgery, radiotherapy techniques, and the expanded use of systemic adjuvant therapy. Thus, we still need to improve our understanding of the biologic and clinical implications of IBTR and seize the opportunity, even more than before, to explore therapeutic strategies in this group of patients.

Over the past several years, neoadjuvant chemotherapy has emerged as a possible alternative to adjuvant chemotherapy for patients with operable breast cancer. Although these approaches are equivalent in improving disease-free and overall survival,¹ neoadjuvant chemotherapy offers some potential advantages, such as the downstaging of breast tumors, with a resulting increase in lumpectomy rates and the ability to correlate clinical and pathologic breast tumor response with outcome.²

In this issue of the Journal of Clinical Oncology, Rouzier et al³ from Institut Curie report on the significance of IBTR after neoadjuvant chemotherapy. Although this is a single-institution experience, it is a sizeable study that evaluates the rate and prognostic importance of IBTR in 257 patients treated with neoadjuvant chemotherapy followed by breast-conserving surgery plus radiotherapy. Results showed the rates of IBTR to be 16% at 5 years and 21.5% at 10 years. Independent predictors of increased risk for IBTR by multivariate analysis included age < 40 years, excision margin 2 mm, S-phase fraction > 4%, and clinical tumor size > 2 cm at the time of surgery. The occurrence of IBTR was an independent and highly significant predictor of distant disease (relative risk = 5.34), as was nodal involvement and negative estrogen-receptor status. After IBTR, approximately 30% of the patients developed metastases at 2 years and approximately 60% did so at 5 years.

The rates of IBTR in Rouzier’s study are considerably higher than those reported in other randomized trials and nonrandomized series of neoadjuvant chemotherapy.^1,4 These results may reflect the variability in margin status (in 11% the margins were involved, in 18% tumor was close to the margin, and in 4% the status of the margins was indeterminate) and the range of radiotherapy dose (between 44 and 64 Gy). In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial, for example, the IBTR rate in the neoadjuvant arm was 7.9% at 5 years¹ and 9.9% at 8 years⁵; these rates were slightly higher compared with those in the adjuvant chemotherapy arm of the study (5.8% at 5 years and 7.1% at 8 years), although the differences were not statistically significant. This nonsignificant increase can be explained, at least to some extent, by the inclusion in the neoadjuvant chemotherapy arm of patients with large tumors who were downstaged to allow lumpectomy. Nevertheless, it underscores the importance of thorough preoperative evaluation of the extent of residual tumor as well as careful intraoperative and postoperative margin assessment by the pathologist to ensure adequate tumor removal in cases in which lumpectomy is considered after significant downstaging by neoadjuvant chemotherapy.

The independent predictors of IBTR after neoadjuvant chemotherapy that Rouzier and his colleagues found are generally similar to those found in other studies in which breast-conserving surgery plus radiotherapy was used either alone or with adjuvant chemotherapy.^6,7 This study similarly confirms several previous reports that identify IBTR as an independent predictor of distant disease in patients treated with lumpectomy plus radiotherapy with or without adjuvant chemotherapy.^6,8-11 After IBTR, the 5-year overall distant recurrence and mortality rates are in the range of 25% to 40%.^8,11 In a recent report from five NSABP node-positive trials, the overall annual mortality rate for the first 5 years after an IBTR was approximately 14%,¹² perhaps indicating that the development of IBTR in node-positive patients might have worse prognostic significance. One factor identified in several studies (including Rouzier et al’s) as a predictor for distant disease after IBTR is the interval between primary surgery and IBTR.^3,6,8 Although this may simply be a reflection of inherent biologic tumor aggressiveness, it may also be due to the fact that some of the late IBTRs may actually represent second primary tumors in the ipsilateral breast rather than true recurrences of the original tumor.

It has been a decade since the seminal publication by Fisher et al⁶ that shed light on the biologic significance of IBTR. That report was based on results from the NSABP B-06 trial, which compared total mastectomy with lumpectomy, with or without breast radiation, in patients with operable breast cancer. Predictors of IBTR and their relationship to predictors of distant disease were identified, demonstrating that IBTR was an independent predictor of distant disease that conferred a 3.41-fold increase in risk. However, given the randomized design of the B-06 study and the fact that the mastectomy control group had overall survival rates similar to those of the two lumpectomy groups, it was logical to conclude that the development of IBTR indicated increased risk for, but was not a cause of, distant metastases, as had been suggested previously by the authors of a report from a nonrandomized study.¹⁰ In the report by Fisher et al,⁶ it was further noted that ". . . an IBTR has importance beyond the need for its removal. Since it is a marker for the propensity of a primary tumor to give rise to distant metastatic disease, additional systemic therapy should be considered when an IBTR is diagnosed." Despite these findings, there continues to be widespread variability in the use of systemic therapy at the time of IBTR. More importantly, over the past decade, there have been no randomized trials evaluating the worth of administering another round of adjuvant chemotherapy at the time of IBTR. One of the main reasons for this has been the fact that, until the development of taxanes, there were no candidate non–cross-resistant regimens with promising activity that could be tested in this setting. However, the demonstration of significant antitumor activity with taxanes in patients resistant to anthracyclines provides the opportunity to test the above question in randomized clinical trials. The NSABP is currently designing such a trial, examining the efficacy of adding a taxane-based chemotherapy regimen in patients with IBTR.

The local management of IBTR will also need to evolve. Although salvage mastectomy is currently the standard surgical treatment for IBTR, a small series has shown that breast conservation plus salvage radiotherapy to the operative area is well tolerated and results in reasonable long-term local control of the disease.¹³ This strategy needs to be further explored and eventually compared directly with salvage mastectomy. Furthermore, because an axillary dissection has usually been performed at the time of primary surgery for breast cancer, there is normally no need to address the issue of the axillary nodes at the time of IBTR. With the evolution of sentinel-node biopsy for primary breast cancer, it might be interesting to explore whether this technique could be of value in identifying the breast drainage patterns after a prior axillary dissection and whether the identification and removal of sentinel nodes might be of value in the management of patients with IBTR. In addition, from a staging standpoint, it is also important to explore the value of identifying the presence of bone marrow micrometastases in patients with IBTR. This approach may prove to have valuable prognostic and therapeutic implications, particularly because, at least currently, axillary staging in these patients is not an option.

Several other important questions surrounding the development of IBTR should be addressed in the future. The significance and optimal management of an invasive IBTR in patients with prior ductal carcinoma-in-situ deserves further study. Because, for these patients, IBTR is the first manifestation of invasive breast cancer, one would expect that the prognosis would be significantly better than in patients who develop invasive IBTR after invasive primary breast cancer. Furthermore, the value of adjuvant chemotherapy in this setting should be no different than in patients with primary invasive breast cancer. Lastly, with the increasing identification of BRCA 1 and 2 mutation carriers, the significance and optimal management of IBTR in those patients will also need to be addressed. Because such women are at significant risk for second primary cancers in the ipsilateral breast, particular care should be taken to differentiate between IBTR and a new primary cancer.

Although significant progress has been made during the past decade in the surgical and adjuvant treatment of primary breast cancer, the same cannot be said for the management of IBTR. As we learn more about the significance of IBTR in various settings and as we develop new agents with significant antitumor activity and novel mechanisms of action, we should attempt to change the natural history of patients with IBTR. There is clearly plenty of room for improvement.

ACKNOWLEDGMENTS

Thanks to Barbara Good for her editorial assistance.

REFERENCES

1. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16: 2672-2685, 1998[Abstract]

2. Fisher B, Mamounas EP: Preoperative chemotherapy: A model for studying the biology and therapy of primary breast cancer. J Clin Oncol 13: 537-540, 1995[Free Full Text]

3. Rouzier R, Extra J-M, Carton M, et al: Primary chemotherapy for operable breast cancer: Incidence and prognostic significance of ipsilateral breast tumor recurrence after breast-conserving surgery. J Clin Oncol 19: 3828-3835, 2001[Abstract/Free Full Text]

4. Bonnadonna G, Veronesi U, Brambilla C, et al: Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. J Natl Cancer Inst 82: 1539-1545, 1990[Abstract/Free Full Text]

5. Wolmark N: Preoperative chemotherapy. Bethesda, MD, National Institutes of Health Consensus Development Conference, November 1-3, 2000

6. Fisher B, Anderson S, Fisher ER, et al: Significance of ipsilateral breast tumor recurrence after lumpectomy. Lancet 338: 327-331, 1991[Medline]

7. Touboul E, Buffat L, Belkacemi Y, et al: Local recurrence and distant metastases after breast-conserving surgery and radiation therapy for early breast cancer. Int J Radiat Oncol Biol Phys 43: 25-38, 1999[Medline]

8. Haffty BG, Fischer D, Beinfield M, et al: Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys 21: 293-298, 1991[Medline]

9. Freedman GM, Fowble BL: Local recurrence after mastectomy or breast conserving surgery and radiation. Oncology 14: 1561-1581, 2000[Medline]

10. Stotter A, Atkinson EN, Fairston BA, et al: Survival following loco-regional recurrence after breast conservation therapy for cancer. Ann Surg 212: 166-172, 1990[Medline]

11. Dalberg K, Mattsson A, Sandelin K, et al: Outcome of treatment for ipsilateral breast tumor recurrence in early breast cancer. Breast Cancer Res Treat 49: 69-78, 1998[Medline]

12. Wapnir I, Anderson S, Tan-Chiu E, et al: Ipsilateral breast tumor recurrence (IBTR) and survival in NSABP node-positive breast cancer protocols. Proc Am Soc Clin Oncol 19: 82a, 2000 (abstr 315)

13. Mullen EE, Deutsch M, Bloomer WD: Salvage radiotherapy for local failures of lumpectomy and breast irradiation. Radiother Oncol 42: 25-29, 1997[Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mamounas, E. P. Search for Related Content PubMed PubMed Citation Articles by Mamounas, E. P. Social Bookmarking                            What's this?