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Perspectives and Risks of Breast-Conservation Therapy for Breast Cancer

From the Departments of Surgery (DHR) and Pathology (NJA), Ioannina University School of Medicine, Greece.

Correspondence: Address correspondence to: Dimitrios H. Roukos, MD, Department of Surgery, Ioannina University School of Medicine, GR-451 10 Ioannina, Greece; Fax: +30-26510-97094; E-mail: droukos{at}cc.uoi.gr

Although breast cancer, with 211,300 new cases expected in 2003 in the United States, continues to be the most common malignant tumor among women, it is a highly treatable disease with a 5-year survival rate of 97% for localized disease in the United States.¹ Logically, scientific efforts have been focused on the improvement of quality of life of these women. As a result, the concept of a less radical surgery has been developed toward replacement of total mastectomy considering the strong desire of women for breast conservation and advances² in the understanding of breast cancer spread mechanisms.

Total mastectomy has been the standardized primary treatment in all stages, early or late, of breast cancer although there is little or no evidence that it is superior to breast-conservation treatment. Earlier results from randomized controlled trials have suggested that there is no significant difference in survival after breast-conservation treatment or total mastectomy.^2a However, because of the long natural history of breast cancer and the lack of long-term follow-up results, breast-conserving treatment has not yet been established the treatment of choice.

Therefore, the recently published 20-year follow-up results of two landmark studies^3,4 are relevant for treatment decision-making. They confirm earlier results that total mastectomy is not superior to breast-conservation treatment with respect to survival, but the rate of local failure was 14.3%³ and 8.8%,⁴ respectively. In an accompanying editorial, it was pointed out that it is time to declare the case against breast-conserving therapy closed and to increase the current low rate of breast-conserving surgery.⁵ These reports and the better quality of life after breast conservation will lead to wider clinical use of breast conservation treatment increasingly replacing total mastectomy in the management of early breast cancer during the next years.

What will be the consequences of this expected trend in the treatment strategy of early-stage breast cancer? Is breast-conservation treatment beneficial in all women with stage I/II breast cancer or are there risks from an over simplicity in decision-making? Can these risks be minimized and how? Randomized controlled trials (RCTs) provide the highest level of evidence but they are limited by the lack of generalizability in each individual patient. What lessons can we take from RCTs available for breast-conserving treatment with respect to their pitfalls and the risks for each individual woman enrolled in these studies?

Scientific data report that breast-conserving surgery is associated with higher rates of close or positive margins than mastectomy. The rate of positive margin on the final excision has been consistently high and ranges from 10% in the National Surgical Adjuvant Breast and Bowel Project (NSABP B-06) trial³ to 48% in the European Organization for Research and Treatment of Cancer (EORTC) trial.⁶ In recent nonrandomized studies a similar high overall rate of close (<2 mm) or positive margin has also been reported ranging from 22%⁷ to 41%.⁸ This variation is attributable to the selection criteria, definition of margin status, extent of conservative surgery (lumpectomy, quadrantectomy, local/wide excision), tumor size, adjuvant treatment, and institution.

Close or positive margin on final resection specimens is clearly associated with increased risk of local failure although the magnitude of this risk cannot accurately be estimated. Long-term data on the use of breast-conserving therapy in patients with positive margins is obviously limited and recurrence rate varies considerably.⁹ In most series the risk of local failure in the treated breast after breast-conserving surgery and irradiation has been shown to be two to four times greater in the presence of a positive or close (<2 mm) margin compared with negative margins.^7–11 Efforts to avoid a re-excision in women with close or positive margins using additional aggressive adjuvant treatment after breast-conserving surgery and whole breast irradiation have been associated with considerable local failures. Additional margin-directed radiation dose escalation,⁸ systemic chemotherapy,^7,8 or tamoxifen^7,8,12 delayed time to recurrence rather than decreased this local failure. These data are of low-level evidence and there is now agreement that despite the availability of effective adjuvant treatment for breast cancer, clear surgical margin remains the cornerstone in breast-conserving treatment.^3,7,8

Relevant basic research strongly supports the important role of clear surgical margins not only for local tumor control but also for the combat of lymphatic spread and lymph node metastases. Padera et al.¹³ recently found in mice that functional lymphatic vessels in the tumor margin are sufficient for lymphatic metastasis and confirmed this observation in patients with lung cancer. Therefore the authors suggest that the tumor margins should be treated aggressively by local treatment, such as surgery and radiation, to combat lymphatic dissemination.

Local recurrence represents the main disadvantage of breast-conserving treatment. In most studies the incidence of local failure after breast-conservation therapy ranges from 10% to 20%,^2a–4,6–8 reflecting the median rate of this adverse effect. In a few studies this rate is reported to be much lower, less than 6%^10,14,15 attributable either to a wider use of current more effective systemic therapy in addition to radiotherapy, as in the NSABP trials conducted after B-06 trial,¹⁵ or both adequate patient selection and treatment.^10,14 Although these results are promising, they are limited by the short 10-year follow-up of these studies. Studies with longer follow-up suggest an increasing risk of late local failure that occurs longer than 10 years after treatment⁸ emphasizing the need for confirmation by longer follow-up data.

Can the risk of local failure after breast-conservation therapy be reduced and how? The best way to achieve this goal may be raised from an understanding of the causes and underlying mechanisms of local failure after breast preservation and the identification of risk factors associated with local recurrence. As Morrow et al. report inappropriate patient selection, inadequate surgery or adjuvant treatment, and/or biologically aggressive disease are responsible for local failure.^2a Multiple clinical, pathologic, and treatment-related risk factors have been reported to be associated with increased risk of local recurrence in the conserved breast. Of these factors, young age,^4,7,8,12 close or positive margins,^7–11 extensive intraductal component (EIC) either only by the presence of positive margin^2a or independently by margin status,⁷ and the non-use of adjuvant systemic chemotherapy in node-negative patients¹⁵ or tamoxifen^7,16,17 are the risk factors for local failure that consistently have been identified and reported in most series.

Late reappearance of a tumor, more than 10 years after breast-conserving therapy, has been demonstrated by long-term follow-up studies to be a serious problem. This late failure should also be considered for treatment decision-making. The incidence of a tumor formation in the ipsilateral breast after breast-conserving surgery and whole breast irradiation increases the time from 0.5% to 0.6% per year for the first 5 years to 1% per year after 10 years.^8,18 Although there is some controversy whether this late tumor appearance in the conserved breast is a true recurrence (secondary tumor) or a new primary malignancy, most of these tumors are located at a remote site and not at or close to the tumor bed suggesting that they are new primaries rather than true recurrences.^4,8,18,19 Irrespective of the nature of these tumors, the data indicate the failure of whole breast irradiation to eliminate the risk of late tumor development in the ipsilateral breast in some women and raises again the question whether total mastectomy would be a preferable procedure for these certain patients.

RCTs are the gold standard for treatment decision-making. However, because of their nature, randomized trials provide evidence of overall probabilities of outcomes, not precise, certain predictions for any individual patient.²⁰ A clear example of this lack of generalizability of RCTs represents the local failure subgroup after breast conservation. Thousands of women enrolled in multiple RCTs comparing breast-conserving treatment with or without adjuvant irradiation, chemotherapy, or tamoxifen and total mastectomy and some of these women were affected by an inappropriate patient selection and treatment. The rate of positive margins after breast-conserving surgery reached 48% in the EORTC trial; among women without irradiation after lumpectomy the local recurrence rate was 39% in the NSABP B-06 trial and a recent meta-analysis²¹ established the effectiveness of radiation in reducing not only the risk of local recurrence but also death from the disease. The lesson from these trials is that an over simplicity in the protocol design is dangerous for some patients enrolled in RCTs and a much more careful analysis of data available is needed for the design of future trials.

Currently, the key question is whether and how to identify the small subgroup of individual women among those with stage I/II breast cancer, who because they are at high risk of early or late local recurrence, would be benefited from mastectomy rather than breast-conservation treatment. A rational approach of this question requires a complex procedure taking into account multiple parameters because there is a strong correlation and interaction between the various variables and risk factors related to local failure. For example, the consistent finding of an increased risk of local recurrence in women younger than 45 or 55 years in most studies may be attributed to an association of young age with EIC positivity, close or positive resection margins,²² and multifocality or multicentricity.^2a Indeed, the combination of multiple risk factors in an individual woman substantially increases risk of local recurrence ranging between 34%⁷ and 55%¹² among women younger than 35 or 45 years with both positive EIC tumors and resection margin.

Another clinically important matter for discussion is whether women with microscopic foci of tumor assessed with sensitive imaging techniques, such as magnetic resonance imaging,²³ should undergo breast-conserving treatment or mastectomy. Because whole breast irradiation substantially reduces risk of local failure it is supported that it is not a step forward to subject women to mastectomy on the basis of unsuspected foci of carcinoma detected by sensitive imaging techniques.⁵ However, long-term follow-up data indicate that whole breast irradiation is unable to control late tumor appearance in all women and it is likely that in some patients these microscopic foci of tumor are responsible for local failure.

By summarizing the data reported it is clear that most but not all women with stage I or II breast cancer benefit from breast-conserving treatment. Decision-making, particularly on younger women, is complex and challenging and requires our special consideration with an in-depth analysis of clinicopathologic criteria and therapeutic options available. As the presence of occult carcinoma detected by modern imaging techniques may be responsible for a late tumor appearance, despite whole breast irradiation after breast-conserving surgery, the total mastectomy option should also be offered to a young woman until new evidence-based data make clear the biological behavior of these microscopic lesions. Whether magnetic resonance imaging or positron emission tomography, in addition to ultrasonography and mammography, should be incorporated into clinical use for identification of these lesions is unclear and under investigation. It is clear that surgical margins free of tumor continue to remain the principal goal of breast-conserving surgery and re-excision or mastectomy cannot be replaced by an additional margin-directed boost. Chemotherapy and/or tamoxifen are effective in reducing risk of local failure in certain subgroups.

It should be noted that some local failures reflecting biologically aggressive disease cannot be eliminated completely and may occur in the chest wall even after mastectomy. Current studies with new biologic markers such as gene expression profiling²⁴ and cyclin E levels²⁵ provide high promises for an increase in the accuracy of the prediction of distant metastases and survival. These data raise hopes that new studies will also lead to a pretreatment identification of patients at high risk of local failures enabling, therefore, a personalized therapy^26,27 and decision-making for each individual woman with early-stage breast cancer.

Received for publication May 23, 2003. Accepted for publication June 10, 2003.

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