End Results of Salvage Therapy After Failure of Breast-Conservation Surgery

Drs. Lannin and Haffty review the biology, clinical management, and outcome of ipsilateral breast tumor recurrence (IBTR) after breast conservation. Their wellwritten review presents the existing data in a fairly balanced fashion, with special emphasis on multidisciplinary management. This commentary will expand on some of the critical points brought up in the review. Incidence of IBTR
Although breast conservation is now an accepted alternative to mastectomy, concerns regarding the occurrence of IBTR remain prevalent. In the review, the IBTR rate for patients who have undergone breast-conserving surgery and radiation is stated to be 5% to 10% at 5 years, 10% to 15% at 10 years, and 15% to 20% at 15 years. Although these numbers are representative of the published literature, it is important to keep in mind that the risk of IBTR for an individual patient would vary based on the clinical presentation. For small tumors excised with widely negative margins, the IBTR rate is likely to be lower. For example, the Milan trial reported that the IBTR incidence was 8.8% at 20 years for invasive cancers 2 cm or smaller excised with a quadrantectomy.[1] It is also important to recognize that most reported studies were conducted in an era when systemic therapy was not as widely utilized. Adjuvant chemotherapy and hormonal therapy have both been shown to decrease the rate of IBTR after breast conservation. Therefore, the IBTR rate is likely to be lower, based on current practice patterns. Prevention of IBTRs
The review notes that a significant portion of patients with IBTRs actually have new primary tumors rather than a recurrence of the original tumor. Differentiating new primaries from true recurrences is often clinically difficult but has prognostic and potentially therapeutic implications. With careful imaging of the breast, attention to margin status, and radiation therapy, a significant number of IBTRs may be preventable, but patients with breast cancer remain at increased risk for new primaries. In the Milan series, 20 of 30 IBTRs were new primaries.[1] The rate of new primaries can be further reduced with hormonal therapy for patients with estrogen receptor-positive disease, but little can be offered systemically to reduce this risk in women with receptor-negative disease. Nevertheless, whole breast irradiation may also decrease the occurrence of new primaries. It will be interesting to see whether the incidence of new primaries will increase with the increasing utilization of partial breast irradiation. A mastectomy, of course, minimizes the risk of new primary breast cancers as well as true local recurrences. In fact, the difference in local recurrence rates observed between patients undergoing radical mastectomy and those treated with breast conservation in the Milan trial (2.3% vs 8.8%) may be mostly attributable to the decrease in second primaries, as two-thirds of the local recurrences in the breastconservation group were thought to be new primaries.[1] However, patients are also at risk of contralateral breast cancer. Thus, one could argue that if a mastectomy is being proposed to prevent new primaries as well as true recurrences, the surgery of choice would actually be a bilateral mastectomy-a fairly aggressive management strategy usually reserved for selected patients. (One such patient population is composed of women with BRCA1/2 mutations.) IBTR: Marker or Cause of Poor Prognosis?
Drs. Lannin and Haffty state that "it now appears that IBTR is both a marker of the underlying biologic aggressiveness of the tumor and a source for further metastasis." Unfortunately, the controversy regarding this question is far from settled. Although several studies, including our own from M. D. Anderson Cancer Center,[ 2] have found that patients with IBTR have an increased risk of systemic recurrence and poorer survival, these data remain only associations. Vicini et al demonstrated that the excess of distant metastases in patients who developed IBTR follows the recurrence in time.[3] These data are interesting, but not strong enough to prove a causal relationship. The National Surgical Adjuvant Breast and Bowel Project B-06 trial found a marginally significant decrease in breast cancer-related deaths among patients who had breast-conserving surgery followed by radiation, compared with patients who had breastconserving surgery only-groups that differed significantly in their IBTR rate (14% vs 39%).[4] However, studies comparing breast conservation with mastectomy have not found a difference in survival between these two groups. Thus, current clinical data seem insufficient to resolve this controversy. We await the results of molecularbased studies, which may indeed determine that in a portion of patients with IBTR, the distant metastases arise from the IBTR rather than from the primary tumor. Treatment Options for IBTR
With increasing interest in breast conservation overall, there has been significant interest in conserving the breast after an IBTR. The data for repeat breast-conserving therapy are limited and, so far, do not support the use of this approach. Outside of a clinical trial, reexcision should only be considered in carefully selected patients. Reexcision followed by radiation may be reasonable for patients who did not receive radiation after their initial surgery. Excision without radiation may be considered for patients with small, low-grade ductal carcinoma in situ. Otherwise, totalmastectomy for IBTR remains the standard of care. Patients with IBTRs are at a threeto fivefold increased risk of distant recurrence. At this time, we are unable to identify patients at risk for distant recurrence. Thus, a more conservative approach would be to offer systemic therapy to all patients with an invasive IBTR. Randomized trials addressing the role of chemotherapy in this population will answer an important clinical question. Hopefully, molecular-targeted therapies will soon further expand our options for these high-risk patients.