Local therapy (surgery and radiation) is an essential component of breast cancer treatment. Yet, based on clinical trial results dating from the 1980s, the magnitude of local therapy interventions has been decreasing. Now, with the emergence of tailored systemic therapies, their increasing use in the neoadjuvant setting, and their high rates of pathologic complete response (pCR), the relevance of local therapy is being questioned. However, given our present inability to assess pathologic response without surgery, the low pCR rates in common subtypes of breast cancer, and the survival advantages with nodal radiation, local therapy remains not only relevant but crucial to a comprehensive breast cancer treatment plan. In the future, as gene profiling of individual patient tumors progresses and allows for precise tailoring of therapy, it is conceivable that surgery and/or radiation would not be required in some patients. However, the notion that brief, low-morbidity local therapy options, which synergize with prolonged and potentially morbid systemic regimens, would not be relevant for most patients is beyond the horizon at the moment.
Local therapy (surgery with or without radiotherapy [RT]) forms the backbone of breast cancer treatment. Surgery was the original treatment for breast cancer, and RT was added around 1900, soon after the discovery of x-rays by Wilhelm Roentgen. These modalities remain the central pillars of all therapeutic plans for breast cancer patients. However, the magnitude of surgical interventions has decreased in recent decades, and breast conservation has replaced mastectomy for many patients, based on randomized trials showing equivalent survival.[1-5] Similarly, routine axillary dissection has given way to sentinel node biopsy for most patients. On the other hand, the role of RT has not diminished; the appropriate use of adjuvant RT contributes to improved survival and remains an important component of current standards of care.
At the same time that the extent of surgery has been decreasing, local control has been increasing. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial (in which chemotherapy was used only for node-positive disease) showed a 14.3% in-breast tumor recurrence rate at 20 years vs recurrence rates of 3.5% to 6.5% in more recent NSABP systemic therapy trials. The reasons for this decrease are multifactorial and include changes in local management, the addition of boost RT, and improvements in systemic therapy, such as the introduction of aromatase inhibitors and the addition of taxanes and anti–human epidermal growth factor receptor 2 (HER2) agents. These improvements can also be attributed to better local therapy, based on improvements in RT and imaging, as well as standardization of surgical techniques and pathologic margin assessment. At the moment, there is no question that adequate local therapy is crucial for local control, which in turn imparts a survival benefit and improved quality of life. Therapy for local recurrences may entail removal of a breast or part of the chest wall, or nodal RT, each with the potential for symptomatic and functional loss, emotional distress, and added cost.
In addition, it has become clear that local control is also dependent on optimal systemic therapy, based on breast cancer subtype. The risk of local recurrence varies with the molecular subtype as determined by estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Large studies have demonstrated higher local recurrence rates according to breast cancer subtype, particularly in HER2-positive patients not treated with trastuzumab and triple-negative patients, with a trend toward higher local recurrence in patients with the luminal B subtype.[16,17] Other work suggests that, even within subtypes, there is remarkable heterogeneity among tumors; there are six different subgroups within the triple-negative subtype, and all have differing sensitivities to different chemotherapies. With the advent of increasingly precise molecular profiling of breast cancer, it is likely that targeted systemic therapy will continue to improve. How this will shift the balance between local and systemic therapeutic options is of considerable interest. Here we review the current status of local therapy for breast cancer and the likely impact of evolving molecular data on the present paradigm.
Current Guidelines: Why Local Therapy Remains Relevant
Surgical resection: the present landscape
Today, the treatment plan for most breast cancer patients begins with an assessment of the type of surgery required. For stage I and II breast cancer patients, breast conservation remains the standard of care: the tumor must be excised with microscopically free margins, and axillary nodes must be evaluated for pathologic evidence of tumor involvement. Mastectomy remains an alternative, although carved-in-stone indications for it continue to shrink. Thus, the pregnant patient, for whom mastectomy used to be the gold standard, can now be reasonably treated with neoadjuvant chemotherapy in the mid-trimester, and breast conservation following delivery can be offered if tumor characteristics allow. Multicentricity, another long-standing indication for mastectomy, is also being reconsidered to determine whether breast conservation might be offered instead. The ongoing American College of Surgeons Oncology Group (ACOSOG) Z1071 trial, a single-arm prospective study, is assessing whether breast conservation is appropriate for selected patients with multicentric invasive breast cancer. Radiation Therapy Oncology Group trial 1014 (see www.rtog.org for protocol information) is exploring the possibility of repeat breast conservation in selected patients with in-breast recurrence and prior RT. Across the board, surgical research on local therapy is focusing on strategies to reduce the burden of surgery on the breast cancer patient. At the same time, the rule of complete surgical excision of the primary tumor site and sufficient nodal evaluation to document pathologic nodal status stands intact.
Resection margin width
After 2 decades of shifting opinions regarding the desirable width of surgical margins for breast-conserving therapy, recent studies are relevant.[22,23] Based on a meta-analysis of 33 studies in women with stage I and II breast cancer (N = 28,162) by the Society of Surgical Oncology and the American Society for Radiation Oncology, there was no increase in local recurrence in studies where free margins were defined as no ink on tumor vs those requiring wider free margins. Correspondingly, a positive margin (ink on tumor) was associated with a twofold increase in the risk of ipsilateral breast tumor recurrence that was not negated by favorable biology, endocrine therapy, or radiation boost. Covariates of endocrine therapy and median year of recruitment did not change the findings. These results suggest that, even as systemic therapy has improved, a free surgical margin, implying a minimal burden of residual disease, remains an important goal in local therapy and retains relevance to oncologic practice. On a closer look at these data, there is a suggestion of better local control with wider margins in older studies, but this difference disappears in more recent studies, underscoring recent improvements—including those in systemic therapy—that may be contributing to better local control. This more parsimonious approach to tumor resection, however, does have the advantage of avoiding re-excision for close margins, thereby avoiding reoperation-associated morbidities and lessening patient distress and costs.
Surgery following neoadjuvant therapy
The most common indication for mastectomy has traditionally been a large tumor or an unfavorable tumor-to-breast-size ratio. In this setting, randomized trials have shown that breast conservation is feasible for many patients following preoperative chemotherapy, with or without anti-HER2 agents, as dictated by the tumor’s biologic profile.[25,26] This applies even for older women following neoadjuvant endocrine therapy with anastrozole or letrozole.[27,28] Despite the insertion of neoadjuvant systemic therapy into the initial treatment plans of stage I/II breast cancer patients, there is no evidence so far that the traditional components of local therapy can be eliminated. Thus, following a clinical or radiologic complete response to neoadjuvant systemic therapy, surgical excision of the tumor site remains standard of care. In the NSABP B-18 trial, in which pre- and postoperative use of the current standard anthracycline regimen were compared, the complete clinical response rate was 36%, and only a quarter of these patients had a pathologic complete response (pCR). When MRI was recently used to predict pCR, 12.5% of women demonstrating a complete radiologic response had pathologic evidence of residual disease upon tumor site resection. Although pCR following systemic treatment is a predictor of locoregional control in NSABP trials,[29,31,32] and although current National Comprehensive Cancer Network (NCCN) guidelines (see www.nccn.org) support the use of neoadjuvant chemotherapy to aid in breast conservation, surgical resection and breast RT remain an integral part of the therapeutic strategy. Also, despite the downstaging of the axilla in 30% to 40% of women who present with biopsy-proven axillary nodal involvement, surgical-pathologic axillary staging with sentinel node biopsy (using two tracers and harvesting of at least two sentinel nodes) remains necessary, to be followed by level I/II node dissection if sentinel nodes remain positive for tumor.
Is neoadjuvant systemic therapy reasonable prior to mastectomy?
In the absence of specific indications (locally advanced disease, a tumor-to-breast-size ratio that does not favor breast conservation in a woman who desires it), some recommend neoadjuvant systemic therapy as a means of evaluating tumor responsiveness to a particular regimen. This strategy has been tremendously useful in the evaluation of new therapies in clinical trials. Outside of clinical trials—where there is no proven follow-up therapy for the patient with a significant residual disease burden once a standard-of-care regimen has been delivered preoperatively—it is questionable. This is particularly true in women with triple-negative breast cancer. NCCN guidelines endorse the use of regimens recommended in the adjuvant setting for preoperative use in order to enable breast conservation, but they caution that the benefits of switching therapies following a limited response are not established. Overall, though, improving systemic therapy has clearly had an impact on the extent of surgical resection deemed necessary for optimal local control.
RT is an integral part of local therapy for breast cancer. The impact of RT on local control has been evident for decades, and data on a survival benefit are accumulating. The use of RT is part and parcel of breast-conserving therapy, and current guidelines allow breast conservation surgery only in patients who can undergo radiation. The 20-year follow-up of the NSABP B-06 trial showed a 14.3% in-breast recurrence rate in women who received postoperative breast radiation vs 39.2% in those who did not.
These findings are echoed in essentially all trials that have tested breast-conserving surgery in early disease, with and without radiation. Further, they are well documented in the overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG), where risk of any recurrence (locoregional or distant) at 10 years was reduced from 35% to 19%,[14,33] and the risk of breast cancer death was reduced by 3.8% in RT-treated women. There was a marked difference in the proportion of first recurrences that were locoregional: 25% in women who did not receive RT vs 8% in those who did. In high-risk women who received RT, there was a concomitant 7% reduction in the absolute risk of death. The EBCTCG analysis identified young age, grade, ER status, tamoxifen use, and extent of surgery as the factors that predict locoregional recurrence, although the extent of surgery parameter is difficult to interpret since the categories were lumpectomy vs sector resection, not categories based on microscopic margin status. In women with positive nodal disease, the 10-year recurrence risk was reduced from 63.7% to 42.5% with the addition of radiation, and the 15-year risk of breast cancer death was reduced from 51.3% to 42.8%.
In the 1990s, RT was also shown to confer a survival benefit in women after mastectomy. Randomized clinical trials demonstrated a survival advantage and a reduction in recurrence when the chest wall and regional lymph nodes were radiated after mastectomy and axillary lymph node dissection in women with positive axillary disease.[34-38] Following mastectomy for node-positive breast cancer, the 10-year locoregional recurrence risk is markedly reduced by the use of RT (from 26% to 8.1%), as is the risk of any recurrence (from 63.5% to 51.9%) and of breast cancer death (from 66.4% to 58.3%). Thus, RT is increasingly recommended for all postmastectomy patients with involved axillary lymph nodes. Even RT in patients with one to three positive nodes, which was long controversial, can now be “strongly considered,” according to NCCN guidelines. Nodal radiation is also increasingly recommended, based on initial results from the National Cancer Institute of Canada (NCIC) MA.20 trial. This trial enrolled 1,832 women undergoing breast conservation; 85% had one to three positive axillary nodes and 91% received adjuvant endocrine therapy; there was sparse use of chemotherapy (5%). At a median follow-up of 62 months, the group receiving regional nodal RT experienced significant improvement in isolated locoregional disease-free survival, with a hazard ratio (HR) of 0.59 (P = .02). The absolute difference was modest (96.8% and 94.5%, for RT vs no RT, respectively). However, distant disease-free survival was also reduced with the use of regional nodal irradiation (5-year risk: 92.4% and 87.0%, respectively; HR = 0.64; P = .002), as was overall survival (5-year risk: 92.3% and 90.7%, respectively; HR = 0.76; P = .07). The potential survival value of nodal RT is further confirmed by results from the European Organisation for Research and Treatment of Cancer (EORTC) 22922 trial, which assessed the value of irradiation to the internal mammary chain, as well as to the breast/chest wall and other nodal fields. Many patients in this trial had relatively early disease (60% had pT1 tumors and 40% were pN0), and again there was a modest improvement in locoregional control. There was also a 3.7% absolute improvement in distant recurrence risk and a 3% absolute improvement in survival. Finally, the AMA-ROS trial (EORTC 22023) compared axillary dissection with axillary RT in women with a positive sentinel node biopsy and found equivalent outcomes, although the noninferiority design was compromised by a lower than expected number of events.
Thus, the current standard of care is to radiate regional lymph nodes when four or more nodes are positive and to strongly consider radiation if one to three nodes are positive. This latter indication for nodal RT is likely to be further consolidated once we have final results from these recent trials (NCIC MA.20, EORTC 22922, and AMAROS). Thus, accumulating evidence for a small but significant absolute improvement in all cancer outcomes appears to be extending—not decreasing—the indications and the extent of RT for breast cancer patients.
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