The sequencing of systemic treatments prior to performing definitive breast cancer surgery has become increasingly common. This approach, often referred to as neoadjuvant systemic therapy, was once reserved for patients who presented with inoperable disease. The initial studies of neoadjuvant chemotherapy demonstrated high response rates and success in converting inoperable disease to disease more amenable to modified radical mastectomy. After this initial success, the focus of research concerning neoadjuvant treatments moved toward investigating whether neoadjuvant chemotherapy could permit breast-conservation therapy in selected patients whose local-regional disease at the time of initial diagnosis would require mastectomy. This strategy also proved to be successful and as clinicians became more familiar with its use, neoadjuvant systemic treatments were extended to patients with early-stage breast cancer. Indeed, some practitioners currently prefer the neoadjuvant approach for any patient for whom chemotherapy is known to be indicated as part of treatment based on the stage of disease or biologic parameters of her disease at the time of diagnosis.

As neoadjuvant treatments have become more common, a number of questions concerning optimizing local-regional therapy have arisen. As noted, one of the first of these questions concerned whether a greater percentage of patients could be safely treated with breast conservation if systemic treatments were given prior to surgery. This question has been the subject of large randomized phase III trials, the results of which consistently have indicated that breast-conservation rates are higher with neoadjuvant chemotherapy use (1). On the basis of these trials, neoadjuvant chemotherapy is now considered to be an appropriate standard for patients who desire a breast-conserving approach but who present with a large primary tumor or unfavorable tumor-tobreast-size ratio.

More recent local-regional treatment clinical trials for patients treated with neoadjuvant chemotherapy have focused on the management of the axilla. Specifically, a number of studies have evaluated whether sentinel lymph node surgery can safely be performed after neoadjuvant treatments rather than at the time of diagnosis for patients who present with clinically lymph node-negative disease. Performing sentinel lymph node surgery after chemotherapy rather than before could decrease overall rates of required axillary dissections. This is because a lower percentage of patients would have pathologically positive sentinel lymph nodes if they first were treated with systemic treatments (i.e., some patients with microscopically positive lymph nodes would have these foci of disease eradicated by the neoadjuvant treatment). Subsequently, surgical trials have investigated whether postchemotherapy sentinel lymph node surgery could be used in patients who present with clinically positive lymph nodes, in the hope that some of these patients who subsequently become clinically lymph node-negative after tumor response to neoadjuvant systemic treatment can avoid an axillary dissection.

The increased use of neoadjuvant chemotherapy has also raised a number of questions within the field of radiation oncology. Indications for radiation and treatment field designs have been historically based on the pathological extent of disease. For example, decisions concerning the use of radiation for regional lymphatic treatment and indications for postmastectomy radiation have historically been based on the number of positive lymph nodes, something that cannot be accurately determined with clinical staging. The ASCO and ASTRO consensus statements regarding the use of postmastectomy radiation recommend the use of radiation for patients with four or more pathologically involved lymph nodes and these recommendations were based on data from patients treated with surgery first (2, 3). Neoadjuvant systemic treatment has the potential to change the pathological extent of the disease in the primary tumor site and the regional lymphatics in nearly all patients and it is unclear how these changes should affect radiation treatment decisions. Therefore, neither the ASCO nor the ASTRO consensus statements were able to address what are appropriate indications for postmastectomy radiation use for patients treated with neoadjuvant chemotherapy.

This chapter will focus on local-regional treatments for patients treated with neoadjuvant systemic therapies. We will review the randomized and nonrandomized data from studies investigating the use of breast conservation after neoadjuvant chemotherapy or hormonal therapy, evaluate the role of sentinel lymph node surgery for patients treated
with neoadjuvant systemic treatments, and review indications for postmastectomy radiation and regional lymph node radiation for patients treated with neoadjuvant treatments. In aggregate these data will highlight that there remain many controversial areas of local-regional treatment management for patients undergoing neoadjuvant systemic treatments. However, local-regional treatment after neoadjuvant chemotherapy remains a very exciting area of clinical research in that data from the initial studies suggest neoadjuvant therapy has the potential to further personalize local-regional treatment decisions. Specifically, it may be feasible to selectively use aggressive local therapies for patients with a poor response to chemotherapy while minimizing the morbidities associated with local-regional treatments for patients with an excellent response. The newly proposed clinical trials to investigate this hypothesis will also be reviewed.

The clinical response rates of primary tumors to neoadjuvant chemotherapy approach 80% to 90%, depending on the biological subtype of disease (4). Potentially, this could convert a large tumor that would require mastectomy into a size that is eligible for a breast-conserving approach. In addition, for patients with moderate-size tumors, the response may permit a more optimal aesthetic outcome after breast-conservation therapy. For both of these considerations to be feasible, the volume of surgical resection would have to be smaller and directed at the residual nidus rather than the original extent of disease.

In some instances, neoadjuvant chemotherapy successfully shrinks large primary tumors to smaller volumes such that the residual nidus of tissue can be resected with good or excellent aesthetic outcomes. However, in other cases tumors respond but the residual disease is diffuse, multifocal, and scattered throughout the original tumor volume. In the early 1990s investigators from MD Anderson examined 143 mastectomy specimens from patients given neoadjuvant chemotherapy to determine patterns of residual disease and their relationship to clinical factors. Only 23% of tumors had clinical and pathological features that would have predicted success with breast conservation. Important criteria included resolution of skin edema, favorable clinical response to neoadjuvant treatment, lack of multicentricity, and lack of extensive lymphovascular space invasion (5). These data highlighted that breast-conservation surgery would be feasible in only selected patients and that careful selection criteria should be used. These data were supported by the heterogeneity of outcome seen in the initial clinical trials, which varied according to the selection criteria used for their populations. For example, studies that included patients with positive surgical margins or inflammatory breast cancer reported higher rates of local recurrence (6, 7). In addition, higher rates of local recurrence were noted in studies that attempted to eliminate surgery completely for the patients who achieved complete clinical resolution of disease (8). In contrast, the studies that had more stringent selection criteria and well-coordinated multidisciplinary teams reported excellent outcomes (9, 10).

These institutional experiences helped set the stage for two large randomized trials that directly compared the outcome of patients treated with neoadjuvant chemotherapy versus adjuvant chemotherapy. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 study randomized 1,523 patients with operable breast cancer to 4 cycles of doxorubicin and cyclophosphamide (AC) either before or after surgical treatment (1, 11, 12) and the European Organisation for Research and Treatment of Cancer (EORTC) 10902 trial randomized 698 patients to 4 cycles of fluorouracil, epirubicin, and cyclophosphamide chemotherapy to be given as neoadjuvant or adjuvant treatment (13). Because the trials did not have an exclusive focus on rates of breast conservation, both studies included patients who were considered candidates for initial breast conservation and candidates who would require an initial mastectomy. The summary of the results of both studies are shown in Table 57-1. Both studies found that rates of breast conservation were higher in the neoadjuvant chemotherapy arm compared to the adjuvant chemotherapy arm (1, 11, 13). In the B-18 study, the improvement in breast-conservation rates from 60% to 68% for patients treated with neoadjuvant chemotherapy showed that 20% of initial mastectomy candidates (8% of 40% patients) could undergo breast-conservation surgery after neoadjuvant chemotherapy. As shown in Table 57-1, both studies reported that the overall ipsilateral breast recurrence risk in patients treated with neoadjuvant chemotherapy was not statistically different from that in patients treated with surgery first (1, 11, 13). However, in the B-18 study, the breast recurrence rate in a subset of patients who initially would have required a mastectomy but were treated with breast conservation after a favorable
response to neoadjuvant chemotherapy was twice that of the patients with smaller tumors who were treated with surgery first (15.7% vs. 7.6%, respectively) (1). In addition, a meta-analysis of the 9 randomized studies comparing neoadjuvant and adjuvant chemotherapy reported that the use of neoadjuvant chemotherapy was associated with an increase in the relative risk of local-regional recurrence relative to adjuvant chemotherapy (relative risk [RR] 1.22, 95% confidence interval [CI] 1.04-1.43) (14). However, this analysis may have less relevance to modern treatment approaches in that it included trials in which surgery was not performed and radiation alone was used as the sole local-regional treatment. In the trials in which surgery was not used after neoadjuvant treatment, the relative risk was 1.53 and the 95% CI was 1.11 to 2.10) (14).

A second and more recent meta-analysis by Mieog and colleagues examined 10 studies and also demonstrated that overall survival was not different between patients receiving neoadjuvant versus adjuvant chemotherapy (HR 0.98, 95% CI 0.87-1.09) (15). In terms of the question of safety of breast-conserving therapy (BCT) after chemotherapy the metaanalysis reported that the mastectomy rate was decreased by 17% in patients receiving neoadjuvant chemotherapy. It is likely that this is an underestimation of the rate of downstaging as many of the women in these studies were likely breast-conserving therapy candidates before they received neoadjuvant chemotherapy. However, the rate of conversation from mastectomy to breast conservation depends in part on the T stage of disease. Ironically, it is the larger T3 tumors that have a higher conversation rate to breast conservation than the T1 or T2 tumors. This is because most T1 or T2 tumors are candidates for breast conservation at the time of diagnosis and it is factors beyond tumor size (e.g., diffuse microcalcificaitons throughout the breast) that lead to recommendations for mastectomy. These factors may be more difficult to overcome with neoadjuvant chemotherapy. In the B-18 trial the breast-conservation rate was no marked different between the adjuvant and neoadjuvant arms for the patients with T1-T2 disease; however, the use of neoadjuvant chemotherapy in the population with T3 disease resulted in an increase in the rate of breast conservation from 3% to 22% (11). Similarly, in the EORTC10902 trial, they looked at the surgical plan prior to starting chemotherapy in the group randomized to neoadjuvant chemotherapy and prior to starting chemotherapy 23% of patients who were thought to require mastectomy were able to have breast-conserving therapy (13). The meta-analysis by Mieog and colleagues showed that there were no differences in localregional recurrences for patients receiving neoadjuvant or adjuvant therapy when stratified by the type of surgery performed (15). They also looked at patients in the EORTC trial and NSABP-18 trial who were downstaged to breast conservation and found no difference in local-regional recurrence rates for patients who were planned to undergo breast conservation and those who were downstaged enough to become breast-conservation candidates.

Studies from the Istituto Nazionale Tumori in Milan and the University of Texas MD Anderson Cancer Center (9, 10) have provided additional data suggesting breast conservation is safe for appropriately selected patients with larger primary tumors that respond favorably to neoadjuvant chemotherapy. The Milan group noted an 85% breast-conservation rate in 536 patients treated with neoadjuvant chemotherapy for a primary tumor 2.5 cm in diameter or larger and reported an excellent 8-year rate of breast recurrence of 6.8% (9). In the initial MD Anderson series, 340 carefully selected patients were treated with breast-conservation therapy after showing a favorable response to chemotherapy (10) had a 5- and 10-year local recurrence rates were 5% and 10%, respectively, despite the fact that 72% of patients initially had clinical stage IIB or III disease. These investigators identified four factors that were independently associated with breast cancer recurrence and local-regional recurrence: clinical N2 or N3 disease, lymphovascular space invasion, a multifocal pattern of residual disease, and residual primary tumor larger than 2 cm in diameter (10). Eighty-four percent of patients had none or just one of these factors and the recurrence rate at 10 years in this group was only 4% (16). In contrast, the 4% of patients with three of these factors had a recurrence rate of 45%. Women with primary clinical T3 or T4 disease were at very low risk of recurrence if the tumor shrank to a solitary nidus or showed a pathologic complete response (pCR), but among patients with T3 or T4 tumors that left a multifocal pattern of residual disease, the breast cancer recurrence rate was 20% (10).

When interpreting the local-regional outcome results of breast conservation after neoadjuvant chemotherapy for patients with advanced disease, it is important to consider that patients with stage III breast cancer are at risk for localregional recurrence even when mastectomy is performed. In addition, patients with advanced disease are at significant risk for distant metastases, which is an additional incentive to avoid removing the entire breast when breast-conserving surgery can be done with acceptably low recurrence rates. To compare local-regional treatment outcomes with those achieved with mastectomy, the investigators from MD Anderson Cancer Center applied the four prognostic criteria associated with breast recurrence in patients treated with neoadjuvant chemotherapy and breast conservation to a cohort of patients treated with neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation (17). These investigators found that for patients who had none or one of these factors, the results with either local-regional treatment approach were excellent and equivalent. Among patients with two factors, a nonsignificant trend was evident toward fewer local-regional recurrences with mastectomy, and for the small cohort of patients with three or four factors, mastectomy with postmastectomy radiation provided a statistically significant benefit compared to breast conservation.

The previously described MD Anderson Prognostic Index based on the factors of clinical N2-N3 disease, lymphovascular invasion, residual pathologic tumor size greater than 2 cm and multifocal residual disease on pathology was more recently validated in an independent patient dataset (18). This study utilized a contemporary population of 551 women who had neoadjuvant chemotherapy, mastectomy, or breast-conserving surgery and radiation treated from 2001 to 2005 and who were not included in the original analysis. For patients undergoing breast-conserving therapy the 5-year local-regional recurrence-free survival rates were 92%, 84%, and 69% when the prognostic index was 0 (n = 91), 1 (n = 82), 2 (n = 38) or 3 or 4 (n = 13) (p = .01). Similar to the previous results, the 5-year local-regional recurrence-free survival rates were similar between patients undergoing mastectomy or breast conservation when the prognostic score was 0, 1, or 2, but mastectomy had an improved local-regional outcome when the prognostic index score was 3 or 4.

A common question raised with respect to performing breast-conserving therapy after neoadjuvant chemotherapy is what volume of breast tissue should be resected. Some tumors will shrink concentrically while others form more of a honeycomb pattern with small pockets of residual disease over the volume of original tumor size. To evaluate this, Boughey et al. studied whether preoperative chemotherapy was able to reduce the volume of tissue excised and the number of breast operations performed (19) and reported that in
patients with T2 or T3 tumors, significantly less tissue was resected when patients received neoadjuvant chemotherapy (p < .004 for volume of tissue resected). At a median follow-up time of 33 months there were only two cases of ipsilateral breast recurrence, one in the neoadjuvant group and one in the adjuvant group, leading them to conclude that it is not necessary to excise the entire prechemotherapy volume of tissue. Therefore, using chemotherapy in the preoperative setting can afford a better overall cosmetic outcome for patients.

Recently, the NSABP updated its experience of breast conservation after neoadjuvant chemotherapy by combining the data from such patients enrolled on B-18 and B-27 and retrospectively analyzing their outcome. The 10-year local-regional recurrence rate was 10.3% in the 1,100 patients treated with neoadjuvant chemotherapy, lumpectomy, and whole breast irradiation (20). In a multivariate analysis, age under 50, positive clinical nodal status, and pathological positive lymph nodes and lack of a complete response in the breast predictive of higher rates of local-regional recurrence. The highest rates of local-regional recurrences were in patients who presented with clinically positive lymph nodes and were found to have pathologically positive lymph nodes after neoadjuvant chemotherapy.

Finally, a recently published study from MD Anderson evaluated the outcome of 2,984 patients who underwent segmental mastectomy and whole breast radiation over a period of approximately 20 years and compared those who underwent surgery first (n = 2,331) versus those who had surgery after neoadjuvant chemotherapy (n = 652) (21). Due to selection biases, the neoadjuvant group had a higher percentage of patients who were younger, had more advanced stage of disease, had high-grade disease, and had estrogenreceptor (ER)- negative tumors. Neoadjuvant chemotherapy resulted in a pathologic complete response in 20% of patients and downstaging in many others as evidenced by the fact that 93% of patients presented with clinical stage II or stage III disease and only 46% had stage II or stage III disease on final pathology (p < .001). With a median follow-up of over 7 years in both groups, the local-regional recurrence-free survival rates were excellent in both groups. Specifically, the 5- and 10-year local-regional recurrence-free survival rates in patients undergoing surgery first noted to be 97.1% and 94.3%, respectively, and in patients receiving neoadjuvant chemotherapy they were 93.4% and 90.3%, respectively. Multivariate analysis revealed that age less than 50, clinical stage III disease, grade III disease, and either ER-negative disease or patients with ER-positive disease who did not receive hormonal therapy were factors associated with local-regional recurrence. Additionally, multifocal disease on final pathology, the presence of lymphovascular invasion, and close or positive margins were also significant factors. When neoadjuvant chemotherapy was added to the model it was not significant, suggesting that after controlling for these other adverse factors there was no difference with respect to local-regional recurrence in patients receiving neoadjuvant chemotherapy compared to those who undergo upfront surgery.