Abstract

The increasing use of chemotherapy before surgery has affected a number of local-regional treatment decisions including surgical and radiation management of the breast, management of axillary lymph nodes, and the indications for postmastectomy radiation. In this monograph, we will focus on surgical and radiation management as components of breast conservation therapy. The early randomized trials that compared neoadjuvant to adjuvant chemotherapy in breast cancer demonstrated that rates of breast conservation can be increased when chemotherapy is sequenced first. This was a direct consequence of high response rates seen with neoadjuvant treatment, which permitted downstaging of a large primary tumor to a volume that permitted breast-conserving surgery. Some initial studies found higher rates of breast recurrences with this approach but over time, with improved multidisciplinary coordination and proper patient selection, rates of breast recurrences have improved to the excellent levels achieved when surgery is performed first. New clinical trials are also ongoing to define the role of sentinel lymph node surgery and regional lymph node radiation.

The use of chemotherapy before performing definitive breast cancer surgery was once reserved for inoperable disease but more recently has become a common approach for stage II and III breast cancer (1). Although the initial studies were unable to achieve a reduction in distant metastases with earlier systemic treatment, they did demonstrate that neoadjuvant chemotherapy could permit a higher percentage of breast cancer patients could be treated with a breast-conserving local-regional therapy. This strategy has subsequently been used to improve the cosmetic outcome of selected patients treated with breast conservation by permitting smaller volumes of breast tissue to be resected.

As neoadjuvant treatments have become more common, a number of questions concerning optimizing local-regional therapy have arisen. This monograph will explore the questions concerning breast conservation surgery and radiation after neoadjuvant chemotherapy. One of the initial questions was whether downstaging of a large primary tumor with a subsequent smaller resection volume would risk leaving a greater volume of residual disease and thereby increase the chance of local recurrence. To date, adequate data has shown that with proper selection criteria and appropriate multidisciplinary coordination, that excellent local control rates can be achieved. Therefore, 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 to breast size ratio.

Rationale and Randomized Trial Data

The clinical response rates of primary tumors to neoadjuvant chemotherapy approach 80%–90%, depending on the biological subtype of disease (2). Such high response rates should potentially convert a large tumor that would require mastectomy into a size that is eligible for a breast-conserving approach. However, for this approach 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 (3). In theory, this approach would be effective when chemotherapy shrinks a tumor to a solitary nidus or achieves a pathological complete response (3). However, some cancers respond with a diffuse pattern of residual multifocal microscopic disease scattered throughout the original tumor volume. Therefore, many initial institutional trials included selection criteria such as resolution of skin edema, favorable clinical response to neoadjuvant treatment, lack of multicentricity, and lack of extensive lymphovascular space invasion (4), and reported excellent initial results (3,4). Other studies that included patients with positive surgical margins or inflammatory breast cancer reported higher rates of local recurrence (5,6). 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 (7).

To date, there has never been a randomized trial that compared the outcome of breast conservation versus mastectomy in patients with large primary tumors who achieve a favorable response to neoadjuvant chemotherapy. Instead the initial neoadjuvant chemotherapy randomized trials were designed to compare this approach against adjuvant chemotherapy. Table 1 reviews the data from these trials. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 study randomized 1523 patients with operable breast cancer to four cycles of doxorubicin and cyclophosphamide either before or after surgical treatment (8,9) and the European Organization for Research and Treatment of Cancer (EORTC) 10902 trial, randomized 698 patients to four cycles of fluorouracil, epirubicin, and cyclophosphamide chemotherapy to be given as neoadjuvant or adjuvant treatment (10). Both studies included patients who were initial candidates for breast conservation and patients who were felt to require mastectomy if surgery was their initial treatment. While neither study found a systemic benefit to earlier sequencing of chemotherapy, both studies found that rates of breast conservation were higher in the neoadjuvant chemotherapy arm compared with the adjuvant chemotherapy arm (8,9). In the B-18 study, the improvement in breast conservation rates from 60% to 68% and in the EORTC trial the rates increased from 22% to 35% (8–10).

Table 1.

Rates of breast conservation, local-regional recurrence, and survival in randomized prospective clinical trials comparing neoadjuvant and adjuvant treatments*

Randomized trial Breast conservation rates Local-regional recurrence rates Survival rates 
NSABP B-18 (8) 
(1523 patients)   16 y 
 Neoadjuvant 68% 13% 55% 
 Adjuvant 60% 10% 55% 
  P = .21 P = .90 
EORTC 10902 (10) 
(698 patients)  10-y estimate 10 y 
 Neoadjuvant 35% 20% 64% 
 Adjuvant 22% 20% 66% 
  HR = 1.0–1.1 P = .54 
  P = .97  
Randomized trial Breast conservation rates Local-regional recurrence rates Survival rates 
NSABP B-18 (8) 
(1523 patients)   16 y 
 Neoadjuvant 68% 13% 55% 
 Adjuvant 60% 10% 55% 
  P = .21 P = .90 
EORTC 10902 (10) 
(698 patients)  10-y estimate 10 y 
 Neoadjuvant 35% 20% 64% 
 Adjuvant 22% 20% 66% 
  HR = 1.0–1.1 P = .54 
  P = .97  

*EORTC = European Organisation for Research and Treatment of Cancer; HR = hazard ratio; NSABP = National Surgical Adjuvant Breast and Bowel Project.

Importantly, the benefits of increasing the rates of breast conservation did not increase the local-regional recurrence rates in the overall trials. For example, the long-term local-regional recurrence in B-18 was 13% in neoadjuvant arm and 10% in the adjuvant arm (P = .21). In the EORTC study both arms has a 20% 10-year rate of local-regional recurrence. While no difference was noted in the arms overall, 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 (15.9% vs 9.9%, respectively) (8).

Meta-analyses

Two meta-analyses have investigated the success of breast conservation after neoadjuvant chemotherapy. The first analyzed data from nine randomized studies comparing neoadjuvant and adjuvant chemotherapy and found that relative risk of local-regional recurrence was 1.22 for patients treated with neoadjuvant chemotherapy compared with those treated with adjuvant chemotherapy (11). One important aspect of this analysis to consider was that the authors included trials in which radiation without surgery was used as local-regional treatment, and in these studies the relative risk of local recurrence was even higher (11). The second meta-analysis reported by Mieog et al. (12) analyzed data from 10 studies and showed equivalent overall survival outcomes with either neoadjuvant versus adjuvant chemotherapy. However, this study reported that the use of neoadjuvant chemotherapy was associated with a 17% lower rate of mastectomy, which was most influenced by higher rates of breast conservation in patients with T3 primary tumors when treatment with neoadjuvant chemotherapy was used. For example, in the NSABP B-18 trial the breast conservation rate showed little difference between the breast conservation rates for the patients with T1,2 disease between the neoadjuvant and adjuvant arms. 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% (8). Importantly, unlike the previous meta-analysis, the meta-analysis by Mieog et al. (12) showed that there were no differences in local-regional recurrences for patients receiving neoadjuvant or adjuvant therapy when stratified by the type of surgery performed. They also looked at patients in the EORTC trial and NSABP-18 trial that 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.

Optimizing Selection Criteria for Breast Conservation After Neoadjuvant Chemotherapy

While randomized trials and meta-analyses provide important comparative data regarding breast conservation therapy after neoadjuvant chemotherapy versus surgery first followed by adjuvant chemotherapy, data from single institutional experiences have been important to help further refine selection criteria for breast conservation after neoadjuvant chemotherapy. An initial MD Anderson series reported on 340 patients treated with breast conservation therapy after showing a favorable response to neoadjuvant chemotherapy (13). The authors reported 5- and 10-year local recurrence rates of 5% and 10%, respectively, despite the fact that 72% of patients initially had clinical stage IIB or III disease. With respect to helping define selection criteria, four factors were identified that independently were 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 2cm in diameter (13). In this series, 84% of patients had 0–1 of these factors and had a 4% recurrence rate at 10 years (14). 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 pathological complete response, but among patients with T3/T4 tumors that left a multifocal pattern of residual disease, the breast cancer recurrence rate was 20% (13).

It is important to note that many of the risk factors for local-regional recurrence after neoadjuvant chemotherapy and breast conservation also predict for recurrence after mastectomy. Therefore, the MD Anderson Cancer Center investigators also 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 (15). They demonstrated that for patients with 0–1 factor, both mastectomy and breast conservation achieved equivalent excellent results. 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 with breast conservation.

As the original MD Anderson Prognostic Index was determined by a single dataset, the authors validated the index in an independent patient dataset (16). This study used a contemporary population of 551 women who had neoadjuvant chemotherapy, mastectomy, or breast-conserving surgery and radiation treated from 2001–2005 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 3–4 (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 3–4.

The NSABP recently updated their data on breast conservation after neoadjuvant chemotherapy by combining the data from patients enrolled on the B-18 and B-27 trials. In their analysis of 1100 patients, they reported an overall 10-year local-regional recurrence rate of 10.3% (17). 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, the MD Anderson investigators further updated their experience and compared it to patients treated with surgery first followed by adjuvant chemotherapy. In a series of 2984 patients that underwent segmental mastectomy and whole breast radiation over a period of approximately 20 years, 2331 patients were treated with surgery first and 652 were treated with neoadjuvant chemotherapy followed by breast-conserving surgery (18). Due to selection biases, the neoadjuvant group had a higher percentage of patients that were younger, had more advanced stage of disease, had high grade disease, and had estrogen receptor-negative tumors. Overall, the 5- and 10-year local-regional recurrence free survival rates in patients undergoing surgery first was 97.1% and 94.3%, respectively versus rates of 93.4% and 90.3%, in patients treated first with neoadjuvant chemotherapy. Multivariate analysis revealed the following factors to be significant predictors of local-regional recurrence: age less than 50, clinical stage III disease, grade III disease, estrogen receptor-negative disease, estrogen receptor-positive disease that did not receive hormonal therapy, multifocal disease on final pathology, the presence of lymphovascular invasion, and close or positive margins. When neoadjuvant chemotherapy versus adjuvant chemotherapy was added to the model it was not significant, suggesting that after controlling for other adverse factors there was no difference with respect to local-regional recurrence in patients receiving neoadjuvant chemotherapy compared with those who undergo upfront surgery. To further investigate this question, they then compared local-regional recurrence-free survival rates by presenting clinical stage. They found there were no differences in recurrences among the stage I, stage II, or stage III patients with respect to the sequencing of chemotherapy and surgery. They therefore concluded that neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or stage III disease and that appropriately selected patients can achieve high rates of local-regional control with breast-conserving therapy with either upfront surgery or neoadjuvant chemotherapy. Finally, their data indicated that the local-regional recurrence after breast conservation was driven by biological factors and not the timing of chemotherapy delivery.

Surgical Approaches for Patients Treated With Neoadjuvant Chemotherapy and Breast Conservation Therapy

For any patients treated with neoadjuvant chemotherapy it is very important to accurately clinically stage the patient before treatment. Our institutional approach is to utilize ultrasound of the breast and regional nodal basins at diagnosis in addition to diagnostic mammography. A clip is placed to mark the primary tumor site and the patient is followed with ultrasound imaging during chemotherapy treatment. Other centers have found value in the use of magnetic resonance imaging, which can help predict the primary tumor response to chemotherapy (19).

At the completion of chemotherapy, ultrasound and mammogram are again performed. Residual calcifications, the marker clip, and other radiographic abnormalities are localized for resection with a margin of normal tissue. During surgery we routinely perform intraoperative pathological and radiographic evaluation. The specimen is oriented, subjected to gross inspection, and radiographed. The pathologist then inks the margins with five different colors, sections the specimen, and radiographs the sections. This allows us to identify areas in which further tissue needs to be resected.

A common question raised with respect to performing breast-conserving therapy after neoadjuvant chemotherapy is the volume of breast tissue that should be resected. To evaluate this, Boughey et al. (20) studied whether preoperative chemotherapy was able to reduce the volume of tissue excised and the number of breast operations performed 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.

Finally, two new trails have opened to investigate the role of sentinel lymph node surgery and regional lymph node radiation in patients treated with neoadjuvant chemotherapy. The ALLIANCE A011202 phase III trial enrolls patients found to have a positive lymph sentinel node(s) after neoadjuvant chemotherapy and compares the standard arm of axillary node dissection plus regional lymph node radiation to sentinel biopsy without a dissection plus regional lymph node radiation. A second randomized trial, NSABP B-51/RTOG 1304, evaluates patients with positive axillary lymph node(s) that converted to negative with treatment with neoadjuvant chemotherapy. Patients treated with breast conservation in this trial are randomized to radiation treatment of the breast alone versus radiation treatment of the breast plus regional lymph nodes.

Conclusion

Sufficient evidence is now available to suggest that breast conservation after neoadjuvant chemotherapy is safe and effective for properly selected patients. Neoadjuvant chemotherapy may permit a breast conservation approach for selected patients with initial tumor sizes that require mastectomy and it does not compromise excellent outcome for patients with early stage disease. Neoadjuvant chemotherapy does increase the complexity of breast conservative treatment and requires a close collaboration between a multidisciplinary team to achieve excellent outcomes.

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