Locoregional Management After Neoadjuvant Chemotherapy

INTRODUCTION

The impetus for trials of neoadjuvant chemotherapy (NAC) in operable breast cancer was the belief that early treatment of subclinical micrometastases would improve survival compared with conventional adjuvant therapy. Although this did not prove to be true, significant reductions in tumor burden in the breast and the axillary nodes were observed with NAC,^1,2 resulting in studies examining NAC use to avoid mastectomy and to decrease the use of axillary lymph node dissection (ALND)—approaches now widely adopted in clinical practice. The NAC model has raised important questions regarding the relative importance of presenting clinical stage and post-NAC stage in determining the risk of locoregional recurrence (LRR), an issue that informs the approach to radiotherapy after surgery. As clinical experience with NAC has increased, it has become apparent that established treatment paradigms for patients undergoing primary surgery are not always appropriate after NAC. Although ongoing clinical trials will address many of these issues, the appropriate use of NAC to de-escalate therapy while awaiting definitive data is controversial. This article will review existing data on surgery of the breast, the axilla, and the use of radiotherapy after NAC and will summarize ongoing trials and unresolved questions.

MANAGEMENT OF THE BREAST AFTER NAC

Early randomized trials comparing 4 cycles of anthracycline-based chemotherapy given preoperatively or postoperatively reported that 23%-27% of patients requiring mastectomy at presentation were eligible for breast-conserving therapy (BCT) after NAC, with greater increases seen in those with larger tumors.^2,3 In more recent Cancer and Leukemia Group B (CALGB) trials of NAC in triple-negative and HER2-positive patients, 42% and 43%, respectively, of patients initially thought to require mastectomy were candidates for BCT after NAC.^4,5 Although pathologic complete response (pCR) is uncommon in women with hormone receptor (HR)–positive/HER2-negative cancers, a single-institution study found that 48% of HR-positive/HER2-negative patients with infiltrating ductal carcinoma requiring mastectomy at presentation were candidates for BCT after NAC, whereas only 16% of those with HR-positive/HER2-negative infiltrating lobular carcinoma became eligible for BCT.⁶ Paradoxically, as pCR rates have increased, a parallel increase in rates of BCT has not occurred. This was noted in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B27 trial in which the addition of a taxane to doxorubicin and cyclophosphamide (AC) doubled the pCR rate from 13.7% to 26.1%, yet BCT rates were 62% after AC and 64% in the doxorubicin, cyclophosphamide, and taxane arm.⁷ In addition, a meta-analysis of 16 randomized trials of BCT and NAC found no association between pCR and BCT rates.⁸ Although pCR is not necessary for BCT, greater tumor response should increase the likelihood of successful BCT. The reported lack of association may be secondary to the fact that many women enrolled in trials of NAC were already eligible for BCT, so differences in the pCR rate did not change the BCT rate. Alternatively, the inability to accurately evaluate the extent of viable tumor after NAC may be responsible. In the CALGB 40603 trial, one third of patients not felt to be candidates for BCT after NAC were found to have had a breast pCR.⁴ Residual suspicious calcifications in the breast are a particular problem limiting the use of BCT after NAC because they rarely resolve, even when there is no viable residual tumor. Several studies have failed to demonstrate a correlation between changes in calcifications and pCR,^9-11 and excision of indeterminate or suspicious calcifications after NAC is necessary, even when it necessitates mastectomy.

Contraindications to BCT after NAC do not differ from those in the primary surgical setting and include the inability to obtain negative margins with a satisfactory cosmetic result, the inability to remove all suspicious microcalcifications, and the inability to safely deliver breast irradiation. The ideal BCT candidate is the patient with a larger, unicentric HR-negative tumor.¹² A common cause of unnecessary mastectomies after NAC is the belief that the entire volume originally occupied by the tumor must be excised as part of the lumpectomy. In a retrospective study, Boughey et al¹³ demonstrated that for T2 and T3 tumors, NAC use reduced the volume of breast tissue resected by half compared with initial surgery, although the median tumor size at presentation did not differ. No differences in re-excision rates (14%) or local recurrence (LR) at 33 months were observed.¹³ A meta-analysis of BCT after NAC found considerable heterogeneity in the amount of tissue excised after NAC, with some studies showing no difference in the lumpectomy volume among patients with no response, partial response, or complete response.¹⁴

The appropriate negative margin width for lumpectomy after NAC is controversial. Although no ink on tumor is accepted for invasive carcinoma in the primary surgery setting,¹⁵ there have been concerns that the scattered buckshot pattern of cell death after NAC could result in a heavy residual tumor burden in patients with a minimal negative margin width. This concern seems to be unwarranted. The NSABP B18 and B27 trials^2,16 used a margin definition of no ink on tumor and reported high local control rates, and 2 single-institution studies have not found negative margin width to be significantly associated with local relapse–free survival after NAC.^17,18

Concerns regarding the safety of BCT after NAC were raised by the Early Breast Cancer Trialists’ Collaborative Group meta-analysis of 4,756 women in 10 randomized trials of NAC versus adjuvant therapy conducted between 1983 and 2002.¹² Although no survival differences were observed, a statistically significant 5.5% increase in LR was seen in the NAC group. When trials with no surgery were eliminated, this decreased to 3.2% (95% CI, 0.6% to 5.8%; P = .01) but, paradoxically, was no higher among patients requiring NAC to downstage to BCT than among patients who were candidates for BCT at presentation but received NAC, suggesting that these findings may reflect less familiarity with the post-NAC evaluation of extent of disease and surgery during this time period.

More recent studies indicate that the degree of response to NAC is predictive of local control. In a retrospective study of 751 patients, Swisher et al¹⁹ found rates of locoregional control exceeding 93% in patients achieving a pCR, and in contrast to what has been observed in the primary surgical setting, LRR-free survival rates did not differ by HR and HER2 status. Failure to achieve a pCR was significantly associated with decreased LRR-free survival in HR-negative patients but not HR-positive patients,¹⁹ the same subtype-specific relationship observed between pCR and overall survival (OS).²⁰ In a meta-analysis of 9 NAC studies, the 10-year LR rate was 6.5%, and estrogen receptor (ER)–negative disease, clinically node-positive disease, lack of axillary pCR, and axillary pN2-3 disease were significantly associated with LR.²¹ These observations suggest opportunities for studying de-escalation of therapy after pCR in subtypes such as HER2-positive or triple-negative breast cancer, which have traditionally been regarded as high risk, or, conversely, intensified therapy to improve locoregional control in patients who do not achieve pCR.

AXILLARY MANAGEMENT AFTER NAC

Early observations from the NSABP B18 trial that NAC reduced the incidence of nodal positivity from 57% in patients having surgery first to 41% in patients having NAC followed by surgery led to studies of the accuracy of sentinel lymph node biopsy (SLNB) after NAC.² Concerns that fibrosis of lymphatic channels after NAC and nonuniform treatment response in the nodes would result in unacceptably high false-negative rates are not supported by clinical evidence. In patients presenting as clinically node negative, study-level meta-analyses involving > 6,000 patients report sentinel node (SN) identification rates of 90%-96% and false-negative rates of 6%-12% (Table 1),^22-26 results similar to those seen in the up-front surgical setting. Concerns that a false-negative SLNB after NAC might lead to higher nodal recurrence rates than observed in the primary surgical setting as a result of chemotherapy-resistant disease are also unsupported by data. In the prospective, multi-institutional GANEA 2 study of SLNB accuracy after NAC, the SN identification rate was 98% in the 589 patients presenting as cN0. At a median follow-up of 36 months, 1 nodal relapse (0.2%) was seen in the 419 patients treated with SLNB alone.²⁷ Nodal recurrence rates of < 1.5% after median follow-up times of 47-51 months have also been reported from single-institution studies,^28,29 and SLNB after NAC has been widely adopted in patients presenting as cN0.

TABLE 1.

Meta-Analyses of Sentinel Lymph Node Biopsy in cN0 Patients After Neoadjuvant Chemotherapy

The high nodal pCR rates in patients presenting with histologically documented nodal metastases^30-32 with current NAC regimens prompted interest in studying SLNB as a means to avoid ALND in this group; 4 prospective, multi-institutional studies have examined this question (Table 2).^27,30,33,34 SN identification rates were lower than those observed in cN0 patients after NAC, ranging from 79.5% to 92.7%, and the overall false-negative rates exceeded the 10% threshold considered acceptable in the up-front surgery setting. However, when a minimum of 2^27,30 or 3^33,34 SNs were obtained, false-negative rates decreased to < 10%. In a study-level meta-analysis including 1,921 patients with biopsy-proven nodal metastases, Tee et al³⁵ reported a 90% SN identification rate and a 14% false-negative rate. Dual-agent mapping reduced the false-negative rate from 19% to 11%, and false-negative rates decreased from 20% with a single SN to 12% with 2 SNs and to 4% with removal of ≥ 3 SNs. The only outcome data on nodal recurrence rates in patients presenting as clinically node positive (cN+) with a negative SLNB after NAC with no ALND are a series of 70 patients with a median follow-up of 61 months; no axillary recurrences were observed.³⁶ At present, for ALND to be avoided with NAC in cN+ patients, ≥ 3 negative SNs should be retrieved. As in the breast, nodal pCR rates vary with HR and HER2 status and are highest in patients with HR-negative/HER2-positive cancers treated with anti-HER2 agents,^31,32 but approximately 20% of HR-positive/HER2-negative patients will have nodal pCR after NAC. In a prospective, single-institution study examining how often ALND is avoided with NAC in cN+ patients, 62 (48%) of 128 consecutive patients had ≥ 3 SNs identified and a nodal pCR.³²

TABLE 2.

Prospective Trials of SLN Biopsy Feasibility in Clinically Node-Positive Patients After Neoadjuvant Chemotherapy

Post-NAC ultrasound and magnetic resonance imaging (MRI) are not helpful in reducing the SLNB false-negative rate in this patient group.^30,37 Clipping the involved node during biopsy and removing this node along with the SNs, a procedure known as targeted axillary dissection, reduced the SLNB false-negative rate to < 7% in retrospective studies.^38,39 The clipped node is not an SN in approximately 20% of patients, although the likelihood of the clipped node being an SN increases with the number of SNs retrieved.³⁸ The contribution of clipping when dual-tracer mapping is used and ≥ 3 SNs are retrieved is unclear at this time, but clipping may allow avoidance of ALND when < 3 negative SNs are retrieved.

Macrometastases in the SN after NAC are an indication for ALND, although, as discussed later, a trial randomly assigning patients to radiotherapy or ALND for residual positive nodes is ongoing. The presence of micrometastases in the SN in the up-front surgery setting is not considered an indication for ALND or axillary radiotherapy⁴⁰ because the risk of additional nodal disease is relatively low (13%), but management in the post-NAC setting is controversial.⁴¹ Moo et al⁴² found that micrometastases in the SN after NAC were associated with the same risk of additional nodal disease as macrometastases (64%) and should be considered an indication for ALND. Micrometastases after NAC have been retrospectively shown to worsen prognosis compared with node-negative patients,^43,44 and their identification may indicate the need for additional systemic therapy.^45,46 There are insufficient data to know whether isolated tumor cells after NAC necessitate ALND.

Whether ALND can be avoided after NAC in patients with locally advanced breast cancer (LABC) presenting with T4 or N2/3 disease is unknown. These patients were not included in the trials of up-front SLNB, so the accuracy of mapping is uncertain. However, in a retrospective study of 321 patients with LABC receiving NAC, pCR rates in the breast and the nodes did not differ from those in patients with earlier-stage disease receiving NAC,⁴⁷ making this area ripe for study.

RADIOTHERAPY AFTER NAC

The increasing use of NAC in patients with operable breast cancer has resulted in treatment dilemmas—caused by a lack of level 1 evidence—for radiation oncologists. The fundamental issue is whether the scope and intensity of locoregional therapy should be based on the risk profile of the pretreatment clinicopathologic features, the tumor extent after NAC, or both. This question is critical to determining the need for postmastectomy radiotherapy (PMRT), the need for comprehensive nodal irradiation, and the use of a chest wall or nodal boosts.

Several studies suggest that the risk profile before NAC should be the primary determinant of subsequent radiation therapy (RT). Buchholz et al⁴⁸ reported a study of 150 postmastectomy patients treated with NAC and 1,031 similar patients treated with adjuvant chemotherapy, all without PMRT. In patients with post-NAC tumor sizes ≤ 5 cm and 1-3 residual positive nodes, the LRR rates for initial clinical stage T3/4 and T1/2 were 46% and 4%, respectively (P = .0019). In a similar study from the same group, Huang et al⁴⁹ examined 676 patients treated with doxorubicin-based NAC followed by mastectomy; 134 patients received PMRT, whereas the remainder (n = 542) did not. The irradiated cohort had a higher residual disease burden after chemotherapy, more close or involved margins, and other risk factors for LRR. Despite this, the 10-year actuarial LRR rate was 11% in the PMRT patients compared with 22% in the no-PMRT group (P = .0001). Differences in LRR in patients with ≥ 4 residual positive lymph nodes or residual primary tumors > 2 cm were particularly striking (10-year rates in the PMRT and no-PMRT groups: 16% v 59%, and 14% v 31%, respectively). Patients presenting with stage I and II disease who had a pCR and patients who had stage II disease with ypN1a (1-3 involved lymph nodes) did not have significant decreases in LRR with PMRT. On multivariable analysis, independent predictors of LRR included radiation use (hazard ratio, 4.7; 95% CI, 2.7 to 8.1), nodal ratio > 2.0, stage IIIB or IV disease, omission of tamoxifen, ER-negative disease, and poor response to induction chemotherapy. PMRT was independently associated with improved cause-specific survival; pCR was not independently associated with locoregional control or cause-specific survival. Garg et al⁵⁰ attempted to further define which patients with clinical stage I and II breast cancer receiving NAC required PMRT in a study of 132 patients treated with doxorubicin-based or paclitaxel NAC followed by mastectomy without PMRT. Although this analysis was limited by small numbers, initial clinical T3N0 disease (LRR, 29%), ≥ 4 positive lymph nodes after chemotherapy, age ≤ 40 years, and the absence of tamoxifen therapy were significantly correlated with higher LRR rates. McGuire et al⁵¹ reported on 106 patients who had a pCR with NAC. Approximately one-third were clinical stage I or II, whereas the remainder were clinical stage III. With a median follow-up of 62 months, the LRR rate was 7.3% with RT compared with 33.3% without RT in patients who had initial clinical stage III disease (n = 74; P = .04). Disease-free survival (DFS) and OS were also improved with PMRT. Thirty-two patients with clinical stage I or II disease had no LRRs. Taken together, these data suggest that the initial prechemotherapy burden of disease cannot be ignored when making decisions regarding the benefit of adjuvant RT. However, these retrospective studies are potentially confounded by selection biases that may be incompletely addressed by the best statistical methods.

Information on outcomes of an unselected group of patients treated with NAC without PMRT or regional nodal irradiation (RNI) in breast-conservation patients comes from the NSABP, which had a long-standing policy of disallowing such treatment. Mamounas et al⁵² reported a pooled analysis of the NSABP B18 and B27 trials, which randomly assigned patients to 4 cycles of AC preoperatively or postoperatively (B18) or to AC plus a taxane preoperatively or postoperatively (B27). The 10-year LRR cumulative incidence was 11.1% for the entire cohort of patients (8.4% local and 2.7% regional). In the combined group of 2,961 eligible patients with complete information, independent predictors of LRR on multivariable analysis included age, clinical tumor size and clinical nodal status before NAC, pathologic breast tumor response in pathologically node-negative patients, and pathologic nodal status in patients having a pCR in the breast. Importantly, in both the mastectomy and the BCT cohorts, cN+ patients with nodal pCR had 10-year LRR rates < 10%-12%, whereas patients with residual node positivity had 10-year LRR rates of 15%-20%. These data support the possible omission of PMRT or RNI in patients with complete nodal responses, especially if coupled with pCR in the breast (10-year LRR rates of 0-7%). Conversely, the NSABP data suggest that patients with residual nodal disease after NAC have a significant LRR risk and would benefit from more-aggressive locoregional therapy.

These data leave room for clinical interpretation on how best to treat post-NAC patients, opening the door to potential practice variations. Locoregional management patterns after NAC in patients with confirmed nodal disease at presentation were described by Haffty et al⁵³ in a secondary analysis of the American College of Surgeons Oncology Group Z1071 trial. Approximately 53% of patients who were node negative after NAC and had BCT received RNI in addition to whole-breast RT. Among node-negative mastectomy patients not having breast reconstruction, 85% received PMRT, compared with 66% of reconstructed patients (P < .001). In patients with residual node positivity after NAC, the RNI rate in BCT patients was 72%, and the PMRT rates were 82% and 90% in reconstructed and nonreconstructed patients, respectively. These data are a clear demonstration of the clinical equipoise in initially node-positive patients who convert to node negativity, particularly those having BCT and mastectomy with reconstruction. With a median follow-up of 5.9 years, Haffty et al⁵⁴ found that PMRT or RNI receipt resulted in lower LRR in the overall group (hazard ratio, 2.35; P = .018), without impact on OS, DFS, or breast cancer–specific survival. LRR rates were decreased in mastectomy patients with residual nodal positivity. No differences were noted after PMRT or RNI in patients with axillary pCR. These data should be viewed in light of their retrospective nature and the selected use of RT in the study population.

Definitive data that should clarify the optimal locoregional strategy after NAC will be provided (in part) by the ongoing NSABP B51/Radiation Therapy Oncology Group 1304 trial, a randomized superiority trial of RNI (in addition to whole-breast RT) or PMRT (v no RT) in biopsy-proven node-positive patients who convert to node negativity after NAC (Fig 1). The study-specified PMRT includes the draining lymph nodes; hence, the trial is fundamentally testing the benefit of RNI. The trial is designed as a superiority trial with omission of RNI/PMRT as the control arm in keeping with the historic NSABP standard. The primary end point is invasive breast cancer recurrence–free interval, with an estimated 5-year cumulative event rate of 14% in the control arm and 9.3% with RNI. Patients are stratified by surgery type (mastectomy v lumpectomy), HR and HER2 status, adjuvant chemotherapy, and pCR in the breast. The target volume for RNI includes the undissected portion of the axilla (the entire axilla for patients undergoing SLNB) and the supraclavicular and internal mammary lymph nodes. Omitting the dissection volume may be associated with lower lymphedema risks⁵⁵ (Fig 2). RT quality assessment is a crucial part of the study monitoring process. As of this writing, approximately 1,315 of the planned 1,636 patients have been enrolled.

FIG 1.

Diagram of ongoing phase III trials of locoregional therapy after neoadjuvant chemotherapy (NAC). Trial schemas are depicted for ongoing studies examining extent of radiation based on response to NAC. ALND, axillary lymph node dissection; Bx, biopsy; ER, estrogen receptor; FNA, fine-needle aspiration; HER2, human epidermal growth factor receptor 2; NSABP, National Surgical Adjuvant Breast and Bowel Project; pCR, pathologic complete response; PMRT, postmastectomy radiation therapy; PR, progesterone receptor; RT, radiation therapy; RTOG, Radiation Therapy Oncology Group; SN, sentinel node; WBRT, whole-breast radiation therapy.

FIG 2.

Coronal projection of axillary clinical target volume excluding axillary lymph node dissection (ALND) changes. Clips from ALND are visible in the low axilla. The axillary clinical target volume (CTV) contour (in red) begins above the visible dissection changes. The supraclavicular CTV contour appears medial and superior to the axillary CTV (orange contour).

The Alliance 011202 trial is examining the optimal approach to patients who remain node positive after NAC, testing the benefit of ALND after a positive SLNB (Fig 1). Patients on both arms receive comprehensive RT to the breast and chest wall and all undissected lymph nodes in the axilla, supraclavicular fossa, and internal mammary spaces. Irradiation of the dissection volume is discouraged but can be delivered in high-risk patients. Unlike the NSABP B51 trial, a chest wall or scar boost is mandated. The trial is a noninferiority study, with an ALND plus RT control arm, and omission of ALND with axillary RT as the experimental de-escalation. The primary end point is invasive breast cancer recurrence–free interval, using a lower boundary threshold of the 90% CI > 0.82. The trial has enrolled the 1,576 intended patients, with additional enrollment under consideration.

Since the launch of these trials, 2 analyses suggesting caution in de-escalation of locoregional therapy after NAC, even in patients with responsive tumors, have been reported. These data are not a substitute for the level 1 evidence that will be reported from the ongoing randomized trials, which will provide definitive answers to these critically important questions. Krug et al⁵⁶ reported a pooled analysis of the randomized GeparTrio, GeparQuattro, and GeparQuinto trials of NAC in abstract form. In 3,481 patients and with a median follow-up of 55.9 months, RT use, compared with no RT, improved 5-year LRR-free survival (90% v 81.5%, respectively; P < .001) and DFS (75.4% v 67.4%, respectively; P < .001). In patients with a pCR in the breast and nodes, the 5-year LRR-free survival was 95.7% with RT compared with 86.6% without RT (hazard ratio, 3.32; 95% CI, 1.00 to 11.08; P = .051), and the 5-year DFS was 86.9% with RT compared with 56.1% without RT (hazard ratio, 3.52; 95% CI, 1.82 to 6.83; P < .001). In a multivariable model adjusting for post-treatment pathologic stage, RT use remained an independent prognostic factor for LR-free survival and DFS.

Stecklein et al⁵⁷ reported 1,289 patients with stage II and III breast cancer presenting with pathologically confirmed nodal involvement who received NAC between 1989 and 2007. With a median follow-up of 10 years, RNI significantly reduced the risk of LRR (hazard ratio, 0.497; P = .02) and any recurrence (hazard ratio, 0.73; P = .04) in a multivariable analysis, independent of whether a breast pCR or an axillary pCR was achieved. Age, grade, margins, and biologic subtype were also independent predictors of LRR. A separate analysis of the nodal pCR group was not performed as a result of insufficient events.

At present, based on the data presented here and the studies of RNI after primary surgery, we consider most off-trial patients with nodal metastases at presentation to be candidates for RNI or PMRT. We acknowledge and discuss with our patients the uncertainty that exists in this area, particularly in patients with an excellent response (eg, a mastectomy patient with an HER2-positive tumor and pCR in breast and nodes). We follow the contouring guidance and the coverage and organ constraints described in the ongoing trials.

FUTURE DIRECTIONS

The high pCR rates seen in patients with HER2-positive and triple-negative breast cancers treated with modern systemic therapy have stimulated interest in the complete avoidance of surgery in these patients if the presence of pCR can be reliably determined with imaging and core needle biopsies. In determining whether this should be a research priority, there are a number of issues to consider. There is no reason to believe that LRR will be decreased with this approach, and patients with pCR are excellent candidates for lumpectomy and SLNB, a surgical approach with minimal morbidity. In the joint analysis of the NSABP B18 and B27 trials, in patients who achieved a pCR determined surgically, LRR was seen in 6%-9% of patients treated with BCT or mastectomy,⁵² indicating that pCR is not a guarantee of freedom from LRR, even in those treated with surgery and RT. The accuracy of MRI to determine breast pCR was 83% in a meta-analysis of studies performed since 2001.⁵⁸ In a prospective single-institution study of 40 patients, the false-negative rate of needle biopsy in predicting breast pCR was 5% (95% CI, 0% to 24%),⁵⁹ but three multi-institutional prospective trials have recently reported false-negative rates of 17.8%, 22.5%, and 37% in substantially larger studies.^60-62 The accurate assessment of pCR has assumed increased importance since the CREATE-X trial and the KATHERINE trial have demonstrated survival benefits for the administration of additional chemotherapy to patients with triple-negative and HER2-positive breast cancer who do not have a pCR after NAC.^45,46 The management of patients without surgery will undoubtedly involve more frequent imaging surveillance and more frequent biopsies, and the long-term acceptability^63,64 and cost effectiveness of this approach are uncertain. It is also uncertain how much of a priority this is for patients and whether surgery is the treatment modality they would most like to eliminate. Concern about recurrence is the factor that moderately to greatly influences surgical decision making for approximately 70% of patients,⁶⁵ and the current trend of patient choice of bilateral mastectomy for the treatment of unilateral cancers suitable for BCT does not suggest a major patient movement toward avoiding surgery. Surgery is a low-cost, effective modality for reliably determining the presence of pCR and for maintaining local control in patients who have a good response to NAC; efforts to eliminate it at this time seem premature. In the future, when imaging may more reliably allow the differentiation between viable residual tumor and post-treatment changes, and when systemic therapy has further improved, this will be an area worthy of study. At present, a more pressing need is to develop innovative strategies for the management of patients who have a poor response to NAC who are at high risk of both distant recurrence and LRR.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Collection and assembly of data: All authors

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Locoregional Management After Neoadjuvant Chemotherapy

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Monica Morrow

Honoraria: Genomic Health

Travel, Accommodations, Expenses: Genomic Health

Atif J. Khan

Employment: Memorial Sloan Kettering Cancer Center

Research Funding: Clovis Oncology

No other potential conflicts of interest were reported.