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Journal of Clinical Oncology, Vol 22, No 12 (June 15), 2004: pp. 2303-2312 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.062
Breast Conservation After Neoadjuvant Chemotherapy: The M.D. Anderson Cancer Center ExperienceFrom the Departments of Radiation Oncology, Surgical Oncology, Biomathematics, Breast Medical Oncology, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Thomas A. Buchholz, MD, Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 97, Houston, TX 77030; e-mail: tbuchhol{at}mdanderson.org
PURPOSE: To determine patterns of local-regional recurrence (LRR) and ipsilateral breast tumor recurrence (IBTR) among patients treated with breast conservation therapy after neoadjuvant chemotherapy. PATIENTS AND METHODS: Between 1987 and 2000, 340 cases of breast cancer were treated with neoadjuvant chemotherapy followed by conservative surgery and radiation therapy. Clinical stage at diagnosis (according to the 2003 American Joint Committee on Cancer system) was I in 4%, II in 58%, and III in 38% of patients. Only 4% had positive surgical margins. RESULTS: At a median follow-up period of 60 months (range, 10 to 180 months), 29 patients had developed LRR, 16 of which were IBTRs. Five-year actuarial rates of IBTR-free and LRR-free survival were 95% and 91%, respectively. Variables that positively correlated with IBTR and LRR were clinical N2 or N3 disease, pathologic residual tumor larger than 2 cm, a multifocal pattern of residual disease, and lymphovascular space invasion in the specimen. The presence of any one of these factors was associated with 5-year actuarial IBTR-free and LRR-free survival rates of 87% to 91% and 77% to 84%, respectively. Initial T category (T1–2 v T3–4) correlated with LRR but did not correlate with IBTR (5-year IBTR-free rates of 96% v 92%, respectively, P = .19). CONCLUSION: Breast conservation therapy after neoadjuvant chemotherapy results in acceptably low rates of LRR and IBTR in appropriately selected patients, even those with T3 or T4 disease. Advanced nodal involvement at diagnosis, residual tumor larger than 2 cm, multifocal residual disease, and lymphovascular space invasion predict higher rates of LRR and IBTR.
Neoadjuvant chemotherapy is considered the standard of care for the management of locally advanced breast cancer and is increasingly being used for women with earlier stage disease. Although this treatment has historically been reserved for those with inoperable breast cancer, findings from both laboratory and clinical studies have garnered enthusiasm for its use in operable breast cancer.1–3 As a result, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has adopted neoadjuvant chemotherapy as standard treatment in their trials of early-stage breast cancer.4 Although neoadjuvant chemotherapy has not been shown to provide a survival advantage over adjuvant chemotherapy, many favor this treatment approach for other reasons, such as allowing assessment of disease response to a particular chemotherapy regimen.5–8 The most clearly recognized benefit of neoadjuvant chemotherapy is that it can increase the proportion of patients who can be treated with breast conservation therapy (BCT). Numerous randomized and nonrandomized prospective studies have convincingly demonstrated that neoadjuvant chemotherapy can allow BCT in some patients for whom mastectomy was initially the preferred option for local-regional control.9–16 The reported proportions of patients who underwent BCT (as opposed to mastectomy) after neoadjuvant chemotherapy range from 13% to 83%, with the wide range of percentages across studies likely reflecting differences in both the inclusion criteria and the selection criteria used to identify candidates for BCT. Despite the growing body of literature demonstrating the feasibility of BCT after neoadjuvant chemotherapy, concerns have been raised as to whether giving chemotherapy first increases the likelihood of local-regional recurrence (LRR) or ipsilateral breast tumor recurrence (IBTR). Indeed, several groups have reported unacceptably high recurrence rates for patients who underwent BCT after neoadjuvant chemotherapy.17–22 As a result of this uncertainty, the medical community has been hesitant to fully embrace BCT for patients who meet criteria for this treatment modality after neoadjuvant chemotherapy. The indications for BCT and specific selection criteria in this particular setting remain controversial. At The University of Texas M.D. Anderson Cancer Center (Houston, TX), we have been performing BCT after neoadjuvant chemotherapy since 1987. The purpose of the current analysis was to report a single-institution experience with use of BCT after neoadjuvant chemotherapy, focusing on the correlation of clinical outcome with patient and pathologic variables.
Patient Population Analysis of existing databases at our institution provided the patient population for this study. A retrospective review of medical records identified 403 cases (in 401 patients) that were treated with BCT (segmental mastectomy followed by radiation therapy) after neoadjuvant chemotherapy at M.D. Anderson Cancer Center between 1987 and 2000. The institutional review board approved the retrospective chart review for the purposes of this study. We excluded cases that had undergone an excisional biopsy (n = 25), cases without an identifiable primary tumor (n = 17), cases with inflammatory carcinoma (n = 14), and cases with systemic metastases at presentation (n = 7). The remaining 340 cases (in 338 patients) served as the population for this study. We did not have information about the choices made by the total number of cases treated with neoadjuvant chemotherapy in our institution between 1987 and 2000. Therefore, we could not determine the number of patients who initially desired BCT but were treated with mastectomy based on treatment recommendations of their physicians. Demographic, clinicopathologic, and treatment variables were abstracted from the medical records of each case. All pathology materials were reviewed at M.D. Anderson Cancer Center before treatment. Clinical and treatment characteristics are shown in Table 1. For the purpose of this analysis, disease in all cases was retrospectively staged according to the 2003 American Joint Committee on Cancer clinical staging guidelines. Nearly all cases (96%) had stage II or stage III disease; only 12 patients (4%) had stage I disease. Initial tumor size in centimeters was not reported because of difficulties in attaining a consensus value as a result of interobserver variability among different examiners, as well as discrepancies between physical examination, mammogram, and ultrasound findings. Instead, we opted to report initial T-stage, which we felt was more accurate in describing the original extent of disease at the primary site. The median age of patients at the time of diagnosis was 47 years (range, 22 to 84 years). Before neoadjuvant chemotherapy was begun, all patients underwent a physical examination, biopsy, and staging work-up. Biopsy findings indicated that 84% of the cases had infiltrating ductal carcinoma. Estrogen-receptor status of the tumor was positive in 39% of cases, negative in 52%, and unknown in 9%.
Treatment The neoadjuvant chemotherapy regimens followed those outlined in institutional protocols that were open during the study period. Indeed, 258 (76%) of the 340 patients were treated on one of five consecutive prospective institutional protocols. The full details of the regimens used have been documented elsewhere.23,24 Most patients were treated with a doxorubicin-containing regimen, with the most common regimen consisting of 500 mg/m2 of fluorouracil administered on days 1 and 4, 50 mg/m2 of doxorubicin given on day 1 as a bolus or as a 72-hour continuous infusion, and 500 mg/m2 of cyclophosphamide given on day 1. Between 1994 and the end of the study period, some patients were treated with a taxane (either paclitaxel only, given weekly or every 3 weeks, or a combination of doxorubicin and docetaxel). The indications for using neoadjuvant chemotherapy during the period of the study were relatively broad. As noted, 76% of the cases included in this study were treated on clinical protocols. Initially, these protocols were limited to patients with locally advanced disease; however, since 1994, these protocols included some patients who were candidates for BCT at diagnosis. The rationale for using neoadjuvant chemotherapy on clinical trials in these patients was that it allowed the efficacy of two chemotherapy regimens to be compared. The most common rationale for using neoadjuvant chemotherapy in the 24% of patients not treated on a clinical trial was to achieve a tumor response that would facilitate BCT, although some cases were treated with neoadjuvant chemotherapy solely on the basis of physician preference. Physical examination, diagnostic mammography, and sonography were typically performed at baseline and after every two chemotherapy cycles to assess clinical response. Patients with progressive disease or minimal response after two to four cycles were considered for alternate chemotherapy regimens. In many of the patients who had a favorable response to chemotherapy, metallic markers were placed at the primary tumor site to facilitate localization at surgery. At the completion of the neoadjuvant chemotherapy, a multidisciplinary team evaluated the cases to determine eligibility for BCT. Guidelines for BCT remained uniform during the study period and included resolution of skin or chest wall involvement (if initially present); lack of multicentric disease or extensive microcalcifications; tumor smaller than 5 cm; and absence of collagen vascular disease or other contraindications for radiation therapy. The breast conservation surgery involved gross excision of the residual primary tumor with a margin of normal tissue. In most cases, no attempt was made to resect the preoperative volume of disease. When final pathology examination indicated positive or unknown margins, patients routinely underwent re-excision at the discretion of the surgeon in an attempt to obtain negative margins, or were considered for mastectomy. Final pathological margins were focally positive in 15 patients (4%) who declined further surgical resection. The choice of axillary procedure was determined by patient and physician preference. Standard level I and II axillary lymph node dissection, with or without sentinel lymph node biopsy, was performed in 276 cases (81%). Forty-one patients (12%) had a sentinel lymph node biopsy alone, and no axillary surgery was performed in the remaining 23 patients (7%). For the majority of the years of this study, tamoxifen was offered only to postmenopausal patients with estrogen-receptor positive tumors. More recently, tamoxifen was also offered to premenopausal patients with estrogen-receptor positive tumors. In total, 131 cases (39%) were treated with tamoxifen. Two hundred sixty-two cases (77%) were treated with adjuvant chemotherapy. All patients were treated with adjuvant external-beam radiation therapy to the affected breast with tangential fields. The median dose to the breast was 50 Gy, delivered in 25 fractions over 5 weeks. All patients received an electron boost to the tumor bed (median dose, 10 Gy). Regional nodal radiation was delivered at the discretion of the radiation oncologist. In all cases, the planned course of radiation therapy was completed.
End Points and Statistical Methods Five-year actuarial rates of LRR-free, IBTR-free, distant metastasis-free, and overall survival were calculated by the Kaplan-Meier method, with comparisons among groups performed with two-sided log-rank tests.25 A Cox proportional hazards model was used to identify variables independently associated with LRR and IBTR.26 Cases with unknown factors were excluded in the initial Cox regression analysis. If a factor did not predict for the end point being analyzed, the cases with unknown values for that factor were added back in, and the Cox regression was repeated with that particular factor dropped. All tests were two-tailed, with a P value of less than .05 considered significant.
Disease characteristics after neoadjuvant chemotherapy are listed in Table 2. The median residual tumor size after neoadjuvant chemotherapy was 1.0 cm (range, 0 to 6.0 cm). Excised breast tissue showed no evidence of invasive disease in 80 patients (24%); of those patients, three had residual ductal carcinoma-in-situ (DCIS) and the remaining 77 cases (23%) had no residual disease. For the purposes of this report, we classified residual tumor morphology as a solitary mass (182 patients), multifocal residual tumor (78 patients), or no residual tumor (80 patients). A multifocal residual tumor was defined as one in which noncontiguous foci were noted in the breast tissue on histologic examination. Typically, these cases were described as having nests of tumor visible on multiple slides and interspersed among fibrosis, necrosis, granulomas, and giant cells. Most patients had no evidence of disease in the lymph nodes, with the number of positive lymph nodes ranging from 0 to 19.
The median follow-up time was 63 months for surviving patients (range, 10 to 180 months). In total, there was evidence of recurrent disease in 56 cases (16%). Twenty-nine cases (9%) developed LRR, resulting in a 5-year actuarial LRR-free survival rate of 91%. Of the 29 LRRs, 16 (55%) were IBTRs, resulting in a 5-year actuarial IBTR-free survival rate of 95%. Seven LRRs (24%) occurred in the supraclavicular fossa, two (7%) in the axilla, two (7%) in the infraclavicular fossa, and two (7%) in the internal mammary nodes. LRR was an isolated first event in 17 patients (59%), occurred simultaneously with distant metastasis in seven (24%), and occurred subsequent to distant metastasis in five patients (17%). Distant metastases developed in 45 patients (13%), leading to a 5-year actuarial distant metastasis-free survival rate of 87%. The 5-year actuarial overall survival rate was 89%. Table 3 shows data that demonstrates how LRR correlates with pretreatment characteristics. Higher T-stage was associated with a higher rate of LRR (P = .09 when T-stages were analyzed independently; P = .03 for clinical T1–T2 v T3–T4). Repeating this analysis to compare clinical T1–T3 with T4 disease showed a lower LRR-free survival rate in the patients with T4 disease (92% v 84%, P = .05). However, the difference in IBTR rate for patients with T3 or T4 disease was not significantly different from that for patients with T1 or T2.
Higher clinical N-stage also associated with a higher rate of LRR. This difference was more pronounced when the comparison was between clinical N0–N1 and N2–N3 disease, for which the 5-year actuarial LRR-free survival rates were 93% and 86%, respectively (P = .03; Fig 1). Advanced nodal disease at presentation was also associated with an increased risk of IBTR.
No other clinical variables were associated with an increased rate of LRR. Specifically, patient age, menopausal status, or the use of tamoxifen also did not correlate with LRR (Table 3). Actuarial LRR rates according to pathologic variables after chemotherapy treatment are shown in Table 4. A residual primary tumor > 2 cm after neoadjuvant chemotherapy was associated with an increased rate of LRR (P = .002; Fig 2). The presence of a multifocal pattern of residual disease after neoadjuvant chemotherapy was associated with an increased risk for LRR (P = .0008); the 5-year LRR-free survival rates for patients with multifocal residual tumor, solitary residual tumor, and no residual disease were 82%, 93%, and 95%, respectively (Fig 3). Finally, the presence of lymphovascular space invasion (LVSI) also correlated with LRR (P < .001); the 5-year actuarial LRR-free survival rate for those with LVSI was 77% as opposed to 94% for those with no evidence of LVSI (Fig 4).
No other associations were found between LRR and other pathologic variables, including margin status, the presence of DCIS in the tumor specimen, estrogen receptor status, involvement of lymph nodes, and pathologic complete response (CR) found in both primary tumor and lymph nodes. IBTR rates according to selected clinical and pathologic variables are shown in Table 5. Three of the factors that predicted for LRR in univariate analyses (advanced nodal involvement at presentation, residual tumor > 2 cm, multifocal residual disease) also predicted for IBTR (P < .05 for all factors). Five-year actuarial IBTR-free survival rates for cases with clinical N2 or N3 disease, residual tumor > 2 cm, or multifocal residual disease were 89%, 87%, and 89%, respectively. LVSI, which was significantly associated with LRR, showed a similar trend that was not significant for IBTR (P = .07). Initial T stage did not predict IBTR when each T stage was analyzed independently (P = .62), when T stages were grouped and analyzed as T1–T2 versus T3–T4 (P = .19), or when T1, T2, and T3 combined into one group was compared with T4 (P = .49). Patients who presented with clinical T1, T2, T3, and T4 breast cancer had 5-year actuarial IBTR-free survival rates of 97%, 96%, 93%, and 92%, respectively (Fig 5). However, when advanced T-stage disease was combined with other variables, significantly increased rates of breast recurrences were noted. Specifically, patients with initial T3 or T4 tumors who had a multifocal pattern of residual disease had higher rates of IBTR. The 5-year IBTR-free survival rates were 96% for those with T1 or T2 disease without a multifocal pattern, 95% for those with T1 or T2 disease with a multifocal pattern, 97% for those with T3 or T4 disease without a multifocal pattern, and 80% for those with T3 or T4 disease with a multifocal pattern (P = .0008).
On multivariate analysis using a forward stepwise Cox logistic regression, significant predictors of LRR included initial N2 or N3 disease (hazard ratio [HR], 3.2; P = .005), pathologic tumor size > 2 cm (HR, 3.2; P = .006), residual multifocal pattern of disease (HR, 2.3; P = .03), and presence of LVSI (HR, 3.1; P = .007). Initial T3 or T4 disease was not significant (HR, 1.7; P = .09). When the multivariate analysis was repeated for IBTR, initial N2 or N3 disease (HR, 3.2; P = .005) and pathologic tumor size > 2 cm (HR, 3.2; P = .006) continued to be significant, but multifocal disease pattern (HR, 2.2; P = .13) and LVSI were no longer significant (HR, 1.7; P = .37). The IBTR hazard ratio for having T3 or T4 disease was 1.8 (P = .29). A pathologic CR in both the primary tumor and axillary lymph nodes was achieved in 67 patients (20%). Ten of these patients (14%) had residual DCIS in the breast without evidence of invasive disease. The pretreatment clinical stage of the 67 patients with a pathologic CR was IIA in 12 patients (18%), IIB in 25 patients (37%), IIIA in 20 patients (30%), IIIB in four patients (6%), and IIIC in six patients (9%). Three patients (4%) with a pathologic CR experienced LRR, all in the ipsilateral breast. The 5-year actuarial LRR-free and IBTR-free survival rates for patients with a pathologic CR were both 93%, and were not statistically different from the LRR-free rate of 90% and the IBTR-free rate of 95% in those patients without a pathologic CR. Excluding patients with residual DCIS from the analysis did not affect the results for LRR-free survival or for IBTR-free survival.
The most clearly established advantage of neoadjuvant chemotherapy is its ability to convert patients who were initially ineligible for BCT into candidates for this treatment strategy. The results of the current study, representing the largest single-institution cohort utilizing BCT after neoadjuvant chemotherapy to date, not only confirm the feasibility of this multimodality approach but, more importantly, demonstrate its effectiveness with respect to clinical outcome. Overall, the observed rates of LRR-free and IBTR-free survival are highly encouraging and compare favorably with those for patients undergoing BCT without neoadjuvant chemotherapy.27–29 In addition, we found that T3 or T4 disease was not associated with elevated rates of IBTR and therefore should not be considered a contraindication for BCT, as long as appropriate selection criteria are used. In general, patients who had any of the following factors after neoadjuvant chemotherapy were not considered candidates for BCT: residual tumor size in excess of 5 cm, residual skin edema, direct skin involvement, or chest-wall fixation, diffuse microcalcifications, multicentric disease, or medical contraindications to the use of radiotherapy. The results of this study are particularly important in view of the concerns based on findings from previous reports that the use of neoadjuvant chemotherapy may increase the risk of LRR and IBTR after BCT. It is worth noting that some of the studies that reported higher rates of LRR after neoadjuvant chemotherapy included large percentages of patients for whom radiation therapy was the only local-regional treatment without an attempt to resect the primary tumor site, and some studies included patients with inflammatory carcinoma.30–33 A large percentage of patients who attain a clinical CR have residual disease detected (invasive or noninvasive) at surgical resection. Therefore, we feel that surgery remains an important component of BCT for all patients treated with neoadjuvant chemotherapy. A few series that included patients who were treated with both surgery and radiation have also reported higher LRR rates. For example, in the Institut Bergonie series, nine (23%) of the 40 patients treated with lumpectomy and radiation experienced LRR.34 Similarly, in the NSABP B-18 trial, the IBTR rate for patients treated with neoadjuvant chemotherapy was twice as high for women who were not suited for BCT at diagnosis than for those who were candidates for BCT at diagnosis (14.5% v 6.9%; P = .04).7 The Institut Curie also reported IBTR rates of 16% at 5 years and 22% at 10 years for patients who underwent BCT after neoadjuvant chemotherapy.20 In contrast to these reports, others have found acceptably low rates of LRR and IBTR. For example, Bonadonna et al35 reported a 5-year IBTR rate of 7% after BCT and neoadjuvant chemotherapy, which is nearly identical to the 6% in the present study. In addition, Cance et al36 recently reported an IBTR rate of 10% among patients with advanced primary tumors treated with BCT after neoadjuvant chemotherapy. Finally, authors from our own institution have previously reported an IBTR rate of 5%.37 Patient selection criteria are probably the major factor responsible for the variation in published rates of LRR and IBTR. Differences in therapeutic approaches may also have contributed to the observed discrepancies in outcome. For instance, 11% of patients from the Institut Curie series had positive margins20 as compared with only 4% in the present study. Our findings indicate that both pretreatment and residual pathologic factors can affect rates of LRR and IBTR for patients treated with BCT after neoadjuvant chemotherapy. Although advanced nodal involvement at presentation seemed to confer an increased risk of LRR and IBTR after BCT and neoadjuvant chemotherapy, disease such as this has historically constituted a therapeutic challenge regardless of treatment strategy. In fact, compared with published reports of LRR-free rates of 74% to 85% among patients undergoing multimodality therapy and mastectomy for locally advanced breast cancer,38–41 our observed rates of LRR appear quite acceptable. Notably, the competing risk of developing distant metastases is significant in patients with advanced breast cancer, and avoidance of mastectomy is an important consideration for women with an already poor prognosis. The identification of multifocal residual tumor as a risk factor for LRR and IBTR after BCT and neoadjuvant chemotherapy raises some intriguing questions. Few data are available regarding how the morphology of residual disease correlates with LRR and IBTR. The Milan group found evidence of multifocal disease in 37 (16%) of 227 quadrantectomy specimens after neoadjuvant chemotherapy; they also reported that this pattern was more prevalent in larger tumors, "probably because these tumors had not been destroyed uniformly by chemotherapy."42 Van der Hage et al43 also suggested that uneven shrinkage and loss of density in tumors after chemotherapy might have important clinical repercussions. However, our report is the first to demonstrate that this phenomenon may indeed be associated with higher recurrence rates. In particular, patients with large tumors who have this pattern of residual tumor on pathologic examination have an IBTR rate of up to 20%. One possible explanation for this finding is that a multifocal pattern of residual disease may reflect incomplete resection, even when negative margins are reported. The multidisciplinary guidelines jointly issued by the American College of Radiology, the American College of Surgeons, the College of American Pathology, and the Society of Surgical Oncology recently addressed this issue. They stated that in the setting of BCT and neoadjuvant chemotherapy, "if viable tumor is present throughout the specimen even if it does not extend to the margin, a further re-excision should be considered."44 In our study, the presence of LVSI after neoadjuvant chemotherapy was also predictive of LRR for patients treated with BCT. Notably, LVSI has also been found to be an independent predictor of LRR in patients treated with BCT in which surgery was performed first and in patients treated with mastectomy.45,46 One limitation of this analysis is that we were unable to retrospectively determine the percentage of patients eligible for BCT upfront, before receiving neoadjuvant chemotherapy. As was the case with NSABP B-18, our data included some patients who were eligible for BCT at the time of diagnosis. One surrogate for BCT eligibility is clinical tumor size. We elected to report this as T stage because there was significant variability in the clinical size of the primary tumor in most patients, whereas T stage was assigned before treatment in all patients. One hundred ten patients (32%) in our analysis had T3 or T4 tumors. As demonstrated in the Results section of our article, patients with T3 or T4 tumors had similar rates of IBTR as those with T1 or T2 tumors (96% v 92%; P = .19). When T-stage was analyzed independently, rates of IBTR-free survival were 97%, 96%, 93%, and 92% at 5 years with a P value of .62. It is very likely that some of the patients with larger T2 disease were also ineligible for BCT at the time of diagnosis because of the tumor to breast size ratio. However, we did not feel we could accurately determine this percentage retrospectively. Similarly, we were unable to determine the proportion of all patients given neoadjuvant chemotherapy who desired a BCT approach and were subsequently deemed appropriate candidates for this form of local-regional therapy. Previously published reports from our institution noted that approximately 20% to 25% of patients with advanced tumors who participated in protocols for neoadjuvant chemotherapy underwent BCT.47–49 Because of the selection criteria used for BCT in our institution, the population of this current study was clearly biased toward patients with a favorable response to neoadjuvant chemotherapy. In those patients with locally advanced disease who have less favorable responses, we continue to advocate for mastectomy with postmastectomy radiation. We believe that the key to successful BCT after neoadjuvant chemotherapy lies in careful patient selection and coordination among treatment specialists. At our institution, a multidisciplinary team reviews most cases before, during, and after neoadjuvant chemotherapy. Uniform and objective criteria (residual tumor size of < 5 cm, no residual skin edema, direct skin involvement, or chest-wall fixation, no diffuse microcalcifications, no multicentric disease, and no medical contraindications to the use of radiotherapy) are applied to all patients to determine their eligibility for BCT. The operative management is closely coordinated among surgeons, pathologists, and radiologists specializing in breast disease, with careful attention paid to margin status. Patients with positive margins are strongly recommended to undergo re-excision if technically feasible. More recently, specimen radiography and postoperative mammography have been routinely performed to ensure complete resection of tumor. In conclusion, the results of this study demonstrate that BCT is a safe and effective alternative to mastectomy for appropriately selected patients treated with neoadjuvant chemotherapy. Patients with large primary tumors who are found to have multifocal residual disease, LVSI, or both are at increased risk of LRR and IBTR, and mastectomy could be considered for such patients. Fortunately, this subgroup represents a relatively small percentage of the patients treated with BCT after neoadjuvant chemotherapy.
The authors indicated no potential conflicts of interest.
Supported by Department of Defense Breast Cancer Research Program Career Development Award BC980154 (T.A.B.). Presented at the 2003 San Antonio Breast Cancer Symposium, San Antonio, TX, December 2003, where Dr Chen was recognized as an AstraZeneca distinguished scholar. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
