Affiliations of authors: Division of Hematology/Oncology, Department of Medicine (LAC, ECD, FC, MLG), Lineberger Comprehensive Cancer Center (RM, LS, DTM), Department of Radiation Oncology (CIS, JH), Department of Surgery (DWO, NK-D), and Department of Biostatistics (DTM), University of North Carolina at Chapel Hill, Chapel Hill
Correspondence to: Lisa A. Carey, MD, Division of Hematology/Oncology, UNC-CH, CB 7305, 3009 Old Clinic Building, Chapel Hill, NC 27599-7305 (e-mail: Lisa_Carey{at}med.unc.edu).
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ABSTRACT |
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INTRODUCTION |
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In this study, we examined the ability of the revised AJCC TNM staging system to predict patient survival after neoadjuvant chemotherapy for breast cancer.
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METHODS |
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Distant diseasefree survival was calculated as the time from the date of diagnosis of primary tumor to the date of the last follow-up, the date of development of distant or regional metastases (i.e., the date of radiologic or clinical documentation of metastatic disease), or the date of death from any cause, whichever occurred first. Distant diseasefree survival did not include local recurrences in the conserved breast or the axilla or on the chest wall. Overall survival was calculated as the time from the date of diagnosis of invasive breast cancer to the date of the last follow-up or death from any cause, whichever occurred first. We used the KaplanMeier method to estimate distant diseasefree survival and overall survival. We used an order-restricted version of the log-rank test (i.e., a trend test) to test for ordered differences between estimated time-to-event curves. We did an exploratory Cox regression was used to examine the impact of clinical covariates on distant diseasefree survival and overall survival. However, the data did not conform to proportional hazards assumptions. Statistical analyses were performed using JMP Version 5 and SAS statistical software, Version 8.2 (both products of the SAS Institute, Inc., Cary, NC). All statistical tests were two-sided. This study was approved by the committee on the Protection of the Rights of Human Subjects of the University of North Carolina at Chapel Hill.
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RESULTS |
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Table 2 presents the patient demographics and tumor characteristics for the 132 patients who were included in this study. Most patients were treated on or according to one of two neoadjuvant regimens that reflected the institutional protocols in place at the University of North Carolina from 1992 through 2000: 84 patients (64%) received anthracycline-based neoadjuvant chemotherapy, and 47 patients (36%) received combined anthracycline/taxanebased neoadjuvant chemotherapy. All patients with estrogen receptor (ER) positive tumors or tumors with unknown ER status were offered adjuvant tamoxifen. All patients underwent either breast-conserving surgery or modified radical mastectomy at the discretion of the treating physicians after multidisciplinary review, and all patients had axillary lymph node dissection. Seventy-two patients (54%) received additional adjuvant chemotherapy; of these, 59 received CMF as mandated by one of the institutional protocols. A total of 115 patients (87%) received adjuvant radiation therapy, and 60 (77%) of 78 patients with ER or progesterone receptor (PR)positive tumors or tumors with unknown hormone receptor status received adjuvant tamoxifen.
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The median follow-up for the cohort was 5 years (range = 1.211.1 years); 5-year distant diseasefree survival was 68% (95% confidence interval [CI] = 59% to 77%), and 5-year overall survival was 74% (95% CI = 65% to 82%). A total of 42 patients (32%) experienced a distant relapse.
The pathologic stage of surgical specimens from patients who had undergone neoadjuvant chemotherapy was strongly associated with both distant diseasefree (Fig. 1, A) and overall (Fig. 1, B) survival. The surgical specimens were fairly well distributed across all pathologic stages, except for an underrepresentation of those at stage IIIB (Table 3). Patients who had pathologic complete response (i.e., their residual tumor after neoadjuvant chemotherapy was stage 0, with no evidence of invasive cancer) had a 5-year distant diseasefree survival of 95% (95% CI = 87% to 100%). Patients whose residual tumors were stage I had a 5-year distant diseasefree survival of 84% (95% CI = 67% to 100%). Patients whose residual tumors were stage IIA, stage IIB, or stage IIIA had similar 5-year distant diseasefree survival, namely, 75% (95% CI = 55% to 96%), 65% (95% CI = 37% to 93%), and 68% (95% CI = 51% to 86%), respectively, although the small numbers of patients in each category limit generalizability. Only three patients had residual stage IIIB tumors, one of whom has relapsed. The 5-year distant diseasefree survival for patients with residual stage IIIC tumors was only 18% (95% CI = 0% to 36%). All 18 of the patients in the stage IIIC group had 10 or more involved axillary lymph nodes; none had residual supraclavicular or infraclavicular lymph node involvement. No patients in the study developed metastatic disease during neoadjuvant chemotherapy. There were statistically significant differences in both distant diseasefree survival (Ptrend<.001) and overall survival (Ptrend<.001) across all pathologic stages. Other variables that were statistically significantly associated with distant diseasefree survival included the presence of inflammatory disease (P<.001), the presence of lymphovascular invasion in the surgical specimen (P<.001), pretreatment stage (P<.001), tumor size (P = .04), clinical nodal status (P<.001), and posttreatment tumor size (P =.02) (data not shown). Distant diseasefree survival was not associated with patient age, race, menopausal status, clinical response rate, or the ER or PR status of the tumor (data not shown). Distant diseasefree survival was also not associated with subsequent receipt of adjuvant chemotherapy (P = .18) or adjuvant tamoxifen (P = .48). Exploratory Cox regression modeling suggested that the relationship of distant diseasefree survival with posttreatment AJCC stage may be more closely associated with number of involved nodes (N) than with extent of residual breast tumor (T) in this high-risk population.
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We found that the revised 2003 AJCC TNM system provided better prognostic discrimination for both distant diseasefree survival (P<.001) and overall survival (P<.001) than the 1988 system it replaced. Table 4 lists several commonly used tumor response classification systems. We applied each system to our data set to evaluate their usefulness for detecting associations between response to therapy and survival. The National Surgical Adjuvant Breast and Bowel Project (NSABP) system (1), which was developed to classify a large group of operable breast cancers, evaluates response in only the breast tumor. This classification system has four categories: pathologic complete response; clinical complete response with pathologic residual tumor; clinical partial response; and clinical nonresponse. The NSABP pathologic complete response category differs from the stage 0 category of the 2003 revised AJCC TNM in that the former but not the latter includes patients who have residual nodal disease. Patients whose residual tumors were classified as pathologic complete response with the NSABP system had 5-year distant diseasefree and overall survival rates of 95% (95% CI = 72% to 99%) and 95% (95% CI =72% to 99%), respectively, rates that were identical to the rates we observed using the revised 2003 AJCC TNM system. However, the other NSABP categories and the NSABP classification method overall did not provide prognostic discrimination when applied to our patient group for either distant diseasefree survival (P = .33) or overall survival (P = .57).
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The M.D. Anderson classification system (3) discriminates between no invasive tumor in breast or axillary lymph nodes (i.e., pathologic complete response) and any residual disease in breast or axillary lymph nodes. Compared with patients who had any residual disease, those who were classified as having a pathologic complete response had statistically significantly better distant diseasefree survival (95% versus 62%; P = .04) but not overall survival (95% versus 70%; P = .10).
The 2002 University of North Carolina surgical classification system (2) classifies response according to whether the patient was a candidate for breast conservation surgery; this system is not used to classify patients with inflammatory breast cancer because they are considered to be inappropriate candidates for breast conservation surgery regardless of their response to treatment. Compared with patients who were not considered candidates for breast conservation surgery, patients who were considered candidates for breast conservation surgery had statistically significantly better 5-year distant diseasefree survival (88% versus 53%; P<.001) and 5-year overall survival (94% versus 52%; P<.001). Table 5 demonstrates how patients in each of the AJCC categories would be classified according to these other four systems.
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DISCUSSION |
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In this study, we examined the usefulness of the 2003 revised AJCC staging criteria for predicting distant relapse and survival. The revised AJCC system includes a designation (yTNM) for staging after a patient receives neoadjuvant chemotherapy. We found that the revised 2003 AJCC TNM staging system was an effective and easy way to measure the extent of pathologic residual disease in both the breast and the axillary lymph nodes after neoadjuvant chemotherapy. This staging method is simple to use because it requires only the pathology report. Furthermore, this method categorizes patients into more than two groups, allowing determination of prognostic groups with excellent, intermediate, and extremely poor outcomes. The revised 2003 AJCC TNM system predicts distant diseasefree survival and overall survival better than does the 1988 version. The fact that approximately half of the patients in our study received further chemotherapy following surgery did not appear to substantially diminish the association we observed between pathologic complete response after neoadjuvant chemotherapy and outcome. This finding may reflect the small number of patients who received adjuvant as well as neoadjuvant chemotherapy or the fact that, even among the subset that received both neoadjuvant and adjuvant chemotherapy, the most effective agents (anthracyclines and taxanes) were administered in the neoadjuvant setting. The use of adjuvant tamoxifen was also not related to outcome. It is possible that this lack of association simply reflects the heterogeneous population of hormone receptornegative and positive tumors; it is also possible that 5 years of follow up suffices to measure the impact of chemotherapy but not that of endocrine therapy.
We also applied several other response classification methods to our data set. Only two methodsthe method used at the Milan Cancer Institute (6) and the method used in our previous work (2)provided statistically significant prognostic ability for both distant diseasefree survival and overall survival. The method used at the Milan Cancer Institute incorporates pathologic results and a clinical assessment of response and, thus, is more complex and prone to interobserver variability than is the AJCC yTNM system. The method used at M.D. Anderson (3), which distinguishes no residual tumor in breast or axilla from any residual tumor in either, provided statistically significant prognostic ability for distant diseasefree survival but not for overall survival in this small data set. The method used previously at the University of North Carolina was easily performed and provided statistically significant prognostic ability for both distant diseasefree and overall survival; however, it is limited in its usefulness because it cannot be applied to inflammatory breast cancers and provides only two prognostic categories. Although the pathologic complete response category was prognostic, the trend test for the method used by the NSABP (1) was not statistically significant for predicting either distant diseasefree survival or overall survival, because there was poor prognostic ability among the three residual disease categories. For all of these methods, pathologic complete response was prognostic but prognostic ability was limited because of the small number of patients who achieved this endpoint.
The amount of residual disease in surgical specimens from patients who have received neoadjuvant chemotherapy is an excellent prognostic factor (5,7,8) and is often used as an intermediate endpoint in assessing the potential of new treatment regimens for nonmetastatic breast cancer. The identification of methods that are easily performed and provide prognostic discrimination will improve these efforts. Other theoretical directions for neoadjuvant therapy should also be considered. For example, the direct linkage of the extent of residual disease to the risk of subsequent relapse implies that achieving maximum tumor kill in the breasteither by defining the number of cycles of chemotherapy according to response or by defining the regimen and the use of noncross-resistant regimens when response is insufficientis a worthwhile and achievable goal. This latter approach has already been suggested by the reports from the NSABP B-27 (7) and Aberdeen (8) trials, in which patients who were randomly assigned to receive a noncross-resistant regimen (anthracycline followed by taxane) had markedly better pathologic complete response than did patients who were randomly assigned to receive anthracycline alone. In the Aberdeen study, the improved pathologic complete response rate was associated with improved relapsefree and overall survival (8). The pathologic extent of disease after neoadjuvant chemotherapy likely reflects the effect of the drugs administered as well as the extent of disease at diagnosis; response classification systems as intermediate endpoints for distant relapse and survival do not distinguish between the effects of these different elements.
The patients in our study who had residual stage IIIC tumors after conventional chemotherapy had a greater than 80% risk of disease recurrence or death and may therefore be candidates for novel therapeutic approaches. Although treatment to achieve minimal or no tumor burden may be an interesting approach for future neoadjuvant studies, such an approach is limited because pathologic staging systems are needed to define residual disease. Therapeutic exploitation of this approach will require improved clinical and radiographic methods to identify residual disease. Such noninvasive approaches may benefit from our finding that TNM staging of the breast and axilla after treatment is an easy and accurate response classification system.
This study is limited by several factors. The data set is small and derives from a heterogeneously treated and high-risk population treated with aggressive multimodality therapy. For this reason, our results may not be generalizable to a lower-risk population, particularly a node-negative population. The size and heterogeneity of both the patient population and treatment also make it difficult to evaluate the impact of additional adjuvant chemotherapy or tamoxifen.
Multiple studies have documented that response to neoadjuvant chemotherapy for breast cancer is an intermediate endpoint for relapse and survival. For this reason, regimens for early-stage breast cancer are increasingly being tested in neoadjuvant chemotherapy trials. The lack of an accurate, simple, and highly discriminating method to assess the intermediate endpoint of response has limited the data that can be derived from these studies. The AJCC system that we examined is simple and reproducible and, in our cohort, accurately predicted both good and poor distant diseasefree survival and overall survival.
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NOTES |
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REFERENCES |
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(1) Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16:267285.
(2) Cance WG, Carey LA, Calvo BF, Sartor C, Sawyer L, Moore DT, et al. Long-term outcome of neoadjuvant therapy for locally advanced breast carcinoma: effective clinical downstaging allows breast preservation and predicts outstanding local control and survival. Ann Surg 2002;236:295302; discussion 3023.[CrossRef][ISI][Medline]
(3) Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 1999;17:4609.
(4) Greene FL, Page DL, Fleming ID, et al., editors. AJCC cancer staging manual. 6th ed. New York (NY):Springer;2002.
(5) Carey LA, Dees EC, Sawyer L, Moore DT, Dressler L, Cowan D, et al. Response to trastuzumab (Herceptin) given with paclitaxel (Taxol) immediately following 4AC as initial therapy for primary breast cancer. Breast Cancer Res Treat 2002;76:424.
(6) Bonadonna G, Valagussa P, Brambilla C, Ferrari L, Moliterni A, Terenziani M, et al. Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 1998;16:93100.
(7) Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. JCO 2003;21:416574.
(8) Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 2002;20:145666.
Manuscript received August 16, 2004; revised May 19, 2005; accepted May 26, 2005.
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