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Originally published as JCO Early Release 10.1200/JCO.2007.11.5352 on December 3 2007 © 2008 American Society of Clinical Oncology. Combined Use of Clinical and Pathologic Staging Variables to Define Outcomes for Breast Cancer Patients Treated With Neoadjuvant Therapy
From the Departments of Surgical Oncology, Bioinformatics and Computational Biology, Breast Medical Oncology, Radiation Oncology, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Surgery, Northwestern University Feinberg School of Medicine; and Robert H. Lurie Comprehensive Cancer Center, Chicago, IL Corresponding author: Kelly K. Hunt, MD, Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 444, Houston, TX 77030; e-mail: khunt{at}mdanderson.org
Purpose Neoadjuvant chemotherapy is being used with increasing frequency for operable breast cancer. We hypothesized that by using clinical and pathologic staging parameters, in conjunction with biologic tumor markers, a novel means of determining prognosis for patients treated with neoadjuvant chemotherapy could be facilitated. Patients and Methods A prospective database of patients treated with neoadjuvant chemotherapy from 1997 to 2003 was reviewed, and 932 patients meeting inclusion criteria were identified. Clinical and pathologic tumor characteristics, treatment regimens, and patient outcomes were recorded. Cox proportional hazards models were used to create two prognostic scoring systems. American Joint Committee on Cancer (AJCC) clinical and pathologic staging parameters and biologic tumor markers were investigated to devise the scoring systems.
Results Median follow-up time was 5 years (range, 0.4 to 9.4 years). Five-year disease-specific survival rate was 96% for patients who experienced a pathologic complete response (pCR; n = 130) compared with 87% for patients who did not have a pCR (n = 802; P = .001). Two scoring systems, based on summing binary indicators for clinical substages Conclusion The scoring systems derived in this work provide a novel means for evaluating prognosis after neoadjuvant therapy. Future work will focus on prospective validation of these scoring systems and refinement of the scoring systems through addition of new biologic markers.
Traditionally, neoadjuvant chemotherapy has been used in the setting of locally advanced or inoperable breast cancer. Over the last decade, use of neoadjuvant chemotherapy has expanded to facilitate increased breast conservation rates and to evaluate new agents.1,2 Furthermore, use of neoadjuvant chemotherapy has allowed oncologists to assess treatment response and thus tailor treatment regimens accordingly, based on changes in tumor burden found during the course of a particular chemotherapy regimen.3 As the use of neoadjuvant chemotherapy has become more prevalent, a need to determine the impact of this treatment on patient outcomes has arisen. Currently, oncologists base patient outcomes on either presenting clinical stage or final pathologic stage, after completion of neoadjuvant chemotherapy. During the past decade, several studies have examined the impact of pathologic response to chemotherapy on patient outcomes, primarily emphasizing the association between pathologic complete response (pCR) and improved overall survival (OS). However, the prognosis for patients who achieve less than a pCR has not been addressed with a great degree of specificity. Existing prognostic data are based primarily on final pathologic assessment of the amount of post-treatment residual disease found in the breast and axilla. Some investigators have stratified patient outcomes by general gradations of pathologic response, whereas others have compared pCR with no pCR.2-6 Carey et al7 studied the utility of the 2003 American Joint Committee on Cancer (AJCC) breast cancer staging system to determine prognosis after neoadjuvant chemotherapy and found that application of final pathology to this staging system facilitated a more precise prediction of patient outcomes compared with previously proposed methods. Although prior reports have shown an association between decreased tumor burden after neoadjuvant chemotherapy and improved patient outcomes, prognostic tools developed thus far have not accounted for both presenting clinical stage and final pathologic stage. Furthermore, the use of biologic markers in conjunction with staging variables, to help further refine patient prognosis after neoadjuvant chemotherapy, has not been previously examined. A clinically practical instrument capable of determining prognosis after neoadjuvant chemotherapy would have significant value to both physicians and patients in establishing a post-treatment dialogue about 5-year expected outcomes and in decision making regarding additional treatment options. We hypothesized that by using both presenting clinical and final pathologic staging parameters, in conjunction with biologic tumor markers, a novel means of determining prognosis for patients treated with neoadjuvant chemotherapy could be facilitated. Here, we describe the development of two new scoring systems using clinical, biologic, and pathologic factors to establish patient prognosis after treatment with neoadjuvant chemotherapy.
A prospective breast cancer database was used to identify 1,159 patients treated at the M.D. Anderson Cancer Center (MDACC) who received neoadjuvant chemotherapy from 1997 to 2003. Individual clinical and pathologic tumor characteristics, treatment regimens, and patient outcomes were recorded. All patient information was examined for accuracy through review of primary source documents. From the original cohort, 227 patients were excluded; 109 had a pretreatment excisional biopsy with no measurable residual disease, 61 had inflammatory breast cancer, seven had a breast sarcoma, 25 did not have an identifiable breast primary, 11 did not undergo axillary surgery, pathologic tumor size was not measured in two, three had systemic metastases at completion of neoadjuvant chemotherapy, and nine had less than three cycles of neoadjuvant chemotherapy. The final study population was composed of 932 patients. The patient distribution for the study group, by clinical stage and pathologic stage, are listed in Appendix Table A1 (online only). Biologic marker status was determined through tumor biopsy before administration of neoadjuvant chemotherapy. All tissues and immunostains were reviewed at MDACC. Patients were treated with either an anthracycline-based, taxane-based, or combination anthracycline/taxane-based neoadjuvant regimen.8 A pCR was defined as no residual invasive disease in the breast and axilla on final pathologic assessment of surgical specimens.
OS, distant metastasis-free survival (DMFS), and disease-specific survival (DSS) were calculated from date of diagnosis to death, distant metastases, or death caused by breast cancer, respectively; patients not experiencing the relevant end point were censored at last follow-up. Five-year OS, DMFS, and DSS were calculated using the Kaplan-Meier method, and differences were examined using the log-rank test.9 Ninety-five percent CIs were calculated using the method of Greenwood.10 A Cox proportional hazards model with backward stepwise exclusion of factors, using a criterion of P < .05 for retention of factors in the model, was used to create the Clinical-Pathologic Scoring System (CPS) from all clinical and pathologic substages.11 Model performance was quantified using Harrell's concordance index.12 After defining the CPS system, a second Cox proportional hazards model, with backward stepwise exclusion of factors and stratified on CPS, was used to test the added significance of estrogen receptor (ER) and progesterone receptor (PR) status, nuclear grade (NG), human epidermal growth factor receptor 2 (HER-2)/neu status, presence of lymphovascular invasion (LVI), patient age at presentation, and number of chemotherapy cycles (three v
Patient Data Clinicopathologic characteristics for patients who did experience a pCR (n = 130) and patients who did not have a pCR (n = 802) in response to neoadjuvant chemotherapy are listed in Table 1. For patients who experienced a pCR, the tumor was ER negative (73.1%), PR negative (63.9%), and NG 3 (90.8%) in the majority of patients. For patients who did not have a pCR, tumors were more commonly ER positive (67.7%), PR positive (54.1%), and either NG 2 (41.4%) or NG 3 (53.9%). Statistically significant differences between clinicopathologic characteristics for patients who did or did not achieve a pCR were found for ER, PR, and HER-2 status; NG; LVI; neoadjuvant chemotherapy regimen; and surgical treatment (P < .05). Patient outcomes for the entire study group at 5 years were 85% OS (95% CI, 82% to 87%), 88% DSS (95% CI, 85% to 90%), and 80% DMFS (95% CI, 77% to 82%). Median follow-up time for the entire study population was 5.0 years (range, 0.4 to 9.4 years).
Disease-Specific Outcomes At 5 years, DSS rate was 96% (95% CI, 91% to 98%) for patients who had a pCR compared with 87% (95% CI, 83% to 89%) for patients who did not have a pCR (P = .001). Presenting clinical stage and pathologic stage after neoadjuvant chemotherapy were determined according to the AJCC staging system, and outcomes based on these data were compared (Figs 1A and 1B). DSS rates at 5 years are listed in Table 2 and compared with outcomes available from the American College of Surgeons National Cancer Database (ACS NCDB) and historical data from stage IIIC patients treated at MDACC.14,15 Outcomes for patients who presented with stage I, IIA, or IIB disease, using AJCC pathologic staging after chemotherapy, were similar to the outcomes for patients from the ACS NCDB who did not receive neoadjuvant chemotherapy. However, patients from our study group who presented with stage IIIA and higher disease had considerably better 5-year survival outcomes than patients reported by the ACS NCDB and historical controls treated at MDACC from 1974 to 1991.14,15
Clinical-Pathologic and Biologic Marker Scoring System Presenting clinical stage and postchemotherapy pathologic stage were used to derive a prognostic model for patient outcomes after neoadjuvant chemotherapy. The Cox proportional hazards model, with clinical and pathologic substages included as potential factors (Fig 1), indicated that clinical stages  stages IIB (hazard ratio [HR] = 2.3; P = .003) or IIIB (HR = 1.9; P = .002) and pathologic stages stages ypIIA (HR = 2.9; P = .001) or ypIIIC (HR = 2.3; P < .0001) were independently associated with a decrease in DSS. There were no significant interactions among the four factors retained in the model. Because HRs for the factors retained in the model were all of similar magnitude, binary indicators were assigned to presenting clinical substages and final (post–neoadjuvant chemotherapy) pathologic substages retained in the model. Overall CPS score was then determined by summing the points as listed in Table 3. Stability of the scoring system was tested by means of a bootstrap analysis of the stepwise model selection procedure (1,000 iterations), which confirmed that the CPS model was robust under variations in the data. A Cox proportional hazards analysis stratified on CPS score was then performed using as candidate factors ER, PR, and HER-2/neu status; NG; LVI; patient age at presentation; and number of chemotherapy cycles (three v four cycles); the results indicated that ER-negative disease (HR = 2.5; P < .0001) and NG 3 tumor pathology (HR = 3.0; P < .0001) were additional independent risk factors for this cohort. Therefore, the scoring system was further refined to incorporate these biologic markers by assigning points for ER-negative disease and NG 3 tumor pathology to create the CPS+EG score (Table 3).
For the CPS system, five groups of patients with scores of 0 to 4 were identified that were associated with decreasing 5-year DMFS and DSS (Table 4; Fig 2A). Inclusion of ER status and NG in the CPS+EG score provided additional prognostic value and allowed for further expansion of the scoring system to a total of seven distinct 5-year DMFS and DSS subgroups (Table 4; Fig 2B). Thus, combining clinical, pathologic, and biologic factors allowed for refining patient prognosis over that of either AJCC clinical stage or pathologic stage alone.
The prognostic information described here represents the most detailed data available on DMF and DSS outcomes for patients treated with neoadjuvant chemotherapy. The scoring systems derived from the data in this study allow assessment of patient prognosis after neoadjuvant chemotherapy by including pretreatment clinical staging and post-treatment pathologic staging. The addition of biologic markers to pretreatment clinical stage and final pathologic stage allowed for further refinement of the prognostic scoring system. These proposed scoring systems can be easily implemented in clinical practice with data routinely gathered at patient presentation and at completion of neoadjuvant chemotherapy and surgical treatment. Neoadjuvant chemotherapy has been standard practice for patients with locally advanced and inoperable breast cancer for several decades. Indications for neoadjuvant chemotherapy have now expanded to patients with large primary tumors, allowing many women with breast cancer the option to pursue breast-conserving surgery. This approach has also allowed oncologists to gain new insights into tumor biology related to response to different chemotherapeutics. As the patient population exposed to neoadjuvant chemotherapy has grown, physicians and patients have attempted to use tumor response to neoadjuvant chemotherapy in determining patient prognosis. To date, methods for accomplishing this have largely depended on the distinction between patients who achieve a pCR and those who do not. Recently, Swisher et al16 proposed a change in the TNM staging system for patients with esophageal cancer after chemoradiotherapy. This system incorporates post-treatment residual tumor volume into the current TNM system and allows for a more accurate assessment of patient outcomes predicated on post-treatment pathology and response to treatment based on initial clinical staging.16 The CPS and CPS+EG systems proposed in our study represent a new means by which clinicians can use objective pretreatment and post-treatment data to discern the impact of neoadjuvant chemotherapy on patient outcomes. The ability to obtain this additional treatment information will allow clinicians to more accurately risk stratify their patients regarding eligibility for clinical trials or novel therapeutics. Furthermore, these scoring systems have the potential to provide patients with more accurate information regarding their prognosis. Using the CPS+EG system, DMFS and DSS outcomes for patients who achieved a pCR were stratified by presenting clinical stage and biologic markers. Specifically, patients achieving a pCR who presented with stage I or IIA disease and who did not have adverse biologic markers had the best projected DMFS and DSS outcomes. Patients who presented with stage IIB or IIIA disease had favorable projected outcomes, whereas patients who presented with stage IIIB or IIIC disease had the least favorable projected outcomes. According to the CPS+EG system, the 5-year DMFS and DSS were considerably affected by addition of adverse biologic markers. Using the CPS+EG system, a patient who presents with stage I or IIA disease and has no adverse biologic markers would have a 98% 5-year DMFS rate and 100% 5-year DSS rate. A stage IIIC patient who experiences a pCR but presents with an ER-negative, NG 3 tumor would be projected to have a 63% 5-year DMFS rate and 72% 5-year DSS rate. This information clearly demonstrates that all patients who experience a pCR are not the same with respect to their expected outcomes. The presence of resistant cancer stem cells in patients who achieve a pCR but ultimately experience relapse may be an explanation for these disparate findings.17,18 These findings also underscore the importance of extent and biology of the primary tumor in dictating the ultimate outcome. Gonzalez-Angulo et al,8 who examined risk factors for recurrence in patients with a pCR, found that premenopausal patients with locally advanced disease and patients who had identification of 10 or fewer axillary lymph nodes (ALNs) in axillary dissection specimens were at highest risk for development of distant metastasis. Previously, investigators have shown the importance of pCR in ALNs in response to neoadjuvant chemotherapy, independent of the response of the primary tumor.19-24 Patients who achieved a pCR in previously documented tumor-positive ALNs had considerably better outcomes than patients who did not, regardless of the response in the primary tumor.20 These findings suggest that biologic differences between the primary tumor and metastatic disease have a significant impact on outcomes after neoadjuvant chemotherapy.20 Using the CPS system, our study revealed that patients with stage IIB or IIIA disease had similar expected outcomes. For patients in these groups who did not achieve a pCR or stage I final pathology in response to therapy, a stable or a partial response yielded outcomes that were moderately favorable, correlating to 5-year DMFS and DSS rates of 72% and 83%, respectively. For patients who presented with stage IIIB or IIIC disease and who had anything less than a pCR or stage I final pathology, outcomes were significantly less favorable. These data indicate that, although clearance of ALNs is important, as exemplified by the favorable scoring associated with stage I final pathology, residual disease in the breast and the burden of disease at presentation continue to be significant factors impacting patient prognosis. Nomograms to predict the probability of response in ALNs, pCR, and 5- and 10-year disease-free outcomes in response to neoadjuvant chemotherapy have been proposed.20,25 Important prognostic factors included in these nomograms were ER status, NG, patient age, presenting tumor size, final pathologic tumor size, and number of tumor-positive ALNs.20,25 Several factors were examined in our current study to help facilitate further refinement of the CPS system. Of all the biologic markers studied, ER-negative disease and NG 3 disease were the only variables that retained independent prognostic significance on multivariate analysis. The importance of ER status and NG in response to chemotherapy has been well documented. Several studies have confirmed that ER-negative and high-grade tumors are more likely to decrease in size in response to chemotherapy.4,26-30 These markers are compelling in that they positively correlate to both achievement of a pCR and to poor prognosis based on the CPS+EG system. These findings have been corroborated by a recently published study by Guarneri et al,26 showing that although ER-negative tumors were more likely to achieve a pCR, these patients had less favorable 5-year overall and progression-free survival rates when compared with patients with ER-positive disease. One proposed explanation for this finding was the beneficial impact of postoperative hormonal therapy available to patients with ER-positive tumors, which could supersede the significance of achieving a pCR in this setting.26 Importantly, the study by Guarneri et al26 did show that achievement of a pCR was an independently favorable prognostic marker, regardless of ER status. Trials are now underway to address the impact of neoadjuvant hormonal therapy on patients with ER-positive disease. Ideally, with the accrual of a larger patient data set, outcome differences between ER-positive and ER-negative patient populations will be evaluated independently to provide more refined prognostic data based on hormone responsiveness. The decreased cellular differentiation that characterizes higher grade lesions has been shown to correlate with several markers of increased proliferation.4,31 Grade 3 lesions have been associated with poor prognosis, and in conjunction with other risk factors, systemic therapy is often recommended for patients with this pathologic subtype because these tumors also tend to have increased responsiveness to chemotherapeutic treatment.32 Accordingly, our study confirms that, as with ER-negative disease, the poorer prognosis associated with NG 3 lesions persists, even for patients who achieve a pCR. Several new biologic markers and genomic panels are actively being studied that may help to further predict response to neoadjuvant or adjuvant therapy. Through the validation of these new markers, we hope to refine the CPS+EG system to allow for an improved understanding of patient prognosis and therapeutic decision making. We propose that the scoring systems presented in our study for determining prognosis after neoadjuvant chemotherapy will aid in the understanding of the true impact of current neoadjuvant chemotherapy regimens on patient outcomes. These scoring systems may also help to more rationally risk stratify patients for design of clinical trials and use of novel therapies after conventional standard therapy has been completed. We acknowledge that the strength of the outcomes generated in this study, most specifically for the CPS+EG model, were limited by low patient numbers in some of the study subgroups. Future work will focus on prospective validation of this scoring system with a larger patient data set and further refinement of the scoring system through addition of biologic markers.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Aman U. Buzdar, AstraZeneca, Genentech, Pfizer Inc Research Funds: Aman U. Buzdar, AstraZeneca, Genentech, Pfizer Inc, Lilly, Taiho, Bristol-Myers Squibb Co, Roche; Gabriel N. Hortobagyi, Novartis Testimony: N/A Other: N/A
Conception and design: Jacqueline S. Jeruss, Janice N. Cormier, Kelly K. Hunt Financial support: Gabriel N. Hortobagyi Administrative support: Gabriel N. Hortobagyi, Kelly K. Hunt Provision of study materials or patients: Ana M. Gonzalez-Angulo, Kelly K. Hunt Collection and assembly of data: Jacqueline S. Jeruss, Elizabeth A. Mittendorf, Aysegul A. Sahin, Aman U. Buzdar Data analysis and interpretation: Jacqueline S. Jeruss, Elizabeth A. Mittendorf, Susan L. Tucker, Janice N. Cormier, Aman U. Buzdar, Gabriel N. Hortobagyi, Kelly K. Hunt Manuscript writing: Jacqueline S. Jeruss, Elizabeth A. Mittendorf, Susan L. Tucker, Ana M. Gonzalez-Angulo, Thomas A. Buchholz, Janice N. Cormier, Kelly K. Hunt Final approval of manuscript: Jacqueline S. Jeruss, Elizabeth A. Mittendorf, Susan L. Tucker, Ana M. Gonzalez-Angulo, Janice N. Cormier, Aman U. Buzdar, Gabriel N. Hortobagyi, Kelly K. Hunt
We thank Stacey C. Tobin, PhD, for her critical review of the manuscript, Shu-wan Kau, RN, for her assistance with database management, and the Breast Cancer Management System Database at the M.D. Anderson Cancer Center.
published online ahead of print at www.jco.org on December 3, 2007. Presented in part at the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX. J.S.J. was named an AstraZeneca Scholar when this work was presented at the 29th Annual San Antonio Breast Cancer Symposium. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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J Clin Oncol 23:9304-9311, 2005 21. Newman LA, Pernick NL, Adsay V, et al: Histopathologic evidence of tumor regression in the axillary lymph nodes of patients treated with preoperative chemotherapy correlates with breast cancer outcome. Ann Surg Oncol 10:734-739, 2003[CrossRef][Medline] 22. Kuerer HM, Sahin AA, Hunt KK, et al: Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg 230:72-78, 1999[CrossRef][Medline] 23. Kuerer HM, Newman LA, Buzdar AU, et al: Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer. Am J Surg 176:502-509, 1998[CrossRef][Medline] 24. Ellis P, Smith I, Ashley S, et al: Clinical prognostic and predictive factors for primary chemotherapy in operable breast cancer. J Clin Oncol 16:107-114, 1998 25. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test, with unknown patients excluded from analysis. This study was approved by the Institutional Review Board of MDACC. 
