Kaplan-Meier curves were used to determine DSS for The University of Texas MD Anderson cohort (A and B) and for the California Cancer Registry (C and D). AIC indicates Akaike information criterion.
eTable 1. Clinicopathologic Characteristics
eTable 2. Patients Unable to Assign a Prognostic Stage to, Excluded From Survival Analysis
eTable 3. Anatomic and Prognostic Stage
eTable 4. Patient Characteristics of the Patients Who Were Able to Be Assigned a Prognostic Stage, as Compared to the Entire Cohort, in the MD Anderson and California Cancer Registry Cohorts
eFigure. Hazard Ratios for Disease-Specific Survival
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Weiss A, Chavez-MacGregor M, Lichtensztajn DY, et al. Validation Study of the American Joint Committee on Cancer Eighth Edition Prognostic Stage Compared With the Anatomic Stage in Breast Cancer. JAMA Oncol. 2018;4(2):203–209. doi:10.1001/jamaoncol.2017.4298
Does the American Joint Committee on Cancer eighth edition breast cancer prognostic stage provide more refined stratification with respect to disease-specific survival than the anatomic stage?
Patients with breast cancer treated with surgery as an initial intervention were identified in a database from The University of Texas MD Anderson Cancer Center (n = 3327, years of treatment 2007-2013, median follow-up of 5 years) and the California Cancer Registry (n = 54 727, years of treatment 2005-2009, median follow-up of 7 years). In both cohorts, the prognostic stage was significantly more accurate than the anatomic stage.
The newly introduced prognostic stage is more accurate than the anatomic stage, supporting its use in clinical practice.
The American Joint Committee on Cancer (AJCC) eighth edition staging manual introduced a new prognostic stage for breast cancer incorporating biologic factors in addition to traditional anatomic factors.
To perform a validation study of the AJCC eighth edition prognostic stage in a single-institution cohort and a large population database.
Design, Setting, and Participants
Patients with breast cancer treated with surgery as an initial intervention were identified in a prospective institutional database from The University of Texas MD Anderson Cancer Center and the California Cancer Registry. Vital status data were complete through December 31, 2016, in The University of Texas MD Anderson cohort and through December 31, 2014, in the California Cancer Registry cohort. Patients receiving neoadjuvant systemic therapy, those with inflammatory or rare breast cancers, and those with unknown clinicopathologic factors were excluded. Factors evaluated included T, N, and M categories and tumor grade, as well as estrogen receptor, progesterone receptor, and HER2 status.
Main Outcomes and Measures
Disease-specific survival was calculated by the Kaplan-Meier method. The Harrell concordance index (C index) was used to quantify models’ predictive performance, and the Akaike information criterion (AIC) was used to compare model fits.
A total of 3327 patients with stage I to IIIC breast cancer treated between 2007 and 2013 at The University of Texas MD Anderson Cancer Center (median follow-up of 5 years) with complete clinicopathologic data were identified. Compared with the AJCC anatomic stage, the prognostic stage upstaged 29.5% of patients and downstaged 28.1%. The prognostic stage (C index, 0.8357 and AIC, 816.8) provided more accurate stratification with respect to disease-specific survival than the anatomic stage (C index, 0.737 and AIC, 1039.8) (P < .001 for the C index). A total of 54 727 patients with stage I to IV breast cancer treated between 2005 and 2009 were identified in the California Cancer Registry (median follow-up of 7 years). The prognostic stage upstaged 31.0% of patients and downstaged 20.6%. The prognostic stage (C index, 0.8426 and AIC, 80 661.68) performed better than the anatomic stage (C index, 0.8097 and AIC, 81 577.89) (P < .001 for the C index).
Conclusions and Relevance
The prognostic stage provided more accurate prognostic information than the anatomic stage alone in both a single-institution cohort and a large population database, thereby supporting its use in breast cancer staging.
The goals of cancer staging are to determine the extent of disease, help implement a treatment plan, and inform prognosis. Historically, the American Joint Committee on Cancer (AJCC) staging system for breast cancer has assigned stage based on tumor size (T), the presence of lymph node involvement (N), and the presence or absence of distant metastasis (M). The T, N, and M categories are determined, and this corresponds with a specific disease stage.
A significant limitation of the breast cancer TNM staging system is that it does not account for biologic factors known to have predictive and prognostic value, including tumor grade, estrogen receptor (ER) and progesterone receptor (PR) status, and HER2 status. Treatment recommendations and the subsequent response to therapy are dictated by these factors.1-4 Therefore, patient prognosis varies within each TNM stage based on biologic features. Recognizing this, the expert panel that recently revised the AJCC staging system incorporated a prognostic stage to take into account biologic factors.5
The prognostic stage was developed using data from 238 265 patients identified in the National Cancer Database treated between 2010 and 2011 in whom complete data were available, including the AJCC TNM stage, tumor grade, and ER, PR, and HER2 status. Prognostic subgroups based on TNM stage, tumor grade, and ER, PR, and HER2 status were determined, and survival calculations were performed. These analyses confirmed that prognosis varied within TNM stage groupings based on tumor biology, leading to the identification of 170 prognostic groups that were assigned to stages 0 to IV.5,6 The present study was undertaken to validate this new AJCC prognostic staging system in patients identified in a single-institution cohort (The University of Texas MD Anderson Cancer Center [hereafter MD Anderson]) and the large population-based California Cancer Registry (CCR) and to compare the relative value of the prognostic stage over the anatomic stage alone. Patients receiving neoadjuvant systemic therapy, those with inflammatory or rare breast cancers, and those with unknown clinicopathologic factors were excluded.
Patients with invasive breast cancer who underwent surgery as the initial intervention at MD Anderson from 2007 to 2013 were identified from a database maintained prospectively in the Department of Breast Surgical Oncology. The database does not include patients initially seen with stage IV disease. Clinicopathologic data were recorded, including pathologic T and N categories, tumor grade, and ER, PR, and HER2 status. The ER status was determined by immunohistochemistry and was recorded as the percentage of cells staining positive. Before 2010, a greater than 10% staining cutoff was used to classify tumors as ER positive. A cutoff of 1% was used for patients treated after 2010, when the American Society of Clinical Oncology/College of American Pathologists guidelines changed.7 The HER2 status was defined as positive if 3+ on immunohistochemistry or fluorescence in situ hybridization demonstrated gene amplification.8 A second cohort was identified from the CCR that included all patients diagnosed as having stage I to IV breast cancer as their first and only primary cancer, with known tumor grade and ER, PR, and HER2 status, treated between 2005 and 2009. Except for patients with stage IV disease, all others underwent surgery as their first intervention. The prognostic stage and the anatomic stage were determined for all patients according to the AJCC eighth edition staging manual. Although the 21-gene Oncotype DX (Genomic Health, Inc) breast recurrence score is included in the prognostic staging system, this was not available in all patients and thus was not used for staging in this study. Distributions of anatomic and prognostic stages were compared in each cohort. The number of patients unable to be assigned a prognostic stage was determined, as well as those whose stage was changed by the new prognostic staging system. Patients with unknown prognostic stage were excluded from survival analyses.
The institutional review boards at The University of Texas MD Anderson Cancer Center and the Cancer Prevention Institute of California approved this study. Informed consent was waived for this retrospective analysis.
Disease-specific survival (DSS) was calculated from the date of diagnosis to the date of death or last contact. Vital status data were complete through December 31, 2016, in the MD Anderson cohort and through December 31, 2014, in the CCR cohort. Any patient alive at those dates was censored at this time. Patients who died from a cause other than breast cancer were censored on the date of death.
Disease-specific survival according to anatomic and prognostic stages was compared in each cohort. The log-rank test was used to compare differences between groups. The Harrell concordance index (C index)9 was calculated for the models using the “survival” package in the R Project for Statistical Computing (The R Foundation).10 The C index measures the proportion of pairs for which the predicted and observed outcomes are concordant and can be interpreted as a measure of the model’s predictive performance. A higher C index indicates a better predictive performance. The Akaike information criterion (AIC)11 was used to compare model fits. A lower AIC indicates a better model. Significance between the C index of the anatomic and prognostic staging models was determined using the “compareC” package in R.12 The χ2 statistic of the log-rank test was used to further calculate the discrimination between groups. A larger χ2 statistic indicates further distance between survival curves, and its P value reflects the statistical significance of this distance. The relationship between anatomic or prognostic stage and DSS was modeled using a Cox proportional hazards regression model. Factors included in the multivariable analysis were patient age, race/ethnicity, surgery type, receipt of chemotherapy, and receipt of radiotherapy. The results were expressed in hazard ratios (95% CIs).
A total of 3327 patients with stage I to IIIC breast cancer treated between 2007 and 2013 at MD Anderson with complete clinicopathologic data were identified. Clinicopathologic characteristics are listed in eTable 1 in the Supplement. In 451 patients (13.6%), a prognostic stage could not be assigned due to the presence of N1mi disease in patients with tumors larger than T1 (n = 96) or uncategorized combinations of T and N categories with grade and hormone receptor (HR) and HER2 status (n = 355). Of these patients unable to be assigned a prognostic stage, the anatomic stage was IA in 81 patients (18.0%), IB in 2 patients (0.4%), IIB in 357 patients (79.2%), and IIIA in 11 patients (2.4%). eTable 2 in the Supplement lists detailed information for patients who could not be assigned a prognostic stage. Compared with the anatomic stage, the prognostic stage upstaged 849 patients (29.5%) and downstaged 807 patients (28.1%). For those in whom the stage changed, the change was by one stage up or down (ie, from IIA to IB or IIB) in 1166 (70.4%), by 2 stages in 454 (27.4%), and by 3 stages in 36 (2.2%). Staging details are listed in eTable 3 in the Supplement.
A total of 54 727 patients with stage I to IV breast cancer treated between 2005 and 2009 were identified in the CCR. Clinicopathologic characteristics are listed in eTable 1 in the Supplement. In 3745 patients (6.8%), a prognostic stage could not be assigned due to the presence of N1mi disease in patients with tumors larger than T1 (n = 1181) or uncategorized combinations of T and N categories with grade and HR and HER2 status (n = 2564). Of these patients, the anatomic stage was IIB in 3556 (95.0%). For patients in whom the prognostic stage could be determined, compared with the anatomic stage, the prognostic stage upstaged 15 794 patients (31.0%) and downstaged 10 488 patients (20.6%). For those in whom the stage changed, the change was by one stage in 17 998 (68.5%), by 2 stages in 7451 (28.4%), and by 3 stages in 833 (3.2%) (eTable 3 in the Supplement).
After excluding patients in whom a prognostic stage could not be determined, 2876 patients from the MD Anderson cohort and 50 982 patients from the CCR cohort were used in survival analyses. Differences between the total patient cohort and those used for survival analyses only are listed in eTable 4 in the Supplement. The median follow-up was 5 years for the MD Anderson cohort and 7 years for the CCR cohort. Five-year DSS rates for both cohorts by anatomic and prognostic stages are summarized in Table 1 and the Figure. In the MD Anderson cohort, the C index for the prognostic stage was 0.8357, and the AIC was 816.8. For the anatomic stage, the C index was 0.737, and the AIC was 1039.8. The higher C index (P < .001) and the lower AIC of the prognostic stage reflect a more accurate model predictive of DSS than the anatomic stage. In the CCR cohort, the C index for the prognostic stage was 0.8426, and the AIC was 80 661.68. For the anatomic stage, the C index was 0.8097, and the AIC was 81 577.89. The higher C index (P < .001) and the lower AIC again indicate a more accurate model.
The larger population-based CCR cohort was then used to look more closely at the discrimination between stages. Anatomic and prognostic staging of IIB and IIIA patients and IIIB and IIIC patients was examined. The χ2 statistic, which measures distance between stages, was 4.1302 (P = .04) for anatomic stage IIB to IIIA vs 23.1143 (P < .001) for prognostic stage IIB to IIIA. Comparing stage IIIB with IIIC, the χ2 statistic was 2.7869 (P = .10) for the anatomic stage vs 135.3551 (P < .001) for the prognostic stage. The larger χ2 statistic seen among prognostic stages represents a larger and statistically significant difference. Next, a multivariable Cox proportional hazards regression model of survival by stage was performed using stage IA as the reference category for all calculations. The hazard ratios for anatomic and prognostic stages are summarized in Table 2 and the eFigure in the Supplement.
It is accepted that biologic factors, including tumor grade and ER, PR, and HER2 status, as well as genomic assays, are critical for patients with breast cancer because they enable selection of appropriate therapy, thereby influencing outcome. The expert panel convened to revise the AJCC staging system, which included 2 of us (G.N.H. and E.A.M.), believed that these factors are as important as the anatomic extent of disease in predicting survival.13 Therefore, the panel thought that it was critical to include biologic factors in the eighth edition staging system for the system to maintain relevance in clinical practice. The panel was challenged by the lack of available level 1 evidence to support the influence of biologic factors on prognosis. To address this, an analysis of the available National Cancer Database data was undertaken to identify prognostic stage groups incorporating T, N, and M categories and tumor grade, as well as ER, PR, and HER2 status. This analysis, which at the time of this writing has not been published, led to the development of a prognostic stage in addition to an anatomic stage in the eighth edition of the AJCC staging manual.5,6 It is important to note that the prognostic stage was determined using a cohort of patients treated for their breast cancer based on the anatomic extent and biology of their disease and would not be applicable to patients not receiving therapy. Before publication of the AJCC eighth edition staging manual, this prognostic stage had not been validated in additional cohorts. In the present study, we have confirmed that the prognostic stage provides more accurate prognostic information than the anatomic stage in both a single-institution cohort and a large population database.
The prognostic stage is consistent with previous work demonstrating the significance of biologic factors in prognosis for patients with breast cancer. In an initial study14 of 3728 patients treated with surgery as the initial intervention at MD Anderson between 1997 and 2006, a staging system was proposed incorporating tumor grade and ER status along with the pathologic stage that better stratified patients with respect to DSS than the pathologic stage alone. A limitation of that analysis was that it predated the routine use of trastuzumab in patients with HER2-positive tumors. To address this, the work was recently updated, and a Bioscore was proposed, which assigns points based on the AJCC TNM pathologic stage, tumor grade, ER status, and HER2 status.15 The Bioscore was validated in a cohort of almost 68 000 patients identified in the CCR, suggesting broad applicability. In addition, data available from MD Anderson and the CCR have been used to investigate the risk score, another staging model.16,17 The risk score was designed to be a simple system whereby the AJCC anatomic stage was complemented by a risk score determined by assigning points based on tumor grade and ER and HER2 status. A point is assigned for each of the following 3 characteristics: grade 3, ER negative, or HER2 negative. The risk score can range from 0 to 4, thereby allowing for significant separation within each anatomic stage category into 4 risk groups determined by biologic factors. Using the risk score, it was shown that within an anatomic stage category the best outcomes were seen among patients with ER-positive breast cancer, and the worst outcomes were seen among patients with triple-negative disease. Similarly, using the AJCC eighth edition prognostic stage, patients with triple-negative disease, regardless of grade, and patients with grade 3 tumors that do not express either ER or HER2 have decreased survival comparable to that of patients one stage higher by seventh edition criteria.5
One notable observation in the present study is the percentage of patients in whom a prognostic stage could not be assigned. Prognostic stages could not be assigned due to the presence of micrometastases (pN1mi) in the lymph nodes of patients with tumors larger than 2 cm or due to uncategorized combinations of T and N categories with tumor grade and HR and HER2 status. With respect to the issue of pN1mi disease in patients with tumors larger than 2 cm, this is a limitation of the AJCC anatomic stage that is unchanged between the seventh and eighth editions. The designation of micrometastases (>0.2 to 2.0 mm) in lymph nodes was incorporated into the AJCC staging system with the sixth edition to address the issue of increased detection of small-volume metastases with enhanced pathologic evaluation of sentinel nodes. Initially, T1n1miM0 disease was classified as stage IIA, the same as T1N1M0 disease. Recognizing that the presence of micrometastases may not have the same influence on prognosis as macrometastases, the seventh edition categorized T1N1miM0 disease as stage IB. The utility of the stage IB designation has previously been questioned.18 To our knowledge, no data have been published looking specifically at the prognostic significance of pN1mi disease in patients with T2 and T3 tumors. Ongoing work by our group is investigating this. With respect to uncategorized combinations of T and N categories with biologic variables, this occurred most often in patients with anatomic stage IIB (T3N0 or T2N1) disease. The issue of uncategorized combinations of T and N categories with tumor grade and HR and HER2 status has been communicated to the AJCC, and we anticipate a forthcoming revision (written communication, Stephen Edge, MD, August 31, 2017).
Another consideration that could influence integration of the prognostic stage, which includes 170 prognostic groups, into clinical practice is the complexity. It is unlikely that clinical decisions regarding treatment recommendations will be made based on the prognostic stage because they are routinely guided by the tumor size, nodal status, receptor status, and the results of genomic profiling. Therefore, the prognostic stage is less likely to be used to facilitate communication between health care professionals and is more likely to be used in counseling patients regarding prognosis if they receive the recommended treatment plan. There may also be a role for incorporating the prognostic stage into clinical trial design to more accurately categorize patients with respect to risk.
One limitation of the present study is that we do not have complete data regarding administration of trastuzumab in HER2-positive patients. In the MD Anderson cohort, 233 of 306 (76.1%) HER2-positive patients received trastuzumab, including 68.8% of patients with stage I disease, 81.1% of patients with stage II disease, and 97.2% of patients with stage III disease. Data regarding trastuzumab administration are not available for the CCR cohort because the registry does not capture specific agents administered; until 2013, trastuzumab use was coded as chemotherapy. Another limitation of the present study is that we did not have Oncotype DX data available. The eighth edition prognostic stage assigns any patient with T1-T2N0, ER-positive, HER2-negative breast cancer with an Oncotype DX breast recurrence score of 10 or less a stage of IA. This is based on data from the Trial Assigning Individualized Options for Treatment (TAILORx),19 which was conducted to refine the clinical utility of the Oncotype DX breast recurrence score. In that trial, 1626 patients identified as being at low risk based on having an Oncotype DX breast recurrence score of 10 or less received adjuvant endocrine therapy without chemotherapy. At 5 years, they had exceptional survival outcomes, including an invasive disease–free survival rate of 93.8%, a 98.7% rate of freedom from breast cancer recurrence at distant or locoregional sites, and an overall survival rate of 98%.19 Additional reports of the prognostic value of the Oncotype DX breast recurrence score in large databases (Surveillance, Epidemiology, and End Results program20 and the Clalit Health Services health maintenance organization21) have provided further evidence in support of using this assay in prognostication. At the time the AJCC eighth edition staging manual went to press, these data from the TAILORx were the only level 1 data available evaluating multigene assays. Since that time, data from the Microarray in Node-Negative Disease and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) trial22 have shown that women with low genomic risk as determined using the MammaPrint (Agendia) 70-gene breast cancer recurrence assay who, despite having high clinical risk, did not receive adjuvant chemotherapy had high 5-year survival rates comparable to those of patients who received chemotherapy. These data are consistent with the AJCC eighth edition prognostic stage, which downgraded tumors with low genomic risk to stage I, and it is anticipated that these data will be incorporated into future editions.13 It is possible that data from ongoing trials evaluating the role of genomic assays in node-positive patients will define a role for inclusion of these assays in the staging of patients with node-positive breast cancer. Given data from the TAILORx19 and the MINDACT trial,22 it would further improve the stratification between the anatomic and prognostic stage groups.
The AJCC eighth edition prognostic stage provides more accurate prognostic information than the anatomic stage. Use of this staging system by cancer registrars will begin in January 2018. Before then, the AJCC will likely address the identified limitations, specifically the current combinations of T, N, and M categories with tumor grade and ER, PR, and HER2 status without a corresponding prognostic stage. Going forward, the prognostic stage will require frequent updates as additional information regarding the prognostic significance of other biologic factors to include Ki-67 and other genomic assays becomes available.
Accepted for Publication: September 26, 2017.
Corresponding Author: Elizabeth A. Mittendorf, MD, PhD, Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1484, Houston, TX 77030 (firstname.lastname@example.org).
Published Online: December 7, 2017. doi:10.1001/jamaoncol.2017.4298
Author Contributions: Dr Mittendorf had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Chavez-MacGregor, Lichtensztajn, Hortobagyi, Giordano, Hunt, Mittendorf.
Acquisition, analysis, or interpretation of data: Weiss, Chavez-MacGregor, Lichtensztajn, Yi, Tadros, Hortobagyi, Mittendorf.
Drafting of the manuscript: Weiss, Hortobagyi, Mittendorf.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Lichtensztajn, Yi, Mittendorf.
Obtained funding: Hortobagyi, Mittendorf.
Administrative, technical, or material support: Tadros, Hortobagyi, Hunt, Mittendorf.
Study supervision: Weiss, Hortobagyi, Mittendorf.
Conflict of Interest Disclosures: Dr Chavez-MacGregor reported being a consultant for Novartis, Pfizer, and Roche. Dr Hortobagyi reported being the principal investigator for clinical trials supported by Novartis; reported being a consultant for Antigen Express, AstraZeneca, Genentech, Novartis, Peregrine, and Pfizer; and reported being the chairman of the scientific advisory committee for Agendia. Dr Hunt reported being a consultant for Armada Health. Dr Mittendorf reported being the principal investigator for clinical trials supported by AstraZeneca, Galena Biopharma, and Genentech and reported being a consultant for Amgen. No other disclosures were reported.
Funding/Support: This work was supported in part by a Cancer Center Support Grant from the National Cancer Institute to The University of Texas MD Anderson Cancer Center (CA016672). Analysis of cancer registry data was supported by the National Cancer Institute under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code §103885; by the Centers for Disease Control and Prevention’s National Program of Cancer Registries under agreement U58DP003862-01 awarded to the California Department of Public Health; and by the National Cancer Institute’s Surveillance, Epidemiology, and End Results program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute. Dr Hortobagyi is supported by grants from the Breast Cancer Research Foundation (BCRF-15-122 and BCRF-16-073). Dr Giordano is supported by grants from the Cancer Prevention Research Institute of Texas (CPRIT RP16067) and the Komen for the Cure Foundation (SA150061). Dr Mittendorf is an R. Lee Clark Fellow of The University of Texas MD Anderson Cancer Center supported by the Jeanne F. Shelby Scholarship Fund.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The ideas and opinions expressed herein are those of the authors, and endorsement by the State of California, California Department of Public Health, National Cancer Institute, and the Centers for Disease Control and Prevention or their contractors and subcontractors is neither intended nor should be inferred.
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