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Recursive Partitioning Identifies Patients at High and Low Risk for Ipsilateral Tumor Recurrence After Breast-Conserving Surgery and Radiation

From the Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA.

Address reprint requests to Gary M. Freedman, MD, Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; email: g_freedman{at}fccc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Recursive partitioning analysis (RPA), a method of building decision trees of significant prognostic factors for outcome, was used to determine subgroups at significantly different risk for ipsilateral breast tumor recurrence (IBTR) in early-stage breast cancer.

PATIENTS AND METHODS: Nine hundred twelve women underwent breast-conserving surgery, axillary dissection, and radiation. Systemic therapy was chemotherapy with or without tamoxifen in 32%, tamoxifen in 27%, or none in 41%. RPA was used to create a decision tree according to predictive variables that classify patients by IBTR risk, and the Kaplan-Meier method was used to calculate 10-year risks. Median follow-up was 5.9 years.

RESULTS: Age was the first split in the partition tree. Patients more than 55 years old had a 4% 10-year IBTR, the only further division being use of tamoxifen or not (2% v 5%, P = .03). For patients 55 years old, extensive intraductal component (EIC) was the next significant split. For EIC-negative tumors, age 35 years and negative margins were associated with a 10-year IBTR of 3%; with close ( 2 mm) or positive margins, 34%. Patients 36 to 55 years old with estrogen receptor–positive tumors receiving tamoxifen had a risk of IBTR of 5%, but had a 20% risk without tamoxifen.

CONCLUSION: This RPA showed that age 55 versus more than 55 years was the most significant factor for IBTR. Patients 35 years old had a low risk of IBTR when tumors were EIC-negative with negative margins. EIC was an independent factor for IBTR for ages 55 years. Use of tamoxifen was the most significant factor for patients older than 55 years, but it resulted in a greater absolute decrease in risk of IBTR for patients 36 to 55 years old.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IPSILATERAL BREAST tumor recurrence (IBTR) occurs in approximately 10% to 20% of patients with stage I to II invasive breast cancer within 10 years of breast-conserving surgery and radiation.^1-13 The identification of risk factors for subsequent IBTR offers the potential to improve on these results. Certain risk factors may be associated with an unacceptably high risk of IBTR, and knowledge of these factors may result in better patient selection for breast-conservation therapy. Greater use of re-excision for breast-conserving surgery or the addition of adjuvant systemic therapy, however, may mitigate the factors for IBTR. The impact on IBTR of clinical and pathologic factors such as young patient age ( 35 years), advanced patient age (> 70 years), race, family history, margin status, extensive intraductal component (EIC), or lymph-vascular invasion were not addressed by most of the prospective randomized trials of breast-conserving surgery and radiation versus mastectomy. Furthermore, some of the retrospective studies analyzing the risk of IBTR in patients treated with breast-conserving surgery and radiation are limited by small patient numbers, missing clinical and/or pathologic data, or absence of multivariate analysis. Multivariate analysis of independent risk factors for outcome in the population as a whole may overlook important interactions between prognostic factors or the relative importance of a certain factor in one subgroup but not another. Recursive partitioning analysis of data is a method of building decision trees with significant independent prognostic factors for outcome.¹⁴ The partitions or splits in the tree identify subgroups of patients at different levels of risks based on combinations of these prognostic factors. The purpose of this study was to use recursive partitioning methodology to determine subgroups of patients at significantly different risks for IBTR after breast-conserving surgery and radiation for early-stage breast cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study population consisted of 912 women with American Joint Committee on Cancer clinical stage I or II breast cancer¹⁵ treated by conservative surgery, axillary lymph node dissection, and radiation between March 1979 and February 1995. Patients with unknown tumor size, method of detection, axillary nodal status, receptor status, or final margins were excluded. The median follow-up of all 912 patients was 5.9 years (range, 0.2 to 17.5 years). Time 0 was defined as the start of radiation therapy. Patients received their definitive radiation therapy at Fox Chase Cancer Center (628 patients), or were treated and/or followed by a single author (B.L.F.) at the Hospital of the University of Pennsylvania (284 patients). The clinical, pathologic, and treatment-related characteristics of the 912 study patients are listed in Tables 1 and 2.

All patients underwent breast-conserving surgery before definitive radiation. Details of the radiation treatment policy during this study period have been previously described.¹⁷ In summary, all patients were treated with radiation using breast tangents to a median dose of 46 Gy. In 22% of patients, treatment also included the supraclavicular region with or without the axillary lymph nodes. Most patients were treated by a 6-MV linear accelerator. The primary tumor bed was boosted in 99% of patients. This boost was delivered with electrons in most patients, with a few having received an interstitial implant or a photon boost in earlier years of the study period. The total dose was generally determined by the extent of surgery and final margin status ranging from a median of 60 Gy with a negative margin to 64 Gy with a close margin to 66 Gy for a positive final margin.

Of the 912 study patients, 74% were estrogen receptor (ER)–positive. Thirty-two percent of patients had chemotherapy with or without tamoxifen, 27% had tamoxifen alone, and 41% had no adjuvant systemic therapy. Of the 53 patients 35 years old, 57% received chemotherapy alone, 2% received tamoxifen alone, 15% received both, and 26% received no adjuvant systemic therapy. Of the 383 patients 36 to 55 years old, 35% received chemotherapy alone, 16% received tamoxifen alone, 15% received both, and 34% received no adjuvant systemic therapy. Of the 476 patients older than 55 years old, 6% received chemotherapy alone, 39% received tamoxifen alone, 7% received both, and 48% received no adjuvant systemic therapy. The chemotherapy regimens used in this study population were cyclophosphamide, methotrexate, and fluorouracil in 76% of patients and doxorubicin and cyclophosphamide in 21% of patients.

The primary end point of the study was an IBTR with (two events) or without (49 events) simultaneous regional recurrence as the first site of failure. IBTR as a first site of failure with a simultaneous distant recurrence (four events), or an IBTR after distant metastases as a first event (one event), were censored. Tree-based methodology was used to recursively partition the covariate space into disjoint regions on the basis of IBTR. For each nodal split, the method of separation was derived from a totally nonparametric application using the Harrington-Fleming classes of two-sample rank statistics that derived the partitioning from between-node separation.¹⁸ Calculations were carried out using STREE software for censored survival data developed by H.P. Zhang.¹⁹ Nodal separation was derived from the maximization of the log-rank statistic as suggested by Ciampi et al²⁰ and Segal.¹⁸ The following factors were evaluated individually as prognostic indicators of IBTR: age (as a continuous variable), menopausal status, race, family history, method of detection, presence of EIC, margin status, ER status, number of positive lymph nodes, histology, lobular carcinoma-in-situ (LCIS), and use of chemotherapy or tamoxifen. Kaplan-Meier methodology was used to determine the IBTR outcomes between each of the terminal nodes.²¹

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The actuarial rate of IBTR for all 912 patients in the study population was 4% at 5 years and 8% at 10 years. The resulting decision tree from the recursive partitioning analysis in the 912 patients is shown in Fig 1. The tree ended in eight terminal nodes whose characteristics and 5- and 10-year rates of IBTR are listed in Table 3.

View larger version (24K): [in this window] [in a new window]   Fig 1. Recursive partitioning analysis tree for 912 patients treated by breast-conserving surgery, axillary node dissection, and radiation.

For patients aged 35 years with EIC-negative tumors, margin status was the only significant prognostic factor for IBTR. Patients aged 35 years and EIC-negative tumor and negative margins (> 2 mm) had a low 10-year risk of IBTR of 3%. However, the subgroup of patients with a final close ( 2 mm) or positive margin had 5- and 10-year risks of IBTR of 13% and 34%, respectively.

For patients between the ages of 36 and 55 years with EIC-negative tumors, the ER status and use of tamoxifen were the significant prognostic factors for IBTR. Patients in this subgroup with ER-negative tumors had 5- and 10-year risks of IBTR of 2% and 9%, respectively. However, in the same group of patients with ER-positive tumors, the 5- and 10-year risks of IBTR were 9% and 20% without tamoxifen and 5% and 5% with tamoxifen, respectively (P = .07).

EIC remained of prognostic importance in patients aged 55 years. Terminal node 1 was not further subdivided in the recursive partitioning tree because of small numbers of patients involved, but further analysis of the data after the recursive partitioning showed an important impact of age within this group. Three of five patients aged 35 years with EIC-positive tumors had an IBTR (actuarial risk at 10 years, 75%), which compared to a 10-year risk of IBTR of 14% in patients aged 36 to 55 years with EIC-positive tumors (P = .0016). The 10-year risk of IBTR in patients aged 36 to 55 years who were EIC-negative was only 9% in comparison. For women older than 55 years, the 5- and 10-year risk estimates of IBTR were 6% and 6% for EIC-positive tumors and 2% and 3% for EIC-negative tumors, respectively.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This series confirms the importance of patient age on the risk of IBTR after breast-conserving surgery and radiation. Age 55 years versus more than 55 years was the most significant factor for predicting the risk of IBTR in our study population. Patients aged more than 55 years had a 10-year risk of IBTR of 4%. This compares most favorably with the range of 10% to 20% at 10 years for all patients with stage I to II invasive breast cancer across series of breast-conserving surgery and radiation.^1-13 This series confirms earlier reports that age more than 55 years defines a subgroup at low risk for subsequent IBTR. Age more than 55 years was associated with a 3% risk of IBTR at 10 years in a series by Fourquet et al,¹³ and a 2% risk at 10 years after quadrantectomy plus radiation by Veronesi et al.²² Veronesi et al reported a higher cumulative incidence of IBTR of 12% at 8 years after tumorectomy plus radiation in women 56 to 70 years old, although this remained lower than the risk reported for women less than 56 years old (24%). When age was entered into this model as a continuous variable, the analysis showed age 55 versus more than 55 years was a better predictor of IBTR than menopausal status. However, when age was entered as a dichotomous variable using less optimal breakpoints, menopausal status substituted for age in the decision tree (data not shown). It is not surprising that an age breakpoint around 55 years and menopausal status would be too closely related to be independent prognostic factors within the same analysis.

Patient age 35 or 40 years has been associated with an increased risk of IBTR after breast-conserving surgery and radiation in most series.^{4-6,11-13,23-32} However, in the present study, women aged 35 years with EIC-negative tumors had a risk of IBTR at 10 years of only 3% with negative margins. Our study population contained few young women with unfavorable features of nonnegative margins or EIC positivity. This likely reflects a selection bias against breast conservation in these women, and appears justified by our finding of a risk of IBTR in women 35 years with close or positive margins of 34% at 10 years. Cowen et al³³ also reported a high 55% rate of IBTR in women 40 years of age with positive margins. The actuarial rate of IBTR for the five patients 35 years old with EIC-positive tumors, only one of whom had a positive margin, was 75% (crude rate, three of five). Therefore, the present study lends further evidence that the increased risk of IBTR in young women may be attributed to an association of young age with EIC positivity and close or positive resection margins.²⁵

The presence of an EIC-positive tumor has been associated with an increased risk of IBTR after breast-conserving surgery and radiation,^{22,25,29,32,34,35} with most series showing this risk of IBTR is limited to those with nonnegative margins.^27,29,34-37 However, in the present series, EIC positivity was a significant prognostic factor for IBTR in patients aged 55 years independent of margin status. The 10-year actuarial rate of IBTR for patients aged 36 to 55 years was 14% in patients with EIC-positive tumors, compared with 9% in those with EIC-negative tumors. Thus, the risk of IBTR in EIC-positive patients may be decreased in these patients by greater extent of breast-conserving surgery and wide negative margins,^{4,22,26,30,37-39} but may not be entirely mitigated, particularly in young women.

In most series, the risk of IBTR after breast-conserving surgery and radiation has been shown to be two to three times greater in the presence of a positive^{5,6,22,29,33,37-41} or close ( 2 mm)^{31,37,39,40,42} margin compared with negative margins. In the present analysis, a close or positive margin had the greatest impact in the subgroup of women aged 35 years. However, margin status did not reach statistical significance in subgroups of women aged 36 to 55 and older than 55 years. There was a low overall risk of IBTR in these subgroups of women, particularly with the use of tamoxifen, which may make small increases in IBTR because of margins being difficult to detect. The correlation of positive excision margins as a surrogate marker of the extent of residual tumor in that quadrant of the breast may also be stronger in young women than in older women based on data from re-excision specimens.⁴³ There also may be many selection factors at work in this study population to account for the fact that these women were accepted for breast conservation but others with involved margins presumably were not. The present analysis cannot address whether these margins were single or multiple, focal or extensive, or "real" margins adjacent to residual breast tissue at risk for disease or adjacent to natural barriers to tumor spread such as the pectoral fascia. Although the magnitude of benefit may be greater in younger women compared with older women, our treatment policy remains to re-excise a positive or close margin in order to minimize the subsequent risk of IBTR.

In the present analysis, in the subgroups of ages 36 to 55 and more than 55 years, tamoxifen was a significant prognostic factor for IBTR. Tamoxifen was the most significant prognostic factor for IBTR in patients older than 55 and was associated with a modest but significant 3% decrease (to 2%, from 5%) in risk of IBTR at 10 years. However, tamoxifen resulted in a greater absolute 15% decrease (to 5%, from 20%) in the 10-year risk of IBTR in patients aged 36 to 55 years with ER-positive tumors. Adjuvant tamoxifen has been associated with a significant decrease in the rate of IBTR after conservative surgery and radiation in other series.^{5,11,32,44-47} Fowble et al⁴⁵ reported a modest decrease in IBTR with and without tamoxifen at 5 years (7% v 4%, P = .21). Dalberg et al⁴⁶ reported a cumulative incidence of IBTR of 12% without tamoxifen versus 3% with tamoxifen at 10 years in patients with negative margins treated by conservative surgery and radiation. Fisher et al⁴⁷ reported similar rates of 10% versus 3% at 10 years in a randomized trial of tamoxifen. There may be in particular an interaction between use of tamoxifen and the observed effect of margin status on IBTR. We previously reported³⁹ a delay in IBTR up to a median of 6.7 years with the use of tamoxifen. Cowen et al^12,33 also reported that adjuvant hormone use increased the local recurrence-free survival with positive margins but not with negative margins up to 10 years after breast-conserving surgery and radiation without chemotherapy.

ER-negative tumors have not had a higher risk of IBTR after breast-conserving surgery and radiation in most series.^{6,12,24,29,34} Similarly, ER-negativity itself did not seem to be associated with an increased risk of IBTR by this recursive partitioning analysis. The 10-year risk of IBTR was 9% for the subgroup 36 to 55 years old who were ER-negative, which was actually superior to the 10-year risk of 20% in patients aged 36 to 55 years who were ER-positive and not treated with tamoxifen. Several other factors entered into this recursive partitioning analysis did not reach prognostic significance. This study confirms the previous reports showing that for clinical tumor sizes 5 cm that are eligible for breast-conserving surgery and radiation, there is no significant difference in the risk of IBTR between T1 and T2 tumors.^{4,7,11,12,28,30,33,34} Positive family history has also been previously shown to lack prognostic significance for IBTR.^34,48-50 This study confirms previous reports that patients with node-positive disease have the same or lower risk of IBTR after breast-conserving surgery and radiation compared with node-negative patients.^{2,4,7,11,22,26,28} The primary tumor histology of invasive lobular versus ductal carcinoma has also been previously reported to lack prognostic significance for IBTR.^51,52 This study is also in agreement with two previous studies that did not show an overall increased risk of IBTR in the presence of LCIS.^53,54 However, there was a three-fold increase in IBTR with LCIS present in the subgroup of patients aged 36 to 55. We have reported this observation recently and have demonstrated a beneficial effect of tamoxifen on decreasing IBTR in women less than 50 years of age with an invasive cancer and LCIS.⁵⁵

Finally, of treatment-related factors, the use of adjuvant chemotherapy did not have a significant impact on the risk of IBTR in this analysis. This is in contrast to other studies that have shown that IBTR is reduced with adjuvant chemotherapy in subgroups of patients with node-positive disease,^2,7,22,26 node-negative disease,^56,57 or focally positive margins³⁸ after breast-conserving surgery and radiation. The present analysis supports our earlier report³⁹ that had used cumulative incidence methodology to show an absence of a decrease in IBTR at 5 or 10 years with adjuvant systemic therapy in patients with negative margins. In that study, patients with positive margins receiving adjuvant systemic therapy had a lower rate of IBTR at 5 years compared with no adjuvant systemic therapy, but had no significant decrease in the ultimate 10-year cumulative incidence of IBTR.

In conclusion, this recursive partitioning analysis identified patient age of 55 versus more than 55 years as the most significant prognostic factor for IBTR after breast-conserving surgery and radiation. The significance of other factors on the risk of IBTR varied by patient age. Patients 35 years had a low risk of IBTR in the setting of EIC-negative tumors, negative final margins, and adjuvant systemic therapy. EIC positivity was an independent risk factor for IBTR in patients 55 years old, whereas EIC and margin status had a smaller prognostic importance for IBTR in older women. Tamoxifen was the most significant prognostic factor for IBTR in patients older than 55 and was found to be associated with a modest but significant 3% decrease in risk at 10 years. However, tamoxifen resulted in a greater absolute 15% decrease in the 10-year risk of IBTR in patients aged 36 to 55 years with ER-positive tumors.

	ACKNOWLEDGMENTS

 
We thank Cindy Rosser for her collection and management of the data for the study population and Katherine Farlow for her preparation of the figures and text of the article.

	NOTES

 
Abstract presented at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.

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Submitted March 23, 2002; accepted June 14, 2002.

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