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The Association Between Biological Subtype and Isolated Regional Nodal Failure After Breast-Conserving Therapy
Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 1, pp. 188–196, 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/10/$–see front matter
doi:10.1016/j.ijrobp.2009.04.059
CLINICAL INVESTIGATION
Breast
THE ASSOCIATION BETWEEN BIOLOGICAL SUBTYPE AND ISOLATED REGIONAL NODAL FAILURE AFTER BREAST-CONSERVING THERAPY JENNIFER Y. WO, M.D.,* ALPHONSE G. TAGHIAN, M.D., PH.D.,y PAUL L. NGUYEN, M.D.,* RITA ABI RAAD, M.D.,y MEERA SREEDHARA, B.A.,z JENNIFER R. BELLON, M.D.,z JULIA S. WONG, M.D.,z MICHELE A. GADD, M.D.,y BARBARA L. SMITH, M.D., PH.D.,y AND JAY R. HARRIS, M.D.z * Harvard Radiation Oncology Program, y Massachusetts General Hospital, and z Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Purpose: To evaluate the risk of isolated regional nodal failure (RNF) among women with invasive breast cancer treated with breast-conserving surgery (BCS) and radiation therapy (RT) and to determine factors, including biological subtype, associated with RNF. Methods and Materials: We retrospectively studied 1,000 consecutive women with invasive breast cancer who received breast-conserving surgery and RT from 1997 through 2002. Ninety percent of patients received adjuvant systemic therapy; none received trastuzumab. Sentinel lymph node biopsy was done in 617 patients (62%). Of patients with one to three positive nodes, 34% received regional nodal irradiation (RNI). Biological subtype classification into luminal A, luminal B, HER-2, and basal subtypes was based on estrogen receptor status–, progesterone receptor status–, and HER-2–status of the primary tumor. Results: Median follow-up was 77 months. Isolated RNF occurred in 6 patients (0.6%). On univariate analysis, biological subtype (p = 0.0002), lymph node involvement (p = 0.008), lymphovascular invasion (p = 0.02), and Grade 3 histology (p = 0.01) were associated with significantly higher RNF rates. Compared with luminal A, the HER-2 (p = 0.01) and basal (p = 0.08) subtypes were associated with higher RNF rates. The 5-year RNF rate among patients with one to three positive nodes treated with tangents alone was 2.4%; we could not identify a subset of these patients with a substantial risk of RNF. Conclusions: Isolated RNF is a rare occurrence after breast-conserving therapy. Patients with the HER-2 (not treated with trastuzumab) and basal subtypes appear to be at higher risk of developing RNF although this risk is not high enough to justify the addition of RNI. Low rates of RNF in patients with one to three positive nodes suggest that tangential RT without RNI is reasonable in most patients. Ó 2010 Elsevier Inc. Breast cancer, Biological subtype, Regional nodal failure.
that perhaps routine RNI may not be necessary (6–9). Moreover, RNI is not without potential complications, including radiation pneumonitis (10), arm lymphedema (11), long-term cardiotoxicity (12), brachial plexopathy (13), and secondary cancers (14, 15). Therefore the risk of RNI should be weighed against an individual’s predicted risk of RNF based on available clinical, pathologic, and molecular factors. Randomized clinical trials from Europe (EORTC [European Organisation for Research and Treatment of Cancer] Protocol 22922-10925) (16) and Canada (MA20 Trial) (17) formally testing the value of RNI have been completed, but the results are currently pending. Recently, microarray gene expression studies have identified and validated the prognostic categorization of breast tumors into distinct biological subtypes (18, 19). Given
INTRODUCTION For early-stage breast cancer, the combination of breastconserving surgery (BCS) and whole-breast radiation therapy (RT) has become a widely accepted alternative to mastectomy, yielding equivalent rates of local control and long-term survival (1). However, the role of adjuvant regional nodal irradiation (RNI) in women with one to three positive nodes treated with breast-conserving therapy is still controversial (2). Proponents of RNI argue that the randomized controlled studies showing an overall survival benefit with postmastectomy irradiation included RNI, and thus RNI in the setting of breast-conserving therapy should be explored (3–5). Retrospective series, however, report low rates of isolated regional nodal failure (RNF), suggesting
Acknowledgments—The authors thank Dr. John Orav, Harvard School of Public Health, Boston, MA for his support in statistical analysis. Received March 6, 2009, and in revised form April 15, 2009. Accepted for publication April 22, 2009.
Reprint requests to: Jay R. Harris, M.D., Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Tel: (617) 632-2291; Fax: (617) 632-2290; E-mail: [email protected] Conflict of interest: none. 188
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the impracticality of performing gene expression profiling studies, recent studies have focused on developing a classification system based on three common molecular markers (20–22): estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu. Specifically, by use of the ER, PR, and HER-2 status of a tumor, biological subtype can be approximated as follows: luminal A (ER-positive or PRpositive and HER-2–negative), luminal B (ER-positive or PR-positive and HER-2–positive), HER-2 (ER-negative, PR-negative, and HER-2–positive), and basal (ER-negative, PR-negative, and HER-2–negative). Recent studies have shown that biological subtypes are clinically meaningful. For instance, the HER-2 and basal subtypes have been shown to confer a higher rate of local recurrence after BCS and RT compared with the luminal A subtype, and they are generally associated with a poorer prognosis (22–26). Currently, the impact of biological subtype on the development of isolated RNF is unknown. The purposes of this study are to evaluate the incidence of RNF among a group of patients with invasive breast cancer treated with BCS and RT by use of contemporary techniques including careful margin assessment, frequent use of sentinel lymph node (SLN) biopsy, and routine use of adjuvant systemic therapy and to determine which factors, including biological subtype, might be associated with isolated RNF. MATERIALS AND METHODS Patient selection From December 1997 to December 2002, 1,000 consecutive women with breast cancer at Dana-Farber Cancer Institute/Brigham and Women’s Hospital (Boston, MA) (n = 572) or Massachusetts General Hospital (Boston, MA) (n = 438) treated with BCS and whole-breast RT were identified. All patients had newly diagnosed, nonmetastatic pT1 to pT2, cN0 or cN1 invasive breast cancer. Patients with prior malignancy (except nonmelanoma skin cancers), synchronous bilateral breast cancer, or treatment with preoperative systemic therapy were excluded. For patients with a metachronous contralateral tumor, only the first side treated was considered in the analysis of RNF.
Treatment characteristics The median age at diagnosis was 55.2 years (range, 27.7–88.7 years). In total, 918 patients (92%) underwent surgical lymph node (LN) evaluation. Sentinel LN biopsy was performed in 617 patients (62%), including 421 patients with SLN biopsy alone and 196 patients with completion axillary lymph node dissection (ALND), whereas 301 patients (30%) underwent ALND alone. The extent of ALND varied by individual surgeon preference but typically included removal of Level I and II LNs. The median numbers of LNs removed for SLN biopsy and ALND were 2 (range, 1–10) and 11 (range, 1–33), respectively. Of 158 patients with a positive SLN biopsy result, 109 (69%) had completion ALND. Among the 49 patients with a positive SLN biopsy result without completion ALND, 39 (80%) received RNI. Whole-breast RT was prescribed to 45 to 50 Gy in 1.8- to 2.0-Gy fractions, plus a tumor-bed boost to 60 to 61 Gy. At the discretion of the radiation oncologist, RNI was given to the supraclavicular nodes/axillary apex via a slightly angled anterior ‘‘supraclavicular’’ photon field or the supraclavicular nodes/full axilla via a slightly
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angled anterior ‘‘supraclavicular/axillary’’ photon field, with or without a posterior axillary boost. Internal mammary chain (IMC) nodes were irradiated either through a partially wide tangential field or a separate mixed electron/photon medial strip. If the IMC nodes were the solitary site of RNI, only patients treated through a separate field were coded as having received RNI. Adjuvant systemic therapy was received by 90% of patients, including 128 (13%) treated with chemotherapy alone, 444 (44%) treated with hormonal therapy alone, and 328 (33%) treated with both; no patient received adjuvant trastuzumab. Among ER-positive or PR-positive patients, 89% received hormonal therapy. Among patients with the HER-2 and basal subtypes, 67% and 74% received chemotherapy, respectively. Eighty-six percent of chemotherapy regimens contained doxorubicin, and ninety-four percent of hormonal therapy regimens included tamoxifen. Patients were seen at follow-up 4 to 6 weeks after completion of RT and then every 6 months thereafter with annual breast imaging. Follow-up time and time to failure were calculated from the date of diagnosis to the first event or last known confirmed date of disease (breast cancer)–free status. The median follow-up time to censored event was 77 months (range, 1.3–123.9 months).
Classification of groups Biological subtype was categorized based on the receptor status of the primary tumor as follows: luminal A (ER-positive or PR-positive and HER-2–negative), luminal B (ER-positive or PR-positive and HER-2–positive), HER-2 (ER-negative, PR-negative, and HER-2–positive), and basal (ER-negative, PR-negative, and HER-2–negative). ER and PR status were assessed by immunohistochemical (IHC) staining. Tumors were only categorized as HER2–positive if they were scored 3 or greater by IHC staining or if they were scored 2 or greater by IHC staining and also showed HER-2 amplification (ratio >2.0) based on fluorescence in situ hybridization. Tumors that scored 2 or greater by IHC staining in the absence of fluorescence in situ hybridization amplification were categorized as HER-2 negative (27, 28).
Statistical methods Additional study covariates included patient age (<40 years vs. 40–49 years vs. 50–59 years vs. $60 years), tumor size (T1 vs. T2), LN positivity (yes vs. no), grade (1/2 vs. 3), ER status (positive vs. negative), lymphovascular invasion (LVI) (present vs. absent), adjuvant systemic therapy (yes vs. no), extranodal extension (present vs. absent), surgical nodal evaluation (clinical vs. SLN biopsy alone vs. ALND), and RNI (yes vs. no). Further subgroup analysis of patients with one to three positive nodes treated with tangential RT alone was performed to further evaluate RNF among this patient population. The primary endpoint of this study was time to isolated RNF. Regional nodal failure was defined as the appearance of tumor in the ipsilateral supraclavicular, axillary, infraclavicular, or IMC nodes. All cases of RNF were confirmed by biopsy unless diagnosed with distant metastases simultaneously. Patients were censored from observation for in-breast recurrence, contralateral breast cancer, secondary malignancy, or distant failure because further dissemination from these sites or systemic therapy may have altered disease progression. Secondary endpoints included any RNF, distant metastases–free survival (DMFS), and cause-specific survival (CSS). Comparisons of tumor and treatment characteristics between patients by biological subtype were performed by use of chi-square and Fisher’s exact tests. The 5-year actuarial estimates of RNF, CSS, and DMFS were calculated by the Kaplan-Meier method. Log-rank
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univariate analysis was performed for the entire cohort and for patients with one to three positive nodes treated with tangents alone. Given the limited number of events and concerns of violating inherent normality assumptions within the log-rank test statistic, Fisher’s exact test was performed to confirm significant findings by log-rank test. When Fisher’s exact test produced nonsignificant findings, the association was deemed nonsignificant. Given the limited number of events, no attempt was made to account for multiple testing, and statistical significance was defined as a p value of 0.05. All analyses were conducted by use of SAS software, version 9.1 (SAS Institute, Cary, NC).
RESULTS Association between biological subtype and other patient characteristics Among the four biological subtypes, there were significant differences in patient and tumor characteristics with respect to T category (p < 0.001), presence of LVI (p = 0.001), node positivity (p < 0.001), histologic grade (p < 0.001), median age (p < 0.001), and presence of extranodal extension (p = 0.002) (Table 1). The HER-2 and basal subtypes were more frequently associated with larger tumors, higher grade, LN involvement, extranodal extension, and younger age compared with the luminal subtypes. In addition, compared with patients with luminal A cancers, patients with the HER-2 and basal subtypes were more likely to undergo surgical nodal evaluation (p < 0.001) and receive, RNI (p = 0.01), and chemotherapy (p < 0.001), largely related to their more advanced stage and younger age. Rates of isolated RNF At a median follow-up of 77 months, isolated RNF had developed in only 6 patients (0.6%) and RNF with simultaneous local or distant failure had developed in 6 patients
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(0.6%). The 5-year actuarial rates of isolated RNF and any RNF were 0.7% and 1.5%, respectively. In addition, an ipsilateral breast recurrence developed as the site of first failure in 19 patients (1.9%), distant metastases developed in 55 patients (5.5%), a contralateral breast recurrence developed in 24 patients (2.4%), 10 patients (1.0%) died without recurrence, a second primary malignancy developed in 51 patients (5.1%), and 771 patients (77.1%) had no evidence of disease. Factors associated with RNF Table 2 summarizes the results of univariate analysis for the entire patient cohort with respect to isolated RNF. On univariate analysis, biological subtype (p = 0.0002), LN positivity (p = 0.002), LVI (p = 0.02), ER negativity (p = 0.0002), and Grade 3 histology (p = 0.005) were associated with significantly higher RNF rates. Compared with luminal A, patients with the HER-2 subtype had a significantly higher risk of isolated RNF (p = 0.01) and patients with the basal subtype had a trend toward a higher RNF rate (p = 0.08). By biological subtype, the 5-year actuarial isolated RNF rates for the luminal A, luminal B, HER-2, and basal subtypes were 0.3%, 0.0%, 5.6%, and 2.0%, respectively. All other study variables were not found to be significant. Patterns of RNI use and RNF Table 3 summarizes the pattern of RNI stratified by nodal involvement. Among 150 patients treated with RNI, 133 (89%) were treated to the supraclavicular/axillary apex region, 106 (71%) were treated to the full axilla, and 51 (34%) were treated to the IMC nodes. Of the node-negative patients, 20 (2.8%) received RNI because of a medial tumor location (n = 10), concerns regarding inadequate axillary
Table 1. Patient baseline characteristics stratified by biological subtype (N = 1,000) Characteristic T1 LVI Node positive 1–3 positive LNs $4 positive LNs Grade 3 Extranodal extension Surgical nodal evaluation SLN biopsy alone ALND RNI Supraclavicular Axillary Internal mammary Systemic therapy Hormonal therapy Chemotherapy Median dose Median age
All patients (N = 1,000) Luminal A (n = 761) Luminal B (n = 88) HER-2 (n = 39) Basal (n = 112) p Value 808 (81) 260 (26) 273 (27) 218 (22) 55 (6) 318 (32) 86 (9) 918 (92) 421 (42) 497 (50) 150 (15) 130 (13) 106 (11) 51 (5) 900 (90) 772 (78) 456 (46) 60 Gy 55 y
644 (85) 179 (24) 187 (25) 153 (20) 34 (4) 153 (20) 57 (7) 686 (90) 331 (44) 355 (47) 96 (13) 82 (11) 61 (8) 35 (5) 702 (92) 676 (89) 286 (38) 60 Gy 56 y
67 (76) 35 (40) 32 (36) 25 (28) 7 (8) 41 (47) 11 (13) 84 (95) 45 (51) 39 (44) 22 (25) 17 (19) 17 (19) 9 (10) 81 (92) 79 (90) 61 (69) 60 Gy 54 y
27 (69) 16 (41) 19 (49) 16 (41) 3 (8) 29 (81) 6 (15) 38 (97) 13 (33) 25 (64) 10 (26) 10 (26) 10 (26) 2 (5) 28 (72) 3 (8) 26 (67) 60 Gy 49 y
70 (63) 30 (27) 35 (31) 24 (21) 11 (10) 95 (88) 12 (11) 110 (98) 32 (29) 78 (70) 22 (20) 21 (19) 18 (16) 5 (4) 89 (79) 14 (13) 83 (74) 61 Gy 53 y
<0.001 0.001 <0.001 0.007 0.07 <0.001 0.002 0.007 0.004 <0.001 0.001 0.008 <0.001 0.02 <0.001 <0.001 <0.001 NS <0.001
Abbreviations: LVI = lymphovascular invasion; LN = lymph node; SLN = sentinel lymph node; ALND = axillary lymph node dissection; NS = not significant; RNI = regional nodal irradiation. Data are presented as No. of patients (%) unless otherwise indicated.
Biological subtype and isolated regional nodal failure d J. Y. WO et al.
Table 2. Univariate analysis for entire patient cohort with respect to isolated RNF (N = 1,000) Characteristic Age at diagnosis <40 y 40–50 y 50–60 y >60 y T category T1 T2 LN status Node negative Node positive Grade 1 or 2 3 Subtype Luminal A* Luminal B HER-2 Basal ER status ER-positive ER-negative LVI Present Absent Adjuvant systemic therapy Yes No Extranodal extension Present Absent Nodal evaluation SLN biopsy alone ALND Neither RNI Yes Node negative 1–3 positive LNs 4–9 positive LNs 10 positive LNs No Node negative 1–3 positive LNs 4–9 positive LNs 10 positive LNs
Total
RNF
No RNF
p Value 0.10
78 252 341 329
2 (2.6) 76 (97.4) 1 (0.4) 251 (99.6) 1 (0.3) 340 (99.7) 2 (0.6) 327 (99.4)
808 192
3 (0.4) 805 (99.6) 3 (1.6) 189 (98.4)
727 273
1 (0.1) 726 (99.9) 5 (1.8) 268 (98.2)
669 318
1 (0.1) 668 (99.9) 5 (1.6) 313 (98.4)
761 88 39 112
2 (0.3) 0 (0) 2 (5.1) 2 (1.8)
849 151
2 (0.2) 4 (2.6)
260 740
4(1.5) 2(0.3)
900 99
4 (0.4) 2 (2.0)
86 165
0 (0) 5 (3.0)
421 497 82
3 (0.7) 2 (0.4) 1 (1.2)
150 20 75 44 11 850 707 143 0 0
2 (1.3) 0 (0) 2 (2.7) 0 (0) 0 (0) 4 (0.5) 1 (0.1) 3 (2.1) 0 (0) 0 (0)
0.04y 0.002z 0.005z
0.0002x 759 (99.7) — 88 (100) 0.63 37 (94.9) <0.001jj 110 (98.2) 0.02{ 0.0002z 847 (99.8) 147 (97.4) 0.02z 256 (98.5) 738 (99.7) 0.04y 896 (99.6) 97 (98.0) 0.11 86 (100) 160 (97.0) 0.61 418 (99.3) 495 (99.6) 81 (98.8) 0.17 148 (98.7) 20 (0) 73 (97.3) 44 (100) 11 (100) 846 (99.5) 706 (99.9) 140 (97.9) 0 (0) 0 (0)
Abbreviations: RNF = regional nodal failure; LN = lymph node; ER = estrogen receptor; LVI = lymphovascular invasion; SLN = sentinel lymph node; ALND = axillary lymph node dissection; RNI = regional nodal irradiation. Data are presented as No. of patients (%). * Luminal A serves as comparison group. y T category (p = 0.09) and adjuvant systemic therapy (p = 0.11) were not significant predictors of RNF. z By Fisher’s exact test, LN positivity (p = 0.007), LVI (p = 0.04), Grade 3 histology (p = 0.015), and ER-negative status (p = 0.006) were significant predictors of RNF. x By chi-square analysis, biological subtype remained a significant predictor (p = 0.0004). jj By Fisher’s exact test with luminal A as baseline, the HER-2 subtype was a significant predictor of RNF (p = 0.01). { The basal subtype trended toward significance (p = 0.08).
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sampling (n = 2), or lack of surgical nodal evaluation (n = 8). One third of patients (75 of 218) with one to three positive nodes and all 55 patients with four or more positive nodes received RNI. Isolated RNF occurred in 0.1% of node-negative patients (n = 1) and 2.3% of patients with one to three positive nodes (n = 5). The 5-year actuarial rates of RNF were higher in patients with one to three positive nodes compared with node-negative patients (2.5% vs. 0.1%, p = 0.0004) (Fig. 1). RNF did not develop in any patients with four or more positive nodes. The median time to isolated RNF was 24.3 months (range, 6.5–56.9 months). The crude rates of axillary, supraclavicular, and IMC recurrence for isolated RNF were 0.4%, 0.3%, and 0.1%, respectively. Table 4 summarizes the sites of RNF, and Table 5 reviews the patient and tumor characteristics of the 6 patients who presented with isolated RNF. Subgroup analysis of patients with one to three positive nodes Table 6 shows the patient and tumor characteristics of patients with one to three positive nodes stratified by RNI. Only surgical nodal evaluation by SLN biopsy alone was found to be significantly different between the two groups. Patients with SLN biopsy alone were significantly more likely to receive RNI than those with ALND (p < 0.0001). Of 143 patients with one to three positive nodes treated with tangential RT alone, 3 (2.1%) had isolated RNF and 1 (0.7%) presented with simultaneous local failure. The actuarial 5-year rate of isolated RNF was 2.4%. On univariate analysis, none of the patient and tumor characteristics were significant (Table 7). However, there was a trend toward higher risk of isolated RNF among the HER- and basal subtypes combined (log-rank p = 0.02, Fisher’s exact p = 0.09). By biological subtype, the actuarial 5-year rates of isolated RNF for the luminal A, luminal B, HER-2, and basal subtypes were 1.2%, 0%, 10%, and 6.7%, respectively. In comparison, of 75 patients with one to three positive nodes treated with RNI, 2 (2.7%) had isolated RNF and none presented with simultaneous local failure. The actuarial 5-year rate of isolated RNF for patients with one to three positive nodes treated with RNI was 2.9%, which was not significantly different than the RNF rates in patients with one to three positive nodes treated with tangents alone (p = 0.74). Prognosis by biological subtype and RNF Distant metastases subsequently developed in 4 of 6 patients with RNF (67%) (median interval from RNF, 24 months; range, 4–52 months). Distant metastases developed in all 3 patients with supraclavicular recurrence and 1 patient with bulky axillary recurrence. Three of these patients subsequently died of metastatic breast cancer (median interval from RNF to death, 27.2 months; range, 4–31 months). For the entire patient cohort, the 5-year actuarial DMFS and CSS rates were 94.3% and 97.7%, respectively. Stratified by biological subtype, the 5-year actuarial DMFS rate was 96.9% for luminal A, 88.9% for luminal B, 87.1% for HER-2, and 83.3% for basal. Compared with luminal A as
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Table 3. Patterns of RNI use and RNF stratified by nodal status Clinical node negative
Pathologic node negative
1–3 Positive LNs
4–9 Positive LNs
10 Positive LNs
82 8 0 7 1 0 0 0 74 1
645 12 1 1 10 0 0 0 633 0
218 75 13 45 6 4 7 2 143 3
44 44 6 19 0 3 16 0 0 0
11 11 0 7 0 0 4 0 0 0
Total RNI used Supraclavicular/axillary apex Supraclavicular/full axilla IMC alone Supraclavicular/IMC Supraclavicular/full axilla/IMC RNF No RNI used RNF
Abbreviations: RNI = regional nodal irradiation; RNF = regional nodal failure; LN = lymph node; IMC = internal mammary. Data are presented as No. of patients.
baseline, the luminal B (p < 0.001), HER-2 (p < 0.001), and basal (p < 0.001) subtypes had significantly worse DMFS rates. In addition, the 5-year actuarial CSS rate was 99.3% for luminal A, 95.1% for luminal B, 89.7% for HER-2, and 91.4% for basal. Compared with luminal A as baseline, the luminal B (p = 0.001), HER-2 (p < 0.001) and basal (p < 0.001) subtypes had significantly worse CSS rates. DISCUSSION We evaluated the risk of isolated RNF among 1,000 consecutive women with invasive breast cancer treated with BCS and RT and sought to determine factors including biological subtype that may be associated with RNF. We found that, overall, isolated RNF was a rare occurrence, with a 5-year actuarial rate of 0.7%, but that rates varied significantly by biological subtype (p = 0.0002). On pair-wise comparison with luminal A as baseline, both the HER-2 (p = 0.01) and basal (p = 0.08) subtypes were associated with higher rates of isolated RNF, although only the HER-2 subtype reached conventional statistical significance. However, none of the patients in this study received adjuvant trastuzumab, which is now the standard of care for most patients with HER-2–positive tumors based on trials showing substantial improvement in disease-free survival including
reductions in local or regional recurrences (27, 28). Thus, in the setting of adjuvant trastuzumab, it is unclear whether results would show a significant difference between the HER-2 and luminal A subtypes. Other significant univariate predictors of isolated RNF that we identified included LN positivity (p = 0.002), LVI (p = 0.02), and Grade 3 histology (p = 0.005). A study by Haffty et al. (29) published in 2006 evaluated 482 women treated at Yale University (New Haven, CT) with BCS and RT with available ER, PR, and HER-2 data. With a median follow-up of 7.9 years, the authors reported 10 nodal relapses among 117 ‘‘triple-negative’’ (basal) patients and found a significantly higher 5-year rate of RNF among triple negative (basal) patients compared with the rest of the study cohort (6% for basal subtype vs. 1% for all others, p = 0.05). This result is similar to our result that shows that patients with the basal subtype compared with patients with the luminal A subtype had a trend toward an increased risk of isolated RNF (p = 0.08). In contrast, Freedman et al. (30) recently evaluated 753 women with known ER, PR, and HER-2 status and found no significant difference in 5-year rates of locoregional recurrence among patients with luminal subtypes (ER- or PR-positive disease), HER-2 subtype, and basal subtype (2.3%, 4.6%, and 3.2%, respectively; p = 0.36). Compared with the findings in our study, the lack of significant
Isolated RNF Rate (%)
2.8 2.4
Table 4. Patterns of failure for isolated RNF
2
p=0.0004
1.6 1.2
Site
0.8 0.4 0
0
12
24
36
48
60
72
84
96
108
120
Time (months) N0 Patients
N1 Patients
Fig. 1. Rate of isolated regional nodal failure (RNF) stratified by nodal status.
Axilla Supraclavicular Axilla and supraclavicular Internal mammary Total
RNF with simultaneous local or Isolated RNF distant metastases Any RNF 2 (0.2) 1 (0.1) 2 (0.2)
2 (0.2) 3 (0.3) 1 (0.1)
4 (0.4) 4 (0.4) 3 (0.3)
1 (0.1) 6 (0.6)
0 (0) 6 (0.6)
1 (0.1) 12 (1.3)
Abbreviation: RNF = regional nodal failure. Data are presented as No. of patients (%).
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Table 5. Overview of patients in whom isolated RNF developed Subtype
Systemic therapy
N0
Luminal A
41
N1
3
39
4 5 6
38 58 83
Patient No.
Age (y)
N stage
Nodal evaluation
RNI
1
79
2
Site of failure
Treatment of failure
N
Clinical
N
Axilla and SCV
N
Axilla
Y
SLN Bx plus ALND SLN Bx
Y
Axilla and SCV
Y Y N
SLN Bx ALND SLN Bx
N N Y
IMC SCV Axilla
ALND plus RT to SCV and axilla Axillary resection and axilla/SCV RT ALND, Vinorelbine, and Trastuzumab Chemotherapy and IMC RT SCV RT ALND, refused additional treatment
Luminal A
Y
N1
HER-2
N1 N1 N1
HER-2 Basal Basal
Abbreviations: RNF = regional nodal failure; RNI = regional nodal irradiation; ALND = axillary lymph node dissection; RT = radiation therapy; SLN Bx = sentinel lymph node biopsy; IMC = internal mammary; SCV = supraclavicular lymph node.
difference in rates of locoregional recurrence between patients with the HER-2 subtype and those with the luminal subtypes may be partially explained by trastuzumab treatment in 22% of patients with the HER-2 subtype in the experience reported by Freedman et al. We also found that isolated RNF among patients with one to three positive nodes treated with tangential RT alone was uncommon, with an actuarial 5-year rate of 2.4%. On univariate analysis, none of the patient and tumor characteristics was significant for RNF in this subset. There was a trend toward a higher risk of isolated RNF among the HER-2 and basal subtypes combined (log-rank p = 0.02, Fisher’s exact p = 0.09) compared with the luminal subtypes. The actuarial 5-year rate of isolated RNF for the HER-2 and basal subtypes combined (i.e., ER-negative cancers) was 8.0% compared with 1.1% for the luminal A and B subtypes (i.e., ER-positive cancers). This difference is similar to that
Table 6. Summary of baseline characteristics for patients with one to three positive LNs with respect to treatment with RNI (n = 218) Characteristic
Total
Total 218 Median follow-up 79.2 mo Median age at diagnosis 50.6 y T1 140 Grade 3 91 Biological subtype Luminal A 153 Luminal B 25 HER-2–positive 16 Basal 24 ER-positive 178 LVI 106 Systemic therapy 215 Extranodal extension 49 SLN biopsy alone 49
No RNI
RNI
143 (66) 75 (34) 78.4 mo 79.1 mo 50.5 y 51.6 y 90 (63) 50 (67) 61 (43) 30 (40) 105 (73) 12 (8) 11 (8) 15 (10) 117 (82) 63 (44) 142 (99) 29 (22) 10 (7)
48 (64) 13 (17) 5 (7) 9 (12) 61 (81) 43 (57) 73 (97) 20 (30) 39 (52)
p Value 0.52 0.72 0.66 0.77 0.24
>0.99 0.07 0.27 0.30 <0.0001
Abbreviations: LN = lymph node; RNI = regional nodal irradiation; ER = estrogen receptor; LVI = lymphovascular invasion; SLN = sentinel lymph node. Data are presented as No. of patients (%) unless otherwise indicated.
found in a retrospective study of 5,688 patients diagnosed between 1989 and 1999 and treated with BCS and RT reported by Truong et al. (31). They also found that among patients with one to three positive nodes treated without RNI, Grade 3 histology (p < 0.001), age lower than 50 years (p = 0.03), number of positive nodes (p = 0.02), and percent positive nodes (p = 0.03) were risk factors for RNF on univariate analysis. We did not find any of these factors significant in our series. This difference may be because of the larger number of patients in their study and their slightly longer follow-up. Another factor is the smaller number of RNFs in our study compared with their series. With a median follow-up of 8.6 years, Truong et al. reported crude rates of RNF of 2.0% and 5.4% among node-negative patients and those with one to three positive nodes, respectively. Our series, in comparison, showed crude incidences of RNF of 0.1% and 2.3%, respectively, among these two patient subsets with a median follow-up of 6.4 years. Among patients with one to three positive nodes treated without RNI combined with age lower than 50 years, Grade 3 histology, or ER-negative tumors, Truong et al. estimated 10-year actuarial RNF rates to be up to 10% to 15%. In contrast, our series showed 5-year actuarial rates of RNF of 3.7% and 8.0% among Grade 3 and ER-negative tumors, respectively. Our lower rate of RNF may be partially explained by our series being more recent with more effective systemic therapy, which is known to lower the risk of local-regional recurrence (32–34). In addition, 15% of patients with one to three positive nodes in our series had micrometastatic disease, thus potentially signifying a lower burden of nodal disease within our patient cohort. We also found that patients in whom RNF developed were at substantial risk of distant metastasis development and cause-specific death, as previously reported by other authors (35), and that IMC recurrences were exceedingly rare, which was also previously reported (7). There are several potential limitations to this study. First, this retrospective study is subject to heterogeneity in treatment patterns and inherent biases in patient selection. A second limitation is that classifications based on ER, PR, and HER-2 status are only approximations of the underlying
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Table 7. Univariate analysis of RNF for pN1 patients treated with tangents alone (n = 143) Characteristic Age at diagnosis <40 y 40–49 y 50–59 y $60 y T category T1 T2 No. of LNs positive 1 LN positive 2 LNs positive 3 LNs positive % LN positive <20% LN positive $20% LN negative Grade 1 or 2 3 Subtype Luminal A Luminal B HER-2–positive Basal ER status ER-positive ER-negative LVI Present Absent Adjuvant systemic therapy Yes No Extranodal extension Present Absent Nodal evaluation SLN biopsy alone ALND
RNF
p Value 0.48
7.7 (1) 1.8 (1) 1.9 (1) 0 (0) 0.94 2.2 (2) 1.9 (1) 0.58 2.9 (3) 0 (0) 0 (0) 0.55 1.7 (2) 0 (0) 0.31 1.2 (1) 3.3 (2) 0.13 0.9 (1) 0.0 (0) 9.1 (1) 6.7 (1) 0.02* 0.8 (1) 7.7 (2) 0.41 3.2 (2) 1.2 (1) 0.90 2.1 (3) 0.0 (0) 0.34 0.0 (0) 3.0 (3) 0.08 10 (1) 1.5 (2)
Abbreviations: RNF = regional nodal failure; LN = lymph node; ER = estrogen receptor; LVI = lymphovascular invasion; SLN = sentinel lymph node; ALND = axillary lymph node dissection. Data are presented as percentage of patients (number of patients). * By Fisher’s exact test, ER status did not maintain statistical significance (p = 0.09).
genotype-based biological subtypes. However, because receptor status information is much more readily available than genotyping, this method appears to have the most clinical applicability. In addition, although the current four-tiered classification of molecular phenotype may provide some insight into biological behavior of these tumors, more recent studies of genomic microarray analyses may suggest that there is much greater biological heterogeneity within these four categories than has been previously recognized and future genomic microarray analyses may further improve the sensitivity of our molecular phenotype classification systems in predicting biological behavior (36, 37). Third, given the very small number of isolated RNFs in this series, the findings of this study are hypothesis generating only and should be further explored in other large database studies. Another
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potential limitation to the study is that by looking at only first events, an inherent bias may be introduced where we may under-report the rate of RNFs in high-risk patients, such as the basal and HER-2 subtypes, given their increased risk for both local and distant failures. However, because of increased competing risks of both local and distant failures among these high-risk patients, we would expect that looking at only first events would bias against, not in favor of, a significant association between high-risk patients and the development of RNF. In addition, multivariate analysis could not be performed because of the small number of isolated RNFs. Moreover, only 143 patients were identified with one to three positive nodes treated with tangents alone, and thus our study had limited statistical power to detect a significant difference based on biological subtype within this subgroup. Lastly, longer follow-up will help in further assessing long-term outcomes. Prior studies have shown that patients with the luminal subtypes, in particular, have protracted disease courses and longer periods to disease recurrence (38). In conclusion, the striking finding in this study is the very low rate of RNF (actuarial 5-year rate, 0.7%) in this patient series. Part of the explanation for this very low rate is the effectiveness of comprehensive RNI to the supraclavicular, axillary, and IMC nodes in preventing the development of RNF among patients with four or more positive nodes: none of 55 such patients had an RNF. The other part of the explanation is the very low rate of RNF in patients with zero to three positive nodes, including even those treated with tangential fields alone. There is a general consensus that RNI is not needed in pN0 patients, but there is still controversy about which, if any, patients with one to three positive nodes should also be treated with RNI. On the basis of the results of our study and other published data, we conclude that the incidence of isolated RNF after BCS, axillary surgery, and tangential RT alone is very uncommon in patients with one to three positive nodes. We believe, however, that RNI should be considered when the axillary surgery is deemed inadequate, for example, a limited Level I axillary dissection and two positive nodes of only five nodes examined. At this time, it is not clear whether any patients with one to three positive nodes and an adequate Level I/II dissection should receive RNI. Given the findings of this study and those of other recent retrospective studies (29, 31), however, it seems reasonable, pending more definitive information, to consider such treatment in patients with several of the following features: non-luminal subtype, young age, high-grade cancer, two or three positive axillary nodes, and cancer with LVI. Randomized clinical trials from Europe (EORTC Protocol 22922-10925) (16) and Canada (MA20 Trial) (17) formally testing the value of nodal irradiation have been completed, but no results are available at this time. Meanwhile, the data from the Oxford Overview showing a link between locoregional recurrence at 5 years and survival at 15 years provides strong evidence that only patients with substantial reductions in 5-year locoregional recurrence will have an improvement in long-term survival rate (34). It is unlikely, we believe, based on the available data, that there is a sizable
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subgroup of patients with one to three positive nodes and an adequate Level I/II dissection who will have a 10% or greater risk of RNF that would justify the use of a third field for purposes of a survival gain. On the other hand, axillary and/or
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supraclavicular recurrences are often difficult to manage and can be highly symptomatic, and RNI can be justified for this reason at a lower level of RNF risk than required for a survival benefit.
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17. Olivotto IA, Chua B, Elliott EA, et al. A clinical trial of breast radiation therapy versus breast plus regional radiation therapy in early-stage breast cancer: The MA20 trial. Clin Breast Cancer 2003;4:361–363. 18. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747–752. 19. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98: 10869–10874. 20. Sorlie T. Molecular portraits of breast cancer: Tumour subtypes as distinct disease entities. Eur J Cancer 2004;40: 2667–2675. 21. Brenton JD, Carey LA, Ahmed AA, et al. Molecular classification and molecular forecasting of breast cancer: Ready for clinical application? J Clin Oncol 2005;23:7350–7360. 22. Sotiriou C, Neo SY, McShane LM, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 2003; 100:10393–10398. 23. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492–2502. 24. Nguyen PL, Taghian AG, Katz MS, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 2008;26: 2373–2378. 25. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100:8418–8423. 26. Kyndi M, Sorensen FB, Knudsen H, et al. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group. J Clin Oncol 2008;26:1419–1426. 27. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–1672. 28. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684. 29. Haffty BG, Yang Q, Reiss M, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 2006;24:5652–5657. 30. Freedman GM, Anderson PR, Li T, et al. Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation. Cancer 2009;115:946–951. 31. Truong PT, Jones SO, Kader HA, et al. Patients with T1 to T2 breast cancer with one to three positive nodes have higher local and regional recurrence risks compared with nodenegative patients after breast-conserving surgery and wholebreast radiotherapy. Int J Radiat Oncol Biol Phys 2009;73: 357–364. 32. Buchholz TA, Tucker SL, Erwin J, et al. Impact of systemic treatment on local control for patients with lymph node-negative breast cancer treated with breast-conservation therapy. J Clin Oncol 2001;19:2240–2246. 33. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-
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negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989;320:479–484. 34. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;366:2087–2106. 35. Harris EE, Hwang WT, Seyednejad F, et al. Prognosis after regional lymph node recurrence in patients with stage I-II breast carcinoma treated with breast conservation therapy. Cancer 2003;98:2144–2151.
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36. Webster LR, Lee SF, Ringland C, et al. Poor-prognosis estrogen receptor-positive breast cancer identified by histopathologic subclassification. Clin Cancer Res 2008;14:6625–6633. 37. Cheang MC, Voduc D, Bajdik C, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 2008;14:1368–1376. 38. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349:1793–1802.
doi:10.1016/j.ijrobp.2009.04.059
CLINICAL INVESTIGATION
Breast
THE ASSOCIATION BETWEEN BIOLOGICAL SUBTYPE AND ISOLATED REGIONAL NODAL FAILURE AFTER BREAST-CONSERVING THERAPY JENNIFER Y. WO, M.D.,* ALPHONSE G. TAGHIAN, M.D., PH.D.,y PAUL L. NGUYEN, M.D.,* RITA ABI RAAD, M.D.,y MEERA SREEDHARA, B.A.,z JENNIFER R. BELLON, M.D.,z JULIA S. WONG, M.D.,z MICHELE A. GADD, M.D.,y BARBARA L. SMITH, M.D., PH.D.,y AND JAY R. HARRIS, M.D.z * Harvard Radiation Oncology Program, y Massachusetts General Hospital, and z Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Purpose: To evaluate the risk of isolated regional nodal failure (RNF) among women with invasive breast cancer treated with breast-conserving surgery (BCS) and radiation therapy (RT) and to determine factors, including biological subtype, associated with RNF. Methods and Materials: We retrospectively studied 1,000 consecutive women with invasive breast cancer who received breast-conserving surgery and RT from 1997 through 2002. Ninety percent of patients received adjuvant systemic therapy; none received trastuzumab. Sentinel lymph node biopsy was done in 617 patients (62%). Of patients with one to three positive nodes, 34% received regional nodal irradiation (RNI). Biological subtype classification into luminal A, luminal B, HER-2, and basal subtypes was based on estrogen receptor status–, progesterone receptor status–, and HER-2–status of the primary tumor. Results: Median follow-up was 77 months. Isolated RNF occurred in 6 patients (0.6%). On univariate analysis, biological subtype (p = 0.0002), lymph node involvement (p = 0.008), lymphovascular invasion (p = 0.02), and Grade 3 histology (p = 0.01) were associated with significantly higher RNF rates. Compared with luminal A, the HER-2 (p = 0.01) and basal (p = 0.08) subtypes were associated with higher RNF rates. The 5-year RNF rate among patients with one to three positive nodes treated with tangents alone was 2.4%; we could not identify a subset of these patients with a substantial risk of RNF. Conclusions: Isolated RNF is a rare occurrence after breast-conserving therapy. Patients with the HER-2 (not treated with trastuzumab) and basal subtypes appear to be at higher risk of developing RNF although this risk is not high enough to justify the addition of RNI. Low rates of RNF in patients with one to three positive nodes suggest that tangential RT without RNI is reasonable in most patients. Ó 2010 Elsevier Inc. Breast cancer, Biological subtype, Regional nodal failure.
that perhaps routine RNI may not be necessary (6–9). Moreover, RNI is not without potential complications, including radiation pneumonitis (10), arm lymphedema (11), long-term cardiotoxicity (12), brachial plexopathy (13), and secondary cancers (14, 15). Therefore the risk of RNI should be weighed against an individual’s predicted risk of RNF based on available clinical, pathologic, and molecular factors. Randomized clinical trials from Europe (EORTC [European Organisation for Research and Treatment of Cancer] Protocol 22922-10925) (16) and Canada (MA20 Trial) (17) formally testing the value of RNI have been completed, but the results are currently pending. Recently, microarray gene expression studies have identified and validated the prognostic categorization of breast tumors into distinct biological subtypes (18, 19). Given
INTRODUCTION For early-stage breast cancer, the combination of breastconserving surgery (BCS) and whole-breast radiation therapy (RT) has become a widely accepted alternative to mastectomy, yielding equivalent rates of local control and long-term survival (1). However, the role of adjuvant regional nodal irradiation (RNI) in women with one to three positive nodes treated with breast-conserving therapy is still controversial (2). Proponents of RNI argue that the randomized controlled studies showing an overall survival benefit with postmastectomy irradiation included RNI, and thus RNI in the setting of breast-conserving therapy should be explored (3–5). Retrospective series, however, report low rates of isolated regional nodal failure (RNF), suggesting
Acknowledgments—The authors thank Dr. John Orav, Harvard School of Public Health, Boston, MA for his support in statistical analysis. Received March 6, 2009, and in revised form April 15, 2009. Accepted for publication April 22, 2009.
Reprint requests to: Jay R. Harris, M.D., Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Tel: (617) 632-2291; Fax: (617) 632-2290; E-mail: [email protected] Conflict of interest: none. 188
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the impracticality of performing gene expression profiling studies, recent studies have focused on developing a classification system based on three common molecular markers (20–22): estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu. Specifically, by use of the ER, PR, and HER-2 status of a tumor, biological subtype can be approximated as follows: luminal A (ER-positive or PRpositive and HER-2–negative), luminal B (ER-positive or PR-positive and HER-2–positive), HER-2 (ER-negative, PR-negative, and HER-2–positive), and basal (ER-negative, PR-negative, and HER-2–negative). Recent studies have shown that biological subtypes are clinically meaningful. For instance, the HER-2 and basal subtypes have been shown to confer a higher rate of local recurrence after BCS and RT compared with the luminal A subtype, and they are generally associated with a poorer prognosis (22–26). Currently, the impact of biological subtype on the development of isolated RNF is unknown. The purposes of this study are to evaluate the incidence of RNF among a group of patients with invasive breast cancer treated with BCS and RT by use of contemporary techniques including careful margin assessment, frequent use of sentinel lymph node (SLN) biopsy, and routine use of adjuvant systemic therapy and to determine which factors, including biological subtype, might be associated with isolated RNF. MATERIALS AND METHODS Patient selection From December 1997 to December 2002, 1,000 consecutive women with breast cancer at Dana-Farber Cancer Institute/Brigham and Women’s Hospital (Boston, MA) (n = 572) or Massachusetts General Hospital (Boston, MA) (n = 438) treated with BCS and whole-breast RT were identified. All patients had newly diagnosed, nonmetastatic pT1 to pT2, cN0 or cN1 invasive breast cancer. Patients with prior malignancy (except nonmelanoma skin cancers), synchronous bilateral breast cancer, or treatment with preoperative systemic therapy were excluded. For patients with a metachronous contralateral tumor, only the first side treated was considered in the analysis of RNF.
Treatment characteristics The median age at diagnosis was 55.2 years (range, 27.7–88.7 years). In total, 918 patients (92%) underwent surgical lymph node (LN) evaluation. Sentinel LN biopsy was performed in 617 patients (62%), including 421 patients with SLN biopsy alone and 196 patients with completion axillary lymph node dissection (ALND), whereas 301 patients (30%) underwent ALND alone. The extent of ALND varied by individual surgeon preference but typically included removal of Level I and II LNs. The median numbers of LNs removed for SLN biopsy and ALND were 2 (range, 1–10) and 11 (range, 1–33), respectively. Of 158 patients with a positive SLN biopsy result, 109 (69%) had completion ALND. Among the 49 patients with a positive SLN biopsy result without completion ALND, 39 (80%) received RNI. Whole-breast RT was prescribed to 45 to 50 Gy in 1.8- to 2.0-Gy fractions, plus a tumor-bed boost to 60 to 61 Gy. At the discretion of the radiation oncologist, RNI was given to the supraclavicular nodes/axillary apex via a slightly angled anterior ‘‘supraclavicular’’ photon field or the supraclavicular nodes/full axilla via a slightly
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angled anterior ‘‘supraclavicular/axillary’’ photon field, with or without a posterior axillary boost. Internal mammary chain (IMC) nodes were irradiated either through a partially wide tangential field or a separate mixed electron/photon medial strip. If the IMC nodes were the solitary site of RNI, only patients treated through a separate field were coded as having received RNI. Adjuvant systemic therapy was received by 90% of patients, including 128 (13%) treated with chemotherapy alone, 444 (44%) treated with hormonal therapy alone, and 328 (33%) treated with both; no patient received adjuvant trastuzumab. Among ER-positive or PR-positive patients, 89% received hormonal therapy. Among patients with the HER-2 and basal subtypes, 67% and 74% received chemotherapy, respectively. Eighty-six percent of chemotherapy regimens contained doxorubicin, and ninety-four percent of hormonal therapy regimens included tamoxifen. Patients were seen at follow-up 4 to 6 weeks after completion of RT and then every 6 months thereafter with annual breast imaging. Follow-up time and time to failure were calculated from the date of diagnosis to the first event or last known confirmed date of disease (breast cancer)–free status. The median follow-up time to censored event was 77 months (range, 1.3–123.9 months).
Classification of groups Biological subtype was categorized based on the receptor status of the primary tumor as follows: luminal A (ER-positive or PR-positive and HER-2–negative), luminal B (ER-positive or PR-positive and HER-2–positive), HER-2 (ER-negative, PR-negative, and HER-2–positive), and basal (ER-negative, PR-negative, and HER-2–negative). ER and PR status were assessed by immunohistochemical (IHC) staining. Tumors were only categorized as HER2–positive if they were scored 3 or greater by IHC staining or if they were scored 2 or greater by IHC staining and also showed HER-2 amplification (ratio >2.0) based on fluorescence in situ hybridization. Tumors that scored 2 or greater by IHC staining in the absence of fluorescence in situ hybridization amplification were categorized as HER-2 negative (27, 28).
Statistical methods Additional study covariates included patient age (<40 years vs. 40–49 years vs. 50–59 years vs. $60 years), tumor size (T1 vs. T2), LN positivity (yes vs. no), grade (1/2 vs. 3), ER status (positive vs. negative), lymphovascular invasion (LVI) (present vs. absent), adjuvant systemic therapy (yes vs. no), extranodal extension (present vs. absent), surgical nodal evaluation (clinical vs. SLN biopsy alone vs. ALND), and RNI (yes vs. no). Further subgroup analysis of patients with one to three positive nodes treated with tangential RT alone was performed to further evaluate RNF among this patient population. The primary endpoint of this study was time to isolated RNF. Regional nodal failure was defined as the appearance of tumor in the ipsilateral supraclavicular, axillary, infraclavicular, or IMC nodes. All cases of RNF were confirmed by biopsy unless diagnosed with distant metastases simultaneously. Patients were censored from observation for in-breast recurrence, contralateral breast cancer, secondary malignancy, or distant failure because further dissemination from these sites or systemic therapy may have altered disease progression. Secondary endpoints included any RNF, distant metastases–free survival (DMFS), and cause-specific survival (CSS). Comparisons of tumor and treatment characteristics between patients by biological subtype were performed by use of chi-square and Fisher’s exact tests. The 5-year actuarial estimates of RNF, CSS, and DMFS were calculated by the Kaplan-Meier method. Log-rank
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univariate analysis was performed for the entire cohort and for patients with one to three positive nodes treated with tangents alone. Given the limited number of events and concerns of violating inherent normality assumptions within the log-rank test statistic, Fisher’s exact test was performed to confirm significant findings by log-rank test. When Fisher’s exact test produced nonsignificant findings, the association was deemed nonsignificant. Given the limited number of events, no attempt was made to account for multiple testing, and statistical significance was defined as a p value of 0.05. All analyses were conducted by use of SAS software, version 9.1 (SAS Institute, Cary, NC).
RESULTS Association between biological subtype and other patient characteristics Among the four biological subtypes, there were significant differences in patient and tumor characteristics with respect to T category (p < 0.001), presence of LVI (p = 0.001), node positivity (p < 0.001), histologic grade (p < 0.001), median age (p < 0.001), and presence of extranodal extension (p = 0.002) (Table 1). The HER-2 and basal subtypes were more frequently associated with larger tumors, higher grade, LN involvement, extranodal extension, and younger age compared with the luminal subtypes. In addition, compared with patients with luminal A cancers, patients with the HER-2 and basal subtypes were more likely to undergo surgical nodal evaluation (p < 0.001) and receive, RNI (p = 0.01), and chemotherapy (p < 0.001), largely related to their more advanced stage and younger age. Rates of isolated RNF At a median follow-up of 77 months, isolated RNF had developed in only 6 patients (0.6%) and RNF with simultaneous local or distant failure had developed in 6 patients
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(0.6%). The 5-year actuarial rates of isolated RNF and any RNF were 0.7% and 1.5%, respectively. In addition, an ipsilateral breast recurrence developed as the site of first failure in 19 patients (1.9%), distant metastases developed in 55 patients (5.5%), a contralateral breast recurrence developed in 24 patients (2.4%), 10 patients (1.0%) died without recurrence, a second primary malignancy developed in 51 patients (5.1%), and 771 patients (77.1%) had no evidence of disease. Factors associated with RNF Table 2 summarizes the results of univariate analysis for the entire patient cohort with respect to isolated RNF. On univariate analysis, biological subtype (p = 0.0002), LN positivity (p = 0.002), LVI (p = 0.02), ER negativity (p = 0.0002), and Grade 3 histology (p = 0.005) were associated with significantly higher RNF rates. Compared with luminal A, patients with the HER-2 subtype had a significantly higher risk of isolated RNF (p = 0.01) and patients with the basal subtype had a trend toward a higher RNF rate (p = 0.08). By biological subtype, the 5-year actuarial isolated RNF rates for the luminal A, luminal B, HER-2, and basal subtypes were 0.3%, 0.0%, 5.6%, and 2.0%, respectively. All other study variables were not found to be significant. Patterns of RNI use and RNF Table 3 summarizes the pattern of RNI stratified by nodal involvement. Among 150 patients treated with RNI, 133 (89%) were treated to the supraclavicular/axillary apex region, 106 (71%) were treated to the full axilla, and 51 (34%) were treated to the IMC nodes. Of the node-negative patients, 20 (2.8%) received RNI because of a medial tumor location (n = 10), concerns regarding inadequate axillary
Table 1. Patient baseline characteristics stratified by biological subtype (N = 1,000) Characteristic T1 LVI Node positive 1–3 positive LNs $4 positive LNs Grade 3 Extranodal extension Surgical nodal evaluation SLN biopsy alone ALND RNI Supraclavicular Axillary Internal mammary Systemic therapy Hormonal therapy Chemotherapy Median dose Median age
All patients (N = 1,000) Luminal A (n = 761) Luminal B (n = 88) HER-2 (n = 39) Basal (n = 112) p Value 808 (81) 260 (26) 273 (27) 218 (22) 55 (6) 318 (32) 86 (9) 918 (92) 421 (42) 497 (50) 150 (15) 130 (13) 106 (11) 51 (5) 900 (90) 772 (78) 456 (46) 60 Gy 55 y
644 (85) 179 (24) 187 (25) 153 (20) 34 (4) 153 (20) 57 (7) 686 (90) 331 (44) 355 (47) 96 (13) 82 (11) 61 (8) 35 (5) 702 (92) 676 (89) 286 (38) 60 Gy 56 y
67 (76) 35 (40) 32 (36) 25 (28) 7 (8) 41 (47) 11 (13) 84 (95) 45 (51) 39 (44) 22 (25) 17 (19) 17 (19) 9 (10) 81 (92) 79 (90) 61 (69) 60 Gy 54 y
27 (69) 16 (41) 19 (49) 16 (41) 3 (8) 29 (81) 6 (15) 38 (97) 13 (33) 25 (64) 10 (26) 10 (26) 10 (26) 2 (5) 28 (72) 3 (8) 26 (67) 60 Gy 49 y
70 (63) 30 (27) 35 (31) 24 (21) 11 (10) 95 (88) 12 (11) 110 (98) 32 (29) 78 (70) 22 (20) 21 (19) 18 (16) 5 (4) 89 (79) 14 (13) 83 (74) 61 Gy 53 y
<0.001 0.001 <0.001 0.007 0.07 <0.001 0.002 0.007 0.004 <0.001 0.001 0.008 <0.001 0.02 <0.001 <0.001 <0.001 NS <0.001
Abbreviations: LVI = lymphovascular invasion; LN = lymph node; SLN = sentinel lymph node; ALND = axillary lymph node dissection; NS = not significant; RNI = regional nodal irradiation. Data are presented as No. of patients (%) unless otherwise indicated.
Biological subtype and isolated regional nodal failure d J. Y. WO et al.
Table 2. Univariate analysis for entire patient cohort with respect to isolated RNF (N = 1,000) Characteristic Age at diagnosis <40 y 40–50 y 50–60 y >60 y T category T1 T2 LN status Node negative Node positive Grade 1 or 2 3 Subtype Luminal A* Luminal B HER-2 Basal ER status ER-positive ER-negative LVI Present Absent Adjuvant systemic therapy Yes No Extranodal extension Present Absent Nodal evaluation SLN biopsy alone ALND Neither RNI Yes Node negative 1–3 positive LNs 4–9 positive LNs 10 positive LNs No Node negative 1–3 positive LNs 4–9 positive LNs 10 positive LNs
Total
RNF
No RNF
p Value 0.10
78 252 341 329
2 (2.6) 76 (97.4) 1 (0.4) 251 (99.6) 1 (0.3) 340 (99.7) 2 (0.6) 327 (99.4)
808 192
3 (0.4) 805 (99.6) 3 (1.6) 189 (98.4)
727 273
1 (0.1) 726 (99.9) 5 (1.8) 268 (98.2)
669 318
1 (0.1) 668 (99.9) 5 (1.6) 313 (98.4)
761 88 39 112
2 (0.3) 0 (0) 2 (5.1) 2 (1.8)
849 151
2 (0.2) 4 (2.6)
260 740
4(1.5) 2(0.3)
900 99
4 (0.4) 2 (2.0)
86 165
0 (0) 5 (3.0)
421 497 82
3 (0.7) 2 (0.4) 1 (1.2)
150 20 75 44 11 850 707 143 0 0
2 (1.3) 0 (0) 2 (2.7) 0 (0) 0 (0) 4 (0.5) 1 (0.1) 3 (2.1) 0 (0) 0 (0)
0.04y 0.002z 0.005z
0.0002x 759 (99.7) — 88 (100) 0.63 37 (94.9) <0.001jj 110 (98.2) 0.02{ 0.0002z 847 (99.8) 147 (97.4) 0.02z 256 (98.5) 738 (99.7) 0.04y 896 (99.6) 97 (98.0) 0.11 86 (100) 160 (97.0) 0.61 418 (99.3) 495 (99.6) 81 (98.8) 0.17 148 (98.7) 20 (0) 73 (97.3) 44 (100) 11 (100) 846 (99.5) 706 (99.9) 140 (97.9) 0 (0) 0 (0)
Abbreviations: RNF = regional nodal failure; LN = lymph node; ER = estrogen receptor; LVI = lymphovascular invasion; SLN = sentinel lymph node; ALND = axillary lymph node dissection; RNI = regional nodal irradiation. Data are presented as No. of patients (%). * Luminal A serves as comparison group. y T category (p = 0.09) and adjuvant systemic therapy (p = 0.11) were not significant predictors of RNF. z By Fisher’s exact test, LN positivity (p = 0.007), LVI (p = 0.04), Grade 3 histology (p = 0.015), and ER-negative status (p = 0.006) were significant predictors of RNF. x By chi-square analysis, biological subtype remained a significant predictor (p = 0.0004). jj By Fisher’s exact test with luminal A as baseline, the HER-2 subtype was a significant predictor of RNF (p = 0.01). { The basal subtype trended toward significance (p = 0.08).
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sampling (n = 2), or lack of surgical nodal evaluation (n = 8). One third of patients (75 of 218) with one to three positive nodes and all 55 patients with four or more positive nodes received RNI. Isolated RNF occurred in 0.1% of node-negative patients (n = 1) and 2.3% of patients with one to three positive nodes (n = 5). The 5-year actuarial rates of RNF were higher in patients with one to three positive nodes compared with node-negative patients (2.5% vs. 0.1%, p = 0.0004) (Fig. 1). RNF did not develop in any patients with four or more positive nodes. The median time to isolated RNF was 24.3 months (range, 6.5–56.9 months). The crude rates of axillary, supraclavicular, and IMC recurrence for isolated RNF were 0.4%, 0.3%, and 0.1%, respectively. Table 4 summarizes the sites of RNF, and Table 5 reviews the patient and tumor characteristics of the 6 patients who presented with isolated RNF. Subgroup analysis of patients with one to three positive nodes Table 6 shows the patient and tumor characteristics of patients with one to three positive nodes stratified by RNI. Only surgical nodal evaluation by SLN biopsy alone was found to be significantly different between the two groups. Patients with SLN biopsy alone were significantly more likely to receive RNI than those with ALND (p < 0.0001). Of 143 patients with one to three positive nodes treated with tangential RT alone, 3 (2.1%) had isolated RNF and 1 (0.7%) presented with simultaneous local failure. The actuarial 5-year rate of isolated RNF was 2.4%. On univariate analysis, none of the patient and tumor characteristics were significant (Table 7). However, there was a trend toward higher risk of isolated RNF among the HER- and basal subtypes combined (log-rank p = 0.02, Fisher’s exact p = 0.09). By biological subtype, the actuarial 5-year rates of isolated RNF for the luminal A, luminal B, HER-2, and basal subtypes were 1.2%, 0%, 10%, and 6.7%, respectively. In comparison, of 75 patients with one to three positive nodes treated with RNI, 2 (2.7%) had isolated RNF and none presented with simultaneous local failure. The actuarial 5-year rate of isolated RNF for patients with one to three positive nodes treated with RNI was 2.9%, which was not significantly different than the RNF rates in patients with one to three positive nodes treated with tangents alone (p = 0.74). Prognosis by biological subtype and RNF Distant metastases subsequently developed in 4 of 6 patients with RNF (67%) (median interval from RNF, 24 months; range, 4–52 months). Distant metastases developed in all 3 patients with supraclavicular recurrence and 1 patient with bulky axillary recurrence. Three of these patients subsequently died of metastatic breast cancer (median interval from RNF to death, 27.2 months; range, 4–31 months). For the entire patient cohort, the 5-year actuarial DMFS and CSS rates were 94.3% and 97.7%, respectively. Stratified by biological subtype, the 5-year actuarial DMFS rate was 96.9% for luminal A, 88.9% for luminal B, 87.1% for HER-2, and 83.3% for basal. Compared with luminal A as
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Table 3. Patterns of RNI use and RNF stratified by nodal status Clinical node negative
Pathologic node negative
1–3 Positive LNs
4–9 Positive LNs
10 Positive LNs
82 8 0 7 1 0 0 0 74 1
645 12 1 1 10 0 0 0 633 0
218 75 13 45 6 4 7 2 143 3
44 44 6 19 0 3 16 0 0 0
11 11 0 7 0 0 4 0 0 0
Total RNI used Supraclavicular/axillary apex Supraclavicular/full axilla IMC alone Supraclavicular/IMC Supraclavicular/full axilla/IMC RNF No RNI used RNF
Abbreviations: RNI = regional nodal irradiation; RNF = regional nodal failure; LN = lymph node; IMC = internal mammary. Data are presented as No. of patients.
baseline, the luminal B (p < 0.001), HER-2 (p < 0.001), and basal (p < 0.001) subtypes had significantly worse DMFS rates. In addition, the 5-year actuarial CSS rate was 99.3% for luminal A, 95.1% for luminal B, 89.7% for HER-2, and 91.4% for basal. Compared with luminal A as baseline, the luminal B (p = 0.001), HER-2 (p < 0.001) and basal (p < 0.001) subtypes had significantly worse CSS rates. DISCUSSION We evaluated the risk of isolated RNF among 1,000 consecutive women with invasive breast cancer treated with BCS and RT and sought to determine factors including biological subtype that may be associated with RNF. We found that, overall, isolated RNF was a rare occurrence, with a 5-year actuarial rate of 0.7%, but that rates varied significantly by biological subtype (p = 0.0002). On pair-wise comparison with luminal A as baseline, both the HER-2 (p = 0.01) and basal (p = 0.08) subtypes were associated with higher rates of isolated RNF, although only the HER-2 subtype reached conventional statistical significance. However, none of the patients in this study received adjuvant trastuzumab, which is now the standard of care for most patients with HER-2–positive tumors based on trials showing substantial improvement in disease-free survival including
reductions in local or regional recurrences (27, 28). Thus, in the setting of adjuvant trastuzumab, it is unclear whether results would show a significant difference between the HER-2 and luminal A subtypes. Other significant univariate predictors of isolated RNF that we identified included LN positivity (p = 0.002), LVI (p = 0.02), and Grade 3 histology (p = 0.005). A study by Haffty et al. (29) published in 2006 evaluated 482 women treated at Yale University (New Haven, CT) with BCS and RT with available ER, PR, and HER-2 data. With a median follow-up of 7.9 years, the authors reported 10 nodal relapses among 117 ‘‘triple-negative’’ (basal) patients and found a significantly higher 5-year rate of RNF among triple negative (basal) patients compared with the rest of the study cohort (6% for basal subtype vs. 1% for all others, p = 0.05). This result is similar to our result that shows that patients with the basal subtype compared with patients with the luminal A subtype had a trend toward an increased risk of isolated RNF (p = 0.08). In contrast, Freedman et al. (30) recently evaluated 753 women with known ER, PR, and HER-2 status and found no significant difference in 5-year rates of locoregional recurrence among patients with luminal subtypes (ER- or PR-positive disease), HER-2 subtype, and basal subtype (2.3%, 4.6%, and 3.2%, respectively; p = 0.36). Compared with the findings in our study, the lack of significant
Isolated RNF Rate (%)
2.8 2.4
Table 4. Patterns of failure for isolated RNF
2
p=0.0004
1.6 1.2
Site
0.8 0.4 0
0
12
24
36
48
60
72
84
96
108
120
Time (months) N0 Patients
N1 Patients
Fig. 1. Rate of isolated regional nodal failure (RNF) stratified by nodal status.
Axilla Supraclavicular Axilla and supraclavicular Internal mammary Total
RNF with simultaneous local or Isolated RNF distant metastases Any RNF 2 (0.2) 1 (0.1) 2 (0.2)
2 (0.2) 3 (0.3) 1 (0.1)
4 (0.4) 4 (0.4) 3 (0.3)
1 (0.1) 6 (0.6)
0 (0) 6 (0.6)
1 (0.1) 12 (1.3)
Abbreviation: RNF = regional nodal failure. Data are presented as No. of patients (%).
Biological subtype and isolated regional nodal failure d J. Y. WO et al.
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Table 5. Overview of patients in whom isolated RNF developed Subtype
Systemic therapy
N0
Luminal A
41
N1
3
39
4 5 6
38 58 83
Patient No.
Age (y)
N stage
Nodal evaluation
RNI
1
79
2
Site of failure
Treatment of failure
N
Clinical
N
Axilla and SCV
N
Axilla
Y
SLN Bx plus ALND SLN Bx
Y
Axilla and SCV
Y Y N
SLN Bx ALND SLN Bx
N N Y
IMC SCV Axilla
ALND plus RT to SCV and axilla Axillary resection and axilla/SCV RT ALND, Vinorelbine, and Trastuzumab Chemotherapy and IMC RT SCV RT ALND, refused additional treatment
Luminal A
Y
N1
HER-2
N1 N1 N1
HER-2 Basal Basal
Abbreviations: RNF = regional nodal failure; RNI = regional nodal irradiation; ALND = axillary lymph node dissection; RT = radiation therapy; SLN Bx = sentinel lymph node biopsy; IMC = internal mammary; SCV = supraclavicular lymph node.
difference in rates of locoregional recurrence between patients with the HER-2 subtype and those with the luminal subtypes may be partially explained by trastuzumab treatment in 22% of patients with the HER-2 subtype in the experience reported by Freedman et al. We also found that isolated RNF among patients with one to three positive nodes treated with tangential RT alone was uncommon, with an actuarial 5-year rate of 2.4%. On univariate analysis, none of the patient and tumor characteristics was significant for RNF in this subset. There was a trend toward a higher risk of isolated RNF among the HER-2 and basal subtypes combined (log-rank p = 0.02, Fisher’s exact p = 0.09) compared with the luminal subtypes. The actuarial 5-year rate of isolated RNF for the HER-2 and basal subtypes combined (i.e., ER-negative cancers) was 8.0% compared with 1.1% for the luminal A and B subtypes (i.e., ER-positive cancers). This difference is similar to that
Table 6. Summary of baseline characteristics for patients with one to three positive LNs with respect to treatment with RNI (n = 218) Characteristic
Total
Total 218 Median follow-up 79.2 mo Median age at diagnosis 50.6 y T1 140 Grade 3 91 Biological subtype Luminal A 153 Luminal B 25 HER-2–positive 16 Basal 24 ER-positive 178 LVI 106 Systemic therapy 215 Extranodal extension 49 SLN biopsy alone 49
No RNI
RNI
143 (66) 75 (34) 78.4 mo 79.1 mo 50.5 y 51.6 y 90 (63) 50 (67) 61 (43) 30 (40) 105 (73) 12 (8) 11 (8) 15 (10) 117 (82) 63 (44) 142 (99) 29 (22) 10 (7)
48 (64) 13 (17) 5 (7) 9 (12) 61 (81) 43 (57) 73 (97) 20 (30) 39 (52)
p Value 0.52 0.72 0.66 0.77 0.24
>0.99 0.07 0.27 0.30 <0.0001
Abbreviations: LN = lymph node; RNI = regional nodal irradiation; ER = estrogen receptor; LVI = lymphovascular invasion; SLN = sentinel lymph node. Data are presented as No. of patients (%) unless otherwise indicated.
found in a retrospective study of 5,688 patients diagnosed between 1989 and 1999 and treated with BCS and RT reported by Truong et al. (31). They also found that among patients with one to three positive nodes treated without RNI, Grade 3 histology (p < 0.001), age lower than 50 years (p = 0.03), number of positive nodes (p = 0.02), and percent positive nodes (p = 0.03) were risk factors for RNF on univariate analysis. We did not find any of these factors significant in our series. This difference may be because of the larger number of patients in their study and their slightly longer follow-up. Another factor is the smaller number of RNFs in our study compared with their series. With a median follow-up of 8.6 years, Truong et al. reported crude rates of RNF of 2.0% and 5.4% among node-negative patients and those with one to three positive nodes, respectively. Our series, in comparison, showed crude incidences of RNF of 0.1% and 2.3%, respectively, among these two patient subsets with a median follow-up of 6.4 years. Among patients with one to three positive nodes treated without RNI combined with age lower than 50 years, Grade 3 histology, or ER-negative tumors, Truong et al. estimated 10-year actuarial RNF rates to be up to 10% to 15%. In contrast, our series showed 5-year actuarial rates of RNF of 3.7% and 8.0% among Grade 3 and ER-negative tumors, respectively. Our lower rate of RNF may be partially explained by our series being more recent with more effective systemic therapy, which is known to lower the risk of local-regional recurrence (32–34). In addition, 15% of patients with one to three positive nodes in our series had micrometastatic disease, thus potentially signifying a lower burden of nodal disease within our patient cohort. We also found that patients in whom RNF developed were at substantial risk of distant metastasis development and cause-specific death, as previously reported by other authors (35), and that IMC recurrences were exceedingly rare, which was also previously reported (7). There are several potential limitations to this study. First, this retrospective study is subject to heterogeneity in treatment patterns and inherent biases in patient selection. A second limitation is that classifications based on ER, PR, and HER-2 status are only approximations of the underlying
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Table 7. Univariate analysis of RNF for pN1 patients treated with tangents alone (n = 143) Characteristic Age at diagnosis <40 y 40–49 y 50–59 y $60 y T category T1 T2 No. of LNs positive 1 LN positive 2 LNs positive 3 LNs positive % LN positive <20% LN positive $20% LN negative Grade 1 or 2 3 Subtype Luminal A Luminal B HER-2–positive Basal ER status ER-positive ER-negative LVI Present Absent Adjuvant systemic therapy Yes No Extranodal extension Present Absent Nodal evaluation SLN biopsy alone ALND
RNF
p Value 0.48
7.7 (1) 1.8 (1) 1.9 (1) 0 (0) 0.94 2.2 (2) 1.9 (1) 0.58 2.9 (3) 0 (0) 0 (0) 0.55 1.7 (2) 0 (0) 0.31 1.2 (1) 3.3 (2) 0.13 0.9 (1) 0.0 (0) 9.1 (1) 6.7 (1) 0.02* 0.8 (1) 7.7 (2) 0.41 3.2 (2) 1.2 (1) 0.90 2.1 (3) 0.0 (0) 0.34 0.0 (0) 3.0 (3) 0.08 10 (1) 1.5 (2)
Abbreviations: RNF = regional nodal failure; LN = lymph node; ER = estrogen receptor; LVI = lymphovascular invasion; SLN = sentinel lymph node; ALND = axillary lymph node dissection. Data are presented as percentage of patients (number of patients). * By Fisher’s exact test, ER status did not maintain statistical significance (p = 0.09).
genotype-based biological subtypes. However, because receptor status information is much more readily available than genotyping, this method appears to have the most clinical applicability. In addition, although the current four-tiered classification of molecular phenotype may provide some insight into biological behavior of these tumors, more recent studies of genomic microarray analyses may suggest that there is much greater biological heterogeneity within these four categories than has been previously recognized and future genomic microarray analyses may further improve the sensitivity of our molecular phenotype classification systems in predicting biological behavior (36, 37). Third, given the very small number of isolated RNFs in this series, the findings of this study are hypothesis generating only and should be further explored in other large database studies. Another
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potential limitation to the study is that by looking at only first events, an inherent bias may be introduced where we may under-report the rate of RNFs in high-risk patients, such as the basal and HER-2 subtypes, given their increased risk for both local and distant failures. However, because of increased competing risks of both local and distant failures among these high-risk patients, we would expect that looking at only first events would bias against, not in favor of, a significant association between high-risk patients and the development of RNF. In addition, multivariate analysis could not be performed because of the small number of isolated RNFs. Moreover, only 143 patients were identified with one to three positive nodes treated with tangents alone, and thus our study had limited statistical power to detect a significant difference based on biological subtype within this subgroup. Lastly, longer follow-up will help in further assessing long-term outcomes. Prior studies have shown that patients with the luminal subtypes, in particular, have protracted disease courses and longer periods to disease recurrence (38). In conclusion, the striking finding in this study is the very low rate of RNF (actuarial 5-year rate, 0.7%) in this patient series. Part of the explanation for this very low rate is the effectiveness of comprehensive RNI to the supraclavicular, axillary, and IMC nodes in preventing the development of RNF among patients with four or more positive nodes: none of 55 such patients had an RNF. The other part of the explanation is the very low rate of RNF in patients with zero to three positive nodes, including even those treated with tangential fields alone. There is a general consensus that RNI is not needed in pN0 patients, but there is still controversy about which, if any, patients with one to three positive nodes should also be treated with RNI. On the basis of the results of our study and other published data, we conclude that the incidence of isolated RNF after BCS, axillary surgery, and tangential RT alone is very uncommon in patients with one to three positive nodes. We believe, however, that RNI should be considered when the axillary surgery is deemed inadequate, for example, a limited Level I axillary dissection and two positive nodes of only five nodes examined. At this time, it is not clear whether any patients with one to three positive nodes and an adequate Level I/II dissection should receive RNI. Given the findings of this study and those of other recent retrospective studies (29, 31), however, it seems reasonable, pending more definitive information, to consider such treatment in patients with several of the following features: non-luminal subtype, young age, high-grade cancer, two or three positive axillary nodes, and cancer with LVI. Randomized clinical trials from Europe (EORTC Protocol 22922-10925) (16) and Canada (MA20 Trial) (17) formally testing the value of nodal irradiation have been completed, but no results are available at this time. Meanwhile, the data from the Oxford Overview showing a link between locoregional recurrence at 5 years and survival at 15 years provides strong evidence that only patients with substantial reductions in 5-year locoregional recurrence will have an improvement in long-term survival rate (34). It is unlikely, we believe, based on the available data, that there is a sizable
Biological subtype and isolated regional nodal failure d J. Y. WO et al.
subgroup of patients with one to three positive nodes and an adequate Level I/II dissection who will have a 10% or greater risk of RNF that would justify the use of a third field for purposes of a survival gain. On the other hand, axillary and/or
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supraclavicular recurrences are often difficult to manage and can be highly symptomatic, and RNI can be justified for this reason at a lower level of RNF risk than required for a survival benefit.
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