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Local Recurrence in Women With Stage I Breast Cancer: Declining Rates Over Time in a Large, Population-Based Cohort
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Breast Cancer
Local Recurrence in Women With Stage I Breast Cancer: Declining Rates Over Time in a Large, Population-Based Cohort Joycelin Canavan, MD, FRCPC,* Pauline T. Truong, MDCM, FRCPC,* Sally L. Smith, MD, FRCPC,* Linghong Lu, MSc,y Mary Lesperance, PhD,y and Ivo A. Olivotto, MD, FRCPCz *Radiation Therapy Program and Breast Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria, British Columbia, Canada; yDepartment of Mathematics and Statistics, University of Victoria, British Columbia, Canada; and zDepartment of Radiation Oncology, Tom Baker Cancer Centre, University of Calgary Received Jul 4, 2013, and in revised form Sep 30, 2013. Accepted for publication Oct 1, 2013.
Summary This large population-based study documented significant changes in the multimodality management of stage I breast cancer over the past 2 decades. More favorable-risk tumors were diagnosed, with increased rates of margin clearance and systemic therapy use. These improvements have contributed to declining local recurrence rates observed over time among patients treated with breast-conserving therapy.
Purpose: To evaluate whether local recurrence (LR) risk has changed over time among women with stage I breast cancer treated with breast-conserving therapy. Methods and Materials: Subjects were 5974 women aged 50 years diagnosis with pT1N0 breast cancer from 1989 to 2006, treated with breast-conserving surgery and radiation therapy. Clinicopathologic characteristics, treatment, and LR outcomes were compared among 4 cohorts stratified by year of diagnosis: 1989 to 1993 (nZ1077), 1994 to 1998 (nZ1633), 1999 to 2002 (nZ1622), and 2003 to 2006 (nZ1642). Multivariable analysis was performed, with year of diagnosis as a continuous variable. Results: Median follow-up time was 8.6 years. Among patients diagnosed in 1989 to 1993, 1994 to 1998, 1999 to 2002, and 2003 to 2006, the proportions of grade 1 tumors increased (16% vs 29% vs 40% vs 39%, respectively, P<.001). Surgical margin clearance rates increased from 82% to 93% to 95% and 88%, respectively (P<.001). Over time, the proportions of unknown estrogen receptor (ER) status decreased (29% vs 10% vs 1.2% vs 0.5%, respectively, P<.001), whereas ER-positive tumors increased (56% vs 77% vs 86% vs 86%, respectively, P<.001). Hormone therapy use increased (23% vs 23% vs 62% vs 73%, respectively, P<.001), and chemotherapy use increased (2% vs 5% vs 10% vs 13%, respectively, P<.001). The 5-year cumulative incidence rates of LR over the 4 time periods were 2.8% vs 1.7% vs 0.9% vs 0.8%, respectively (Gray’s test, P<.001). On competing risk multivariable analysis, year of diagnosis was significantly associated with decreased LR (hazard ratio, 0.92 per year, PZ.0003). Relative to grade 1 histology, grades 2, 3, and unknown were associated with increased LR. Hormone therapy use was associated with reduced LR. Conclusion: Significant changes in the multimodality management of stage I breast cancer have occurred over the past 2 decades. More favorable-risk tumors were diagnosed, and margin clearance and systemic therapy use increased. These changes contributed to the observed declining LR rates among patients treated with breast-conserving therapy. Ó 2014 Elsevier Inc.
Reprint requests to: Joycelin Canavan, MD, FRCPC, BC Cancer Agency, Vancouver Island Centre, 2410 Lee Ave, Victoria, BC, Canada V8R 6V5. Tel: (250) 519-5577; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 88, No. 1, pp. 80e86, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.10.001
Presented in part at the Canadian Association of Radiation Oncologists Annual Meeting, Ottawa, Ontario, Canada, September 12-15, 2012. Conflict of interest: none.
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Introduction Breast-conserving therapy is the standard of care for most women with early stage breast cancer. After breast-conserving surgery, whole-breast radiation therapy (RT) has been shown in randomized trials and meta-analyses to improve local control and provide survival rates similar to those of mastectomy (1-4). Advances in breast cancer screening, surgical techniques, and adjuvant therapy have improved local control and survival in patients with earlystage breast cancer. Increased awareness and use of mammographic screening have contributed to earlier diagnoses of smaller tumors. Improved surgical technique and pathologic evaluation have led to more accurate margin assessments and assignment of pathologic stages (5). Prospective trials (6,7) and single-institution series (8,9) have emerged with reports of declining local recurrence (LR) rates after breast-conserving therapy in women with early stage breast cancer. In a United Kingdom trial examining 1410 women with T1-3 N0-1 M0 breast cancer treated with breast-conserving surgery and radiation therapy between 1986 and 1998, 5-year LR was 8% (95% confidence interval [CI], 6.5%-9.5%) (6). In contrast, a more contemporary UK trial testing fractionation regimens in 4451 women between 1998 and 2002 reported a lower 5-year LR rate of 3.1% (95% CI, 2.6%-3.7%) (7). While these findings suggest that LR risks may be diminishing over time, comparisons among different studies are limited by variations in diagnostic, surgical, pathologic or stage distribution that could influence LR risk trends. This study examined whether local recurrence risk has changed over time among women consecutively diagnosed with stage I breast cancer treated with breast-conserving surgery and RT, using population-based data from a Canadian provincial cancer institution.
Methods and Materials Study subjects An institutional database with prospectively collected information on demographics, treatment, and outcomes in referred patients was used to identify the subjects of this analysis. The study cohort included 5974 women aged 50 years diagnosed with pT1N0 invasive breast cancer between 1989 and 2006. All patients were treated with breast-conserving surgery and adjuvant breast RT. The study excluded patients with in situ breast cancer, node-positive disease, unknown nodal status, distant metastasis, and patients treated with mastectomy.
Study variables and outcomes Demographic, tumor, and treatment characteristics were compared among 4 cohorts stratified by year of diagnosis: 1989 to 1993 (nZ1077), 1994 to 1998 (nZ1633), 1999 to 2002 (nZ1622), and 2003 to 2006 (nZ1642). Clinicopathologic characteristics analyzed were age at diagnosis (50-65 vs >65 years); histology; tumor size (0.1-0.5, 0.6-1, 1.1-2 cm, respectively); grade (1, 2, 3, unknown); lymphovascular invasion (LVI) (absent, present, unknown); margin status (negative 2 mm; close <2 mm; positive Z tumor touching ink; or unknown); and estrogen receptor (ER) status (positive, negative, unknown). Close margin status was
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prospectively captured at our institution from July 1, 2001, onward. Assessment of ER status evolved over time during the study period. Prior to 1995, ligand binding assay was used. The use of immunohistochemistry (IHC) techniques subsequently increased and became routine for patients diagnosed from 1995 to 2006. During the study period, the criteria for ER positivity was staining of at least 10% nuclei based on IHC with 6F11 antibody. The standard fractionation for breast RT used throughout the study period was a hypofractionated prescription of 42.5 to 44 Gy in 16 fractions, similar to that used in a Canadian trial that demonstrated equivalent LR and cosmesis compared to conventional fractionation RT (10). Adjuvant systemic therapy was analyzed as “yes” or “no”. Type of systemic treatment was classified as chemotherapy, hormone therapy, both, or none. The primary outcome was local recurrence, defined as the first site of recurrence involving the ipsilateral breast.
Data analysis Five- and 10-year LR estimates were computed using the Kaplan-Meier (KM) method. LR risk was also analyzed in a competing risk scenario, where death was considered a competing event. When there is more than one type of event and the events are not independent, KM estimates may be biased because they treat competing risks of the event of interest as censored. Under the competing risk setting, instead of treating death outcome simply as censored, the hazard of death is taken into account when considering the hazard of local recurrence. Here, cumulative incidence rates were calculated using the competing risks method (11). Gray’s test, which compares cumulative incidence rates of the subgroups for the event of interest (12), was performed to compare the cumulative incidences of LR among 4 time periods. Multivariable analysis was performed using Cox proportional hazards modeling with year of diagnosis as a continuous variable. Multivariable analysis was also performed to evaluate the effect of covariates on the cumulative incidence function (13). Multivariable analysis in the presence of competing risk events was proposed by Fine and Gray, who adopted a proportional hazards model for the subdistribution hazard of the event of interest, where the subdistribution hazard was directly related to the cumulative incidence and was defined as the hazard of failing from a given event, given that a subject had survived or had already failed due to a different event (13). The variables in the multivariable analysis were year of diagnosis, age, histology, tumor size, grade, LVI, ER status, margin, and use of systemic therapy. All statistical tests were 2-tailed, with significance established at a P value of <.05. All analyses were conducted using SPSS, version 20, and R software. The study was approved by the institutional research ethics board.
Results The median follow-up time was 8.6 years. Table 1 summarizes data comparing clinicopathologic characteristics among the 4 time periods. The mean age at diagnosis was similar in the 4 cohorts. The mean tumor size was similar among cohorts. Among patients diagnosed in 1989 to 1993, 1994 to 1998, 1999 to 2002, and 2003 to 2006, the proportions of grade 1 tumors increased over time
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Table 1
Comparisons of clinicopathologic characteristics among 4 time periods
Characteristic Age at diagnosis (y) Mean (range) 50-65 >65 Menopausal status Premenopausal Postmenopausal Unknown Histology Ductal Lobular Other Tumor size (cm) Mean (range) 0.1-0.5 cm 0.6-1.0 cm 1.1-2.0 cm Grade 1 2 3 Unknown LVI Absent Present Unknown Margins Negative Close Positive Unknown ER status Positive Negative Unknown Systemic therapy use Yes No Type of systemic therapy Chemotherapy Hormone therapy Both None
1989-1993 (NZ1077)
1994-1998 (NZ1633)
1999-2002 (NZ1622)
2003-2006 (NZ1642)
n (%)
n (%)
n (%)
n (%)
64 (50-87) 580 (53.9%) 497 (46.1%)
64 (50-87) 934 (57.2%) 699 (42.8%)
63 (50-87) 979 (60.4%) 643 (39.6%)
64 (50-91) 986 (60.0%) 656 (40.0%)
.002
68 (6.3%) 994 (92.3%) 15 (1.4%)
113 (6.9%) 1481 (90.7%) 39 (2.4%)
142 (8.8%) 1470 (90.6%) 10 (0.6%)
175 (10.7%) 1450 (88.3%) 17 (1.0%)
<.001
1012 (94.0%) 56 (5.2%) 9 (0.8%)
1495 (91.5%) 127 (7.8%) 11 (0.7%)
1495 (92.2%) 119 (7.3%) 8 (0.5%)
1513 (92.1%) 121 (7.4%) 8 (0.5%)
.17
P
1.2 106 373 598
(0.1-2.0) (9.8%) (34.6%) (55.5%)
1.2 108 555 970
(0.1-2.0) (6.6%) (34.0%) (59.4%)
1.2 149 511 962
(0.1-2.0) (9.2%) (31.5%) (59.3%)
1.2 160 518 964
(0.1-2.0) (9.7%) (31.5%) (58.7%)
169 549 273 86
(15.7%) (51.0%) (25.3%) (8.0%)
472 824 291 46
(28.9%) (50.5%) (17.8%) (2.8%)
650 678 263 31
(40.1%) (41.8%) (16.2%) (1.9%)
638 658 339 7
(38.9%) (40.1%) (20.6%) (0.4%)
<.001
.007
827 (76.8%) 215 (20.0%) 35 (3.2%)
1415 (86.7%) 169 (10.3%) 49 (3.0%)
1458 (89.9%) 105 (6.5%) 59 (3.6%)
1481 (90.2%) 125 (7.6%) 36 (2.2%)
<.001
886 0 93 98
1524 0 88 21
1546 43 31 2
1441 158 38 5
(87.8%) (9.6%) (2.3%) (0.3%)
<.001
(82.3%) (0%)* (8.6%) (9.1%)
(93.3%) (0%)* (5.4%) (1.3%)
(95.3%) (2.7%) (1.9%) (0.1%)
599 (55.6%) 170 (15.8%) 308 (28.6%)
1260 (77.2%) 204 (12.5%) 169 (10.3%)
1393 (85.9%) 210 (12.9%) 19 (1.2%)
1407 (85.7%) 227 (13.8%) 8 (0.5%)
<.001
263 (24.4%) 814 (75.6%)
433 (26.5%) 1200 (73.5%)
1105 (68.1%) 517 (31.9%)
1320 (80.4%) 322 (19.6%)
<.001
15 239 9 814
51 349 33 1200
123 1114 83 322
<.001
(1.4%) (22.2%) (0.8%) (75.6%)
(3.1%) (21.4%) (2.0%) (73.5%)
102 946 57 517
(6.3%) (58.3%) (3.5%) (31.9%)
(7.5%) (67.8%) (5.1%) (19.6%)
Abbreviations: ER Z estrogen receptors; LVI Z lymphovascular invasion. Test statistics applied to known values only. * Close margin status was prospectively captured only after July 1, 2001.
(16% vs 29% vs 40% vs 39%, respectively, P<.001). Rates of LVI declined over the 4 time periods (20% vs 10% vs 7% vs 8%, respectively, P<.001). During the 4 time periods, surgical margin clearance rates increased (82% vs 93% vs 95% vs 88%, respectively, P<.001). The proportions of patients with unknown ER status decreased (29% vs 10% vs 1.2% vs 0.5%, respectively, P<.001), whereas the proportions of ER-positive tumors increased (56% vs 77% vs 86% vs 86%, respectively, P<.001). Increased use of adjuvant systemic therapy with hormone therapy (23% vs
23% vs 62% vs 73%, respectively) and chemotherapy (2% vs 5% vs 10% vs 13%, respectively) were also observed over the 4 time periods (all, P<.001).
Local recurrence outcomes Comparison of KM local recurrence-free survival over the 4 time periods is shown in Figure 1, while the cumulative incidence of
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Fig. 1. Comparison of Kaplan-Meier local recurrence-free survival over the 4 time periods.
Fig. 2. Comparison of cumulative incidence rates of local recurrence over the 4 time periods.
local recurrence over the 4 time periods under the competing risks setting is shown in Figure 2. Among patients diagnosed in 1989 to 1993, 1994 to 1998, 1999 to 2002, and 2003 to 2006, 5-year KM LR rates were 3.0% versus 1.8% versus 1.0% versus 0.8% (logerank P<.001), and 10-year LR rates in the first 3 time periods were 6.3% versus 3.2% versus 2.4% (logerank P<.001). Corresponding 5-year cumulative incidences of LR were 2.8% versus 1.7% versus 0.9% versus 0.8% over the 4 time periods (Gray’s test P<.001) and 10-year cumulative incidences of LR in the first 3 time periods were 5.7% versus 3.0% versus 2.2% (Gray’s test P<.001).
after breast-conserving therapy in 1355 patients with T1-2N0 breast cancer. In patients treated from 1970 to 1993 compared to those treated from 1994 to 1996, the 5-year LR rates declined from 9.1% to 1.4%, respectively, among patients aged 50 years and from 2.6% to 1.2%, respectively, among patients aged >50 years (9). The current study corroborates these findings and further provides more recent population-based LR trends among patients diagnosed and treated in contemporary time periods up to 2006. In this study’s multivariable analysis, year of diagnosis, grade 1 histology, and hormone therapy use were factors significantly associated with reduced LR risk after breast-conserving therapy. In interpreting these results in the context of the observed changes in tumor and treatment characteristics over time, factors that can contribute to the observed diminishing LR rates likely include screening mammography, leading to diagnosis of early stage disease with favorable tumor characteristics, improved surgical technique and margin clearance rates, and increased use of adjuvant systemic therapy, particularly hormone therapy in recent years. Advances in mammographic screening over the past decades have led to increased detection of early stage, favorable risk breast cancers (14-17). Consistent with the current study’s findings that more patients have diagnoses with smaller tumors, grade 1 histology, and absence of LVI in recent years, investigators from the Breast Cancer Surveillance Consortium reported that screen-detected cancers are smaller, of lower grade, and are less likely to have axillary node involvement (14). Other investigators have similarly observed that screen-detected breast cancers have more favorable characteristics including lower T and N stages, low-grade histology, no LVI, and hormone receptor-positive disease (15-17). Redondo et al (15) reported that breast cancer recurrence rates were significantly lower among screened patients than among unscreened patients after adjusting for tumor size. Taken together, it is likely that populationbased screening practices have contributed to increased diagnosis of early disease with favorable tumor biology, resulting in the lower LR rates observed among patients diagnosed in recent years. Surgical management of early breast cancer has evolved over time. In the current analysis, the rates of margin clearance increased substantially over the 4 study periods. At our institution, clear margin
Multivariable analyses Table 2 shows the multivariable analyses using Cox regression and competing risk modeling. Both analyses yielded similar findings. In the competing risk multivariable analysis, year of diagnosis was significantly associated with LR, with a hazard ratio (HR) of 0.92 per year (95% CI, 0.88-0.96; PZ.0003), indicating that LR declined over time. Grades 3, 2, and unknown were associated with increased LR relative to grade 1 disease. Use of hormone therapy was associated with reduced LR.
Discussion This longitudinal outcomes study provides documentation that at the population level, LR rates are declining in women with pT1N0 breast cancer treated with breast-conserving therapy. Other institutional series have reported declining LR rates over time. Investigators from the William Beaumont Hospital evaluated patterns of disease recurrence over time from 1981 to 1996 in 607 patients with stages I to II breast cancer treated with breastconserving surgery and RT. Reduced 5-year and 12-year LR rates were observed in recent years (8% and 21% in 1980-1985 vs 1% and 9% in 1986-1990, PZ.001) (8). Similarly, investigators from the MD Anderson Cancer Center reported declining 5-year LR rates
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Table 2
Multivariable analysis of local recurrence in the entire cohort Single-cause multivariable analysis
Competing risks multivariable analysis
Variable
Hazard ratio
95% CI
P
Hazard ratio
95% CI
P
Diagnosis year (continuous variable) Age at diagnosis Menopausal status Premenopausal vs postmenopausal Unknown vs postmenopausal Tumor size (cm) Grade 2 vs 1 3 vs 1 Unknown vs 1 Lymphovascular invasion Positive vs negative Unknown vs negative Estrogen receptor Negative vs positive Unknown vs positive Histology: lobular vs ductal/other Margins Positive vs negative Close vs negative Unknown/missing vs negative Systemic therapy Hormones alone vs none Chemotherapy alone vs none Both vs none
0.93 b coef: 0.073 .99
0.89-0.97 .97-1.02
0.92 b coef: 0.082 0.99
0.88-0.96 0.97-1.01
1.43 0.97 0.87
0.86-2.38 0.30-3.10 0.62-1.21
1.40 0.91 0.83
0.85-2.31 0.29-2.87 0.60-1.17
1.60 2.67 2.59
1.05-2.44 1.66-4.31 1.25-5.39
1.59 2.58 2.60
1.04-2.43 1.61-4.13 1.25-5.43
0.73 0.55
0.42-1.25 0.20-1.55
0.70 0.55
0.39-1.24 0.21-1.45
0.81 0.91 0.83
0.51-1.27 0.59-1.39 0.44-1.59
0.81 0.90 0.84
0.51-1.28 0.59-1.36 0.44-1.61
1.56 2.21 0.95
0.92-2.66 0.78-6.21 0.46-1.97
1.52 2.12 1.01
0.90-2.58 0.77-5.94 0.48-2.13
0.55 1.31 1.15
0.35-0.85 0.63-2.70 0.46-2.86
.001 .57 .38 .17 .97 .39 <.001 .03 <.001 .01 .28 .25 .26 .63 .36 .65 .58 .17 .10 .13 .89 .02 .007 .47 .76
0.56 1.30 1.17
0.35-0.88 0.63-2.71 0.47-2.92
.0003 .17 .40 .19 .87 .29 <.001 .03 <.001 .01 .23 .22 .23 .62 .36 .60 .60 .22 .12 .15 .98 .03 .01 .48 .73
Abbreviations: coef Z coefficient; CI Z confidence interval.
was defined as 2 mm, close margin as <2 mm, and positive margin as tumor touching an inked margin. Of note, close margin was only prospectively captured in our database from 2001 onward, which accounted for 0% close margin rates in the earlier 2 time periods. Many studies have examined the impact of margin status on local control after breast-conserving therapy (18-22). Although the definition of margin status can vary widely, there is general consensus that LR risk is higher in patients with positive margins, warranting consideration of re-excision (18-22). Results are more diverse with regard to the association between close margins and LR risk. The current study did not find close or positive margins to be associated with higher LR risk on multivariable analysis. In a meta-analysis of 21 studies with data for margin status and LR outcomes, investigators from the University of Sydney, Australia, reported that while margin status had a prognostic effect on LR, the threshold distance for declaring negative margins was weakly associated with LR, and adjustment for adjuvant therapy removed the significance of this prognostic effect (18). Consistent with this and the current study’s observation, investigators from Harvard University reported that close margins, <2 mm, and maximally resected close or positive margins were not associated with increased LR compared to negative margins in the modern era of routine adjuvant systemic therapy (22). Adjuvant systemic therapy has been demonstrated to improve local control after breast-conserving surgery (23-25). In the current analysis, chemotherapy and hormone therapy use increased over time among patients with pT1N0 breast cancer. At our institution, both estrogen receptor assessment and institutional policies regarding hormone therapy use have evolved over time. Over the span of the study, the proportion of patients with unknown ER status
significantly decreased from 29% in 1989 to 1993, when quantitative measurement of cytosol protein was the standard, to 10% in 1994 to 1998 and 0.5% in 2003 to 2006 as IHC methods were instituted after 1995. This suggests that most of the tumors with unknown ER status in earlier years may have been classified as ER-positive if immunohistochemical staining had been available during that time. In 1981, institutional treatment policy introduced adjuvant tamoxifen for postmenopausal women with positive ER or unknown ER with high risk of relapse (26). The definition of high risk was initially based on the presence of positive nodes, but since 1982, women with negative nodes were included if LVI or neural invasion was present in the primary tumor (27). In 1997, the definition of high risk was extended to include women with grade 3 tumors measuring >2 cm and remained consistent through 2006. These institutional policies expanding the use of hormone therapy likely contributed to the observed reductions in LR rates over time. During the study period, histologic grade was assessed using the Scarf-Bloom-Richardson and Nottingham grading systems (28-30). While there are known interobserver variations, consensus guidelines have improved standardization of grading assessment (28-30). Similar to studies which have identified grade 3 histology to be associated with higher LR risk after breast conservation therapy (31), the current analysis found high grade to be associated with increased LR. Concerns have been raised regarding whether LR risks may be elevated among patients with grade 3 breast cancer treated with hypofractionated breast RT, such as that used during the entire study period in our cohort (10). However, prospective and retrospective analyses specifically examining this question have not shown LR differences in women with grade
Volume 88 Number 1 2014 3 disease treated with hypofractionated compared to conventional fractionated RT regimens (32, 33). The current study is limited by its retrospective design with inherent biases in patient and treatment selection. Pathologic evaluation of factors such as grade, LVI, margins, and hormone receptors changed over time and can vary among pathologists affecting the observed outcomes. Despite this, improved standardization of pathologic assessment has been shown with the increased availability of consensus guidelines on breast cancer pathologic evaluation and reporting (28, 29, 34, 35). Although the median follow-up was more than 8 years, longer follow-up is needed to provide confirmation of declining LR risk after breastconserving therapy over time. Despite these limitations, the analysis provides population-based data from a large cohort of patients managed in a universal access cancer care system with consistent consensus-based treatment policies and prospective follow-up data collection. These data are, thus, of value in contributing to the growing literature showing improved local control outcomes as multimodality care from diagnosis to treatment improved for women with early stage breast cancer.
Conclusions Significant changes in tumor characteristics, surgical techniques, and adjuvant systemic therapy for breast cancer have occurred over the past 2 decades. This has resulted in the diagnoses of more favorable risk tumors, higher rates of margin clearance, and increased systemic therapy use. These changes contribute to the observed declining rates of LR at the population level among women with early stage breast cancer treated with breast-conserving surgery and radiation therapy.
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International Journal of Radiation Oncology Biology Physics 32. Herbert C, Nichol A, Olivotto I, et al. The impact of hypofractionated whole breast radiotherapy on local relapse in patients with grade 3 early breast cancer: A population-based cohort study. Int J Radiat Oncol Biol Phys 2012;82:2086-2092. 33. Haviland JS, Yarnold JR, Bentzen SM. Hypofractionated radiotherapy for breast cancer [letter]. N Engl J Med 2010;362:18431844. 34. Rakha EA, Martin S, Lee AH, et al. The prognostic significance of lymphovascular invasion in invasive breast carcinoma. Cancer 2012; 118:3670-3680. 35. Evangelou E, Kyzas PA, Trikalinos T. Comparison of the diagnostic accuracy of lymphatic endothelium markers: Bayesian approach. Mod Pathol 2005;18:1490-1497.
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Breast Cancer
Local Recurrence in Women With Stage I Breast Cancer: Declining Rates Over Time in a Large, Population-Based Cohort Joycelin Canavan, MD, FRCPC,* Pauline T. Truong, MDCM, FRCPC,* Sally L. Smith, MD, FRCPC,* Linghong Lu, MSc,y Mary Lesperance, PhD,y and Ivo A. Olivotto, MD, FRCPCz *Radiation Therapy Program and Breast Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria, British Columbia, Canada; yDepartment of Mathematics and Statistics, University of Victoria, British Columbia, Canada; and zDepartment of Radiation Oncology, Tom Baker Cancer Centre, University of Calgary Received Jul 4, 2013, and in revised form Sep 30, 2013. Accepted for publication Oct 1, 2013.
Summary This large population-based study documented significant changes in the multimodality management of stage I breast cancer over the past 2 decades. More favorable-risk tumors were diagnosed, with increased rates of margin clearance and systemic therapy use. These improvements have contributed to declining local recurrence rates observed over time among patients treated with breast-conserving therapy.
Purpose: To evaluate whether local recurrence (LR) risk has changed over time among women with stage I breast cancer treated with breast-conserving therapy. Methods and Materials: Subjects were 5974 women aged 50 years diagnosis with pT1N0 breast cancer from 1989 to 2006, treated with breast-conserving surgery and radiation therapy. Clinicopathologic characteristics, treatment, and LR outcomes were compared among 4 cohorts stratified by year of diagnosis: 1989 to 1993 (nZ1077), 1994 to 1998 (nZ1633), 1999 to 2002 (nZ1622), and 2003 to 2006 (nZ1642). Multivariable analysis was performed, with year of diagnosis as a continuous variable. Results: Median follow-up time was 8.6 years. Among patients diagnosed in 1989 to 1993, 1994 to 1998, 1999 to 2002, and 2003 to 2006, the proportions of grade 1 tumors increased (16% vs 29% vs 40% vs 39%, respectively, P<.001). Surgical margin clearance rates increased from 82% to 93% to 95% and 88%, respectively (P<.001). Over time, the proportions of unknown estrogen receptor (ER) status decreased (29% vs 10% vs 1.2% vs 0.5%, respectively, P<.001), whereas ER-positive tumors increased (56% vs 77% vs 86% vs 86%, respectively, P<.001). Hormone therapy use increased (23% vs 23% vs 62% vs 73%, respectively, P<.001), and chemotherapy use increased (2% vs 5% vs 10% vs 13%, respectively, P<.001). The 5-year cumulative incidence rates of LR over the 4 time periods were 2.8% vs 1.7% vs 0.9% vs 0.8%, respectively (Gray’s test, P<.001). On competing risk multivariable analysis, year of diagnosis was significantly associated with decreased LR (hazard ratio, 0.92 per year, PZ.0003). Relative to grade 1 histology, grades 2, 3, and unknown were associated with increased LR. Hormone therapy use was associated with reduced LR. Conclusion: Significant changes in the multimodality management of stage I breast cancer have occurred over the past 2 decades. More favorable-risk tumors were diagnosed, and margin clearance and systemic therapy use increased. These changes contributed to the observed declining LR rates among patients treated with breast-conserving therapy. Ó 2014 Elsevier Inc.
Reprint requests to: Joycelin Canavan, MD, FRCPC, BC Cancer Agency, Vancouver Island Centre, 2410 Lee Ave, Victoria, BC, Canada V8R 6V5. Tel: (250) 519-5577; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 88, No. 1, pp. 80e86, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.10.001
Presented in part at the Canadian Association of Radiation Oncologists Annual Meeting, Ottawa, Ontario, Canada, September 12-15, 2012. Conflict of interest: none.
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Introduction Breast-conserving therapy is the standard of care for most women with early stage breast cancer. After breast-conserving surgery, whole-breast radiation therapy (RT) has been shown in randomized trials and meta-analyses to improve local control and provide survival rates similar to those of mastectomy (1-4). Advances in breast cancer screening, surgical techniques, and adjuvant therapy have improved local control and survival in patients with earlystage breast cancer. Increased awareness and use of mammographic screening have contributed to earlier diagnoses of smaller tumors. Improved surgical technique and pathologic evaluation have led to more accurate margin assessments and assignment of pathologic stages (5). Prospective trials (6,7) and single-institution series (8,9) have emerged with reports of declining local recurrence (LR) rates after breast-conserving therapy in women with early stage breast cancer. In a United Kingdom trial examining 1410 women with T1-3 N0-1 M0 breast cancer treated with breast-conserving surgery and radiation therapy between 1986 and 1998, 5-year LR was 8% (95% confidence interval [CI], 6.5%-9.5%) (6). In contrast, a more contemporary UK trial testing fractionation regimens in 4451 women between 1998 and 2002 reported a lower 5-year LR rate of 3.1% (95% CI, 2.6%-3.7%) (7). While these findings suggest that LR risks may be diminishing over time, comparisons among different studies are limited by variations in diagnostic, surgical, pathologic or stage distribution that could influence LR risk trends. This study examined whether local recurrence risk has changed over time among women consecutively diagnosed with stage I breast cancer treated with breast-conserving surgery and RT, using population-based data from a Canadian provincial cancer institution.
Methods and Materials Study subjects An institutional database with prospectively collected information on demographics, treatment, and outcomes in referred patients was used to identify the subjects of this analysis. The study cohort included 5974 women aged 50 years diagnosed with pT1N0 invasive breast cancer between 1989 and 2006. All patients were treated with breast-conserving surgery and adjuvant breast RT. The study excluded patients with in situ breast cancer, node-positive disease, unknown nodal status, distant metastasis, and patients treated with mastectomy.
Study variables and outcomes Demographic, tumor, and treatment characteristics were compared among 4 cohorts stratified by year of diagnosis: 1989 to 1993 (nZ1077), 1994 to 1998 (nZ1633), 1999 to 2002 (nZ1622), and 2003 to 2006 (nZ1642). Clinicopathologic characteristics analyzed were age at diagnosis (50-65 vs >65 years); histology; tumor size (0.1-0.5, 0.6-1, 1.1-2 cm, respectively); grade (1, 2, 3, unknown); lymphovascular invasion (LVI) (absent, present, unknown); margin status (negative 2 mm; close <2 mm; positive Z tumor touching ink; or unknown); and estrogen receptor (ER) status (positive, negative, unknown). Close margin status was
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prospectively captured at our institution from July 1, 2001, onward. Assessment of ER status evolved over time during the study period. Prior to 1995, ligand binding assay was used. The use of immunohistochemistry (IHC) techniques subsequently increased and became routine for patients diagnosed from 1995 to 2006. During the study period, the criteria for ER positivity was staining of at least 10% nuclei based on IHC with 6F11 antibody. The standard fractionation for breast RT used throughout the study period was a hypofractionated prescription of 42.5 to 44 Gy in 16 fractions, similar to that used in a Canadian trial that demonstrated equivalent LR and cosmesis compared to conventional fractionation RT (10). Adjuvant systemic therapy was analyzed as “yes” or “no”. Type of systemic treatment was classified as chemotherapy, hormone therapy, both, or none. The primary outcome was local recurrence, defined as the first site of recurrence involving the ipsilateral breast.
Data analysis Five- and 10-year LR estimates were computed using the Kaplan-Meier (KM) method. LR risk was also analyzed in a competing risk scenario, where death was considered a competing event. When there is more than one type of event and the events are not independent, KM estimates may be biased because they treat competing risks of the event of interest as censored. Under the competing risk setting, instead of treating death outcome simply as censored, the hazard of death is taken into account when considering the hazard of local recurrence. Here, cumulative incidence rates were calculated using the competing risks method (11). Gray’s test, which compares cumulative incidence rates of the subgroups for the event of interest (12), was performed to compare the cumulative incidences of LR among 4 time periods. Multivariable analysis was performed using Cox proportional hazards modeling with year of diagnosis as a continuous variable. Multivariable analysis was also performed to evaluate the effect of covariates on the cumulative incidence function (13). Multivariable analysis in the presence of competing risk events was proposed by Fine and Gray, who adopted a proportional hazards model for the subdistribution hazard of the event of interest, where the subdistribution hazard was directly related to the cumulative incidence and was defined as the hazard of failing from a given event, given that a subject had survived or had already failed due to a different event (13). The variables in the multivariable analysis were year of diagnosis, age, histology, tumor size, grade, LVI, ER status, margin, and use of systemic therapy. All statistical tests were 2-tailed, with significance established at a P value of <.05. All analyses were conducted using SPSS, version 20, and R software. The study was approved by the institutional research ethics board.
Results The median follow-up time was 8.6 years. Table 1 summarizes data comparing clinicopathologic characteristics among the 4 time periods. The mean age at diagnosis was similar in the 4 cohorts. The mean tumor size was similar among cohorts. Among patients diagnosed in 1989 to 1993, 1994 to 1998, 1999 to 2002, and 2003 to 2006, the proportions of grade 1 tumors increased over time
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Table 1
Comparisons of clinicopathologic characteristics among 4 time periods
Characteristic Age at diagnosis (y) Mean (range) 50-65 >65 Menopausal status Premenopausal Postmenopausal Unknown Histology Ductal Lobular Other Tumor size (cm) Mean (range) 0.1-0.5 cm 0.6-1.0 cm 1.1-2.0 cm Grade 1 2 3 Unknown LVI Absent Present Unknown Margins Negative Close Positive Unknown ER status Positive Negative Unknown Systemic therapy use Yes No Type of systemic therapy Chemotherapy Hormone therapy Both None
1989-1993 (NZ1077)
1994-1998 (NZ1633)
1999-2002 (NZ1622)
2003-2006 (NZ1642)
n (%)
n (%)
n (%)
n (%)
64 (50-87) 580 (53.9%) 497 (46.1%)
64 (50-87) 934 (57.2%) 699 (42.8%)
63 (50-87) 979 (60.4%) 643 (39.6%)
64 (50-91) 986 (60.0%) 656 (40.0%)
.002
68 (6.3%) 994 (92.3%) 15 (1.4%)
113 (6.9%) 1481 (90.7%) 39 (2.4%)
142 (8.8%) 1470 (90.6%) 10 (0.6%)
175 (10.7%) 1450 (88.3%) 17 (1.0%)
<.001
1012 (94.0%) 56 (5.2%) 9 (0.8%)
1495 (91.5%) 127 (7.8%) 11 (0.7%)
1495 (92.2%) 119 (7.3%) 8 (0.5%)
1513 (92.1%) 121 (7.4%) 8 (0.5%)
.17
P
1.2 106 373 598
(0.1-2.0) (9.8%) (34.6%) (55.5%)
1.2 108 555 970
(0.1-2.0) (6.6%) (34.0%) (59.4%)
1.2 149 511 962
(0.1-2.0) (9.2%) (31.5%) (59.3%)
1.2 160 518 964
(0.1-2.0) (9.7%) (31.5%) (58.7%)
169 549 273 86
(15.7%) (51.0%) (25.3%) (8.0%)
472 824 291 46
(28.9%) (50.5%) (17.8%) (2.8%)
650 678 263 31
(40.1%) (41.8%) (16.2%) (1.9%)
638 658 339 7
(38.9%) (40.1%) (20.6%) (0.4%)
<.001
.007
827 (76.8%) 215 (20.0%) 35 (3.2%)
1415 (86.7%) 169 (10.3%) 49 (3.0%)
1458 (89.9%) 105 (6.5%) 59 (3.6%)
1481 (90.2%) 125 (7.6%) 36 (2.2%)
<.001
886 0 93 98
1524 0 88 21
1546 43 31 2
1441 158 38 5
(87.8%) (9.6%) (2.3%) (0.3%)
<.001
(82.3%) (0%)* (8.6%) (9.1%)
(93.3%) (0%)* (5.4%) (1.3%)
(95.3%) (2.7%) (1.9%) (0.1%)
599 (55.6%) 170 (15.8%) 308 (28.6%)
1260 (77.2%) 204 (12.5%) 169 (10.3%)
1393 (85.9%) 210 (12.9%) 19 (1.2%)
1407 (85.7%) 227 (13.8%) 8 (0.5%)
<.001
263 (24.4%) 814 (75.6%)
433 (26.5%) 1200 (73.5%)
1105 (68.1%) 517 (31.9%)
1320 (80.4%) 322 (19.6%)
<.001
15 239 9 814
51 349 33 1200
123 1114 83 322
<.001
(1.4%) (22.2%) (0.8%) (75.6%)
(3.1%) (21.4%) (2.0%) (73.5%)
102 946 57 517
(6.3%) (58.3%) (3.5%) (31.9%)
(7.5%) (67.8%) (5.1%) (19.6%)
Abbreviations: ER Z estrogen receptors; LVI Z lymphovascular invasion. Test statistics applied to known values only. * Close margin status was prospectively captured only after July 1, 2001.
(16% vs 29% vs 40% vs 39%, respectively, P<.001). Rates of LVI declined over the 4 time periods (20% vs 10% vs 7% vs 8%, respectively, P<.001). During the 4 time periods, surgical margin clearance rates increased (82% vs 93% vs 95% vs 88%, respectively, P<.001). The proportions of patients with unknown ER status decreased (29% vs 10% vs 1.2% vs 0.5%, respectively, P<.001), whereas the proportions of ER-positive tumors increased (56% vs 77% vs 86% vs 86%, respectively, P<.001). Increased use of adjuvant systemic therapy with hormone therapy (23% vs
23% vs 62% vs 73%, respectively) and chemotherapy (2% vs 5% vs 10% vs 13%, respectively) were also observed over the 4 time periods (all, P<.001).
Local recurrence outcomes Comparison of KM local recurrence-free survival over the 4 time periods is shown in Figure 1, while the cumulative incidence of
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Fig. 1. Comparison of Kaplan-Meier local recurrence-free survival over the 4 time periods.
Fig. 2. Comparison of cumulative incidence rates of local recurrence over the 4 time periods.
local recurrence over the 4 time periods under the competing risks setting is shown in Figure 2. Among patients diagnosed in 1989 to 1993, 1994 to 1998, 1999 to 2002, and 2003 to 2006, 5-year KM LR rates were 3.0% versus 1.8% versus 1.0% versus 0.8% (logerank P<.001), and 10-year LR rates in the first 3 time periods were 6.3% versus 3.2% versus 2.4% (logerank P<.001). Corresponding 5-year cumulative incidences of LR were 2.8% versus 1.7% versus 0.9% versus 0.8% over the 4 time periods (Gray’s test P<.001) and 10-year cumulative incidences of LR in the first 3 time periods were 5.7% versus 3.0% versus 2.2% (Gray’s test P<.001).
after breast-conserving therapy in 1355 patients with T1-2N0 breast cancer. In patients treated from 1970 to 1993 compared to those treated from 1994 to 1996, the 5-year LR rates declined from 9.1% to 1.4%, respectively, among patients aged 50 years and from 2.6% to 1.2%, respectively, among patients aged >50 years (9). The current study corroborates these findings and further provides more recent population-based LR trends among patients diagnosed and treated in contemporary time periods up to 2006. In this study’s multivariable analysis, year of diagnosis, grade 1 histology, and hormone therapy use were factors significantly associated with reduced LR risk after breast-conserving therapy. In interpreting these results in the context of the observed changes in tumor and treatment characteristics over time, factors that can contribute to the observed diminishing LR rates likely include screening mammography, leading to diagnosis of early stage disease with favorable tumor characteristics, improved surgical technique and margin clearance rates, and increased use of adjuvant systemic therapy, particularly hormone therapy in recent years. Advances in mammographic screening over the past decades have led to increased detection of early stage, favorable risk breast cancers (14-17). Consistent with the current study’s findings that more patients have diagnoses with smaller tumors, grade 1 histology, and absence of LVI in recent years, investigators from the Breast Cancer Surveillance Consortium reported that screen-detected cancers are smaller, of lower grade, and are less likely to have axillary node involvement (14). Other investigators have similarly observed that screen-detected breast cancers have more favorable characteristics including lower T and N stages, low-grade histology, no LVI, and hormone receptor-positive disease (15-17). Redondo et al (15) reported that breast cancer recurrence rates were significantly lower among screened patients than among unscreened patients after adjusting for tumor size. Taken together, it is likely that populationbased screening practices have contributed to increased diagnosis of early disease with favorable tumor biology, resulting in the lower LR rates observed among patients diagnosed in recent years. Surgical management of early breast cancer has evolved over time. In the current analysis, the rates of margin clearance increased substantially over the 4 study periods. At our institution, clear margin
Multivariable analyses Table 2 shows the multivariable analyses using Cox regression and competing risk modeling. Both analyses yielded similar findings. In the competing risk multivariable analysis, year of diagnosis was significantly associated with LR, with a hazard ratio (HR) of 0.92 per year (95% CI, 0.88-0.96; PZ.0003), indicating that LR declined over time. Grades 3, 2, and unknown were associated with increased LR relative to grade 1 disease. Use of hormone therapy was associated with reduced LR.
Discussion This longitudinal outcomes study provides documentation that at the population level, LR rates are declining in women with pT1N0 breast cancer treated with breast-conserving therapy. Other institutional series have reported declining LR rates over time. Investigators from the William Beaumont Hospital evaluated patterns of disease recurrence over time from 1981 to 1996 in 607 patients with stages I to II breast cancer treated with breastconserving surgery and RT. Reduced 5-year and 12-year LR rates were observed in recent years (8% and 21% in 1980-1985 vs 1% and 9% in 1986-1990, PZ.001) (8). Similarly, investigators from the MD Anderson Cancer Center reported declining 5-year LR rates
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Table 2
Multivariable analysis of local recurrence in the entire cohort Single-cause multivariable analysis
Competing risks multivariable analysis
Variable
Hazard ratio
95% CI
P
Hazard ratio
95% CI
P
Diagnosis year (continuous variable) Age at diagnosis Menopausal status Premenopausal vs postmenopausal Unknown vs postmenopausal Tumor size (cm) Grade 2 vs 1 3 vs 1 Unknown vs 1 Lymphovascular invasion Positive vs negative Unknown vs negative Estrogen receptor Negative vs positive Unknown vs positive Histology: lobular vs ductal/other Margins Positive vs negative Close vs negative Unknown/missing vs negative Systemic therapy Hormones alone vs none Chemotherapy alone vs none Both vs none
0.93 b coef: 0.073 .99
0.89-0.97 .97-1.02
0.92 b coef: 0.082 0.99
0.88-0.96 0.97-1.01
1.43 0.97 0.87
0.86-2.38 0.30-3.10 0.62-1.21
1.40 0.91 0.83
0.85-2.31 0.29-2.87 0.60-1.17
1.60 2.67 2.59
1.05-2.44 1.66-4.31 1.25-5.39
1.59 2.58 2.60
1.04-2.43 1.61-4.13 1.25-5.43
0.73 0.55
0.42-1.25 0.20-1.55
0.70 0.55
0.39-1.24 0.21-1.45
0.81 0.91 0.83
0.51-1.27 0.59-1.39 0.44-1.59
0.81 0.90 0.84
0.51-1.28 0.59-1.36 0.44-1.61
1.56 2.21 0.95
0.92-2.66 0.78-6.21 0.46-1.97
1.52 2.12 1.01
0.90-2.58 0.77-5.94 0.48-2.13
0.55 1.31 1.15
0.35-0.85 0.63-2.70 0.46-2.86
.001 .57 .38 .17 .97 .39 <.001 .03 <.001 .01 .28 .25 .26 .63 .36 .65 .58 .17 .10 .13 .89 .02 .007 .47 .76
0.56 1.30 1.17
0.35-0.88 0.63-2.71 0.47-2.92
.0003 .17 .40 .19 .87 .29 <.001 .03 <.001 .01 .23 .22 .23 .62 .36 .60 .60 .22 .12 .15 .98 .03 .01 .48 .73
Abbreviations: coef Z coefficient; CI Z confidence interval.
was defined as 2 mm, close margin as <2 mm, and positive margin as tumor touching an inked margin. Of note, close margin was only prospectively captured in our database from 2001 onward, which accounted for 0% close margin rates in the earlier 2 time periods. Many studies have examined the impact of margin status on local control after breast-conserving therapy (18-22). Although the definition of margin status can vary widely, there is general consensus that LR risk is higher in patients with positive margins, warranting consideration of re-excision (18-22). Results are more diverse with regard to the association between close margins and LR risk. The current study did not find close or positive margins to be associated with higher LR risk on multivariable analysis. In a meta-analysis of 21 studies with data for margin status and LR outcomes, investigators from the University of Sydney, Australia, reported that while margin status had a prognostic effect on LR, the threshold distance for declaring negative margins was weakly associated with LR, and adjustment for adjuvant therapy removed the significance of this prognostic effect (18). Consistent with this and the current study’s observation, investigators from Harvard University reported that close margins, <2 mm, and maximally resected close or positive margins were not associated with increased LR compared to negative margins in the modern era of routine adjuvant systemic therapy (22). Adjuvant systemic therapy has been demonstrated to improve local control after breast-conserving surgery (23-25). In the current analysis, chemotherapy and hormone therapy use increased over time among patients with pT1N0 breast cancer. At our institution, both estrogen receptor assessment and institutional policies regarding hormone therapy use have evolved over time. Over the span of the study, the proportion of patients with unknown ER status
significantly decreased from 29% in 1989 to 1993, when quantitative measurement of cytosol protein was the standard, to 10% in 1994 to 1998 and 0.5% in 2003 to 2006 as IHC methods were instituted after 1995. This suggests that most of the tumors with unknown ER status in earlier years may have been classified as ER-positive if immunohistochemical staining had been available during that time. In 1981, institutional treatment policy introduced adjuvant tamoxifen for postmenopausal women with positive ER or unknown ER with high risk of relapse (26). The definition of high risk was initially based on the presence of positive nodes, but since 1982, women with negative nodes were included if LVI or neural invasion was present in the primary tumor (27). In 1997, the definition of high risk was extended to include women with grade 3 tumors measuring >2 cm and remained consistent through 2006. These institutional policies expanding the use of hormone therapy likely contributed to the observed reductions in LR rates over time. During the study period, histologic grade was assessed using the Scarf-Bloom-Richardson and Nottingham grading systems (28-30). While there are known interobserver variations, consensus guidelines have improved standardization of grading assessment (28-30). Similar to studies which have identified grade 3 histology to be associated with higher LR risk after breast conservation therapy (31), the current analysis found high grade to be associated with increased LR. Concerns have been raised regarding whether LR risks may be elevated among patients with grade 3 breast cancer treated with hypofractionated breast RT, such as that used during the entire study period in our cohort (10). However, prospective and retrospective analyses specifically examining this question have not shown LR differences in women with grade
Volume 88 Number 1 2014 3 disease treated with hypofractionated compared to conventional fractionated RT regimens (32, 33). The current study is limited by its retrospective design with inherent biases in patient and treatment selection. Pathologic evaluation of factors such as grade, LVI, margins, and hormone receptors changed over time and can vary among pathologists affecting the observed outcomes. Despite this, improved standardization of pathologic assessment has been shown with the increased availability of consensus guidelines on breast cancer pathologic evaluation and reporting (28, 29, 34, 35). Although the median follow-up was more than 8 years, longer follow-up is needed to provide confirmation of declining LR risk after breastconserving therapy over time. Despite these limitations, the analysis provides population-based data from a large cohort of patients managed in a universal access cancer care system with consistent consensus-based treatment policies and prospective follow-up data collection. These data are, thus, of value in contributing to the growing literature showing improved local control outcomes as multimodality care from diagnosis to treatment improved for women with early stage breast cancer.
Conclusions Significant changes in tumor characteristics, surgical techniques, and adjuvant systemic therapy for breast cancer have occurred over the past 2 decades. This has resulted in the diagnoses of more favorable risk tumors, higher rates of margin clearance, and increased systemic therapy use. These changes contribute to the observed declining rates of LR at the population level among women with early stage breast cancer treated with breast-conserving surgery and radiation therapy.
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