- Email: [email protected]
Adjuvant Radiation Improves Survival in Older Women Following Breast-Conserving Surgery for Estrogen Receptor–Negative Breast Cancer
Original Study
Adjuvant Radiation Improves Survival in Older Women Following Breast-Conserving Surgery for Estrogen ReceptoreNegative Breast Cancer Emily C. Daugherty,1 Michael R. Daugherty,2 Jeffrey A. Bogart,1 Anna Shapiro1 Abstract Given the lack of endocrine therapy for estrogen receptorenegative (ERL) breast tumors and growing elderly population, we hypothesized adjuvant radiation following breast-conservation surgery would benefit patients ‡ 70 years. We used the Surveillance, Epidemiology, and End Results database, with a large representative sample size, and found significant overall and cancer-specific survival benefit compared with surgery alone. Adjuvant radiotherapy should be discussed in elderly patients who are ERL. Purpose: Published prospective trials have questioned the role of post-lumpectomy radiotherapy in older women with early-stage, estrogen receptorepositive (ERþ) breast cancer. As the population with ER tumors may be at greater risk for relapse, particularly given that endocrine therapy is not effective, we hypothesize the addition of radiation would be of benefit in patients age 70. Methods and Materials: The Surveillance, Epidemiology, and End Results database was queried from 1998 to 2011 for patients age 70 years receiving breast-conserving surgery for T1, ER invasive ductal carcinoma. Patients were separated into 2 cohorts: those treated with and without adjuvant radiotherapy. Chi-square analysis, unpaired t test and Kaplan-Meier log-rank were used to compare patient and tumor characteristics as well as overall and cancer-specific survival between the cohorts. Results: Overall, 3685 patients received radiation and 1493 patients received lumpectomy alone. Patients treated with adjuvant radiation were younger (median age 76 vs. 78 years, P < .0001). Patients who received radiation had improved overall survival, with 5-year survival rates of 81.0% versus 61.7% without radiation (P < .0001). Cancerspecific survival was also improved with radiotherapy, with 5-year cancer-specific survival rates of 93.1% versus 85.0% (P < .0001). Conclusions: This analysis of the SEER database demonstrates that women ages 70 and older treated with lumpectomy and radiotherapy for ER, early-stage breast cancer have improved overall survival and breast cancerespecific survival compared with patients treated with lumpectomy alone. This information may help in the decision-making process for this patient population. Clinical Breast Cancer, Vol. -, No. -, 1-7 ª 2016 Elsevier Inc. All rights reserved. Keywords: Breast conservation, Elderly, ER-negative, Radiotherapy, SEER
Introduction Radiation therapy has been a mainstay of adjuvant therapy following breast-conserving surgical management of breast cancer, and the addition of radiation therapy has been shown to Presented at the 32nd Annual Miami Breast Cancer Conference, Miami, FL, February 26, 2015. 1
Department of Radiation Oncology, Upstate Cancer Center Department of Urology, SUNY Upstate Medical University, Syracuse, NY
2
Submitted: Nov 17, 2015; Revised: May 23, 2016; Accepted: Jun 17, 2016 Address for correspondence: Emily C. Daugherty, MD, Department of Radiation Oncology, Upstate Cancer Center, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210 E-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2016.06.017
significantly decrease the incidence of ipsilateral breast tumor recurrences and reduce breast cancer mortality in prospective trials.1,2 Although the role of radiotherapy is well accepted in younger women, the degree of clinical benefit of routine post-lumpectomy radiation in older women has been questioned in a number of prospective studies. Studies evaluating this question have generally limited enrollment to older patients with favorable, estrogen receptorepositive (ERþ) tumors, and the results can support consideration of omitting radiation after lumpectomy in select patients.3-9 However, findings from these studies evaluating ERþ patients cannot be extrapolated to those patients with estrogen receptorenegative (ER) tumors. Unfortunately, there are limited data regarding the role of post-lumpectomy radiotherapy in older patients with ER tumors. As the population with ER tumors may
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Adjuvant Radiation After Lumpectomy Improves Survival for Elderly ER-Negative Patients be at greater risk for relapse, particularly given the lack of efficacy of endocrine therapy, we hypothesize that the addition of radiation would have a differential benefit in patients older than 70.
Methods and Materials
Characteristics
Patients were identified from the Surveillance, Epidemiology, and End Results (SEER)-18 registries database. We selected only women age 70 or older treated with breast-conserving surgery for T1N0M0 ductal ER breast cancer from the years of 1998 to 2011. Breastconserving surgery was identified from SEER site-specific surgery codes and defined as partial mastectomy, not otherwise specified (NOS); less than total mastectomy, NOS; partial mastectomy with nipple resection; segmental mastectomy; lumpectomy or reexcision of biopsy site for residual disease. Patient demographics and tumor characteristics were collected, including age, race, year of diagnosis, primary site location, grade, pathologic T stage, radiation sequence, ER status, progesterone receptor (PR) status, and laterality. HER2/neu status was available only for patients treated after 2010 in this database and was not included in analysis. The T stage of all patients was divided into 4 categories: T1mic, T1a, T1b, and T1c. Patients were then divided into 2 groups: those undergoing adjuvant radiation therapy and those who had no radiation therapy. Unpaired t tests and c2 analysis were used to compare patient demographics and tumor characteristics between the cohorts. Kaplan-Meier log-rank tests were used to compare overall and cancer-specific survival between the 2 groups. To account for differences between groups, we used Cox regression models adjusting for age, race, grade, PR status, laterality, and T stage. Statistical analyses were conducted using GraphPad Prism (version 6 for Macintosh; GraphPad Software, La Jolla CA, www.graphpad.com) and Stata 14 (StataCorp, College Station, TX). Statistical significance was set at P < .05. There are no financial disclosures, conflicts of interest, and/or acknowledgements for any of the authors. There were no grants or other funding provided for this article.
Age, years
Results
2
-
Table 1 Patient Demographics and Baseline Tumor Characteristics
A total of 5178 patients were identified who met inclusion criteria. Overall, 3685 patients received radiation and 1493 patients did not receive radiation. Fourteen patients were excluded who had unknown race as well as 32 with unknown radiation status. Patient demographics and tumor characteristics are provided in Table 1. The median age of patients treated with radiation was 76 years (interquartile range [IQR] 72-79 years), whereas those not given radiation had a median age of 78 years (IQR 74-84 years) (P < .0001). Most patients in this analysis were white and there was no difference seen between groups with regard to race (P ¼ .089). There was no difference seen in tumor grade between the cohorts (P ¼ .91) and most tumors were poorly differentiated in both those treated with radiation and without radiation (57.8% and 56.3%, respectively). There was also no difference seen in PR status between the groups with the predominance of tumors being PR negative (PR) (93.1% and 92.4%, radiation and nonradiation cohorts, respectively). Median follow-up for patients was 56 and 40 months for radiation and nonradiation cohorts, respectively. Median overall survival was 139 months for those who received radiation, whereas those
Clinical Breast Cancer Month 2016
Mean
Radiation No Radiation (n [ 3685) (n [ 1493)
P <.0001a
76.1
78.3
Median
76
78
SD
4.5
5.2
70-74
1578 (42.8%)
447 (29.9%)
75-79
1205 (32.7%)
403 (27.0%)
80-84
665 (18.0%)
323 (21.6%)
85
237 (6.4%)
320 (21.4%)
Age Distribution, years
.0885b
Race White
3152 (85.5%)
1294 (86.7%)
Black
359 (9.7%)
149 (10.0%)
Other
174 (4.7%)
50 (3.4%) .9111b
Grade 1
234 (6.4%)
93 (6.3%)
2
1123 (30.5%)
462 (30.9%)
3
2129 (57.8%)
841 (56.3%)
69 (1.9%)
25 (1.7%)
4/undifferentiated
.7501b
PR status þ
PR
227 (6.2%)
95 (6.4%)
PR
3430 (93.1%)
1379 (92.4%) .2014b
Laterality Left
1892 (51.4%)
796 (53.3%)
Right
1792 (48.6%)
697 (46.7%) <.0001a
T-stage T1mic
179 (4.9%)
55 (3.7%)
T1a
394 (10.7%)
136 (9.1%)
T1b
1132 (30.8%)
376 (25.2%)
T1c
1980 (53.7%)
926 (62.0%)
Data are presented as number of patients, with percentage in parentheses, unless otherwise specified. Abbreviation: PR ¼ progesterone receptor. a Unpaired t test. b 2 c analysis.
patients not treated with radiation had a median overall survival of 88 months. Patients treated with radiation had an improved 5-year overall survival compared with those not given radiation: 81.0% versus 61.7%, respectively (P < .0001) (Table 2). In addition, patients receiving adjuvant radiation also had an improvement in 5year cancer-specific survival compared with the nonradiation cohort: 93.1% versus 85.0%, respectively (P < .0001). Median cancerspecific survival was not met for either group. Figure 1 displays the Kaplan-Meier curves for overall survival and cancer-specific survival. Patients treated with radiation experienced an improved overall and cancer-specific survival for T1a, T1b, and T1c tumors (Figures 2 and 3). Supplemental data including confidence intervals and number of individuals at risk for Figures 1-3 is available in Supplemental Tables 1-4. There was no statistically significant difference detected in T1mic tumors.
Emily C. Daugherty et al Table 2 Five-Year Survival Outcomes Radiation No Radiation 5-year overall survival Median, mo 5-year cancer-specific survival Median, mo
81.0%
61.7%
139
88
93.1%
85.0%
Not reached
Not reached
P <.0001 <.0001
Table 3 reports the results of our univariate analysis. Using a Cox regression model adjusted for age, race, grade, PR status, laterality, and T stage, addition of radiotherapy was found to be a significant predictor of both overall survival (P < .0001) as well as cancer-specific survival (P < .0001). In this same analysis, patient age and T stage were each found to be significant predictors of overall and cancerspecific survival (P < .0001). In addition, tumor grade was found to be significant predictor of cancer-specific survival (P ¼ .003). Complete results of multivariable analyses are found in Table 4.
Discussion The long-term results of CALGB 9343 suggest that tamoxifen alone, without adjuvant radiotherapy, may be an option for patients older than 70 with ERþ, early-stage breast cancer. The results of the current SEER analysis demonstrate that caution needs to be used in extrapolating that result to patients older than 70 with ER, earlystage breast cancer. In fact, the current analysis demonstrated that despite being age 70 or older, women with ER breast cancer who receive adjuvant radiation experience both a significant overall and cancer-specific survival benefit when compared with those in whom radiation was omitted. These findings are in contrast to CALGB 9343, which did not show that adjuvant radiotherapy was associated with a survival benefit in an elderly ERþ population,7,8,10 although it is worth noting that CALGB 9343 was not powered to detect a small overall survival benefit and there was a statistically significant improvement in local tumor control in the radiotherapy cohort. In comparison with CALGB 9343, 5-year overall survival rates in the radiation cohort from our analysis were found to be similar, 87% versus 81%, respectively.7 Given the more biologically aggressive biology of ER hormone receptor status and lack of maintenance endocrine therapy, such as tamoxifen, a slightly lower survival rate is to be expected.
Our analysis of the SEER data revealed a significant breast cancerespecific survival benefit to the addition of radiation following breast-conservation surgery. This is important given the potential impact of medical comorbidities on overall survival for women older than 70. The finding that a local therapy significantly improves cancer-specific survival emphasizes the importance of at least considering radiotherapy in this population.2 According to Social Security Administration data, a woman turning 65 in 2015 is expected to live, on average, to age 86.6 years.11 Given that most ER breast cancer recurrences occur within 5 years of diagnosis, even patients predicted to have limited life spans would stand to benefit from treatment. Numerous studies have shown that women of all ages with ER breast cancer experience higher rates of recurrence and higher breast cancerespecific mortality.6,12,13 It has been reported that up to 40% of women older than 80 at diagnosis die of their breast cancer. Moreover, among patients who are ER and PR, the elderly were more like to die from breast cancer than those of younger age groups.14,15 In addition, Jatoi et al,16 when evaluating breast cancer mortality rates in the United States from 1990 to 2003 based on age and hormone-receptor status, reported that the only subgroup without any significant decline in mortality rates was women 70 or older with ER status. To our knowledge, studies have not been published documenting increased toxicity of post-lumpectomy radiation in the elderly population, yet numerous studies have reported the underutilization of radiation in older patients with breast cancer.12,13,17-19 Similar research has found that omission of radiation specifically in patients age 70 and older who are ER is associated with an increase in breast cancerespecific mortality.12,20 One population-based analysis by Weiss et al14 found that elderly patients who are ER had both higher breast cancerespecific death and underutilization of radiotherapy. Their data suggested that in the older population, ER breast cancer should be a separate entity from ERþ breast cancer and likewise should be treated more aggressively. The 2 cohorts were similar for all patient characteristics, including patient race, tumor grade, PR status, and laterality, except for patient age. Patients in the radiation cohort were statistically almost 2 years younger than the nonradiation arm. One could postulate that perhaps the slightly younger radiation cohort may have had fewer comorbidities, which could have influenced decision making toward radiation based on their performance status.21 A SEER analysis by Schonberg et al22 evaluated
Figure 1 Outcomes Based on Survival Analyses for Radiation and Nonradiation Cohorts With Kaplan-Meier Plots of Overall Survival (A) and Cancer-Specific Survival (B)
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Adjuvant Radiation After Lumpectomy Improves Survival for Elderly ER-Negative Patients Figure 2 Kaplan-Meier Plot of Overall Survival Based on T-Stage Subtypes: (A) T1mic; (B) T1a; (C) T1b; (D) T1c
patients age 80 and older who were ERþ regarding the utilization of adjuvant radiation therapy after lumpectomy and found that treatment was not limited to women in good health with minimal medical comorbidities; in fact, their data suggested that women with significant high risk of 5-year mortality received radiation and, equally, up to 45% of women without morbidities affecting life expectancy did not receive radiation. Increased age was found to be predictive of radiation omission in these patients who were ERþ, but only in patients aged 90 and older. Further studies are needed to specifically evaluate such outcomes in the ER population. Although the elderly population can be heterogeneous, it is unlikely age is the primary contributing factor to the marked differences seen in overall survival in our analysis and could not account for differences in breast cancerespecific survival.23
The current study is strengthened by its large sample size, which encompasses multiple geographic areas and is representative of the US population. As any SEER analysis, data are limited in that it is retrospective and subject to inaccuracies in data entering. The SEER database lacks information on patient comorbidities and performance status and, as such, the study is subject to selection bias. The SEER database also lacks information that would contribute to this analysis and would potentially impact patient outcomes. For example, data regarding chemotherapy use was not available, HER2/neu status was not reported before 2010, and radiotherapy parameters such as dose and fractionation schedule also could not be elicited. It is theoretically possible that the survival benefits may be related to a proportion of patients who received chemotherapy as well for their receptor-negative disease.
Figure 3 Kaplan-Meier Plot of Cancer-Specific Survival Based on T-Stage Subtypes: (A) T1mic; (B) T1a; (C) T1b; (D) T1c
4
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Clinical Breast Cancer Month 2016
Emily C. Daugherty et al Table 3 Univariate Analysis of Survival Outcomes Overall Survival
Cancer-Specific Survival
Hazard Ratio
95% CI
P
Hazard Ratio
95% CI
P
1.111
1.099-1.123
<.0001
1.069
1.048-1.090
<.0001
Age Race
.101
White
.483
Reference
Reference
Black
1.114
0.938-1.321
1.190
0.876-1.617
Other
0.775
0.574-1.046
0.904
0.540-1.515
Grade
.037
.0002
1
Reference
2
1.199
0.960-1.499
Reference 2.097
3
1.323
1.068-1.638
2.890
1.657-5.041
4/undifferentiated
1.131
0.764-1.676
3.182
1.475-6.965
PR status PR
þ
PR
.856
.253
Reference 0.983
Reference 0.813-1.188
1.265
Laterality
0.844-1.894
.3883
Left
Reference
Right
0.957
.236 Reference
0.865-1.058
0.893
0.739-1.076
<.0001
T-stage T1mic
1.182-3.719
Reference
<.0001 Reference
T1a
1.155
0.806-1.654
1.476
0.638-3.412
T1b
1.246
0.900-1.726
1.633
0.755-3.532
T1c
1.895
1.381-2.599
3.583
1.694-7.576
Radiation
2.073
1.869-2.297
2.030
1.798-2.633
<.0001
One could postulate in such a population-based analysis that if a patient was deemed appropriate for radiotherapy, perhaps the patient would have a higher chance of being treated with adjuvant chemotherapy as well. Although guidelines state specifically that the decision to deliver adjuvant chemotherapy should not be agebased, administration of chemotherapy in the elderly is certainly selectively used and has higher known rates of treatment breaks, hospitalization, dose reductions, and higher risk for trastuzumabinduced cardiomyopathy.14,24
Conclusions This analysis of the SEER database demonstrates that women ages 70 and older treated with lumpectomy and radiotherapy for ER, early-stage breast cancer have improved overall survival and breast cancerespecific survival compared with patients treated with lumpectomy without radiotherapy. These survival differences remained when adjusting for patient and tumor factors. This is in contrast to published findings for similar age patients with ERþ disease. As more than 25% of elderly patients with ER tumors in the SEER database did not receive post-lumpectomy radiotherapy, this analysis should be considered in the decision-making process. A thorough discussion of the risk-to-benefit ratio in elderly oncology patients should occur with attention to individualized goals of treatment.
<.0001
Clinical Practice Points Adjuvant radiation following breast-conserving surgery has been
well established in the management of early-stage breast cancer, as it has been shown to decrease the incidence of ipsilateral breast tumor recurrences and also to reduce breast cancer mortality. Large prospective trials have shown for elderly patients with favorable, estrogen receptorepositive (ERþ) pathology, omission of radiation after lumpectomy can be considered. However, women with estrogen receptorenegative (ER) disease were typically not included in these trials, and given their higher risk for relapse as well as lack of effective endocrine therapy, we hypothesized that adjuvant radiation would benefit women 70 years or older with early-stage, ER tumors. Our analysis of the Surveillance, Epidemiology, and End Results (SEER) database, which included more than 5000 patients, demonstrated a significant 5-year overall- and cancer-specific survival benefit. This is contrary to known prospective data in similar populations with ERþ disease. Given that most ER breast cancer recurrences occur within 5 years of diagnosis, even patients predicted to otherwise have limited life spans may benefit from adjuvant radiotherapy. A thorough discussion of the risk-to-benefit ratio in applicable, elderly oncology patients should occur with attention to both individualized goals of treatment and results of this analysis.
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Adjuvant Radiation After Lumpectomy Improves Survival for Elderly ER-Negative Patients Table 4 Cox Proportional Hazards Model Overall Survival Age
Cancer-Specific Survival
Hazard Ratio
95% CI
P
Hazard Ratio
95% CI
P
1.101
1.089-1.113
<.0001
1.057
1.036-1.079
<.0001
Race
.195
White
Reference
Black
1.144
0.959-1.364
1.139
0.832-1.600
Other
0.905
0.665-1.232
1.027
0.601-1.754
Grade
.192 Reference
2
1.119
0.893-1.402
1.977
3
1.214
0.976-1.511
2.601
1.452-4.657
4/undifferentiated
1.205
0.808-1.798
3.337
1.517-7.341
PR
þ
PR
Reference
.538
Reference 0.954
Reference 0.786-1.158
1.159
0.766-1.754
.152
Left
Reference
Right
0.915
.137 Reference
0.825-1.015
0.832
0.686-1.009
<.0001
T-stage T1mic
1.089-3.591
.601
Laterality
Reference
<.0001 Reference
T1a
1.274
0.829-1.958
1.968
T1b
1.275
0.855-1.901
2.002
0.732-5.476
T1c
1.837
1.243-2.714
3.954
1.473-10.618
Radiation
1.757
1.577-1.958
2.030
1.665-2.475
<.0001
Disclosure The authors have stated they have no conflicts of interest.
Supplemental Data Supplemental tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.clbc.2016.06.017.
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-
.003
1
PR status
6
.698
Reference
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0.681-5.686
<.0001
8. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004; 351:971-7. 9. Palta M, Palta P, Bhavsar NA, Horton JK, Blitzblau RC. The use of adjuvant radiotherapy in elderly patients with early-stage breast cancer: changes in practice patterns after publication of Cancer and Leukemia Group B 9343. Cancer 2015; 121:188-93. 10. Smith BD, Gross CP, Smith GL, Galusha DH, Bekelman JE, Haffty BG. Effectiveness of radiation therapy for older women with early breast cancer. J Natl Cancer Inst 2006; 98:681-90. 11. Calculators: life expectancy. Available at: ssa.gov/planners/lifeexpectancy.htm. Accessed: March 8, 2015. 12. Shen X, Anne PR, Keith SW, et al. Radiation therapy use and outcomes among older women with ER-positive and ER-negative stage I breast cancer. Am J Clin Oncol 2014; 37:241-7. 13. Pierga JY, Girre V, Laurence V, et al. Characteristics and outcome of 1755 operable breast cancers in women over 70 years of age. Breast 2004; 13:369-75. 14. Weiss A, Noorbakhsh A, Tokin C, Chang D, Blair SL. Hormone receptor-negative breast cancer: undertreatment of patients over 80. Ann Surg Oncol 2013; 20: 3274-8. 15. Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol 2012; 13:e148-60. 16. Jatoi I, Chen BE, Anderson WF, Rosenberg PS. Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J Clin Oncol 2007; 25:1683-90. 17. Albert JM, Liu DD, Shen Y, et al. Nomogram to predict the benefit of radiation for older patients with breast cancer treated with conservative surgery. J Clin Oncol 2012; 30:2837-43. 18. Tesarova P. Breast cancer in the elderly—should it be treated differently? Rep Pract Oncol Radiother 2012; 18:26-33. 19. Le Saux O, Ripamonti B, Bruyas A, et al. Optimal management of breast cancer in the elderly patient: current perspectives. Clin Interv Aging 2015; 10:157-74. 20. Wojcieszynski A, Shen X, Mishra MV, Anne PR, Showalter TN. Radiation and survival in women over 70 with T1 N0 M0 ER-negative breast cancer from 1990 to 2007: a population-based analysis. J Clin Oncol 2011; 29:a1037.
Emily C. Daugherty et al 21. Patnaik JL, Byers T, Diguiseppi C, Denberg TD, Dabelea D. The influence of comorbidities on overall survival among older women diagnosed with breast cancer. J Natl Cancer Inst 2011; 103:1101-11. 22. Schonberg MA, Marcantonio ER, Ngo L, Silliman RA, McCarthy EP. Does life expectancy affect treatment of women aged 80 and older with early stage breast cancers? J Geriatr Oncol 2012; 3:8-16.
23. Gennari R, Curigliano G, Rotmensz N, et al. Breast carcinoma in elderly women: features of disease presentation, choice of local and systemic treatments compared with younger postmenopasual patients. Cancer 2004; 101:1302-10. 24. Dimitrakopoulos FI, Kottorou A, Antonacopoulou AG, Makatsoris T, Kalofonos HP. Early-stage breast cancer in the elderly: confronting an old clinical problem. J Breast Cancer 2015; 18:207-17.
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Adjuvant Radiation After Lumpectomy Improves Survival for Elderly ER-Negative Patients Supplemental Table 1 Supplemental Data Applicable to Figure 1 No. of Individuals at Risk (Re: Figure 1) Months 0 12 24 36 48 60 72 84 96 108 120 132 144 156
Radiation
No Radiation
3660 3320 2915 2491 2086 1740 1400 1107 830 604 439 272 144 58
1473 1269 1049 827 657 521 399 305 226 169 109 58 30 14
Supplemental Table 2 Supplemental Data Applicable to Figure 1: 5-Year Overall and Cancer-Specific Survival 5-Year Overall and Cancer-Specific Survival for All Patients (95% Confidence Interval) (Re: Figure 1) Overall Survival
Radiation No Radiation
7.e1
-
5-Year Overall Survival (%)
95% CI
81.0 61.7
79.5%-82.4% 58.5%-64.6%
Clinical Breast Cancer Month 2016
Cancer-Specific Survival
P
5-Year Cancer-Specific Survival (%)
95% CI
P
<.0001 <.0001
93.1 85.0
92.1%-94.1% 82.7%-87.3%
<.0001 <.0001
Emily C. Daugherty et al Supplemental Table 3 Supplemental Data Applicable to Figures 2 and 3: No. of Individuals at Risk No. of individuals at Risk (Re: Figures 2 and 3) T1mic
T1a
T1b
T1c
Months
RT
No RT
RT
No RT
RT
No RT
RT
No RT
0 12 24 36 48 60 72 84 96 108 120 132 144 156
178 159 129 111 86 66 51 38 26 20 18 13 6 5
55 53 46 39 32 26 20 15 11 8 5 3 e e
391 352 314 261 222 174 148 119 91 62 48 31 14 6
135 114 100 81 63 47 37 30 25 19 13 8 5 4
1123 1031 908 784 669 564 469 374 281 207 149 96 45 20
372 320 270 222 187 157 123 97 69 52 34 19 14 7
1968 1778 1564 1335 1109 936 732 576 434 316 227 132 68 29
911 786 634 485 376 292 220 165 123 92 59 30 13 5
Abbreviation: RT ¼ radiation therapy.
Supplemental Table 4 Supplemental Data Applicable to Figures 2 and 3: 5-Year Overall and Cancer-Specific Survival 5-Year Overall and Cancer-Specific Survival (95% Confidence Interval) (Re: Figures 2 and 3) Overall Survival 5-Year Overall Survival (%)
95% CI
T1mic
Cancer-Specific Survival
P
5-Year Cancer-Specific Survival (%)
95% CI
.1013
Radiation
86.6
80.5%-92.7%
No Radiation
78.9
66.4%-91.2%
Radiation
87.3
83.3%-91.2%
No Radiation
64.5
54.8%-74.1%
95.9 100
92.4%-99.5% e
<.0001
T1a
.0025 96.8
94.6%-99.0%
90.6
84.6%-96.6%
95.0
93.5%-96.6%
91.6
88.2%-95.1%
<.0001
T1b Radiation
82.9
80.3%-85.5%
No Radiation
72.9
67.4%-77.8%
.0020
<.0001
T1c
P .4577
<.0001
Radiation
78.3
76.2%-80.4%
91.0
89.5%-92.5%
No Radiation
55.8
52.0%-59.6%
80.3
77.1%-83.6%
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Adjuvant Radiation Improves Survival in Older Women Following Breast-Conserving Surgery for Estrogen ReceptoreNegative Breast Cancer Emily C. Daugherty,1 Michael R. Daugherty,2 Jeffrey A. Bogart,1 Anna Shapiro1 Abstract Given the lack of endocrine therapy for estrogen receptorenegative (ERL) breast tumors and growing elderly population, we hypothesized adjuvant radiation following breast-conservation surgery would benefit patients ‡ 70 years. We used the Surveillance, Epidemiology, and End Results database, with a large representative sample size, and found significant overall and cancer-specific survival benefit compared with surgery alone. Adjuvant radiotherapy should be discussed in elderly patients who are ERL. Purpose: Published prospective trials have questioned the role of post-lumpectomy radiotherapy in older women with early-stage, estrogen receptorepositive (ERþ) breast cancer. As the population with ER tumors may be at greater risk for relapse, particularly given that endocrine therapy is not effective, we hypothesize the addition of radiation would be of benefit in patients age 70. Methods and Materials: The Surveillance, Epidemiology, and End Results database was queried from 1998 to 2011 for patients age 70 years receiving breast-conserving surgery for T1, ER invasive ductal carcinoma. Patients were separated into 2 cohorts: those treated with and without adjuvant radiotherapy. Chi-square analysis, unpaired t test and Kaplan-Meier log-rank were used to compare patient and tumor characteristics as well as overall and cancer-specific survival between the cohorts. Results: Overall, 3685 patients received radiation and 1493 patients received lumpectomy alone. Patients treated with adjuvant radiation were younger (median age 76 vs. 78 years, P < .0001). Patients who received radiation had improved overall survival, with 5-year survival rates of 81.0% versus 61.7% without radiation (P < .0001). Cancerspecific survival was also improved with radiotherapy, with 5-year cancer-specific survival rates of 93.1% versus 85.0% (P < .0001). Conclusions: This analysis of the SEER database demonstrates that women ages 70 and older treated with lumpectomy and radiotherapy for ER, early-stage breast cancer have improved overall survival and breast cancerespecific survival compared with patients treated with lumpectomy alone. This information may help in the decision-making process for this patient population. Clinical Breast Cancer, Vol. -, No. -, 1-7 ª 2016 Elsevier Inc. All rights reserved. Keywords: Breast conservation, Elderly, ER-negative, Radiotherapy, SEER
Introduction Radiation therapy has been a mainstay of adjuvant therapy following breast-conserving surgical management of breast cancer, and the addition of radiation therapy has been shown to Presented at the 32nd Annual Miami Breast Cancer Conference, Miami, FL, February 26, 2015. 1
Department of Radiation Oncology, Upstate Cancer Center Department of Urology, SUNY Upstate Medical University, Syracuse, NY
2
Submitted: Nov 17, 2015; Revised: May 23, 2016; Accepted: Jun 17, 2016 Address for correspondence: Emily C. Daugherty, MD, Department of Radiation Oncology, Upstate Cancer Center, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210 E-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2016.06.017
significantly decrease the incidence of ipsilateral breast tumor recurrences and reduce breast cancer mortality in prospective trials.1,2 Although the role of radiotherapy is well accepted in younger women, the degree of clinical benefit of routine post-lumpectomy radiation in older women has been questioned in a number of prospective studies. Studies evaluating this question have generally limited enrollment to older patients with favorable, estrogen receptorepositive (ERþ) tumors, and the results can support consideration of omitting radiation after lumpectomy in select patients.3-9 However, findings from these studies evaluating ERþ patients cannot be extrapolated to those patients with estrogen receptorenegative (ER) tumors. Unfortunately, there are limited data regarding the role of post-lumpectomy radiotherapy in older patients with ER tumors. As the population with ER tumors may
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Adjuvant Radiation After Lumpectomy Improves Survival for Elderly ER-Negative Patients be at greater risk for relapse, particularly given the lack of efficacy of endocrine therapy, we hypothesize that the addition of radiation would have a differential benefit in patients older than 70.
Methods and Materials
Characteristics
Patients were identified from the Surveillance, Epidemiology, and End Results (SEER)-18 registries database. We selected only women age 70 or older treated with breast-conserving surgery for T1N0M0 ductal ER breast cancer from the years of 1998 to 2011. Breastconserving surgery was identified from SEER site-specific surgery codes and defined as partial mastectomy, not otherwise specified (NOS); less than total mastectomy, NOS; partial mastectomy with nipple resection; segmental mastectomy; lumpectomy or reexcision of biopsy site for residual disease. Patient demographics and tumor characteristics were collected, including age, race, year of diagnosis, primary site location, grade, pathologic T stage, radiation sequence, ER status, progesterone receptor (PR) status, and laterality. HER2/neu status was available only for patients treated after 2010 in this database and was not included in analysis. The T stage of all patients was divided into 4 categories: T1mic, T1a, T1b, and T1c. Patients were then divided into 2 groups: those undergoing adjuvant radiation therapy and those who had no radiation therapy. Unpaired t tests and c2 analysis were used to compare patient demographics and tumor characteristics between the cohorts. Kaplan-Meier log-rank tests were used to compare overall and cancer-specific survival between the 2 groups. To account for differences between groups, we used Cox regression models adjusting for age, race, grade, PR status, laterality, and T stage. Statistical analyses were conducted using GraphPad Prism (version 6 for Macintosh; GraphPad Software, La Jolla CA, www.graphpad.com) and Stata 14 (StataCorp, College Station, TX). Statistical significance was set at P < .05. There are no financial disclosures, conflicts of interest, and/or acknowledgements for any of the authors. There were no grants or other funding provided for this article.
Age, years
Results
2
-
Table 1 Patient Demographics and Baseline Tumor Characteristics
A total of 5178 patients were identified who met inclusion criteria. Overall, 3685 patients received radiation and 1493 patients did not receive radiation. Fourteen patients were excluded who had unknown race as well as 32 with unknown radiation status. Patient demographics and tumor characteristics are provided in Table 1. The median age of patients treated with radiation was 76 years (interquartile range [IQR] 72-79 years), whereas those not given radiation had a median age of 78 years (IQR 74-84 years) (P < .0001). Most patients in this analysis were white and there was no difference seen between groups with regard to race (P ¼ .089). There was no difference seen in tumor grade between the cohorts (P ¼ .91) and most tumors were poorly differentiated in both those treated with radiation and without radiation (57.8% and 56.3%, respectively). There was also no difference seen in PR status between the groups with the predominance of tumors being PR negative (PR) (93.1% and 92.4%, radiation and nonradiation cohorts, respectively). Median follow-up for patients was 56 and 40 months for radiation and nonradiation cohorts, respectively. Median overall survival was 139 months for those who received radiation, whereas those
Clinical Breast Cancer Month 2016
Mean
Radiation No Radiation (n [ 3685) (n [ 1493)
P <.0001a
76.1
78.3
Median
76
78
SD
4.5
5.2
70-74
1578 (42.8%)
447 (29.9%)
75-79
1205 (32.7%)
403 (27.0%)
80-84
665 (18.0%)
323 (21.6%)
85
237 (6.4%)
320 (21.4%)
Age Distribution, years
.0885b
Race White
3152 (85.5%)
1294 (86.7%)
Black
359 (9.7%)
149 (10.0%)
Other
174 (4.7%)
50 (3.4%) .9111b
Grade 1
234 (6.4%)
93 (6.3%)
2
1123 (30.5%)
462 (30.9%)
3
2129 (57.8%)
841 (56.3%)
69 (1.9%)
25 (1.7%)
4/undifferentiated
.7501b
PR status þ
PR
227 (6.2%)
95 (6.4%)
PR
3430 (93.1%)
1379 (92.4%) .2014b
Laterality Left
1892 (51.4%)
796 (53.3%)
Right
1792 (48.6%)
697 (46.7%) <.0001a
T-stage T1mic
179 (4.9%)
55 (3.7%)
T1a
394 (10.7%)
136 (9.1%)
T1b
1132 (30.8%)
376 (25.2%)
T1c
1980 (53.7%)
926 (62.0%)
Data are presented as number of patients, with percentage in parentheses, unless otherwise specified. Abbreviation: PR ¼ progesterone receptor. a Unpaired t test. b 2 c analysis.
patients not treated with radiation had a median overall survival of 88 months. Patients treated with radiation had an improved 5-year overall survival compared with those not given radiation: 81.0% versus 61.7%, respectively (P < .0001) (Table 2). In addition, patients receiving adjuvant radiation also had an improvement in 5year cancer-specific survival compared with the nonradiation cohort: 93.1% versus 85.0%, respectively (P < .0001). Median cancerspecific survival was not met for either group. Figure 1 displays the Kaplan-Meier curves for overall survival and cancer-specific survival. Patients treated with radiation experienced an improved overall and cancer-specific survival for T1a, T1b, and T1c tumors (Figures 2 and 3). Supplemental data including confidence intervals and number of individuals at risk for Figures 1-3 is available in Supplemental Tables 1-4. There was no statistically significant difference detected in T1mic tumors.
Emily C. Daugherty et al Table 2 Five-Year Survival Outcomes Radiation No Radiation 5-year overall survival Median, mo 5-year cancer-specific survival Median, mo
81.0%
61.7%
139
88
93.1%
85.0%
Not reached
Not reached
P <.0001 <.0001
Table 3 reports the results of our univariate analysis. Using a Cox regression model adjusted for age, race, grade, PR status, laterality, and T stage, addition of radiotherapy was found to be a significant predictor of both overall survival (P < .0001) as well as cancer-specific survival (P < .0001). In this same analysis, patient age and T stage were each found to be significant predictors of overall and cancerspecific survival (P < .0001). In addition, tumor grade was found to be significant predictor of cancer-specific survival (P ¼ .003). Complete results of multivariable analyses are found in Table 4.
Discussion The long-term results of CALGB 9343 suggest that tamoxifen alone, without adjuvant radiotherapy, may be an option for patients older than 70 with ERþ, early-stage breast cancer. The results of the current SEER analysis demonstrate that caution needs to be used in extrapolating that result to patients older than 70 with ER, earlystage breast cancer. In fact, the current analysis demonstrated that despite being age 70 or older, women with ER breast cancer who receive adjuvant radiation experience both a significant overall and cancer-specific survival benefit when compared with those in whom radiation was omitted. These findings are in contrast to CALGB 9343, which did not show that adjuvant radiotherapy was associated with a survival benefit in an elderly ERþ population,7,8,10 although it is worth noting that CALGB 9343 was not powered to detect a small overall survival benefit and there was a statistically significant improvement in local tumor control in the radiotherapy cohort. In comparison with CALGB 9343, 5-year overall survival rates in the radiation cohort from our analysis were found to be similar, 87% versus 81%, respectively.7 Given the more biologically aggressive biology of ER hormone receptor status and lack of maintenance endocrine therapy, such as tamoxifen, a slightly lower survival rate is to be expected.
Our analysis of the SEER data revealed a significant breast cancerespecific survival benefit to the addition of radiation following breast-conservation surgery. This is important given the potential impact of medical comorbidities on overall survival for women older than 70. The finding that a local therapy significantly improves cancer-specific survival emphasizes the importance of at least considering radiotherapy in this population.2 According to Social Security Administration data, a woman turning 65 in 2015 is expected to live, on average, to age 86.6 years.11 Given that most ER breast cancer recurrences occur within 5 years of diagnosis, even patients predicted to have limited life spans would stand to benefit from treatment. Numerous studies have shown that women of all ages with ER breast cancer experience higher rates of recurrence and higher breast cancerespecific mortality.6,12,13 It has been reported that up to 40% of women older than 80 at diagnosis die of their breast cancer. Moreover, among patients who are ER and PR, the elderly were more like to die from breast cancer than those of younger age groups.14,15 In addition, Jatoi et al,16 when evaluating breast cancer mortality rates in the United States from 1990 to 2003 based on age and hormone-receptor status, reported that the only subgroup without any significant decline in mortality rates was women 70 or older with ER status. To our knowledge, studies have not been published documenting increased toxicity of post-lumpectomy radiation in the elderly population, yet numerous studies have reported the underutilization of radiation in older patients with breast cancer.12,13,17-19 Similar research has found that omission of radiation specifically in patients age 70 and older who are ER is associated with an increase in breast cancerespecific mortality.12,20 One population-based analysis by Weiss et al14 found that elderly patients who are ER had both higher breast cancerespecific death and underutilization of radiotherapy. Their data suggested that in the older population, ER breast cancer should be a separate entity from ERþ breast cancer and likewise should be treated more aggressively. The 2 cohorts were similar for all patient characteristics, including patient race, tumor grade, PR status, and laterality, except for patient age. Patients in the radiation cohort were statistically almost 2 years younger than the nonradiation arm. One could postulate that perhaps the slightly younger radiation cohort may have had fewer comorbidities, which could have influenced decision making toward radiation based on their performance status.21 A SEER analysis by Schonberg et al22 evaluated
Figure 1 Outcomes Based on Survival Analyses for Radiation and Nonradiation Cohorts With Kaplan-Meier Plots of Overall Survival (A) and Cancer-Specific Survival (B)
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Adjuvant Radiation After Lumpectomy Improves Survival for Elderly ER-Negative Patients Figure 2 Kaplan-Meier Plot of Overall Survival Based on T-Stage Subtypes: (A) T1mic; (B) T1a; (C) T1b; (D) T1c
patients age 80 and older who were ERþ regarding the utilization of adjuvant radiation therapy after lumpectomy and found that treatment was not limited to women in good health with minimal medical comorbidities; in fact, their data suggested that women with significant high risk of 5-year mortality received radiation and, equally, up to 45% of women without morbidities affecting life expectancy did not receive radiation. Increased age was found to be predictive of radiation omission in these patients who were ERþ, but only in patients aged 90 and older. Further studies are needed to specifically evaluate such outcomes in the ER population. Although the elderly population can be heterogeneous, it is unlikely age is the primary contributing factor to the marked differences seen in overall survival in our analysis and could not account for differences in breast cancerespecific survival.23
The current study is strengthened by its large sample size, which encompasses multiple geographic areas and is representative of the US population. As any SEER analysis, data are limited in that it is retrospective and subject to inaccuracies in data entering. The SEER database lacks information on patient comorbidities and performance status and, as such, the study is subject to selection bias. The SEER database also lacks information that would contribute to this analysis and would potentially impact patient outcomes. For example, data regarding chemotherapy use was not available, HER2/neu status was not reported before 2010, and radiotherapy parameters such as dose and fractionation schedule also could not be elicited. It is theoretically possible that the survival benefits may be related to a proportion of patients who received chemotherapy as well for their receptor-negative disease.
Figure 3 Kaplan-Meier Plot of Cancer-Specific Survival Based on T-Stage Subtypes: (A) T1mic; (B) T1a; (C) T1b; (D) T1c
4
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Clinical Breast Cancer Month 2016
Emily C. Daugherty et al Table 3 Univariate Analysis of Survival Outcomes Overall Survival
Cancer-Specific Survival
Hazard Ratio
95% CI
P
Hazard Ratio
95% CI
P
1.111
1.099-1.123
<.0001
1.069
1.048-1.090
<.0001
Age Race
.101
White
.483
Reference
Reference
Black
1.114
0.938-1.321
1.190
0.876-1.617
Other
0.775
0.574-1.046
0.904
0.540-1.515
Grade
.037
.0002
1
Reference
2
1.199
0.960-1.499
Reference 2.097
3
1.323
1.068-1.638
2.890
1.657-5.041
4/undifferentiated
1.131
0.764-1.676
3.182
1.475-6.965
PR status PR
þ
PR
.856
.253
Reference 0.983
Reference 0.813-1.188
1.265
Laterality
0.844-1.894
.3883
Left
Reference
Right
0.957
.236 Reference
0.865-1.058
0.893
0.739-1.076
<.0001
T-stage T1mic
1.182-3.719
Reference
<.0001 Reference
T1a
1.155
0.806-1.654
1.476
0.638-3.412
T1b
1.246
0.900-1.726
1.633
0.755-3.532
T1c
1.895
1.381-2.599
3.583
1.694-7.576
Radiation
2.073
1.869-2.297
2.030
1.798-2.633
<.0001
One could postulate in such a population-based analysis that if a patient was deemed appropriate for radiotherapy, perhaps the patient would have a higher chance of being treated with adjuvant chemotherapy as well. Although guidelines state specifically that the decision to deliver adjuvant chemotherapy should not be agebased, administration of chemotherapy in the elderly is certainly selectively used and has higher known rates of treatment breaks, hospitalization, dose reductions, and higher risk for trastuzumabinduced cardiomyopathy.14,24
Conclusions This analysis of the SEER database demonstrates that women ages 70 and older treated with lumpectomy and radiotherapy for ER, early-stage breast cancer have improved overall survival and breast cancerespecific survival compared with patients treated with lumpectomy without radiotherapy. These survival differences remained when adjusting for patient and tumor factors. This is in contrast to published findings for similar age patients with ERþ disease. As more than 25% of elderly patients with ER tumors in the SEER database did not receive post-lumpectomy radiotherapy, this analysis should be considered in the decision-making process. A thorough discussion of the risk-to-benefit ratio in elderly oncology patients should occur with attention to individualized goals of treatment.
<.0001
Clinical Practice Points Adjuvant radiation following breast-conserving surgery has been
well established in the management of early-stage breast cancer, as it has been shown to decrease the incidence of ipsilateral breast tumor recurrences and also to reduce breast cancer mortality. Large prospective trials have shown for elderly patients with favorable, estrogen receptorepositive (ERþ) pathology, omission of radiation after lumpectomy can be considered. However, women with estrogen receptorenegative (ER) disease were typically not included in these trials, and given their higher risk for relapse as well as lack of effective endocrine therapy, we hypothesized that adjuvant radiation would benefit women 70 years or older with early-stage, ER tumors. Our analysis of the Surveillance, Epidemiology, and End Results (SEER) database, which included more than 5000 patients, demonstrated a significant 5-year overall- and cancer-specific survival benefit. This is contrary to known prospective data in similar populations with ERþ disease. Given that most ER breast cancer recurrences occur within 5 years of diagnosis, even patients predicted to otherwise have limited life spans may benefit from adjuvant radiotherapy. A thorough discussion of the risk-to-benefit ratio in applicable, elderly oncology patients should occur with attention to both individualized goals of treatment and results of this analysis.
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Adjuvant Radiation After Lumpectomy Improves Survival for Elderly ER-Negative Patients Table 4 Cox Proportional Hazards Model Overall Survival Age
Cancer-Specific Survival
Hazard Ratio
95% CI
P
Hazard Ratio
95% CI
P
1.101
1.089-1.113
<.0001
1.057
1.036-1.079
<.0001
Race
.195
White
Reference
Black
1.144
0.959-1.364
1.139
0.832-1.600
Other
0.905
0.665-1.232
1.027
0.601-1.754
Grade
.192 Reference
2
1.119
0.893-1.402
1.977
3
1.214
0.976-1.511
2.601
1.452-4.657
4/undifferentiated
1.205
0.808-1.798
3.337
1.517-7.341
PR
þ
PR
Reference
.538
Reference 0.954
Reference 0.786-1.158
1.159
0.766-1.754
.152
Left
Reference
Right
0.915
.137 Reference
0.825-1.015
0.832
0.686-1.009
<.0001
T-stage T1mic
1.089-3.591
.601
Laterality
Reference
<.0001 Reference
T1a
1.274
0.829-1.958
1.968
T1b
1.275
0.855-1.901
2.002
0.732-5.476
T1c
1.837
1.243-2.714
3.954
1.473-10.618
Radiation
1.757
1.577-1.958
2.030
1.665-2.475
<.0001
Disclosure The authors have stated they have no conflicts of interest.
Supplemental Data Supplemental tables accompanying this article can be found in the online version at http://dx.doi.org/10.1016/j.clbc.2016.06.017.
References 1. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347: 1233-41. 2. Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011; 378:1707-16. 3. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341:2061-7. 4. Lewis JH, Kilgore ML, Goldman DP, et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 2003; 21:1383-9. 5. Townsley CA, Selby R, Siu LL. Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. J Clin Oncol 2005; 23: 3112-24. 6. Nagar H, Yan W, Christos P, Chao KS, Nori D, Ravi A. Older Patients with early-stage breast cancer: adjuvant radiation therapy and predictive factors for cancer-related death [e-pub ahead of print]. Am J Clin Oncol 2014. http://dx.doi. org/10.1097/COC.0000000000000144. 7. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013; 31: 2382-7.
-
.003
1
PR status
6
.698
Reference
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0.681-5.686
<.0001
8. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004; 351:971-7. 9. Palta M, Palta P, Bhavsar NA, Horton JK, Blitzblau RC. The use of adjuvant radiotherapy in elderly patients with early-stage breast cancer: changes in practice patterns after publication of Cancer and Leukemia Group B 9343. Cancer 2015; 121:188-93. 10. Smith BD, Gross CP, Smith GL, Galusha DH, Bekelman JE, Haffty BG. Effectiveness of radiation therapy for older women with early breast cancer. J Natl Cancer Inst 2006; 98:681-90. 11. Calculators: life expectancy. Available at: ssa.gov/planners/lifeexpectancy.htm. Accessed: March 8, 2015. 12. Shen X, Anne PR, Keith SW, et al. Radiation therapy use and outcomes among older women with ER-positive and ER-negative stage I breast cancer. Am J Clin Oncol 2014; 37:241-7. 13. Pierga JY, Girre V, Laurence V, et al. Characteristics and outcome of 1755 operable breast cancers in women over 70 years of age. Breast 2004; 13:369-75. 14. Weiss A, Noorbakhsh A, Tokin C, Chang D, Blair SL. Hormone receptor-negative breast cancer: undertreatment of patients over 80. Ann Surg Oncol 2013; 20: 3274-8. 15. Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol 2012; 13:e148-60. 16. Jatoi I, Chen BE, Anderson WF, Rosenberg PS. Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J Clin Oncol 2007; 25:1683-90. 17. Albert JM, Liu DD, Shen Y, et al. Nomogram to predict the benefit of radiation for older patients with breast cancer treated with conservative surgery. J Clin Oncol 2012; 30:2837-43. 18. Tesarova P. Breast cancer in the elderly—should it be treated differently? Rep Pract Oncol Radiother 2012; 18:26-33. 19. Le Saux O, Ripamonti B, Bruyas A, et al. Optimal management of breast cancer in the elderly patient: current perspectives. Clin Interv Aging 2015; 10:157-74. 20. Wojcieszynski A, Shen X, Mishra MV, Anne PR, Showalter TN. Radiation and survival in women over 70 with T1 N0 M0 ER-negative breast cancer from 1990 to 2007: a population-based analysis. J Clin Oncol 2011; 29:a1037.
Emily C. Daugherty et al 21. Patnaik JL, Byers T, Diguiseppi C, Denberg TD, Dabelea D. The influence of comorbidities on overall survival among older women diagnosed with breast cancer. J Natl Cancer Inst 2011; 103:1101-11. 22. Schonberg MA, Marcantonio ER, Ngo L, Silliman RA, McCarthy EP. Does life expectancy affect treatment of women aged 80 and older with early stage breast cancers? J Geriatr Oncol 2012; 3:8-16.
23. Gennari R, Curigliano G, Rotmensz N, et al. Breast carcinoma in elderly women: features of disease presentation, choice of local and systemic treatments compared with younger postmenopasual patients. Cancer 2004; 101:1302-10. 24. Dimitrakopoulos FI, Kottorou A, Antonacopoulou AG, Makatsoris T, Kalofonos HP. Early-stage breast cancer in the elderly: confronting an old clinical problem. J Breast Cancer 2015; 18:207-17.
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Adjuvant Radiation After Lumpectomy Improves Survival for Elderly ER-Negative Patients Supplemental Table 1 Supplemental Data Applicable to Figure 1 No. of Individuals at Risk (Re: Figure 1) Months 0 12 24 36 48 60 72 84 96 108 120 132 144 156
Radiation
No Radiation
3660 3320 2915 2491 2086 1740 1400 1107 830 604 439 272 144 58
1473 1269 1049 827 657 521 399 305 226 169 109 58 30 14
Supplemental Table 2 Supplemental Data Applicable to Figure 1: 5-Year Overall and Cancer-Specific Survival 5-Year Overall and Cancer-Specific Survival for All Patients (95% Confidence Interval) (Re: Figure 1) Overall Survival
Radiation No Radiation
7.e1
-
5-Year Overall Survival (%)
95% CI
81.0 61.7
79.5%-82.4% 58.5%-64.6%
Clinical Breast Cancer Month 2016
Cancer-Specific Survival
P
5-Year Cancer-Specific Survival (%)
95% CI
P
<.0001 <.0001
93.1 85.0
92.1%-94.1% 82.7%-87.3%
<.0001 <.0001
Emily C. Daugherty et al Supplemental Table 3 Supplemental Data Applicable to Figures 2 and 3: No. of Individuals at Risk No. of individuals at Risk (Re: Figures 2 and 3) T1mic
T1a
T1b
T1c
Months
RT
No RT
RT
No RT
RT
No RT
RT
No RT
0 12 24 36 48 60 72 84 96 108 120 132 144 156
178 159 129 111 86 66 51 38 26 20 18 13 6 5
55 53 46 39 32 26 20 15 11 8 5 3 e e
391 352 314 261 222 174 148 119 91 62 48 31 14 6
135 114 100 81 63 47 37 30 25 19 13 8 5 4
1123 1031 908 784 669 564 469 374 281 207 149 96 45 20
372 320 270 222 187 157 123 97 69 52 34 19 14 7
1968 1778 1564 1335 1109 936 732 576 434 316 227 132 68 29
911 786 634 485 376 292 220 165 123 92 59 30 13 5
Abbreviation: RT ¼ radiation therapy.
Supplemental Table 4 Supplemental Data Applicable to Figures 2 and 3: 5-Year Overall and Cancer-Specific Survival 5-Year Overall and Cancer-Specific Survival (95% Confidence Interval) (Re: Figures 2 and 3) Overall Survival 5-Year Overall Survival (%)
95% CI
T1mic
Cancer-Specific Survival
P
5-Year Cancer-Specific Survival (%)
95% CI
.1013
Radiation
86.6
80.5%-92.7%
No Radiation
78.9
66.4%-91.2%
Radiation
87.3
83.3%-91.2%
No Radiation
64.5
54.8%-74.1%
95.9 100
92.4%-99.5% e
<.0001
T1a
.0025 96.8
94.6%-99.0%
90.6
84.6%-96.6%
95.0
93.5%-96.6%
91.6
88.2%-95.1%
<.0001
T1b Radiation
82.9
80.3%-85.5%
No Radiation
72.9
67.4%-77.8%
.0020
<.0001
T1c
P .4577
<.0001
Radiation
78.3
76.2%-80.4%
91.0
89.5%-92.5%
No Radiation
55.8
52.0%-59.6%
80.3
77.1%-83.6%
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