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Open Access

Peer-reviewed

Research Article

The effect of adjuvant radiotherapy after breast-conserving surgery in elderly women with T1-2N0 estrogen receptor-negative breast cancer

  • Can Chen ,

    Contributed equally to this work with: Can Chen, Runlu Wang

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Software

    Affiliation Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China

    ⨯
  • Runlu Wang ,

    Contributed equally to this work with: Can Chen, Runlu Wang

    Roles Data curation, Formal analysis

    Affiliation Respiratory Division, The Second Hospital of Hebei Medical University, Shijiazhuang, China

    ⨯
  • Bing Wang,

    Roles Data curation, Formal analysis

    Affiliation Department of Rheumatology and Immunology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China

    ⨯
  • Yue Wu,

    Roles Formal analysis, Writing – original draft

    Affiliation Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China

    ⨯
  • Jingting Jiang

    Roles Writing – review & editing

    jiangjingting@suda.edu.cn

    Affiliation Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China

    ⨯

Abstract

Purpose

To evaluate whether adjuvant radiotherapy (RT) following breast-conserving surgery (BCS) results in better survival among women ≥ 70 years with T1-2N0 estrogen receptor (ER)-negative breast cancer.

Methods

In this retrospective cohort study, we included patients who met the inclusion criteria between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) program. Univariate and Multivariate Cox proportional analysis were used to identify the risk factors for overall survival (OS) and breast cancer-specific survival (BCSS). Kaplan-Meier survival analysis was used to compare the prognosis of patients with or without adjuvant RT. Propensity score matching (PSM) was applied to perform a 1:1 matched case-control analysis.

Results

A total of 4201 women were included in this study, with a median follow-up time of 64 months (range: 0–107 months). Of these patients, 2811 (66.9%) received adjuvant RT, while 1390 (33.1%) did not. Patients who did not receive adjuvant RT were more likely to be aged ≥ 80 years old, have a single marital status, larger tumors, and HER2-positive status (p < 0.05). Multivariate Cox proportional analysis indicated that receiving adjuvant RT was an independent factor associated with better OS and BCSS before and after PSM (P < 0.001). The survival curves before and after PSM showed that patients achieved an improved OS and BCSS from adjuvant RT (P < 0.005). In the subgroup analysis, there was no survival benefit trend from adjuvant RT in patients who were ≥ 80 years, or those with T1mic+T1a, T1b tumors.

Conclusions

The use of RT following BCS in older women with T1-2N0 ER-negative breast cancer is associated with improve OS and BCSS. However, the potential benefit may be relatively limited for patients ≥ 80 years, or those with T1mic+T1a, T1b tumors.

Citation: Chen C, Wang R, Wang B, Wu Y, Jiang J (2023) The effect of adjuvant radiotherapy after breast-conserving surgery in elderly women with T1-2N0 estrogen receptor-negative breast cancer. PLoS ONE 18(8): e0288078. https://doi.org/10.1371/journal.pone.0288078

Editor: Daniele Ugo Tari, Local Health Authority Caserta: Azienda Sanitaria Locale Caserta, ITALY

Received: March 30, 2023; Accepted: June 19, 2023; Published: August 3, 2023

Copyright: © 2023 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data are available from the Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence ‐ SEER 18 Regs Custom Data (with additional treatment fields), Available at: https://seer.cancer.gov/data/.

Funding: This work was supported by the National Natural Science Foundation of China (81972869, 32270955); the Key R&D Program of Jiangsu Province (BE2022719); Social Development Science and Technology Project of Changzhou (CE20215030); the Science and Technology Planning Project of Changzhou (CJ20210158). The funder has no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Breast cancer has become the most common cancer worldwide, with nearly 2.3 million new cases in 2020 [1]. Adjuvant radiotherapy (RT) following Breast-conserving surgery (BCS) is the standard treatment for early stage breast cancer. Advanced age is a well-established prognostic factor associated with a decreased risk of tumor recurrence [2–4], and various randomized clinical trials (RCTs) have demonstrated slight improvement in local control of breast cancer in elderly patients, but no impact on distant metastasis-free or disease-specific survival has been observe [5–7], which suggests adjuvant RT may have a reduced benefit in elderly patients.

Several prospective studies showed a modest decrease in local recurrence when RT was added to elderly women with stage I ER-positive breast cancer receiving tamoxifen, but no difference was observed in terms of breast-cancer specific survival (BCSS) [6,8–12]. As a result, the National Comprehensive Cancer Network guidelines allow for the use of BCS plus endocrine therapy without adjuvant RT for this subset of patients [13]. However, it is currently not known whether omitting RT is also a safe alternative for elderly women with ER-negative breast cancer.

Our study aimed to evaluate the benefit of adjuvant RT after BCS among women ≥ 70 years with T1-2N0 ER-negative breast cancer.

Materials and methods

Patient selection

The Surveillance, Epidemiology, and End Results (SEER) program is recognized as the authoritative source of cancer diagnosis, treatment, and survival data in the United States, covering approximately 28% of the population. We enrolled patients from the SEER program between 2010 and 2015 who had complete follow-up information and met the following criteria: 1) women diagnosed with breast cancer and aged ≥ 70 years; 2) stage T1-2N0 disease; 3) estrogen receptor (ER)-negative disease; 4) treated with or without adjuvant RT following BCS. Patients who were diagnosed with metastatic disease at breast cancer diagnosis, and who received systemic therapy before BCS were excluded (Fig 1). Notably, this study was considered exempt from the approval process of the Institutional Review Board as it used de-identified data from the SEER program.

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Fig 1. Flow chart of the inclusion and exclusion criteria.

https://doi.org/10.1371/journal.pone.0288078.g001

Measures

The following variables were included in this study: age at diagnosis, race/ethnicity, marital status, tumor Histology, grade, tumor (T) stage, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, chemotherapy use, and adjuvant RT use. The primary endpoints were overall survival (OS) and breast cancer-specific survival (BCSS). OS was defined as the time from breast cancer diagnosis to death from any cause, and BCSS was defined as the time from the date of breast cancer diagnosis to the date of death from breast cancer.

Statistical analysis

The chi-square test was used to compare the baseline characteristics of patients between the groups. Cox proportional hazard models were used to determine the prognostic factors for OS and BCSS. To reduce potential confounding in the retrospective studies, a 1:1 propensity score matching (PSM) method was used to create the matched cohorts. Kaplan-Meier survival analysis and log-rank tests were performed to compare the survival among different groups. All tests were two-sided, and P-value < 0.05 was applied to indicate statistical significance.

Result

Patient characteristics

A total of 4201 patients were included in the final analysis with a median age of diagnosis of 75 years (range: 70–99 years). The majority of patients were White (n  =  3375, 80.3%), single marital status (n  =  2451, 58.3%), PR-negative (n  =  3947, 94.0%), HER2-negative (n  =  3347, 79.7%), and did not receive chemotherapy (n  =  2547, 60.6%). Of these patients, 2,811 (66.9%) received adjuvant RT, while 1390 (33.1%) patients did not. Notably, there were no significant differences in the percentage of patients receiving adjuvant RT over time (P = 0.182) (Fig 2). Demographic and clinical characteristics information of patients before and after PSM were shown in Table 1.

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Fig 2. Change in the use of adjuvant radiotherapy following breast-conserving surgery between 2010 and 2015.

https://doi.org/10.1371/journal.pone.0288078.g002

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Table 1. Patient demographic and clinical characteristics information before and after PSM.

https://doi.org/10.1371/journal.pone.0288078.t001

Predictors associated with receiving adjuvant RT

The multivariate logistic regression analysis showed that age, marital status, T stage, and HER2 status were found to be strong predictors of radiation administration. Patients aged ≥ 80 years, with a single marital status, T2 stage disease, and HER2 positive status were less likely to receive postoperative RT (Table 2).

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Table 2. Predictors of receipt of adjuvant radiotherapy using multivariable analysis.

https://doi.org/10.1371/journal.pone.0288078.t002

Survival analyses in the whole SEER cohort

During a median follow-up period of 64 months (range: 0–107 months) in the whole SEER cohort, 1233 (29.4%) patients died, with 487 (39.5%) of those deaths attributed to breast cancer. At 5 years, the OS and BCSS for the entire cohort were 73.7% and 88.0%, respectively, and at 8 years, these rates decreased to 60.4% and 83.9%, respectively. All baseline characteristics were analyzed through univariable and multivariate analysis to assess the impact on OS and BCSS. Univariate analysis showed that older age (≥ 80 years), single marital status, poorer tumor differentiation grade (III and IV), and higher T stage (T1c and T2) were associated with worse OS and BCSS, while adjuvant RT was strongly associated with improved survival (OS: HR 0.48, 95% CI 0.43–0.54, p < 0.001; BCSS: HR 0.56, 95% CI 0.47–0.67, p < 0.001). Multivariate analysis revealed that adjuvant RT was an independent prognostic factor for both OS and BCSS (p < 0.001) (Table 3). Furthermore, Kaplan-Meier curve analysis demonstrated that patients who received adjuvant RT had better OS (P < 0.001) and BCSS (P < 0.001) compared to those who did not (Fig 3A and 3B).

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Fig 3. Kaplan–Meier curves for all patients with and without adjuvant radiotherapy.

(A) OS curve of the non-RT group versus RT group before PSM; (B) BCSS curve of the non-RT group versus RT group before PSM; (C) OS curve of the non-RT group versus RT group after PSM; (D) BCSS curve of the non-RT group versus RT group after PSM.

https://doi.org/10.1371/journal.pone.0288078.g003

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Table 3. Univariate and multivariate analyses of OS and BCSS before PSM.

https://doi.org/10.1371/journal.pone.0288078.t003

Survival analysis in propensity score-matched cohort

In the matched cohort, univariate analysis revealed similar prognostic factors for OS and BCSS as the unmatched cohort, including age, marital status, Grade, T stage, chemotherapy, and radiotherapy (Table 4). The multivariate analysis indicated that adjuvant RT was an independent prognostic factor for both OS and BCSS; the OS (HR 0.62, 95% CI 0.54–0.70, p < 0.001) and BCSS (HR 0.71, 95% CI 0.58–0.88, p = 0.002) of patients who received postoperative RT were better than those who did not (Table 4). Additionally, age, T stage, and chemotherapy were independent indicators for both OS and BCSS. Furthermore, patients who received postoperative RT experienced a significant improvement in OS (5-year OS: 75.2% vs. 63.2%; 8-year OS: 60.7% vs. 47.8%, p < 0.001) and BCSS (5-year BCSS: 87.7% vs. 84.2%; 8-year BCSS: 83.4% vs. 79.0%, p = 0.003) compared to those who did not (Fig 3C and 3D).

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Table 4. Univariate and multivariate analyses of OS and BCSS after PSM.

https://doi.org/10.1371/journal.pone.0288078.t004

Survival analysis stratified by clinical characteristics

In order to identify a specific subgroup of breast cancer patients who may benefit from adjuvant RT, we conducted an exploratory subgroup analysis in the propensity score matched cohort. Our findings suggest that patients respond differently to adjuvant RT depending on several factors. Specifically, the administration of adjuvant RT was significantly associated with prolonged OS in patients with a younger age (< 80 years), and those with a higher T stage. Moreover, adjuvant RT is associated with improved OS regardless of tumor grade, marital status, and HER2 status. These observations suggest that postoperative RT may serve as an effective treatment option for breast cancer patients with specific clinical and pathological characteristics. To visualize the relationship between each patient characteristic and the receipt of adjuvant RT, we plotted the hazard ratio and 95% confidence interval for OS in Fig 4.

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Fig 4. The forest plots of sub-group analysis.

https://doi.org/10.1371/journal.pone.0288078.g004

Discussion

The benefits of adjuvant RT for elderly women with early stage ER-negative breast cancer remain uncertain due to the limited research conducted in this population. In a meta-analysis of 17 randomized trials investigating adjuvant RT after BCS, only 23 women aged ≥ 70 years and had T1-T2N0 ER-negative breast cancer were included. This particular group of women represented less than 1% of the total population studied. The study demonstrated that patients with ER-negative breast cancer have an increased risk of tumor recurrence [7]. According to Other studies, both prospective and retrospective, it seems likely that patients with ER-negative tumors may not receive the same advantages from adjuvant RT as those with ER-positive tumors [14]. Therefore, it is possible that the increased danger of tumor recurrence in patients with ER-negative tumors may not necessarily translate into heightened benefits from adjuvant RT. In the era of precise medicine and personalized treatment, it is extremely important to understand the prognostic value of adjuvant RT particularly for elderly women who have ER-negative tumors.

In our study, the proportion of patients aged ≥ 70 years with T1-T2N0 ER-negative breast cancer who received RT after BCS was not significantly different from 2010 to 2015 (P = 0.182). Moreover, we found that age, marital status, tumor grade, and HER2 status were the main factors associated with RT decision, which is consistent with previous clinical practice [15,16]. Numerous studies have demonstrated that older breast cancer patients with ER-negative tumors have higher rates of recurrence and breast cancer-specific mortality [17–19]. Furthermore, within the cohort of patients with ER-negative and PR-negative breast cancer, older individuals are more prone to die from the disease than their younger counterparts [20,21]. Although radiotherapy may lead to acute and chronic treatment-related toxicity, as well as increased medical costs [22,23], researchers have discovered that its use does not have a negative impact on the quality of life of elderly patients [5,24,25]. A study conducted by Weiss et al. based on population analysis revealed that older patients with ER-negative breast cancer had a higher breast cancer-specific mortality rate and lower utilization of radiotherapy. Their findings indicate that ER-negative breast cancer should be considered a distinct entity from ER-positive breast cancer and should be treated with more aggressive methods [20]. In our study, we found that the use of adjuvant radiation after BCS in older women with T1-2N0 ER-negative breast cancer is associated with improve OS and BCSS before and after PSM.

It is still uncertain whether a specific group of elderly women with early-stage ER-negative tumors may not need adjuvant RT. Our findings have demonstrated an improve OS among all subgroups of patients according to Marital status or Grade or HER2 status after BCS with RT; However, when analyzing patients aged ≥ 80 years, or those with T1mic+T1a, T1b tumors, the difference in OS with and without RT is no longer statistically significant. In addition, previous studies have shown that radiotherapy does not significantly reduce the risk of local regional recurrence in older age [2–4] or earlier T stage [7,26,27]. These studies will help guide management decisions for women ≥ 70 years with T1-2N0 ER-negative breast cancer.

Our study used a population-based cancer registry; unlike single-institution studies, which inevitably have a referral bias, the SEER database provides a more realistic clinical practice environment with information from all levels of healthcare institutions. Although there are many strengths of this study including the large sample size, PSM test and subgroup analysis, we acknowledge some limitations to our study. First, there were no information regarding postoperative RT in the SEER database, including clinical target volume and radiation regimen, which may cause confusion. Second, data on chemotherapy, such as regimen and courses, were also unavailable, so that further case-control studies failed to be performed. Finally, the SEER database did not include local recurrence and disease-free survival, which made the local control benefit of radiation therapy unanalyzable.

Conclusions

The use of adjuvant RT is associated with improve OS and BCSS among elderly women ≥ 70 years with T1-2N0 ER-negative breast cancer. However, the potential benefit may be relatively limited in the subgroups of women ≥ 80 or with T1mic+T1a, T1b tumors.

Acknowledgments

The authors acknowledge the efforts of the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER database.

References

  1. 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians. 2021;71(3):209–49. Epub 2021/02/05. pmid:33538338.
  2. 2. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet (London, England). 2005;366(9503):2087–106. Epub 2005/12/20. pmid:16360786.
  3. 3. Liljegren G, Holmberg L, Bergh J, Lindgren A, Tabár L, Nordgren H, et al. 10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 1999;17(8):2326–33. Epub 1999/11/24. pmid:10561294.
  4. 4. Veronesi U, Marubini E, Mariani L, Galimberti V, Luini A, Veronesi P, et al. Radiotherapy after breast-conserving surgery in small breast carcinoma: long-term results of a randomized trial. Annals of oncology: official journal of the European Society for Medical Oncology. 2001;12(7):997–1003. Epub 2001/08/28. pmid:11521809.
  5. 5. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. The Lancet Oncology. 2015;16(3):266–73. Epub 2015/02/01. pmid:25637340.
  6. 6. Hughes KS, Schnaper LA, Bellon JR, Cirrincione CT, Berry DA, McCormick B, 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. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2013;31(19):2382–7. Epub 2013/05/22. pmid:23690420; PubMed Central PMCID: PMC3691356 are found at the end of this article.
  7. 7. Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, 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 (London, England). 2011;378(9804):1707–16. Epub 2011/10/25. pmid:22019144; PubMed Central PMCID: PMC3254252.
  8. 8. Hughes KS, Schnaper LA, Berry D, Cirrincione C, McCormick B, Shank B, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. The New England journal of medicine. 2004;351(10):971–7. Epub 2004/09/03. pmid:15342805.
  9. 9. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr., Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. The New England journal of medicine. 1999;341(27):2061–7. Epub 1999/12/30. pmid:10615079.
  10. 10. Lewis JH, Kilgore ML, Goldman DP, Trimble EL, Kaplan R, Montello MJ, et al. Participation of patients 65 years of age or older in cancer clinical trials. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2003;21(7):1383–9. Epub 2003/03/29. pmid:12663731.
  11. 11. Townsley CA, Selby R, Siu LL. Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2005;23(13):3112–24. Epub 2005/04/30. pmid:15860871.
  12. 12. 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(2):188–93. Epub 2014/12/10. pmid:25488523.
  13. 13. Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, et al. NCCN Guidelines Insights: Breast Cancer, Version 1.2017. Journal of the National Comprehensive Cancer Network: JNCCN. 2017;15(4):433–51. Epub 2017/04/14. pmid:28404755.
  14. 14. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2008;26(14):2373–8. Epub 2008/04/17. pmid:18413639.
  15. 15. Yang SP, Tan LL, Zhou P, Lian CL, Wu SG, He ZY. The addition of radiotherapy to breast-conserving surgery improves survival for elderly patients with early breast cancer. Frontiers in oncology. 2022;12:917054. Epub 2022/12/13. pmid:36505844; PubMed Central PMCID: PMC9727219.
  16. 16. Reyes SA, Williams AD, Arlow RL, De La Cruz LM, Anderson DN, Ugras S, et al. Changing practice patterns of adjuvant radiation among elderly women with early stage breast cancer in the United States from 2004 to 2014. The breast journal. 2020;26(3):353–67. Epub 2019/09/21. pmid:31538703.
  17. 17. Nagar H, Yan W, Christos P, Chao KSC, Nori D, Ravi A. Older Patients With Early-stage Breast Cancer: Adjuvant Radiation Therapy and Predictive Factors for Cancer-related Death. American journal of clinical oncology. 2017;40(3):300–5. Epub 2014/10/22. pmid:25333731.
  18. 18. Shen X, Anne PR, Keith SW, Wojcieszynski A, Mishra MV, Bar-Ad V, et al. Radiation therapy use and outcomes among older women with ER-positive and ER-negative stage I breast cancer. American journal of clinical oncology. 2014;37(3):241–7. Epub 2012/12/18. pmid:23241502.
  19. 19. Pierga JY, Girre V, Laurence V, Asselain B, Diéras V, Jouve M, et al. Characteristics and outcome of 1755 operable breast cancers in women over 70 years of age. Breast (Edinburgh, Scotland). 2004;13(5):369–75. Epub 2004/09/30. pmid:15454191.
  20. 20. Weiss A, Noorbakhsh A, Tokin C, Chang D, Blair SL. Hormone receptor-negative breast cancer: undertreatment of patients over 80. Annals of surgical oncology. 2013;20(10):3274–8. Epub 2013/07/11. pmid:23838924.
  21. 21. Biganzoli L, Wildiers H, Oakman C, Marotti L, Loibl S, Kunkler I, 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). The Lancet Oncology. 2012;13(4):e148–60. Epub 2012/04/04. pmid:22469125.
  22. 22. Ali AA, Xiao H, Tawk R, Campbell E, Semykina A, Montero AJ, et al. Comparison of health utility weights among elderly patients receiving breast-conserving surgery plus hormonal therapy with or without radiotherapy. Current medical research and opinion. 2017;33(2):391–400. Epub 2016/11/08. pmid:27819160; PubMed Central PMCID: PMC5344798.
  23. 23. Carvalho Í T, Rezende ACP, Bernardo RJC. Pros and cons of radiotherapy omission in elderly breast cancer patients following breast conservative surgery. Translational cancer research. 2020;9(Suppl 1):S236–s41. Epub 2020/01/01. pmid:35117967; PubMed Central PMCID: PMC8797552.
  24. 24. Prescott RJ, Kunkler IH, Williams LJ, King CC, Jack W, van der Pol M, et al. A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial. Health technology assessment (Winchester, England). 2007;11(31):1–149, iii-iv. Epub 2007/08/03. pmid:17669280.
  25. 25. Le Saux O, Ripamonti B, Bruyas A, Bonin O, Freyer G, Bonnefoy M, et al. Optimal management of breast cancer in the elderly patient: current perspectives. Clinical interventions in aging. 2015;10:157–74. Epub 2015/01/23. pmid:25609933; PubMed Central PMCID: PMC4293298.
  26. 26. Albert JM, Liu DD, Shen Y, Pan IW, Shih YC, Hoffman KE, et al. Nomogram to predict the benefit of radiation for older patients with breast cancer treated with conservative surgery. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2012;30(23):2837–43. Epub 2012/06/27. pmid:22734034; PubMed Central PMCID: PMC3410401 are found at the end of this article.
  27. 27. Eaton BR, Jiang R, Torres MA, Kahn ST, Godette K, Lash TL, et al. Benefit of adjuvant radiotherapy after breast-conserving therapy among elderly women with T1-T2N0 estrogen receptor-negative breast cancer. Cancer. 2016;122(19):3059–68. Epub 2016/06/22. pmid:27328114; PubMed Central PMCID: PMC5030146.