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Long-term age-dependent failure pattern after breast-conserving therapy or mastectomy among Danish lymph-node-negative breast cancer patients

      Abstract

      Purpose

      To describe long-term failure pattern after early-stage breast cancer in relation to local treatment (breast-conserving therapy (BCT) or mastectomy) and age.

      Materials and methods

      Cohort study with balanced 5-year age groups and prospectively collected data; 813 Danish lymph-node-negative breast cancer patients diagnosed in 1989–98 and treated with mastectomy (N = 515) or BCT (N = 298) and no adjuvant systemic treatment.

      Results

      The 20-year local recurrence (LR) risk was 20% after BCT; 8.7% after mastectomy. LR developed in mastectomy patients within the first 10 years; in BCT patients throughout the entire 20-year period. Younger patients’ (⩽45 years) 20-year LR risk was generally higher than older patients’ (>45 years) (19% vs. 5%, p < 0.001).
      In younger patients, LR was significantly associated with distant metastasis (DM) (hazard ratio (HR) = 2.7(1.8–4.2)) and 20-year breast-cancer mortality (HR = 2.7(1.7–4.4)). BCT was associated with higher 20-year breast-cancer mortality (HR = 1.5(1.0–2.4)) and higher 20-year all-cause mortality (HR = 1.7(1.2–2.5)) than mastectomy.
      In older patients, LR was not associated with DM, and breast-cancer mortality was similar for BCT and mastectomy.

      Conclusion

      BCT patients with no adjuvant systemic treatment developed LR throughout 20-year period and faced higher LR risk than mastectomy patients. LR was associated with DM among younger patients, and younger BCT patients had higher mortality than younger mastectomy patients.

      Keywords

      Breast-conserving therapy (BCT) and mastectomy have been considered equivalent modalities for local treatment of early-stage breast cancer patients since the late 1980s [
      • Veronesi U.
      • Cascinelli N.
      • Mariani L.
      • et al.
      Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer.
      ,
      • 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.
      ,
      • Blichert-Toft M.
      • Nielsen M.
      • During M.
      • et al.
      Long-term results of breast conserving surgery vs. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol.
      ,
      • van Dongen J.A.
      • Voogd A.C.
      • Fentiman I.S.
      • et al.
      Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial.
      ,
      • Arriagada R.
      • Le M.G.
      • Guinebretiere J.M.
      • et al.
      Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients.
      ,
      • Poggi M.M.
      • Danforth D.N.
      • Sciuto L.C.
      • et al.
      Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial.
      ]. Young age at diagnosis has been a strong predictor for local recurrence (LR), especially after BCT [
      • Voogd A.C.
      • Nielsen M.
      • Peterse J.L.
      • et al.
      Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials.
      ,
      • de Bock G.H.
      • van der Hage J.A.
      • Putter H.
      • et al.
      Isolated loco-regional recurrence of breast cancer is more common in young patients and following breast conserving therapy: long-term results of European Organisation for Research and Treatment of Cancer studies.
      ,
      • Early Breast Cancer Trialists’ Collaborative Group
      (EBCTCG): Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials.
      ,
      • Vrieling C.
      • Collette L.
      • Fourquet A.
      • et al.
      Can patient-, treat- and pathology-related characteristics explain the high local recurrence rate following breast-conserving therapy in young patients?.
      ].
      A concern is whether the increased incidence of LR in young patients translates into poor survival. A review of six randomized controlled trials comparing mastectomy and BCT [
      • Cao J.Q.
      • Olson R.A.
      • Tyldesley S.K.
      Comparison of recurrence and survival rates after breast-conserving therapy and mastectomy in young women with breast cancer.
      ] reported similar overall survival (OS) after BCT and mastectomy although the incidence of LR was significantly higher among BCT patients than among mastectomy patients in four of the trials. However, the proportion of young breast cancer patients was low (12–23%). Young breast cancer patients have been studied as a separate group only in a handful of cohort studies [
      • Bantema-Joppe E.J.
      • de M.L.
      • Visser O.
      • et al.
      Early-stage young breast cancer patients: impact of local treatment on survival.
      ,
      • Kroman N.
      • Holtveg H.
      • Wohlfahrt J.
      • et al.
      Effect of breast-conserving therapy versus radical mastectomy on prognosis for young women with breast carcinoma.
      ,
      • van der Sangen M.J.
      • van de Wiel F.M.
      • Poortmans P.M.
      • et al.
      Are breast conservation and mastectomy equally effective in the treatment of young women with early breast cancer? Long-term results of a population-based cohort of 1,451 patients aged </=40 years.
      ,
      • Mahmood U.
      • Morris C.
      • Neuner G.
      • et al.
      Similar survival with breast conservation therapy or mastectomy in the management of young women with early-stage breast cancer.
      ,
      • Jeon Y.W.
      • Choi J.E.
      • Park H.K.
      • et al.
      Impact of local surgical treatment on survival in young women with T1 breast cancer: long-term results of a population-based cohort.
      ,
      • Cao J.Q.
      • Truong P.T.
      • Olivotto I.A.
      • et al.
      Should women younger than 40 years of age with invasive breast cancer have a mastectomy? 15-year outcomes in a population-based cohort.
      ], but these studies use a mixture of different TNM stages, a variety of adjuvant systemic treatments, and a somewhat short follow-up of less than 10 years.
      A meta-analysis from EBCTCG evaluating the effect of radiotherapy (RT) after different types of breast cancer surgery [
      • Darby S.
      • McGale P.
      • Correa C.
      • Taylor 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.
      ] indicated that one breast cancer death could be avoided after 15 years for every four LR avoided after 5 years. However, this association has been questioned, and mortality may depend also on tumor characteristics [
      • Kyndi M.
      • Overgaard M.
      • Nielsen H.M.
      • et al.
      High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of DBCG 82 b&c.
      ] and intrinsic tumor subtypes [
      • Kyndi M.
      • Sorensen F.B.
      • Knudsen H.
      • et al.
      Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group.
      ]. It accordingly remains unclear whether an increased LR rate [
      • Tanis E.
      • van de Velde C.J.
      • Bartelink H.
      • et al.
      Locoregional recurrence after breast-conserving therapy remains an independent prognostic factor even after an event free interval of 10 years in early stage breast cancer.
      ] among young breast cancer patients leads to higher mortality [
      • de la Rochefordiere A.
      • Asselain B.
      • Campana F.
      • et al.
      Age as prognostic factor in premenopausal breast carcinoma.
      ,
      • Kroman N.
      • Jensen M.B.
      • Wohlfahrt J.
      • et al.
      Factors influencing the effect of age on prognosis in breast cancer: population based study.
      ].
      We therefore aimed to describe the long-term pattern of failure after early-stage breast cancer as a function of age and local treatment, and to investigate if LR was associated with higher risk of distant metastasis (DM) and mortality.

      Patients and methods

      Study population and treatment

      The study cohort included 813 lymph-node-negative patients with tumor size <5 cm and no previous cancer. Included were all histological tumor types except invasive ductal carcinoma grade II/III. All patients had given informed consent to be enrolled in the DBCG-89a-protocol [
      • Christiansen P.
      • Al-Suliman N.
      • Bjerre K.
      • et al.
      Recurrence pattern and prognosis in low-risk breast cancer patients–data from the DBCG 89-A programme.
      ,
      • Ewertz M.
      • Kempel M.M.
      • During M.
      • et al.
      Breast conserving treatment in Denmark, 1989–1998. A nationwide population-based study of the Danish Breast Cancer Co-operative Group.
      ] administered by the Danish Breast Cancer Group (DBCG). Data were collected prospectively. All patients received partial axillary dissection and were advised to receive mastectomy (with no other treatment) or lumpectomy and whole-breast RT of the residual breast (48 Gy in 24 fractions+ boost of 10–16 Gy in 5–8 fractions) [
      • Overgaard M.
      • Christensen J.J.
      Postoperative radiotherapy in DBCG during 30 years. Techniques, indications and clinical radiobiological experience.
      ]. No patients received adjuvant systemic treatment.
      The study cohort had a balanced proportion of patients within each 5-year age group. Geographical inclusion criteria were used to secure an unbiased cohort (Sup. Fig. 1): Young patients were included nationwide; old patients from a particular region of Denmark. Patients with known BRCA mutations were excluded (N = 10).

      Patient follow-up

      Patients were followed with clinical examination biannually for 5 years and then annually for up to 10 years. They went off-study in case of any breast cancer event, immigration, or death. Complete 20-year follow-up data (including consecutive registration of all breast cancer events for every patient) were obtained from the Danish Civil Registration System, the National Pathology Register, and general practitioners (GP), and by reviewing the patients’ medical records (Sup. Fig. 1).

      Primary endpoints and statistical analysis

      Endpoints considered included LR defined as tumor growth (excluding ductal carcinoma in situ) in the ipsilateral chest wall, breast, or overlying skin; regional recurrence (RR) defined as tumor growth in ipsilateral axillary or infraclavicular lymph nodes; contralateral breast cancer (CC) defined as tumor growth in the contralateral breast; and distant metastasis (DM) defined as tumor growth in all other regions. LR developed simultaneous (within a month) with RR or CC was registered as RR or CC, respectively. LR/RR/CC occurring more than a month after DM was not taken into account.
      Cumulative incidence curves for LR, RR, and DM were calculated using a competing risk model. Time-to-event was defined as the interval between the date of surgery and the occurrence of the event of interest. In the absence of LR or RR, the observation time was censored at the earliest of the following competing events: other breast cancer events, other malignant disease, or death. In the absence of DM, the observation time was censored at the earliest of either other malignant disease or death. Follow-up was continued until return date of the letter from the GP, reading date of the electronic medical records, or death. Overall survival was described by Kaplan–Meier plots, counted from the date of surgery to the date death; and patients were censored from follow-up at 1 March 2016. For breast-cancer mortality, other causes of death were recorded as competing events, and a cummulative incidence curve were calculated. Crude hazard ratios (HR) were computed for all end-points using Cox proportional hazards regression. If the assumption of proportional hazard could not be accomplished, a risk difference was calculated using the pseudo-value approach. Cox multivariate regression analyses were performed separately for younger and older patients using DM, breast cancer mortality, and all-cause mortality, adjusting for local treatment, tumor size and histological type. Assumptions of proportional hazards were tested graphically using –ln(–ln(survival) vs. –ln(analysis time) plots and by testing zero slopes of scaled Schoenfeld residuals. Groups were compared using the chi-square test. Level of significance was 5%, and all estimated P values were two-sided. All statistical tests were performed using STATA version 12.1 (StataCorp, College Station, Texas, USA).
      Definition of age: Failure pattern for each 5-year age group was listed (Sup. Table 1). Among patients developing LR, a distinct difference was observed between the age groups 41–45 and 46–50. Overall, patients ⩽45 years (=younger) had a much higher frequency of DM than patients >45 years (=older). Based on this difference, age was dichotomized using 45 years as the cut-point.

      Results

      Distribution of clinical–pathological parameters

      The study population’s clinical–pathological parameters are shown in Table 1. BCT was performed in 37% (N = 298), mastectomy in 63% (N = 515). Overall, BCT patients were younger (p < 0.001) and had a much lower proportion of large tumors (21–50 mm) (p < 0.001) than mastectomy patients.
      Table 1Patient characteristics.
      AllMastectomyBCT
      AllYoungerOlderAllYoungerOlder
      Total81351563%27834%23729%29837%17522%12315%
      Tumor characteristic
      Tumor size
       ⩽10 mm24530%13226%7728%5523%11338%6034%5343%
       11–20 mm36144%21842%11642%10243%14348%8548%5847%
       21–50 mm17922%14528%7326%7231%3411%2213%1210%
       Unknown, but <50 mm284%204%124%83%83%85%0
      Histological diagnose
       Invasive ductal carcinoma55869%34567%19570%15063%21372%12270%9174%
       Invasive lobular carcinoma13416%9819%4516%5323%3612%2112%1512%
       Other carcinomas12115%7214%3814%3414%4916%3218%1714%
      Treatment: breast conserving therapy (BCT) vs. mastectomy.
      Age: younger (⩽45 year) vs. older (>45).

      Failure patterns

      Failure patterns as a function of local treatment and age appear in Table 2 and Sup. Fig. 1. The frequency of LR was higher among BCT patients than among mastectomy patients, regardless of age: younger (28% vs. 14%, p < 0.001) and older (10% vs. 3% p < 0.001). The risk of developing DM simultaneously with LR or later was high among younger patients – about 1 DM for every 2 LR: BCT (47 LR:19 DM) and mastectomy (40 LR:21 DM). In contrast, among older patients developing LR, only 1 developed DM; BCT (11:0) and mastectomy (6:1).
      Table 2Failure pattern as a function of local treatment and age.
      MastectomyBCT
      AllYoungerOlderAllYoungerOlder
      All81351563%27834%23729%29837%17522%12315%
      No recurrence52565%34066%17262%16871%18562%9253%9375%
      LR total10413%469.0%4014%62.5%5819%4727%118.9%
       LR637.8%244.7%196.8%52.1%3913%2816%118.9%
       LR later DM344.2%173.3%165.8%10.4%175.7%179.7%0
       Sim LR-DM70.9%51.0%51.8%020.7%21.1%0
      RR total253.0%132.6%82.9%52.0%124.0%116.3%10.8%
       RR10(3)1.2%7(3)1.4%6(3)2.2%10.4%31.0%31.7%0
       RR later DM9(5)1.1%4(3)0.8%2(1)0.7%2(2)0.8%5(2)1.7%5(2)2.9%0
       Sim RR-DM60.7%20.4%020.8%41.3%31.7%10.8%
      CC total698.6%5210%259.0%2711%175.7%105.7%75.7%
       CC56(1)6.9%418.0%196.8%229.3%15(1)5.0%8(1)4.6%75.7%
       CClater DM11(1)1.4%91.7%51.8%41.7%2(1)0.7%2(1)1.1%0
       Sim CC-DM2(1)0.3%2(1)0.4%1(1)0.4%10.4%000
       DM as 1 event9011%6412%3312%3113%268.7%158.6%118.9%
      DM total15920%10320%6222%4117%5619%4425%1210%
      Patients with a breast cancer event were defined with one of the following: LR, LR later DM, simLR-DM, RR, RR, simRR-DM, CC, CClater DM, simCC-DM as 1 event and DM total.
      Sim = simultaneous events diagnosed within the same month.
       = includes simLR-RR/simLR–CC, (number of simultaneous event).

      Local failure

      The median follow-up was 17.2 years (range 0.5–24.6). Overall, after 20 years of follow-up, the cumulative incidence proportion (CIP) of LR was 13% (11–15) (Fig. 1A); within the first 7 years, it was 7.0% (5.2–8.57) (Fig. 1A, Sup. Table 2).
      Figure thumbnail gr1
      Fig. 120-Year cumulative incidence of local recurrence (A, B), RR (C, D) and DM (E, F) as a function of BCT (red) and mastectomy (blue). (D–F) The same plot; with one exception the cohort was subdivided into a younger (⩽45) and older (>45) group.
      After BCT, the 20-year CIP of LR was 20% (15–25); and patients developed LR throughout the 20-year period, regardless of age. The 20-year CIP of LR was higher among younger than among older patients; risk difference (RD) = 18% (9.0–27) (Fig. 1B). Younger patients had a higher CIP of both early LR (0–7 years) and late LR (>7–20 years) (Sup. Table 2).
      After mastectomy, the 20-year CIP of LR was 8.7% (6.3–11.2); and it was significantly higher among younger than older patients; RD = 11% (7.0–16) (Fig. 1B). Younger patients developed LR within the first 10 years after surgery (except for 3 events recorded after), and the frequency of LR was highest within the first 5 years. Older patients developed LR within the first 5 years after surgery.
      BCT patients had a significantly higher 20-year CIP of LR than mastectomy patients; RD = 11% (6.1–17) (Fig. 1A). The 7-year CIP of LR was not significantly different between BCT and mastectomy patients (Sup. Table 2), but BCT patient had a higher CIP of late LR (>7–20 year); RD = 13% (7.9–19).
      The results were consistent if simultaneous events of LR and RR/CC were included in the 20-year CIP of LR: Mastectomy (younger: 16% vs. older 3.8%) and BCT (younger: 30% vs. older 10%).

      Regional failure

      Overall, the 20-year CIP of RR was 3.3% (2.0–4.6), and there was no significant difference between BCT and mastectomy patients; HR = 1.4(0.7–3.5) (Fig. 1C). The 20-year CIP of RR within the BCT group was higher among younger than among older patients; RD = 5.8% (1.7–9.9) (Fig. 1D).

      Distant metastasis

      Overall, the 20-year CIP of DM was 20% (17–23), and no difference was observed between BCT and mastectomy patients; HR = 0.9(0.7–1.3) (Fig. 1E).
      Within the BCT group, the 20-year CIP of DM was higher among younger patients than older patients; RD = 17% (8.0–26), but there was no significant difference observed between the age groups within the mastectomy group (Fig. 1F).
      Among younger patients, no significant difference in DM was seen between local treatments; RD = 4.6% (−4.1–13); however, older mastectomy patients had a higher 20-year CIP of DM; RD = 8.3% (0.8–18) (Fig. 1F).

      Survival

      The median follow-up on vital status was 19.6 years (range 0.5–26.1). The 20-year breast-cancer mortality and 20-year overall survival were similar in BCT and mastectomy patients, 16% vs. 18% (HR = 1.0(0.7–1.4)) and 71% vs. 68% (HR = 1.0(0.8–1.2)), respectively (Fig. 2A/B). Among younger patients, the 20-year breast-cancer mortality was similar for BCT and mastectomy patients, 22% vs. 18%, 1.3(0.9–2.0); but the 20-year overall survival was poorer after BCT, 72% vs. 80% (HR = 0.7(0.5.0–1.0), (Fig. 2C/D). Among older patients, the breast-cancer mortality was similar as well (BCT: 8.9% vs. mastectomy: 20%, HR = 0.6(0.3–1.1), but BCT patients had a significantly better 20-year overall survival (71% vs. 54%, HR = 1.9(1.0–3.5)) (Fig. 2E/F).
      Figure thumbnail gr2
      Fig. 2Breast-cancer mortality (A, C and E) and overall survival (B, D and F) after 20 years of follow-up, comparison of BCT (red) and mastectomy (blue). (A and B) All patients. (C and D) Younger patients (⩽45). (E and F) older patients (>45).
      Causes of death are shown in Table 3. Among younger patients, only 2 died from heart disease and both had received BCT. Compared with mastectomy patients, BCT patients had a higher frequency of “second primary cancer” (p = 0.007), most of which were associated with the lung (6/8). Among older patients, the frequency of different death causes was not significantly different between the treatment groups, and in both groups only few patients died from heart disease.
      Table 3Causes of death.
      AllMastectomyBCT
      AllYoungOldAllYoungOld
      Total81351566%27834%23729%29834%17522%12315%
      Alive54066%34066%21778%12352%20067%12069%8065%
      All-cause death27334%17534%6122%11448%9833%5531%4335%
      Causes of death
       Breast cancer14618%9218%5219%4017%5418%4123%1311%
       Heart disease192%102%0.104%93%21%76%
       Second primary cancer364%214%21%198%155%85%76%
       Other causes699%5110%62%4519%186%32%1512%
       Unknown30.4%10.2%10.4%0.20.7%10.6%10.8%
      In the adjusted analysis (Table 4), tumor size was significantly associated with each endpoint irrespective of age and treatment. Among younger patients, invasive lobular cancer had a worse prognosis than invasive ductal carcinoma, whereas histological type had no impact among older patients. Within the younger group, those who developed LR had a higher risk of DM (HR: = 2.7(1.8–4.2)) and a higher risk of 20-year breast cancer mortality (HR = 2.7(1.7–4.4)). Compared with mastectomy patients, BCT patients had a higher 20-year breast cancer mortality (HR = 1.5(1.0–2.4)) and 20-year all-cause mortality (HR = 1.7(1.2–2.5)). However, among older patients, LR was not associated with DM (HR = 0.4(0.1–3.1)); and BCT patients’ 20-year breast-cancer mortality was not significantly different from that of mastectomy patients (HR = 0.6(0.3–1.1)).
      Table 4Multivariate analysis for younger (upper part) and older patients: DM, breast-cancer mortality and all-cause mortality.
      Distant metastasisBreast-cancer mortalityAll-cause mortality
      Model includes LR, RR, CCModel includes LR, RR, CCModel includes LR, RR, CC
      HR95% CIHR95% CIHR95% CIHR95% CIHR95% CIHR95% CI
      Younger patient, ⩽45
      BCT vs. Mas1.4(0.9–2.0)1.1(0.7–1.7)1.5(1.02.4)1.2(0.8–1.9)1.7(1.22.5)1.4(1.02.1)
      LR vs. no LR2.7(1.8–4.2)2.7(1.7–4.4)2.1(1.3–3.2)
      RR vs. no RR2.5(1.0–5.8)3.2(1.3–7.6)2.2(1.0–5.3)
      CC vs. no CC1.4(0.6–3.1)1.8(0.8–4.0)1.5(0.8–3.0)
      Tumor size
       11–20 vs. ⩽10 mm2.8(1.6–5.0)2.5(1.54.7)3.0(1.6–5.7)2.9(1.5–5.5)2.0(1.2–3.2)1.9(1.2–3.2)
       >20 vs. ⩽10 mm4.1(2.2–7.8)3.5(1.96.7)4.5(2.29.0)3.9(1.9–7.9)2.5(1.44.5)2.3(1.3–4.2)
      Histologic type
       Lobular vs. ductal1.5(0.9–2.5)1.5(0.9–2.5)1.8(1.13.2)1.9(1.13.1)1.7(1.02.7)1.7(1.02.8)
       Other vs. ductal0.8(0.4–1.5)0.9(0.5–1.6)0.9(0.5–1.6)1.0(0.5–1.8)1.0(0.6–1.7)1.1(0.6–1.9)
      Older patients, >45
      BCT vs. Mas0.6(0.3–1.1)0.6(0.3–1.2)0.6(0.3–1.1)0.6(0.3–1.2)0.7(0.5–1.1)0.8(0.5–1.1)
      LR vs. no LR0.4(0.1 –3.1)0.4(0.1–2.9)0.7(0.3 –1.6)
      RR vs. no RR3.2(0.8–14)3.7(0.9–16)1.8(0.4–7.6)
      CC vs. no CC0.7(0.2–1.9)0.7(0.2–1.9)1.0(0.6–1.7)
      Tumor size
       11–20 vs. ⩽10 mm2.4(1.1–5.4)2.3(1.0–5.1)2.4(1.15.2)2.2(1.0–5.0)1.3(0.9–1.9)1.3(0.8–1.9)
       >20 vs. ⩽10 mm2.5(1.0–6.1)2.5(1.0–6.1)2.6(1.1–6.3)2.6(1.1–6.4)1.5(1.02.4)1.5(1.0–2.4)
      Histologic type
       Lobular vs. ductal0.7(0.3–1.4)0.7(0.3–1.5)0.7(0.3–1.5)0.7(0.3–1.6)1.3(0.9–1.9)1.3(0.9–1.9)
       Other vs. ductal0.8(0.3–1.7)0.8(0.3–1.8)0.8(0.3–1.8)0.8(0.3–1.8)0.8(0.5–1.3)0.8(0.5–1.3)
      For each endpoint, an analysis was performed with and without including local recurrence (LR), regional recurrence (RR), and contralateral cancer (CC). Hazard ratios in bold if p < 0.05.
      As demonstrated in the adjusted analysis, tumor size was associated with DM and survival, and Table 1 showed a significantly lower proportion of large tumors in the BCT group. A sub-analysis was therefore performed within the young group, restricted to tumors below 2 cm (Sup. Fig. 2). After 20 years, younger BCT patients had a higher breast-cancer mortality than younger mastectomy patients, 20% vs. 13% (HR = 1.7(1.0–2.9)).

      Discussion

      This cohort study with complete long-term follow-up data showed that BCT patients developed LR throughout the 20-year period and had a higher risk of LR than mastectomy patients.
      Younger patients’ LR was linked to DM (HR = 2.7(1.7–4.4)), and younger BCT patients had an increased adjusted breast-cancer mortality (HR = 1.5(1.0–2.4)) and all-cause mortality (HR = 1.7(1.2–2.5)) than mastectomy patients. In contrast, older patients’ LR was not linked to DM, and older BCT patients had similar adjusted breast-cancer mortality than mastectomy patients. Only few patients died of heart disease, and their death was not associated with BCT.
      Similar levels of survival after BCT and mastectomy are reported in several randomized trials including mainly post-menopausal patients [
      • Veronesi U.
      • Cascinelli N.
      • Mariani L.
      • et al.
      Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer.
      ,
      • 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.
      ,
      • Blichert-Toft M.
      • Nielsen M.
      • During M.
      • et al.
      Long-term results of breast conserving surgery vs. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol.
      ,
      • van Dongen J.A.
      • Voogd A.C.
      • Fentiman I.S.
      • et al.
      Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial.
      ,
      • Arriagada R.
      • Le M.G.
      • Guinebretiere J.M.
      • et al.
      Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients.
      ,
      • Poggi M.M.
      • Danforth D.N.
      • Sciuto L.C.
      • et al.
      Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial.
      ]. Recently, several large cohort studies described a better survival after BCT [
      • Agarwal S.
      • Pappas L.
      • Neumayer L.
      • et al.
      Effect of breast conservation therapy vs mastectomy on disease-specific survival for early-stage breast cancer.
      ,
      • Fisher S.
      • Gao H.
      • Yasui Y.
      • et al.
      Survival in stage I-III breast cancer patients by surgical treatment in a publicly funded health care system.
      ,
      • Hwang E.S.
      • Lichtensztajn D.Y.
      • Gomez S.L.
      • et al.
      Survival after lumpectomy and mastectomy for early stage invasive breast cancer: the effect of age and hormone receptor status.
      ,
      • Hartmann-Johnsen O.J.
      • Karesen R.
      • Schlichting E.
      • et al.
      Survival is better after breast conserving therapy than mastectomy for early stage breast cancer: a registry-based follow-up study of Norwegian women primary operated between 1998 and 2008.
      ,
      • Hofvind S.
      • Holen A.
      • Aas T.
      • et al.
      Women treated with breast conserving surgery do better than those with mastectomy independent of detection mode, prognostic and predictive tumor characteristics.
      ]. These findings confirm our results among older patients. In contrast, the survival difference between younger BCT and mastectomy patients observed in the present study was found neither in a meta-analysis [
      • Vila J.
      • Gandini S.
      • Gentilini O.
      Overall survival according to type of surgery in young (</=40 years) early breast cancer patients: A systematic meta-analysis comparing breast-conserving surgery versus mastectomy.
      ] of six studies comprising 22,598 young patients below the age of 40 years, nor in a cohort study that was not included in the meta-analysis [
      • Cao J.Q.
      • Truong P.T.
      • Olivotto I.A.
      • et al.
      Should women younger than 40 years of age with invasive breast cancer have a mastectomy? 15-year outcomes in a population-based cohort.
      ]. These inconsistencies may arise because these studies included mastectomy patients with significantly worse prognostic markers (e.g., lymph-node-positive tumors, large tumors, and higher histological grade) and because they used different systemic treatments in the two groups and had a shorter follow-up (i.e., most had follow-up shorter than 10 years). The importance of long follow-up is demonstrated in one of the studies [
      • van der Sangen M.J.
      • van de Wiel F.M.
      • Poortmans P.M.
      • et al.
      Are breast conservation and mastectomy equally effective in the treatment of young women with early breast cancer? Long-term results of a population-based cohort of 1,451 patients aged </=40 years.
      ] which reported a significantly lower incidence of DM after BCT among young patients during the first 7 years after surgery and a significantly higher incidence of DM from 7 to 15 years after surgery. A similar, non-significant reversal of survival risk was reported by Mahmood et al. [
      • Mahmood U.
      • Morris C.
      • Neuner G.
      • et al.
      Similar survival with breast conservation therapy or mastectomy in the management of young women with early-stage breast cancer.
      ].
      Long-term follow-up is also necessary to demonstrate a difference in LR after BCT and mastectomy. In a study of 1451 young breast cancer patients [
      • van der Sangen M.J.
      • van de Wiel F.M.
      • Poortmans P.M.
      • et al.
      Are breast conservation and mastectomy equally effective in the treatment of young women with early breast cancer? Long-term results of a population-based cohort of 1,451 patients aged </=40 years.
      ], young mastectomy patients developed LR only within the first 6 years (6%), whereas BCT patients experienced LR throughout the whole 15-year period. Adjuvant systemic therapy following BCT reduced the 15-year LR risk form 33% to 16%. Similar results were reported in another cohort study of 1874 young patients [
      • Arriagada R.
      • Le M.G.
      • Guinebretiere J.M.
      • et al.
      Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients.
      ], where the 15-year LR risk was 36% after BCT and 12% after mastectomy. In contrast, among 965 young patients most of whom also received systemic treatment, Cao et al. found no difference in the 15-year LR risk between BCT and mastectomy patients, (14% vs. 15%) [
      • Cao J.Q.
      • Truong P.T.
      • Olivotto I.A.
      • et al.
      Should women younger than 40 years of age with invasive breast cancer have a mastectomy? 15-year outcomes in a population-based cohort.
      ].
      The nature of the observed late LR after BCT is unclear. A few studies have tried to explore whether it is a ‘true recurrence’ or a new primary tumor in the residual breast [
      • Veronesi U.
      • Marubini E.
      • Del V.M.
      • et al.
      Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events.
      ,
      • Gujral D.M.
      • Sumo G.
      • Owen J.R.
      • et al.
      Ipsilateral breast tumor relapse: local recurrence versus new primary tumor and the effect of whole-breast radiotherapy on the rate of new primaries.
      ,
      • McGrath S.
      • Antonucci J.
      • Goldstein N.
      • et al.
      Long-term patterns of in-breast failure in patients with early stage breast cancer treated with breast-conserving therapy: a molecular based clonality evaluation.
      ]. In a subset of patients from the EORTC boost trial [
      • Bartelink H.
      • Maingon P.
      • Poortmans P.
      • et al.
      Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.
      ], Vrieling found that primary tumors with the presence of ductal carcinoma in situ had a higher incidence of LR more than 10 years after primary surgery [
      • Vrieling C.
      • Van-Werkhoven E.
      • Poortmans P.
      • et al.
      The impact of pathological factors on long-term local control in the EORTC boost no-boost trial.
      ], indicating that late LR may be new primary tumors.
      In our study, LR was significantly associated with an increased risk of DM among younger patients, and a potential higher proportion of insufficient pathologically free margin in the young group could not explain the finding [
      • Bodilsen A.
      • Bjerre K.
      • Offersen B.V.
      • et al.
      The Influence of Repeat Surgery and Residual Disease on Recurrence After Breast-Conserving Surgery: A Danish Breast Cancer Cooperative Group Study.
      ] Within the BCT group, for every 2 LR among younger patients, 1 developed DM. Among older patients, this ratio was 11:0. The EBCTCG meta-analysis, which evaluated the effect of RT after breast conserving surgery, suggested that RT reduced “any first recurrence” by about 1/2 and reduced breast-cancer mortality by about 1/6. [
      • Darby S.
      • McGale P.
      • Correa C.
      • Taylor 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.
      ]. The association between LR and premature death is heterogeneous [
      • Kyndi M.
      • Overgaard M.
      • Nielsen H.M.
      • et al.
      High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of DBCG 82 b&c.
      ,
      • Kyndi M.
      • Sorensen F.B.
      • Knudsen H.
      • et al.
      Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group.
      ,
      • Arvold N.D.
      • Taghian A.G.
      • Niemierko A.
      • et al.
      Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy.
      ], and patients with a good prognosis (e.g., small tumor, grade I, luminal A subtype) had the smallest absolute 5-year LR risk reduction after RT, but the highest 15-year mortality reduction compared with those whose tumor characteristics were less favorable. The present study demonstrated that age affects the association between LR and DM as well; hence, this association was found only among the younger patients. No association between LR and survival was found in the EORTC boost trial [
      • Bartelink H.
      • Maingon P.
      • Poortmans P.
      • et al.
      Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.
      ] and the randomized trials comparing BCT with mastectomy [
      • Veronesi U.
      • Cascinelli N.
      • Mariani L.
      • et al.
      Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer.
      ,
      • 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.
      ,
      • Blichert-Toft M.
      • Nielsen M.
      • During M.
      • et al.
      Long-term results of breast conserving surgery vs. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol.
      ,
      • van Dongen J.A.
      • Voogd A.C.
      • Fentiman I.S.
      • et al.
      Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial.
      ,
      • Arriagada R.
      • Le M.G.
      • Guinebretiere J.M.
      • et al.
      Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients.
      ,
      • Poggi M.M.
      • Danforth D.N.
      • Sciuto L.C.
      • et al.
      Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial.
      ]. We speculate that this may be so because these studies included mainly postmenopausal women; furthermore, 1/5 of the patients had less favorable tumor characteristics (lymph-node positive). In both subgroups (age older than 45 years and lymph-node positive patients), the association between LR and DM was less outspoken or non-existent.
      Our analysis was not based on data from a randomized clinical trial wherefore selection bias and confounding may exist, leading to divergent results as demonstrated when SEER observational data were compared with randomized data [
      • Henson K.E.
      • Jagsi R.
      • Cutter D.
      • McGale P.
      • et al.
      Inferring the effects of cancer treatment: divergent results from Early Breast Cancer Trialists’ Collaborative Group meta-analyses of randomized trials and observational data from SEER registries.
      ]. However, a study evaluating the implementation of BCT as a routine procedure in Denmark (DBCG 89-program) displayed an equal failure pattern and improved survival in comparison with women from the clinical randomized DBCG 82 tm protocol evaluating BCT vs. mastectomy [
      • Lyngholm C.D.
      • Laurberg T.
      • Alsner J.
      • et al.
      Failure pattern and survival after Breast Conserving Therapy. Long-term results of the Danish Breast Cancer Group (DBCG) 89 TM-cohort.
      ]. The procedure for data collecting used in this study, was also used in the present study.
      Our study has several strengths, including the large cohort (comprising all young lymph-node-negative patients in Denmark within a 10 year-period who received local treatment only), complete registration of incident breast cancer, and complete follow-up data on mortality and LRs within 20 years. Selection bias due to non-response or loss to follow-up is therefore an unlikely explanation for our findings. Information on breast cancer and all-cause mortality had high validity [
      • Jensen A.R.
      • Overgaard J.
      • Storm H.H.
      Validity of breast cancer in the Danish Cancer Registry. A study based on clinical records from one county in Denmark.
      ,
      • Pedersen C.B.
      The Danish Civil Registration System.
      ], which minimized the potential risk of information bias.
      The patients were guided to receive BCT or mastectomy based on information provided by the surgeons. As expected, patients having mastectomy had larger tumors than those who underwent BCT. Inversely, tumor-related prognostic factors, like histological type, grade, and ER-status, did not contribute to the choice of surgical procedure as these factors were assessed postoperatively. Thus, one would assume that the mastectomy group would have higher mortality as large tumor size is a strong prognostic marker for survival [
      • Mirza A.N.
      • Mirza N.Q.
      • Vlastos G.
      • et al.
      Prognostic factors in node-negative breast cancer: a review of studies with sample size more than 200 and follow-up more than 5 years.
      ]. Yet, we found that younger BCT patients had higher breast-cancer mortality after 20 years, and their overall survival was poor. Particularly surprising was the higher incidence of lung cancer after BCT. Unfortunately, information on smoking status was not available and we can therefore only speculate as to the cause of this excess incidence. However, the possibility of radiation-induced second lung cancer cannot be ruled out [
      • Grantzau T.
      • Thomsen M.T.
      • Vaeth M.
      • et al.
      Second primary cancers after adjuvant radiotherapy in early breast cancer patients: A national population based study under the Bansih Breast Cancer Group (DBCG).
      ].
      Almost all of the patients in our study would have received adjuvant anti-hormonal therapy, chemotherapy, and/or Trastuzumab if they had been treated according to present-day guidelines. This evidently affects the generalizability of our findings to today’s clinical practice. Systemic treatment reduces LR [
      • van der Sangen M.J.
      • van de Wiel F.M.
      • Poortmans P.M.
      • et al.
      Are breast conservation and mastectomy equally effective in the treatment of young women with early breast cancer? Long-term results of a population-based cohort of 1,451 patients aged </=40 years.
      ,
      • de la Rochefordiere A.
      • Asselain B.
      • Campana F.
      • et al.
      Age as prognostic factor in premenopausal breast carcinoma.
      ,
      • Buchholz T.A.
      • Tucker S.L.
      • Erwin J.
      • et al.
      Impact of systemic treatment on local control for patients with lymph node-negative breast cancer treated with breast-conservation therapy.
      ,
      • Mannino M.
      • Yarnold J.R.
      Local relapse rates are falling after breast conserving surgery and systemic therapy for early breast cancer: can radiotherapy ever be safely withheld?.
      ] and may improve survival, especially in young patients who undergo BCT [
      • Bantema-Joppe E.J.
      • de M.L.
      • Visser O.
      • et al.
      Early-stage young breast cancer patients: impact of local treatment on survival.
      ]. However, LR rates have decreased over the past decades, and a 10-year LR risk at 2–3% has been published [
      • Aalders K.C.
      • Postma E.L.
      • Strobbe L.J.
      • van der Heiden-van der Loo
      • Sonke G.S.
      • Boersma L.J.
      • et al.
      Contemporary locoregional recurrence rates in young patients with early-stage breast cancer.
      ,
      • Bartelink H.
      • Bourgier C.
      • Elkhuizen P.
      Has partial breast irradiation by IORT or brachytherapy been prematurely introduced into the clinic?.
      ]; however, long-term data from this period are lacking. The low 5–10-year LR rate seen today would likely reduce the observed survival difference between young patient receiving BCT and mastectomy in the present study.
      Nevertheless, it is noteworthy that two-thirds of the study population had no recurrence after 20 years even if they received no adjuvant systemic treatment.

      Conclusion

      Patients treated with BCT and no adjuvant systemic treatment developed LR throughout the whole 20-year period, and they had an increased risk of LR. Among younger patients (⩽45 years of age), LR was associated with DM, and younger BCT patients had an increased breast-cancer and all-cause mortality compared with mastectomy patients. In contrast, older patients (>45 years of age) receiving BCT did not have an increased mortality. When future treatment guidelines for young lymph-node-negative patients are to be updated, the possibility of a negative impact of BCT on survival in this cohort should be taken into account.

      Conflict of interest statement

      The authors declare no relevant potential conflicts of interest to disclose.

      Acknowledgements

      Financial Support was got by the Danish Cancer Society and The Center for Interventional Research in Radiation Oncology (CIRRO).

      Appendix A. Supplementary data

      References

        • Veronesi U.
        • Cascinelli N.
        • Mariani L.
        • et al.
        Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer.
        N Engl J Med. 2002; 347: 1227-1232
        • 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: 1233-1241
        • Blichert-Toft M.
        • Nielsen M.
        • During M.
        • et al.
        Long-term results of breast conserving surgery vs. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol.
        Acta Oncol. 2008; 47: 672-681
        • van Dongen J.A.
        • Voogd A.C.
        • Fentiman I.S.
        • et al.
        Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial.
        J Natl Cancer Inst. 2000; 92: 1143-1150
        • Arriagada R.
        • Le M.G.
        • Guinebretiere J.M.
        • et al.
        Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients.
        Ann Oncol. 2003; 14: 1617-1622
        • Poggi M.M.
        • Danforth D.N.
        • Sciuto L.C.
        • et al.
        Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial.
        Cancer. 2003; 98: 697-702
        • Voogd A.C.
        • Nielsen M.
        • Peterse J.L.
        • et al.
        Differences in risk factors for local and distant recurrence after breast-conserving therapy or mastectomy for stage I and II breast cancer: pooled results of two large European randomized trials.
        J Clin Oncol. 2001; 19: 1688-1697
        • de Bock G.H.
        • van der Hage J.A.
        • Putter H.
        • et al.
        Isolated loco-regional recurrence of breast cancer is more common in young patients and following breast conserving therapy: long-term results of European Organisation for Research and Treatment of Cancer studies.
        Eur J Cancer. 2006; 42: 351-356
        • Early Breast Cancer Trialists’ Collaborative Group
        (EBCTCG): Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials.
        N Engl J Med. 1995; 333: 1444-1455
        • Vrieling C.
        • Collette L.
        • Fourquet A.
        • et al.
        Can patient-, treat- and pathology-related characteristics explain the high local recurrence rate following breast-conserving therapy in young patients?.
        Eur J Cancer. 2003; 39: 932-944
        • Cao J.Q.
        • Olson R.A.
        • Tyldesley S.K.
        Comparison of recurrence and survival rates after breast-conserving therapy and mastectomy in young women with breast cancer.
        Curr Oncol. 2013; 20: e593-e601
        • Bantema-Joppe E.J.
        • de M.L.
        • Visser O.
        • et al.
        Early-stage young breast cancer patients: impact of local treatment on survival.
        Int J Radiat Oncol Biol Phys. 2011; 81: e553-e559
        • Kroman N.
        • Holtveg H.
        • Wohlfahrt J.
        • et al.
        Effect of breast-conserving therapy versus radical mastectomy on prognosis for young women with breast carcinoma.
        Cancer. 2004; 100: 688-693
        • van der Sangen M.J.
        • van de Wiel F.M.
        • Poortmans P.M.
        • et al.
        Are breast conservation and mastectomy equally effective in the treatment of young women with early breast cancer? Long-term results of a population-based cohort of 1,451 patients aged </=40 years.
        Breast Cancer Res Treat. 2010; 127: 207-215
        • Mahmood U.
        • Morris C.
        • Neuner G.
        • et al.
        Similar survival with breast conservation therapy or mastectomy in the management of young women with early-stage breast cancer.
        Int J Radiat Oncol Biol Phys. 2012; 83: 1387-1393
        • Jeon Y.W.
        • Choi J.E.
        • Park H.K.
        • et al.
        Impact of local surgical treatment on survival in young women with T1 breast cancer: long-term results of a population-based cohort.
        Breast Cancer Res Treat. 2013; 138: 475-484
        • Cao J.Q.
        • Truong P.T.
        • Olivotto I.A.
        • et al.
        Should women younger than 40 years of age with invasive breast cancer have a mastectomy? 15-year outcomes in a population-based cohort.
        Int J Radiat Oncol Biol Phys. 2014; 90: 509-517
        • Darby S.
        • McGale P.
        • Correa C.
        • Taylor 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: 1707-1716
        • Kyndi M.
        • Overgaard M.
        • Nielsen H.M.
        • et al.
        High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of DBCG 82 b&c.
        Radiother Oncol. 2009; 90: 74-79
        • Kyndi M.
        • Sorensen F.B.
        • Knudsen H.
        • et al.
        Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group.
        J Clin Oncol. 2008; 26: 1419-1426
        • Tanis E.
        • van de Velde C.J.
        • Bartelink H.
        • et al.
        Locoregional recurrence after breast-conserving therapy remains an independent prognostic factor even after an event free interval of 10 years in early stage breast cancer.
        Eur J Cancer. 2012; 48: 1751-1756
        • de la Rochefordiere A.
        • Asselain B.
        • Campana F.
        • et al.
        Age as prognostic factor in premenopausal breast carcinoma.
        Lancet. 1993; 341: 1039-1043
        • Kroman N.
        • Jensen M.B.
        • Wohlfahrt J.
        • et al.
        Factors influencing the effect of age on prognosis in breast cancer: population based study.
        BMJ. 2000; 320: 474-478
        • Christiansen P.
        • Al-Suliman N.
        • Bjerre K.
        • et al.
        Recurrence pattern and prognosis in low-risk breast cancer patients–data from the DBCG 89-A programme.
        Acta Oncol. 2008; 47: 691-703
        • Ewertz M.
        • Kempel M.M.
        • During M.
        • et al.
        Breast conserving treatment in Denmark, 1989–1998. A nationwide population-based study of the Danish Breast Cancer Co-operative Group.
        Acta Oncol. 2008; 47: 682-690
        • Overgaard M.
        • Christensen J.J.
        Postoperative radiotherapy in DBCG during 30 years. Techniques, indications and clinical radiobiological experience.
        Acta Oncol. 2008; 47: 639-653
        • Agarwal S.
        • Pappas L.
        • Neumayer L.
        • et al.
        Effect of breast conservation therapy vs mastectomy on disease-specific survival for early-stage breast cancer.
        JAMA Surg. 2014; 149: 267-274
        • Fisher S.
        • Gao H.
        • Yasui Y.
        • et al.
        Survival in stage I-III breast cancer patients by surgical treatment in a publicly funded health care system.
        Ann Oncol. 2015; 26: 1161-1169
        • Hwang E.S.
        • Lichtensztajn D.Y.
        • Gomez S.L.
        • et al.
        Survival after lumpectomy and mastectomy for early stage invasive breast cancer: the effect of age and hormone receptor status.
        Cancer. 2013; 119: 1402-1411
        • Hartmann-Johnsen O.J.
        • Karesen R.
        • Schlichting E.
        • et al.
        Survival is better after breast conserving therapy than mastectomy for early stage breast cancer: a registry-based follow-up study of Norwegian women primary operated between 1998 and 2008.
        Ann Surg Oncol. 2015; 22: 3836-3845
        • Hofvind S.
        • Holen A.
        • Aas T.
        • et al.
        Women treated with breast conserving surgery do better than those with mastectomy independent of detection mode, prognostic and predictive tumor characteristics.
        Eur J Surg Oncol. 2015; 41: 1417-1422
        • Vila J.
        • Gandini S.
        • Gentilini O.
        Overall survival according to type of surgery in young (</=40 years) early breast cancer patients: A systematic meta-analysis comparing breast-conserving surgery versus mastectomy.
        Breast. 2015; 24: 175-181
        • Veronesi U.
        • Marubini E.
        • Del V.M.
        • et al.
        Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events.
        J Natl Cancer Inst. 1995; 87: 19-27
        • Gujral D.M.
        • Sumo G.
        • Owen J.R.
        • et al.
        Ipsilateral breast tumor relapse: local recurrence versus new primary tumor and the effect of whole-breast radiotherapy on the rate of new primaries.
        Int J Radiat Oncol Biol Phys. 2011; 79: 19-25
        • McGrath S.
        • Antonucci J.
        • Goldstein N.
        • et al.
        Long-term patterns of in-breast failure in patients with early stage breast cancer treated with breast-conserving therapy: a molecular based clonality evaluation.
        Am J Clin Oncol. 2010; 33: 17-22
        • Bartelink H.
        • Maingon P.
        • Poortmans P.
        • et al.
        Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial.
        Lancet Oncol. 2015; 16: 47-56
        • Vrieling C.
        • Van-Werkhoven E.
        • Poortmans P.
        • et al.
        The impact of pathological factors on long-term local control in the EORTC boost no-boost trial.
        Eur Cancer Congr. 2015; (abstract number: 2.15)
        • Bodilsen A.
        • Bjerre K.
        • Offersen B.V.
        • et al.
        The Influence of Repeat Surgery and Residual Disease on Recurrence After Breast-Conserving Surgery: A Danish Breast Cancer Cooperative Group Study.
        Ann Surg Oncol. 2015; 22: 476-485
        • Arvold N.D.
        • Taghian A.G.
        • Niemierko A.
        • et al.
        Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy.
        J Clin Oncol. 2011; 29: 3885-3891
        • Henson K.E.
        • Jagsi R.
        • Cutter D.
        • McGale P.
        • et al.
        Inferring the effects of cancer treatment: divergent results from Early Breast Cancer Trialists’ Collaborative Group meta-analyses of randomized trials and observational data from SEER registries.
        J Clin Oncol. 2016; 34: 803-809
        • Lyngholm C.D.
        • Laurberg T.
        • Alsner J.
        • et al.
        Failure pattern and survival after Breast Conserving Therapy. Long-term results of the Danish Breast Cancer Group (DBCG) 89 TM-cohort.
        Acta Oncol. 2016; ([Epub ahead of print]): 1-10https://doi.org/10.3109/0284186X.2016.1156741
        • Jensen A.R.
        • Overgaard J.
        • Storm H.H.
        Validity of breast cancer in the Danish Cancer Registry. A study based on clinical records from one county in Denmark.
        Eur J Cancer Prev. 2002; 11: 359-364
        • Pedersen C.B.
        The Danish Civil Registration System.
        Scand J Public Health. 2011; 39: 22-25
        • Mirza A.N.
        • Mirza N.Q.
        • Vlastos G.
        • et al.
        Prognostic factors in node-negative breast cancer: a review of studies with sample size more than 200 and follow-up more than 5 years.
        Ann Surg. 2002; 235: 10-26
        • Grantzau T.
        • Thomsen M.T.
        • Vaeth M.
        • et al.
        Second primary cancers after adjuvant radiotherapy in early breast cancer patients: A national population based study under the Bansih Breast Cancer Group (DBCG).
        Radiother Oncol. 2013; 106: 42-49
        • Buchholz T.A.
        • Tucker S.L.
        • Erwin J.
        • et al.
        Impact of systemic treatment on local control for patients with lymph node-negative breast cancer treated with breast-conservation therapy.
        J Clin Oncol. 2001; 19: 2240-2246
        • Mannino M.
        • Yarnold J.R.
        Local relapse rates are falling after breast conserving surgery and systemic therapy for early breast cancer: can radiotherapy ever be safely withheld?.
        Radiother Oncol. 2009; 90: 14-22
        • Aalders K.C.
        • Postma E.L.
        • Strobbe L.J.
        • van der Heiden-van der Loo
        • Sonke G.S.
        • Boersma L.J.
        • et al.
        Contemporary locoregional recurrence rates in young patients with early-stage breast cancer.
        J Clin Oncol. 2016;
        • Bartelink H.
        • Bourgier C.
        • Elkhuizen P.
        Has partial breast irradiation by IORT or brachytherapy been prematurely introduced into the clinic?.
        Radiother Oncol. 2012; 104: 139-142