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Comparative effectiveness study of breast-conserving surgery and mastectomy in the general population: A NCDB analysis

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Oncotarget. 2015; 6:40127-40140. https://doi.org/10.18632/oncotarget.5394

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Kai Chen _, Jieqiong Liu, Liling Zhu, Fengxi Su, Erwei Song and Lisa K. Jacobs

Abstract

Kai Chen1,2,3,*, Jieqiong Liu1,2,3,*, Liling Zhu1,2, Fengxi Su1,2, Erwei Song1,2, Lisa K. Jacobs3

1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

2Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

3Departments of Surgery and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

*These authors have contributed equally to this work

Correspondence to:

Lisa K. Jacobs, e-mail: ljacob14@jhmi.edu

Kai Chen, e-mail: chenkai23@mail.sysu.edu.cn

Keywords: breast cancer, breast-conserving surgery, mastectomy

Received: August 12, 2015     Accepted: August 29, 2015     Published: October 19, 2015

ABSTRACT

Purpose: Recent studies have revealed that breast-conserving surgery (BCS) with radiotherapy (RT) led to better survival than mastectomy in some populations. We compared the efficacy of BCS+RT and mastectomy using the National Cancer Database (NCDB, USA).

Methods: Non-metastatic breast cancers in the NCDB from 2004–2011 were identified.The Kaplan-Meier method, Coxregression and propensity score analysis were used to compare the overall survival (OS) among patients with BCS+RT, mastectomy alone and mastectomy+RT.

Results: A total of 160,880 patients with a median follow-up of 43.4 months were included. The respective 8-year OS values were 86.5%, 72.3% and 70.4% in the BCS+RT, mastectomy alone and mastectomy+RT group, respectively (P < 0.001). After exclusion of patients with comorbidities, mastectomy (alone or with RT) remained associated with a lower OS in N0 and N1 patients. However, the OS of mastectomy+RT was equivalent to BCS+RT in N2–3 patients. Among patients aged 50 or younger, the OS benefit of BCS+RT over mastectomy alone was statistically significant (HR1.42, 95% CI 1.16–1.74), but not clinically significant (<5%) in N0 patients, whereas in N2–3 patients, the OS of BCS+RT was equivalent to mastectomy+RT (85.2% vs. 84.8%). The results of the propensity analysis were similar.

Conclusions: BCS+RT resulted in improved OS compared with mastectomy ± RT in N0 and N1 patients. In N2–3 patients, BCS+RT has an OS similar to mastectomy+RT when patients with comorbidities were excluded. Among patients aged 50 or younger, the OS of BCS+RT is equivalent to mastectomy ± RT.


Comparative effectiveness study of breast-conserving surgery and mastectomy in the general population: A NCDB analysis | Chen | Oncotarget

INTRODUCTION

The long-term survival of early-stage breast cancer patients is equivalent to either breast-conserving surgery (BCS) plus radiation therapy (RT) or modified radical mastectomy, as demonstrated in several prospective randomized controlled trials (RCTs) [16]. However, participants in RCT sare highly selected and may not represent the general population. Although RCT scan provide the least biased estimates for treatment comparisons, their results may not correspond to actual clinical situations [7]. In daily routine practice, physicians make decisions based on many uncontrolled factors and apply the results of RCTs to a broader range of patients. Therefore, observational studies are relied on to provide additional information regarding the comparative effectiveness of different treatments in the general population [7]. Abdulkarim, et al reported that in T1–2N0M0 triple-negative (TN) patients, modified radical mastectomy without RT significantly increased the risk of local failure compared with BCS+RT [8]. This interesting finding was also observed in Adkins’ study [9] but not in that by Zumsteg [10]. In addition, studies using data from national cancer registries [1113] reported similar findings: that BCS+RT was associated with improved survival compared with mastectomy alone or mastectomy with RT.

In general, the findings from observational studies suffer from selection bias. For example, it is possible that patients who receive BCS+RT are more likely to have fewer comorbidities, which contributes to its superior survival rates. Information about comorbidities was usually unavailable in previous studies [11, 13].Here, we retrospectively compared the long-term overall survival (OS) between BCS and mastectomy using the National Cancer Database (NCDB). The NCDB is a joint program of the Commission on Cancer of the American College of Surgeons and the American Cancer Society [7]. It includes more than 1,500 commission-accredited cancer programs in the United States and contains detailed tumor pathology information. Additionally, the insurance type, comorbidities (Charlson-Deyo score) and days of inpatient stay were collected, which enable us to identify patients with low/high comorbidities. We hypothesized that by using a large national cohort of breast cancer patients, this analysis would provide additional evidence in the relative effectiveness of the association between local therapy (BCS vs. mastectomy) and clinical outcomes. To minimize the influence of “confounding by indications”, we planned to perform subgroup analyses by comorbidities or age. We hypothesized that in patients with no/few comorbidities, or younger age, there would be no differences of OS between BCS and mastectomy.

RESULTS

We identified 160,880 patients who fit the inclusion and exclusion criteria. The median age was 60 years old, and 59.1%, 34.1% and 6.0% of the patients had AJCC Stage I, II and III disease, respectively. A total of 126,569(78.7%), 26,130(16.2%) and 8,181(5.1%) patients had received BCS+RT, mastectomy alone and mastectomy+RT, respectively. As shown in Table 1, patients in the BCS group were more likely to have private insurance, fewer comorbid diseases (CD score = 0), lower tumor burden (smaller tumor and/or negative nodes), and fewer hormone receptor-positive diseases. Additionally, BCS patients were wealthier and had a higher education level, and the majority of women (83.9%) received surgery at clinics without inpatient stays after surgery.

Table 1: Clinicopathological features of included patients

Surgery

P

BCS+RT n = 126,569

Mastectomy Alonen = 26,130

Mastectomy+RT n = 8,181

n

%

n

%

n

%

Facility Type

 1: Community Cancer Program

13,675

10.8

3,480

13.3

963

11.8

<0.001

 2: Comprehensive Community Cancer Program

76,163

60.2

16,039

61.4

4,850

59.3

 3: Academic/Research Program

36,500

28.8

6,582

25.2

2,358

28.8

 9: Other Specified Types Of Cancer Programs

231

0.2

29

0.1

10

0.1

Primary Payor

 0: Not Insured

2,048

1.6

632

2.4

307

3.8

<0.001

 1: Private Insurance

78,123

61.7

11,151

42.7

4,651

56.9

 2: Medicaid

6,573

5.2

1,963

7.5

898

11.0

 3: Medicare

38,745

30.6

12,173

46.6

2,253

27.5

 4: Other Government

1,080

0.9

211

0.8

72

0.9

City Type

 Metropolitan

109,539

86.5

21,269

81.4

6,807

83.2

<0.001

 Urban

15,167

12.0

4,190

16.0

1,223

14.9

 Rural

1,863

1.5

671

2.6

151

1.8

Distance

 <10_Miles

72,677

57.4

14,326

54.8

4,447

54.4

<0.001

 >10_Miles

53,892

42.6

11,804

45.2

3,734

45.6

Median Income Quartiles 2008–2012

 <$47999

43,364

34.3

11,675

44.7

3,520

43.0

<0.001

 $48000+

83,205

65.7

14,455

55.3

4,661

57.0

Percent No High School Degree 2008–2012

 >=13%

44,585

35.2

11,813

45.2

3,635

44.4

<0.001

 <13%

81,984

64.8

14,317

54.8

4,546

55.6

Age Group

 <=60

68,492

54.1

10,463

40.0

5,008

61.2

<0.001

 >60

58,077

45.9

15,667

60.0

3,173

38.8

Race

 White

109,050

86.2

21,731

83.2

6,525

79.8

<0.001

 African American

12,782

10.1

2,946

11.3

1,173

14.3

 Others

4,737

3.7

1,453

5.6

483

5.9

Charlson-Deyo Score

 0

109,623

86.6

20,216

77.4

6,785

82.9

<0.001

 1

14,559

11.5

4,662

17.8

1,129

13.8

 2

2,387

1.9

1,252

4.8

267

3.3

T-Stage

 T1

98,660

77.9

15,001

57.4

2,841

34.7

<0.001

 T2

27,909

22.1

11,129

42.6

5,340

65.3

N-Stage

 N0

98,236

77.6

17,756

68.0

1,236

15.1

<0.001

 N1

23,480

18.6

7,114

27.2

3,276

40.0

 N2

3,776

3.0

938

3.6

2,622

32.0

 N3

1,077

0.9

322

1.2

1,047

12.8

Stage

 I

82,728

65.4

11,725

44.9

689

8.4

<0.001

 II

39,022

30.8

13,148

50.3

3,845

47.0

 III

4,819

3.8

1,257

4.8

3,647

44.6

Grade

 I

30,644

24.2

4,213

16.1

744

9.1

<0.001

 II

54,309

42.9

11,114

42.5

3,180

38.9

 III

41,616

32.9

10,803

41.3

4,257

52.0

Estrogen Receptor

 Negative

24,873

19.7

7,218

27.6

2,205

27.0

<0.001

 Positive

101,696

80.3

18,912

72.4

5,976

73.0

Progesterone Receptor

 Negative

36,308

28.7

9,812

37.6

3,047

37.2

<0.001

 Positive

90,261

71.3

16,318

62.4

5,134

62.8

Laterality

 Right

62,677

49.5

12,643

48.4

4,018

49.1

<0.001

 Left

63,892

50.5

13,487

51.6

4,163

50.9

Primary Site

 Central

4,554

3.6

1,907

7.3

550

6.7

<0.001

 LIQ

8,133

6.4

1,669

6.4

415

5.1

 LOQ

9,714

7.7

2,063

7.9

694

8.5

 UIQ

308

0.2

162

0.6

38

0.5

 UOQ

35,575

28.1

8,962

34.3

2,977

36.4

 Nipple

17,925

14.2

3,014

11.5

650

7.9

 Others

50,360

39.8

8,353

32.0

2,857

34.9

Lymphovascular Invasion

 Negative

37,013

29.2

6,293

24.1

1,286

15.7

<0.001

 Positive

7,562

6.0

1,790

6.9

1,394

17.0

 Unknown

81,994

64.8

18,047

69.1

5,501

67.2

Chemotherapy

 No

68,989

54.5

14,128

54.1

1,156

14.1

<0.001

 Yes

57,580

45.5

12,002

45.9

7,025

85.9

Days Of Inpatient Stay

 0

106,199

83.9

5,537

21.2

2,126

26.0

<0.001

 1

14,138

11.2

13,287

50.8

3,965

48.5

 >1

6,232

4.9

7,306

28.0

2,090

25.5

BCS,breast-conserving surgery; RT, Radiation therapy; LIQ, lower-inner quadrant; LOQ, lower-outer quadrant; UIQ, Upper-inner quadrant; UOQ, Upper-outer quadrant; NS, non-significant;

Survival benefit of BCS over mastectomy in the entire study cohort

With a median follow-up of 43.4 months, the respective 5-year and 8-year OS values were 93.2% and 86.5% in the BCS+RT group, 83.5% and 72.3% in the mastectomy-alone group, and 83.0% and 70.4% in the mastectomy+RT group, respectively (log-rank test; P < 0.001). Univariate (Supplementary Table 1) and multivariate analyses (Supplementary Table 2A) revealed that mastectomy (alone or with RT) was significantly associated with a lower 5-year and 8-year overall survival in patients with N0, N1 and N2–3 disease compared with BCS+RT (Figure 1A1C, Table 2).

Kaplan-Meier survival analysis of the entire population A&#x2013;C. and in patients with &#x201C;Less/No comorbid conditions&#x201D; D&#x2013;F. Analysis were performed separately in N0 (A, D), N1 (B, E) and N2&#x2013;3 (C, F) patients.

Figure 1: Kaplan-Meier survival analysis of the entire population A–C. and in patients with “Less/No comorbid conditions” D–F. Analysis were performed separately in N0 (A, D), N1 (B, E) and N2–3 (C, F) patients.

Table 2: Survival benefit of BCS+RT over mastectomy+/-RT varied across patients with different comorbid diseases or age

Survival benefit of BCS over mastectomy in patients with fewer/no comorbidities

A total of 124,642 patients with a CD score of 0 and days of inpatient stay ≤1 were considered to have fewer/no comorbid diseases and were included in this analysis (Table 2, Figure 2). In N0 patients, BCS+RT (vs. mastectomy alone) increased the 5-year and 8-year OS by 5.0% and 7.8%, respectively. After adjustment, mastectomy alone (vs. BCS+RT) was significantly associated with a lower OS (HR 1.38, 95% CI 1.28–1.49) (Supplementary Table 2B). In N1 patients, mastectomy (alone or with RT) was significantly correlated with a lower OS (Table 2, Figure 2B). However, among N2–3 patients, mastectomy+RT (vs. BCS+RT) was no longer associated with a lower OS after adjustment (HR 1.12, 95% CI 0.97–1.28). The 5-year OS benefit of BCS+RT over mastectomy+RT was less than 5% (Figure 2A).

A. Improvement of OS in N0, N2&#x2013;3 patients. The benefit of 5-year and 8-year OS was calculated by comparing BCS+RT with mastectomy alone in N0 patients, and with mastectomy+RT in N2&#x2013;3 patients.

Figure 2: A. Improvement of OS in N0, N2–3 patients. The benefit of 5-year and 8-year OS was calculated by comparing BCS+RT with mastectomy alone in N0 patients, and with mastectomy+RT in N2–3 patients. B. Improvement of OS in N1 patients. The survival benefit of BCS+RT over mastectomy alone or with RT was shown as indicated. BCS, breast-conserving surgery; M, Mastectomy; RT, radiation therapy.

Survival benefit of BCS over mastectomy varied by age

Among patients aged 50 or younger, the 5-year and 8-year survival benefit of BCS+RT (vs. mastectomy alone or with RT) was significantly lower than that of patients with age ≥50yrs (Figure 2, 3 Supplementary Table 2C). BCS+RT over mastectomy alone was statistically significant (HR 1.42, 95% CI 1.16–1.74) but not clinically significant (5-year: 2.9%; 8-year: 4.8%) in N0 patients. In N1 and N2–3 patients, BCS+RT over mastectomy+RT was not significantly correlated with an improved OS (Table 2 Supplementary Table 2C). The survival benefit of BCS+RT vs. mastectomy (alone or with RT) in patients older than 50 were similar to the entire population (Table 2, Figure 2, 3 Supplementary table 2d).

Kaplan-Meier survival analysis of the patients with age &#x2264;50 A&#x2013;C. and age &#x003E; 50 D&#x2013;F. respectively.

Figure 3: Kaplan-Meier survival analysis of the patients with age ≤50 A–C. and age > 50 D–F. respectively. Analysis was performed separately in N0 (A, D), N1 (B, E) and N2–3 (C, F) patients.

Propensity score analysis of OS

We used propensity scores to create strata in which the possibility of having a specific treatment (BCS+RT vs. mastectomy ± RT) was similar for all patients in the same strata, regardless of their actual received treatment. Using a Cox-regression model stratified by propensity score quintile, we found that mastectomy alone (vs. BCS+RT) was associated with a worse OS in N0 (HR 1.75, 95% CI 1.66–1.85) and N1 patients(HR 1.73, 95% CI 1.60–1.88). Mastectomy+RT vs. BCS+RT was correlated with a lower OS in N1 patients (HR 1.24, 95% CI 1.10–1.39), but not in N2–3 patients (HR 1.09, 95% CI 0.98–1.21).

Survival benefit of post-mastectomy radiotherapy (PMRT)

In the entire cohort, the 5-year OS benefit of PMRT (mastectomy+RT vs. mastectomy alone) was 2.3%, 5.7% and 21.0% in N0, N1 and N2–3 patients, respectively (Table 2, Figure 1A-1C). After the exclusion of patients with comorbid conditions, the respective OS benefit of PMRT was less than 5% in N0 and N1 patients, and 15.9% in N2–3 patients (Table 2, Figure 1D-1F). Among patients aged 50 or younger, there was no benefit of PMRT in N0 and N1 patients, while in N2–3 patients, the OS benefit of PMRT was 11.3% (Table 2, Figure 3).

DISCUSSION

Recent studies of the comparative effectiveness of BCS+RT vs. mastectomy

Randomized controlled trials had demonstrated that BCS has an equivalent long-term survival to mastectomy [3, 4, 6, 1418] in early-stage breast cancer patients. The comparative effectiveness of BCS+RT vs. mastectomy in non-clinical-trial population has been investigated in administrative, observational database. Hwang, et al [13] identified 112,154 stage I and II breast cancer patients from the large population-based prospective California Cancer Registry. The authors observed that women who underwent BCS+RT had improved breast cancer specific survival(BCSS) and OS compared with those treated by mastectomy, and the survival benefit of BCS+RT was greater among “ ≥50yrs & HR+” women. Brooks, et al [19] used the instrumental variable method to study the SEER-Medicare database and reported that higher mastectomy rates were associated with reduced survival. Other studies using data from national cancer registries in Norway [12], Canada [20] and the US [11, 21] reported similar findings (Table 3).

Table 3: Comparative effectiveness studies comparing clinical outcomes of patients receiving BCS and mastectomy in non-clinical trial population

Fisher et al [20]. used data from Alberta Cancer Registry (Canada) and showed that the survival benefit of BCS+RT vs. mastectomy was less significant in stage I patients, than in stage II or III patients. The underlying reason may due to the low risk of relapse events in stage I patients, rendering the survival advantages of BCS+RT less likely to be noted. However, there were two limitations of their study: 1) They did not distinguish patients who received PMRT from those who did not. Additionally, they stratified the analysis by cancer stage, rather than N-stage. Thus, in the stage II strata that contained both node-negative and node-positive patients, the comparison of BCS vs. mastectomy was significantly confounded by the unknown PMRT status. 2) The proportion of patients with non-standard treatment (e.g. PMRT in N0 patients after mastectomy, or no PMRT in N2–3 patients after mastectomy) in their mastectomy group was unknown. Therefore, the accuracy and generalizability of their results were influenced.

In our study, we stratified the survival analysis by N-stage. We compared BCS+RT vs. mastectomy alone, BCS+RT vs. mastectomy alone vs. mastectomy+RT, BCS+RT vs. mastectomy+RT in N0, N1 and N2 patients, respectively. We believe that our design is clearer in purpose and more informative for clinical practices. Our study showed that in N0 patients that PMRT is not recommended, BCS+RT had better OS than mastectomy alone; whereas in N2–3 patients that PMRT is routinely performed, BCS+RT has equivalent OS to mastectomy+RT after adjustment (Table 2, Figure 1). These results suggested the importance of RT in the comparison of BCS and mastectomy using administrative database.

The impact of comorbid conditions and age

Confounding by indication is the major limitation for most retrospective studies. Specifically, patients with fewer comorbid conditions are more likely to receive BCS+RT and these patients are more likely to have better OS than those with many comorbidites. Land. et al [22] determined that patients with more comorbid conditions were more likely to die from breast cancer as well as other causes, using data from the Danish Breast Cancer Cooperative Group Registry. A study by Hwang et al [13] using the California Cancer Registry database showed that patients who received BCS+RT were less likely to die from cardiovascular disease, or chronic lower respiratory diseases. They inferred that mastectomy patients were more likely to have comorbid diseases, which may have influenced the surgical decision. Hence, we performed subgroup analysis by excluding patients with severe comorbidities. In the NCDB, the Charlson-Deyo (CD) score has been used to describe comorbid conditions. We defined patients with CD score = 0 (no comorbid conditions) and days of inpatient stay ≤1 as “low/no comorbidity” patients. In this subgroup of women, the 5-year OS benefit of BCS+RT was 5.0% in N0 patients (vs. mastectomy alone), and 2.9% in N2–3 patients (vs. mastectomy+RT). Compared with the results derived from our entire study population, the survival benefit of BCS+RT over mastectomy (alone or with RT) was decreased, suggesting that the significant survival benefit of BCS+RT in previous studies might be partially due to comorbid conditions. Subgroup analysis in patients with comorbidities was not performed, because the effect of “confounding by indication” may be more significant in these patients.

Survival analysis was also stratified by age. As shown in Table 2 and Figure 3, the 5-year and 8-year OS benefit of BCS+RT was less than 5% in patients aged 50 or younger, regardless of nodal status. The survival advantages of BCS+RT in patients older than 50 were similar to the entire population. Our result is consistent with previous studies. A population-based study by Cao et al [23] found that 965 patients aged 20 to 39 years with breast cancer treated from 1989 to 2003 showed no difference in the 15-year rates of BCSS. Similar results were observed in other studies [24, 25]. The findings from these studies, together with ours, reveal the oncological safety of BCS+RT, particularly in young patients.

Benefit of less extensive surgery: is it possible?

More extensive surgery may theoretically lead to better or at least equivalent outcomes as less extensive surgery in cancer treatment. Is it possible that the opposite may be true? Studies in animal models have suggested that the surgical trauma of normal tissue promotes the implantation or growth of circulating tumor cells [2629]. Thus, with mastectomy, would a larger wound produce more cytokines to activate the distant dormant tumor cells? There is evidence from clinical studies indicating such a possibility. A randomized controlled trial published in Lancet [30] compared the efficacy of laparoscopy-assisted colectomy and open colectomy for the treatment of non-metastatic colon cancer in terms of tumor relapse and CSS. With lesser surgical treatment, laparoscopy-assisted colectomy had a significantly higher CSS. Further studies of these hypothesis and exploration of the underlying mechanisms are needed.

Benefit of PMRT

The benefit of PMRT in patients with N1 disease is controversial. A subgroup analysis of DBCG 82 randomized trials [31] suggested a similar OS benefit of RT in patients with N1 and N2–3 disease. Likewise, an EBCTCG meta-analysis using individual data from 22 trials [32, 33] revealed that PMRT reduced the rate of mortality in breast cancer patients, which was independent of the number of lymph nodes involved. The National Comprehensive Cancer Network (NCCN) guidelines [34] also recommend strong consideration of PMRT in N1 patients. However, our study demonstrated that PMRT was associated with an improved 5-year OS in N2–3 patients rather than N0 or N1 patients (Table 2). Our study was not the first to question the need for PMRT in N1 patients. He, et al [35] reported that, in patients with T1–2 and N1 diseases, the survival benefit of PMRT was present only in high-risk patients. Huo, et al [36] analyzed 93,793 and 36,299 T1–2N1 breast cancer patients in the NCDB and SEER database and showed that PMRT improved OS among patients with 3 positive nodes or 2 positive nodes with tumors 2–5 cm in size, but had no benefit in patients with 1 positive node or 2 positive nodes with tumor ≤2 cm. McBride, et al [37] also observed that the benefit of PMRT on local control was highly dependent on the era of treatment: PMRT reduced the risk of 5-year LRR in patients treated in an early era (1978–1998), but not in those treated in a later era (2000–2007), when the use of sentinel lymph node surgery, taxane chemotherapy, and aromatase inhibitors was routine. Taken together, we may reconsider the benefit of PMRT on OS among N1 breast cancer patients. Further randomized controlled studies addressing this issue are warranted.

Limitations

In this observational study, we were not able to retrieve information such as multifocality, EIC, HER2 status, BRCA status, body-mass index, detailed chemotherapy, endocrine therapy, targeted therapy and cancer-specific survival (CSS) from the NCDB. Thus, the selection biases cannot be completely diminished, although we used propensity score analysis. 1) BRCA mutation-positive patients would tend to receive mastectomy. However, a recent study showed that the 10-year OS is similar between patients with or without the BRCA mutation [38]. In addition, HER2 status is not expected to be associated with the choice of surgery (mastectomy vs. BCS). Therefore, the failure to match for BRCA status or HER2 status would not have a significant impact on our analysis. 2) Patients with positive margins, who were converted to mastectomy from BCS, were likely associated with multifocal DCIS or EIC. Hence, the inability to match for multifocality is a major limitation of this study. 3). Lack of information of BCSS in the NCDB is another limitation of our study. However, a summary of previous studies [8, 9, 12, 20] showed that the survival benefit of BCS+RT (over mastectomy) on BCSS was similar to that of OS (Table 3). Thus, we think that OS is also a valid endpoint for our study. 4) We are not able to ensure that the chemotherapy treatments were completely comparable between groups.

MATERIALS AND METHODS

Data collection

We searched the NCDB registry data between 2004 and 2011 and identified female patients with a T1–2N0–3M0 infiltrating duct breast carcinoma diagnosis. The following information was collected: facility type (community cancer program, comprehensive community cancer program, academic/research program, other program); primary payer (not insured, private insurance, Medicaid, Medicare, other government); city type (metropolitan, urban, rural); distance to hospital; median income of the state/area (2008–2012) where the patient lived; the percentage of population without a high school degree of the state/area where the patient lived; age; race; T stage; N stage; AJCC stage; laterality (left or right breast); estrogen receptor (ER) status; progesterone receptor (PR) status; grade; surgery of primary site; radiation; survival (months); vital status; primary site (LIQ, lower-inner quadrant; LOQ, lower-outer quadrant; UIQ, Upper-inner quadrant; UOQ, Upper-outer quadrant; nipple; others); days of inpatient stay; Charlson-Deyo (CD) score; lymphovascular invasion status; chemotherapy(administered as first course treatment); and hormonal therapy (administered as first course treatment). For the breast surgery code,we used the NAACCR item #1290 coding rules (breast, C50.0–C50.9, http://ncdbpuf.facs.org/?q=content/breast). We defined codes 20–24 as BCS and codes 41 and 51 as mastectomy.

The data within the NCDB are rendered anonymous; therefore, the study was exempt from the Johns Hopkins Medicine Institutional Review Board review, and no consent was required.

Inclusion and exclusion criteria

We had rigorous inclusion and exclusion criteria for patient selection. All of the included patients met the following inclusion and exclusion criteria.

Inclusion criteria

  1. Female, T1–2N0–3M0 breast cancer patients, diagnosis after 2004.

  2. Infiltrating ductal breast carcinoma (histology coding 8500) with confirmed pathology diagnosis.

  3. Patients with grossly and microscopically negative margins.

Exclusion criteria

  1. Patients with previous diagnosis of breast cancer or any malignant tumors (In this study, patients with the sequence number code of 00 or 01 were included)

  2. Patients with pure DCIS or stage 0 disease.

  3. Patients with unknown information for any of the included variables, except for lymphovascular invasion.

  4. Patients with bilateral breast cancers.

  5. Patients with a pathological tumor size larger than 5 cm.

  6. Patients with a history of RT.

  7. Patients who did not receive RT after BCS.

  8. Patients who received hormone therapy for ER- and PR- disease.

  9. Patients who did not receive hormone therapy for ER+ or PR+ disease.

Statistical analyses

The chi-square test was used to compare the demographic and clinicopathological features of patients among three groups: the BCS + RT group; the mastectomy-alone group; and the mastectomy + RT group. Kaplan-Meier survival analysis and an unadjusted Cox proportional hazards model were used to compare the overall survival (OS) of patients who received the different treatments, as a univariate approach. Significant factors revealed by univariate analysis were incorporated into multivariate analysis (adjusted Cox proportional hazards model) and the model was used through out the entire study. In subgroup analysis, we planned to assess the effect of surgery type on OS in patients stratified by N-stages, comorbidities and ages. The variables that were used for stratification were not included in the multivariate model during subgroup analysis.

Propensity analysis was used to compare treatment groups within strata to minimize selection bias or a lack of covariate balance. We considered that age, facility type, primary payer, primary sites, income, urban type, education, distance to hospital, CD score, race, tumor grade, ER, PR, T stage and N stage were all potential determinants for the choice of surgery. Thus, all of these variables were included as conditioning variables in a logistic model, with surgery type (BCS+RT vs. mastectomy alone or RT) as the outcome variable. The propensity score was then calculated as the probability of receiving a mastectomy (alone or with RT) for each individual. We stratified the patients into quintiles, in which patients had a similar likelihood of having received a given treatment. Using the Cox model, we estimated the effect of different treatments (BCS+RT, mastectomy alone or mastectomy+RT) on OS, with the baseline survival function varied across strata by including quintiles of the propensity scores as stratification variables.

All P values are two sided. P values <0.05 were considered statistically significant. A survival difference larger than 5% was considered clinically significant. Statistical analyses were performed using Stata/MP, version 13.0 (StataCorp LP, College Station, TX, USA).

CONCLUSIONS

This analysis of a large national cohort of patients demonstrates that BCS+RT provides a superior OS to mastectomy (alone or with RT) in N0 and N1 patients, regardless of comorbid conditions. In N2–3 patients, the survival benefit of BCS+RT (vs. mastectomy+RT) was eliminated when patients with comorbid conditions were excluded. Among patients aged 50 or younger, the BCS+RT OS is equivalent to mastectomy (alone or with RT). Because mastectomy is significantly more invasive than BCS+RT, we recommend greater efforts at educating patients to undergo BCS+RT rather than mastectomy in our routine practice, particularly for low-risk N0/N1 women.

ACKNOWLEDGMENT AND FUNDING

The data used in the study was derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology used or the conclusions drawn from these data by the investigator. This study was supported by the National Natural Science Foundation of China (Grant# 81402201), National Natural Science Foundation of Guangdong Province (Grant# 2014A030310070), and Grant [2013]163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

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