Supplementary table 1. PRISMA checklist (Moher et al. 2009)

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Supplementary table 1. PRISMA checklist (Moher et al. 2009)

Section/topic # Checklist item Reported

on page #

TITLE

Title 1 Identify the report as a systematic review, meta-

analysis, or both.

1

ABSTRACT

Structured Summary 2 Provide a structured summary including, as applicable:

background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

2

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known.

3 Objectives 4 Provide an explicit statement of questions being

addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

3

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

3

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

3-4

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

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Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

4

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

4

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

4

Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

5

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).

4

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.

4

Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

4

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

4

RESULTS

Study selection 17 Give numbers of studies screened, assessed for

eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram

5

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

5

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

5

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for

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each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

5

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

5

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their

relevance to key groups (e.g., healthcare providers, users, and policy makers).

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Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

8

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

8

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

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Supplementary Table 2. Risk of bias and quality assessment of observational studies per outcome using the NewCastle Ottawa tool: Cohort studies

Study Representativ eness exposed

cohort

Selection of non- exposed cohort

Ascertain ment of exposure

Absence of outcome of interest at

start of study

Compara bility of cohorts on

the basis of design or analysis

Assessm ent of outcome

Follow- up enough

for outcome to occur

Adequ acy of follow up of cohorts

Score Quality

Sanges * * * * ** * - - 7 Medium

Corso * * * * ** * * * 9 High

Li * * * * - * - - 5 Low

He * * * * ** * - - 7 Medium

Kim * * * * ** * * * 9 High

Millis * * * * ** * - - 7 Medium

Supplementary Table 3. Characteristics of variables for each study included.

First author (year)

Variables IDC, N(%) MBC, N(%) P value*

Sanges (2020)

- Age

<35 35-49 50-69 70+

Missing - Tumor size

pT0 pT1 pT2 pT3 pT4 pTx Tis Missing

- Lymph node status pN0

pN+

Missing - Metastasis

M0 M1

34 (4.6) 214 (28.8) 354 (47.6) 141 (19.0) 1 (0.1)

1 (0.13) 285 (38.3) 337 (45.3) 32 (4.3) 43 (5.8) 18 (2.4) 1 (0.13) 27 (3.6)

395 (53.1) 270 (36.3) 79 (10.6)

649 (87.2) 95 (12.8)

3 (6.5) 8 (17.4) 26 (56.5)

9 (19.6) 0 (0)

0 13 (28.3) 22 (47.8) 9 (19.6)

2 (4.3) 0 0 0

30 (65.2) 15 (32.6) 1 (2.2)

41 (89.1) 5 (10.9)

0.38

0.02

0.42

0.88

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- TNM stage I

II III IV Missing

- Lymph-node ratio

<0.2 0.21-0.65

>0.65 Missing

- Proliferation index (Ki-67)

<14%

15-30%

≥30%

Missing

- Type of surgery Matectomy Quadrantectomy Lumpectomy Missing

- Adjuvant chemotherapy Yes

No

- Adjuvant radiotherapy Yes

No

188 (25.3) 306 (41.1) 137 (18.4) 28 (3.8) 85 (11.4)

520 (69.9) 75 (10.1)

47 (6.3) 102 (13.7)

54 (7.3) 110 (14.8) 542 (72.8) 38 (5.1)

244 (32.8) 342 (46)

14 (1.9) 144 (19.4)

436 (58.6) 308 (41.4)

258 (34.7) 468 (62.9)

10 (21.7) 24 (52.2) 9 (19.6)

2 (4.3) 1 (2.2)

38 (82.6) 5 (10.9)

1 (2.2) 2 (4.3)

2 (4.3) 5 (10.9) 38 (82.6)

1 (2.2)

19 (41.3) 21 (45.7) 2 (4.3) 4 (8.7)

29 (63.0) 17 (37.0)

19 (41.3) 27 (58.7)

0.29

0.16

0.51

0.18

0.66

0.53

Corso (2020)

- Age

<40 40-49 50-59 60-69 70+

- Tumor size pT0 pT1 pT2 pT3

- Lymph-node status pN0

15 (13.3) 22 (19.5) 28 (24.8) 29 (25.7) 19 (16.8)

41 (36.3) 67 (59.3) 5 (4.4)

82 (72.6)

15 (13.3) 26 (23.0) 27 (23.9) 24 (21.2) 21 (18.6)

41 (36.3) 67 (59.3) 5 (4.4)

82 (72.6)

>0.05

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pN+

- Proliferation index (Ki-67)

<20%

≥20%

Missing

- Type of surgery and radiotherapy Mastectomy without radiotherapy Mastectomy with radiotherapy

Mastectomy with radiotherapy unknow Quadrantectomy without radiotherapy Quadrantectomy with radiotherapy

Quadrantectomy with radiotherapy unknow - Adjuvant systemic treatment

No adjuvant therapy ET

CT CT+ET Missing

31 (27.4)

6 (5.3) 106 (93.8)

1 (0.9)

13 (11.5) 14 (12.4)

0 (0) 9 (8.0) 77 (68.1)

0 (0)

11 (9.7) 1 (0.9) 92 (81.4)

8 (7.1) 1 (0.9)

31 (27.4)

8 (7.1) 105 (93.0)

0 (0)

27 (23.9) 13 (11.5) 5 (4.4) 12 (10.6) 55 (48.7) 1 (8.8)

5 (4.4) 1 (0.9) 103 (91.2)

4 (3.5) 0 (0)

>0.05

0.01

0.24

Kim (2020) . . .

Millis (2018)

- Age (mean ± SD) - Tumor size (mean ± SD) - Pathologic stage

I II III IV - LVI

- Locoregional treatment

Lumpectomy without radiotherapy Lumpectomy with radiotherapy Mastectomy without radiotherapy Mastectomy with radiotherapy - Chemotherapy

58.2 (± 13.5) 26.4

(±26.4mm) 303541 (47.2) 270100 (42.0) 58521 (9.1) 10932 (1.7) 152413 (23.7)

50161 (7.8) 273316 (42.5) 218652 (34.0) 100323 (15.6) 509975 (79.3)

63 (±14.2) 40

(±33.7mm) 988 (26.8) 2230 (60.5)

369 (10.0) 99 (2.7) 597 (16.2)

324 (8.8) 1220 (33.1) 1467 (39.8) 675 (18.3) 2694 (73.1)

0.001

<0.001

He (2019)

- Age

18-49 6430 (30.2)

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≥50 - Tumor size

≤2 cm

>2 cm Unknown - T stage

T1 T2/T3 T4 Tx

- Node status Negative Positive Unknown - Metastasis

M0 M1

- AJCC stage I

II/III IV

- Radiation therapy None/unknown Done

- Chemotherapy None/unknown Done

14891 (69.8)

9208 (43.2) 11831 (55.5)

282 (1.3)

9100 (42.7) 10787 (50.6)

1335 (6.3) 99 (0.5)

12441 (58.4) 7810 (36.7)

70 (0.3)

20178 (94.6) 1143 (5.4)

7560 (35.5) 12618 (59.2)

1143 (5.4)

10805 (50.7) 10516 (49.3)

5113 (24.0) 16208 (76.0)

.

Li (2019)

- Age, median (IQR) - Tumor size

≤2

>2 and ≤5

>5

- Lymph node status pN0

pN+

Unknown - Grade

I II

56.26 (20-79)

8437 (44.9) 7771 (41.3) 2588 (13.8)

12312 (65.5) 6429 (34.2)

56 (0.3)

296 (1.6) 3027 (16.1)

59.5 (26-79)

154(26.3) 298 (50.9) 134 (22.8)

431 (73.5) 152 (25.9)

3 (0.5)

20 (3.4) 81 (13.8)

<0.01

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IDC, invasive ductal carcinoma; MBC, metaplastic breast cancer.

P*value extracted from 𝑋

²

square tests.

Supplementary Figure 1. Funnel plot related to OS scenario III

Undifferentiated carcinoma - AJCC stage

I II III IV

- Chemotherapy No/Unknown Yes

- Radiotherapy No

Yes Unknown

15324 (81.5) 149 80.8)

6802 (36.2) 8060 (42.9) 2717 (14.5) 1217 (6.5)

13659 (72.7) 5138 (27.3)

8291 (44.1) 8553 (45.5) 1932 (10.3)

465 (79.4) 20 (3.4)

138 (23.5) 326 (55.6) 84 (14.3)

38 (6.5)

397 (67.7) 189 (32.3)

274 (46.8) 277 (47.2) 35 (6.0)

<0.01

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Supplementary Figure 2. Funnel plot related to DFS scenario