# Supplementary Material S7 — GRADE Summary of Findings (SoF) Table

**Umbrella review:** Axillary management after neoadjuvant chemotherapy in node-positive breast cancer
**Framework:** GRADE (Guyatt 2008; GRADE handbook, 2024 update)
**Bodies of evidence:** 33 included systematic reviews + pivotal primary trials (Z1071, RISAS, KEYNOTE-522, NEOSENTI-TURK, OPBC-07, Montagna 2024)

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## Patient/population, intervention, comparison

- **Population:** Adult women with biopsy-proven node-positive (cT1-4 / cN1-3) primary breast cancer scheduled for neoadjuvant systemic therapy (NAC, with or without HER2-targeted agents and immune checkpoint inhibition).
- **Intervention:** Targeted axillary dissection (TAD = SLNB + clipped-node biopsy) following NAC, with omission of axillary lymph node dissection (ALND) when ypN0.
- **Comparator:** Routine ALND (or SLNB-only without targeted clip retrieval).
- **Setting:** Multidisciplinary breast cancer centers, Europe / North America / Asia / Oceania.

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## Summary of Findings table

| # | Outcome (timeframe) | Effect estimate (anchor SRs / trials) | № of SRs (≈ participants) | Certainty (GRADE) | Reasons for downgrade / upgrade | Importance |
|---|---|---|---|---|---|---|
| 1 | **Nodal pathologic complete response (ypN0), overall** at surgery after NAC | ~37–40% (range across SRs 30–45%) — Samiei 2021 *JAMA Surg* (n=57,531) 37%; An 2025 *Ann Surg Oncol* NCDB (n=47,483) 40.0%; Z1071/Boughey 2013 41.0%; Chen 2021 37.3% | 12 SRs (≈ 88,000 cumulative; deduplication caveat) | **Moderate ⊕⊕⊕○** | –1 risk of bias (all SRs Critically Low on AMSTAR-2 conservative scoring; 32/33 no protocol; 33/33 no list of excluded studies) | Critical |
| 2 | **ypN0 in HR-/HER2+ subtype** | 65.7% (95% CI 53.1–76.4%) — Samiei 2021 60%; van Amstel 2024 RISAS 72%; Mukhtar 2025 lobular HER2+ 72.7% | 6 SRs (≈ 12,000) | **Moderate ⊕⊕⊕○** | –1 risk of bias (AMSTAR-2). Heterogeneity I²=90% expected from regimen mix (single vs dual HER2 blockade); direction unequivocal | Critical |
| 3 | **ypN0 in HR+/HER2- subtype** | 21.2% (95% CI 13.8–31.1%) — Samiei 2021 18%; Vasigh 2024 NAC 14.9%; van Amstel 2024 7%; Boughey 2022 cohort 24.8%; Omranipour 2020 39% | 8 SRs (≈ 30,000) | **Low ⊕⊕○○** | –1 risk of bias (AMSTAR-2); –1 inconsistency (I²=99.9%; pooled range 7–39%, fivefold variability beyond what regimen alone explains; Boughey 2022 sub-cells span 2.6–35.8% on Ki67/age strata) | Critical |
| 4 | **ypN0 in TNBC subtype** (chemo-only era / chemo-IO era) | Chemo-only: 48.0% (95% CI 47.6–48.4%, I²=0%) — Samiei 2021 48%; Chen 2021 50.8%; van Amstel 2024 45%; Mukhtar 2025 IDC TNBC 51.2%. Chemo-IO: 67–86% — KEYNOTE-522 Kuemmel 2026 pembro 76.7% vs control 69.9%; Woodfin 2023 86%; Perry 2025 67% | 7 SRs (≈ 15,000); chemo-IO data largely from primary trials, only Abdulla 2026 and Wang 2025 begin pooling chemo-IO era | **Low ⊕⊕○○** | –1 risk of bias (AMSTAR-2); –1 indirectness (existing SRs predominantly predate KEYNOTE-522; chemo-IO standard of care not yet integrated in pooled SR estimates) | Critical |
| 5 | **False-negative rate (FNR) of TAD vs SLNB-only** | TAD 1.4–4.2% (Boughey 2016 with clipped-node retrieval 1.4%; Caudle 2016 MDACC 1.4%; Simons 2022 RISAS 3.4%; deWild 2024 BJS pooled 4512 patients) **vs** SLNB-only 12.6% (Z1071 12.6%; SN FNAC 8.4%; SENTINA 14.2%; GANEA-2 11.9%) | 5 SRs (Simons 2019, Swarnkar 2021, Pantiora 2023, deWild 2024, Boland 2025) + 4 prospective trials (≈ 4,500 TAD-evaluated patients) | **Moderate ⊕⊕⊕○** | –1 risk of bias (AMSTAR-2; possible selection in retrospective TAD cohorts); **+1 large effect** (relative FNR reduction ≈ 70–90%, RR ≈ 0.2–0.3, meeting GRADE threshold). Boland 2025 I²=24.3% (low) | Critical |
| 6 | **5-year axillary recurrence after omitting ALND in TAD-confirmed ypN0** | 1.0% (95% CI 0.49–2.0%) — anchored on Montagna 2024 *JAMA Oncol* multicenter cohort n=1144; supported by 4 SRs and OPBC-07 (Lancet Oncol 2025, n=1585 ypN1mi subset) | 4 SRs + 1 dominant prospective multicenter cohort (≈ 1,500–2,000 specifically followed for this outcome) | **Low ⊕⊕○○** | –1 risk of bias (Montagna dominates; selection by ypN0; AMSTAR-2 limitations of supporting SRs); –1 indirectness (single dominant cohort; limited generalizability to chemo-IO era and to centers without standardized clip retrieval) | Critical |
| 7 | **5-year locoregional recurrence (TAD-confirmed ypN0)** | ~2.7% (range across SRs 1.5–4.5%); NEOSENTI-TURK Cabioglu 2025: 5-yr DSS 98.7% cN1 vs 96.8% cN2-3 | 4 SRs (Simons 2019, deWild 2024, Boland 2025, Abdulla 2026); ≈ 6,000 participants | **Low ⊕⊕○○** | –1 risk of bias (AMSTAR-2; retrospective dominance); –1 imprecision (low event rate; CIs wide in absolute terms when stratified; many cohorts <5-yr median follow-up) | Important |
| 8 | **Overall survival, TAD vs ALND** | No statistically significant difference at median follow-up ~36 months (HR clusters around 1.0; CIs cross unity) | 2 SRs (Simons 2019, Abdulla 2026) + retrospective registry NEOSENTI-TURK | **Very Low ⊕○○○** | –1 risk of bias (AMSTAR-2 + selection: ypN0 = favorable-prognosis cohort by definition); –1 indirectness (36-mo follow-up too short for OS in a low-risk cohort; relevant horizon is 5–10 yr); –1 imprecision (few events, wide CIs, OIS not met) | Critical |

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## Legend

- ⊕⊕⊕⊕ **High** — We are very confident that the true effect lies close to the estimate.
- ⊕⊕⊕○ **Moderate** — We are moderately confident; the true effect is likely close, but there is a possibility it is substantially different.
- ⊕⊕○○ **Low** — Our confidence is limited; the true effect may be substantially different from the estimate.
- ⊕○○○ **Very Low** — We have very little confidence; the true effect is likely to be substantially different.

**Importance** (per GRADE handbook §5.1.2):
- **Critical** — outcome essential for the recommendation (ypN0 rates, FNR, axillary recurrence, OS).

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## Notes

1. **Risk of bias anchoring.** The –1 for risk of bias across all outcomes reflects the conservative AMSTAR-2 abstract-only scoring (33/33 SRs Critically Low). After full-text rescoring (planned before final manuscript submission), it is likely that several SRs — particularly Yu 2024, Wang 2025, Sabine de Wild 2024, Pantiora 2023 — will move to Low or Moderate confidence; if so, the –1 risk-of-bias downgrade may become 0 for outcomes where these SRs are the primary contributors. The certainty levels in this table will be updated accordingly.
2. **Cumulative N.** Where indicated, the participant count is approximate and not de-duplicated across SRs (the same primary cohorts — e.g., NCDB, MDACC, Z1071 — appear in multiple SRs).
3. **Publication bias** was not assessable because 24/33 SRs did not report funnel plots or Egger's test (AMSTAR-2 item 15). No empirical signal of asymmetry was identified in the SRs that did assess it; we therefore did not downgrade for this domain in any outcome.
5. **Two reviewers** (S. Cervera Bonet, D. Duque) independently rated every outcome. Inter-rater agreement was high; disagreements (1 in domain coding for Outcome 4 indirectness) resolved by discussion.

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## References

1. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. *BMJ* 2008;336:924–926. doi:10.1136/bmj.39489.470347.AD
2. Schünemann HJ, Brożek J, Guyatt GH, Oxman AD, eds. *GRADE Handbook*. Updated 2024. https://gdt.gradepro.org/app/handbook/handbook.html
3. Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2. *BMJ* 2017;358:j4008.
4. Pollock M, Fernandes RM, Becker LA, et al. Chapter V: Overviews of Reviews. *JBI Manual for Evidence Synthesis* 2024.

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*Generated as part of `paper_umbrella/06_supplementary/`. Linked from main manuscript Methods §2.4 (Certainty assessment) and Results §3.6 (Summary of Findings).*
