Breast
Five datasets on late and locoregional risk after mastectomy or lumpectomy + WBI. Four are prognostic or retrospective and one is randomized (SAKK 23/82). All feed PMRT and regional nodal RT selection.
EBCTCG 20-year recurrence after 5 years of endocrine therapy
ForER+ T1-T2, 0-9 nodes, disease-free after 5y adjuvant endocrine therapy
TL;DRAfter stopping endocrine therapy at 5y, distant recurrence in years 5-20 ran from 13% (T1N0) to 41% (T2N4–9), at a steady annual rate.
In ER+ T1-T2 early breast cancer disease-free at 5 years, this frames the extension discussion around TN status, with T1N0 still carrying 13% distant risk over years 5 to 20; it does not address genomic-assay-selected or trastuzumab-treated HER2+ pts. The longer read
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EBCTCG individual patient data meta-analysis of 88 trials. Kaplan-Meier and Cox regression, stratified by trial and treatment, from year 5 to year 20.
62,923 women with ER-positive T1-T2 disease, 0-9 positive nodes, diagnosed before age 75, scheduled to stop endocrine therapy at 5 years and event-free at year 5. 63% tamoxifen, 17% AI, 20% a tamoxifen-AI sequence; all had lymph-node dissection.
Distant recurrence, any breast-cancer event (distant, locoregional, contralateral), and death from breast cancer by log-rank subtraction.
Recurrences continued at a steady rate from year 5 to 20 in every TN category. Given TN status, grade and Ki-67 carried only moderate independent value after year 5; PR and HER2 status were not predictive.
| Nodal status | T1 | T2 |
|---|---|---|
| N0 | 13% | 19% |
| N1–3 | 20% | 26% |
| N4–9 | 34% | 41% |
| Grade | Distant recurrence | Any recurrence or contralateral BC |
|---|---|---|
| Low | 10% | 17% |
| Moderate | 13% | 22% |
| High | 17% | 26% |
| Nodal status | Distant recurrence | Death from breast cancer |
|---|---|---|
| N0 | 22% | 15% |
| N1–3 | 31% | 28% |
| N4–9 | 52% | 49% |
The source restates EBCTCG data that 5y tamoxifen cut recurrence by about 30% in years 5-10 versus no therapy. Extension trials such as ATLAS and MA.17 test the intervention; this analysis supplies the untreated baseline risk that their proportional benefit acts on.
Grade and Ki-67 were often locally assessed, and Ki-67 was available in only 7692 pts. Few pts received trastuzumab (2%), and treatment eras predate modern staging and systemic therapy.
No TN subgroup had a late risk low enough to dismiss extension outright, even low-grade T1N0 at 10% distant recurrence. Whether extension actually lowers mortality, and in whom it outweighs toxicity, is left to randomised data.
Large multi-trial IPD prognostic analysis, not a randomised test of extension. Quantifies baseline late risk; extended-therapy benefit must come from separate randomised trials.
- Does a genomic low-risk score identify pts safe to stop at 5 years?
- Does extended endocrine therapy reduce breast-cancer mortality, not just recurrence?
- How much do modern-era treatments lower these late risks?
📚 Sources · 📄 1 paper
SAKK 23/82
ForGood-risk ILRR after mastectomy, post excision + RT, TAM-naive
TL;DR5-yr DFS 61% vs 40% with tamoxifen after excision + RT for good-risk post-mastectomy ILRR; OS unchanged (median 11.5 vs 11.2 yr, P=0.79).
For the RT reader, failure after excision plus 5000 cGy at 200 cGy/fx was mostly further local recurrence, and TAM mainly reduced that, not distant spread. Endocrine therapy works here as a local-control partner to chest wall RT. ILRR is also not always a metastatic marker: about 30% stayed relapse-free on local therapy alone.
In a postmenopausal woman with ER+ isolated chest wall or nodal recurrence after mastectomy, resected and irradiated, this supports adding endocrine therapy for DFS. It does not cover premenopausal pts, who gained no DFS, or pts who already had adjuvant TAM. The longer read
Even after excision plus 5000 cGy at 200 cGy/fx, further local recurrence was the dominant failure, and TAM mainly reduced it. The trial supports full-dose curative-intent RT for good-risk ILRR combined with endocrine therapy as a local-control partner, not a replacement.
The DFS gain from TAM was confined to postmenopausal women (5-yr 61% vs 33%, P=0.006) and did not translate into OS. Because pts with prior adjuvant TAM were excluded, the trial does not say which agent to use for today's endocrine-pretreated ER+ ILRR.
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Phase III randomized, central telephone randomization at SAKK, stratified by menopausal status, adjuvant chemo and axillary nodes at diagnosis. 178 randomized, 11 ineligible (6%). Median f/u 11.6 yr for surviving pts.
Good-risk ILRR after mastectomy: first recurrence in the ipsilateral chest wall, shoulder, neck or upper arm, or in regional nodes. Eligibility required an ER+ recurrence, or ER unknown with DFI >12 mo and <4 nodules ≤3 cm. Pts with prior adjuvant TAM were excluded.
Every pt had radical excision, then 5000 cGy at 200 cGy/fx, 5 days a week, to the involved region. RT was fixed across arms, so the trial tests systemic therapy added to full local therapy.
Tamoxifen 20 mg/d orally until progression vs observation.
DFS favored TAM (log-rank P=0.053, Gehan-Wilcoxon P=0.008), with no OS difference (P=0.79). The benefit was confined to postmenopausal pts (5-yr DFS 61% vs 33%, P=0.006). In the multivariate model, TAM and DFI >12 mo predicted longer DFS.
| Endpoint | TAM | Observation | P |
|---|---|---|---|
| Median DFS | 6.5 yr | 2.7 yr | 0.053 log-rank; 0.008 Gehan-Wilcoxon |
| 5-yr DFS | 61% | 40% | n/a |
| Median OS | 11.5 yr | 11.2 yr | 0.79 |
| 5-yr OS | 73% | 79% | n/a |
| Subgroup | TAM | Observation | P |
|---|---|---|---|
| Premenopausal DFS | 60% | 60% | n/a |
| Postmenopausal DFS | 61% | 33% | 0.006 |
| Premenopausal OS | 67% | 90% | 0.175 |
| Postmenopausal OS | 75% | 75% | n/a |
No deaths from pulmonary embolism or endometrial cancer attributable to TAM in either menopausal group.
The authors describe this as the only randomized trial of systemic therapy for ILRR to reach its accrual goal. IBCSG Trial 27 was opened to test chemotherapy vs local treatment alone in LRR, a question this trial does not address.
The early-weighted test carries the DFS result while log-rank misses 0.05. The menopausal split rests on small subgroups. Receptor status was not determined in about a third of pts.
The DFS benefit has persisted since the first analysis, but OS is unchanged, possibly because there were few events and competing mortality in postmenopausal pts. The premenopausal OS deficit with TAM is unexplained and nonsignificant, so it reads as noise more than harm.
Mature phase III, but small, 1980s accrual, borderline log-rank DFS and no OS gain. Backs current endocrine therapy after resected ILRR without defining it for TAM-pretreated pts.
- Aromatase inhibitor benefit after ILRR in tamoxifen-pretreated pts
- Role of chemotherapy for poor-risk ILRR
- Optimal RT dose and volume after ILRR excision
📚 Sources · 📄 1 paper
Node-negative post-mastectomy LRR and prognostic factors
ForNode-negative breast, T1-3, mastectomy + ALND, no PMRT
TL;DR10y LRR 6.0% overall in N0 post-mastectomy pts without PMRT, rising to 40.6% with 3 risk factors (size >2 cm, margin <2 mm, premenopausal, LVI).
Chest wall was the failure site in 80.4% of total LRRs, which is the basis for the authors' chest wall-only field proposal in high-risk N0. The 3-factor stratum (10y LRR 40.6% ± 13.8%) sits near the node-positive LRR range where PMRT gained survival, but its wide error makes it a threshold argument, not an indication.
In node-negative pts after mastectomy with T2+ tumor, deep margin <2 mm and LVI (or premenopausal with any 2 of these), this supports discussing chest wall PMRT; it does not extend to N0 pts with 0 or 1 factors (10y LRR 1.2% and 10.0%). The longer read
Chest wall was the failure site in 80.4% of total LRRs, supporting chest wall-only fields over regional nodal coverage in high-risk N0. The 3-factor stratum (10y LRR 40.6% ± 13.8%) frames a risk threshold for discussing PMRT, not proof of benefit.
13 details 1 trial watching
Retrospective single-institution cohort (Massachusetts General Hospital), 1980-2000, identified via tumor registry and breast center databases. Median f/u 100 mo. LRR estimated by cumulative incidence (CIF); KM results reported as slightly higher, not substantially different.
877 node-negative invasive cases (870 pts) after mastectomy + axillary dissection, no PMRT; T4 excluded. Median age 64, median 15 nodes examined. Systemic therapy in 276 cases (148 hormones alone, 74 chemo alone, 54 both).
Total LRR (first event, with or without simultaneous distant mets) and isolated LRR (no distant mets for ≥4 mo). Only total LRR reported for prognostic factors.
10y total LRR 6.0%. Size >2 cm, deep margin <2 mm, premenopausal status and LVI independent on MVA with similar HRs (range 2.6 to 3.8). 3 factors: 10y LRR 40.6%; only 1 pt had all 4.
| Risk factors | 10y LRR |
|---|---|
| 0 | 1.2% ± 0.9% |
| 1 | 10.0% ± 2.9% |
| 2 | 17.9% ± 7.5% |
| 3 | 40.6% ± 13.8% |
| Factor | Adverse | Favorable | p |
|---|---|---|---|
| Deep margin | Close 22%, positive 21% | Negative 5.1% | <0.001 |
| LVI | Present 19.8% | Other 5.0% | 0.0001 |
| Tumor size | >2 cm 11% | ≤2 cm 3.1% | 0.001 |
| Menopausal status | Pre 11.1% | Post 5.1% | 0.01 |
| Grade | G3 10%, G2 5.3% | G1 0% | 0.03 |
| Site | Isolated LRR | Total LRR |
|---|---|---|
| Chest wall | 28 (87.5%) | 37 (80%) |
| Axilla | 2 (6%) | 3 (7%) |
| Supraclavicular | 1 (3%) | 5 (11%) |
| IMC | 1 (3%) | 1 (2%) |
No RT delivered. Chest wall was the site in 87.5% of isolated and 80.4% of total failures, so the authors propose chest wall-only PMRT without regional nodes for high-risk N0 to limit toxicity.
Converges with the IBCSG analysis of 1,275 N0 women on size, LVI and menopausal status, and adds margin status, which IBCSG could not assess. The M. D. Anderson series (141 N0 pts) did not report absolute LRR for its N0 subset.
Most cases (601/877) had no systemic therapy, so absolute risks likely overstate the modern setting. Receptor subtype not reported. LVI not recorded was pooled with absent, and the risk count assumes equal weights.
Authors suggest considering PMRT for postmenopausal pts with all 3 of T2+, close/positive margin and LVI, and premenopausal pts with any 2. Benefit of PMRT in these strata is inferred from risk level, never tested.
Retrospective single-institution 1980-2000 cohort with no PMRT arm; stepwise risk model unvalidated, high-risk strata small with wide SEs. Defines who might benefit, not benefit itself.
- Does chest wall-only PMRT reduce LRR in high-risk node-negative pts? recruiting Trial Evaluating Role of Post Mastectomy Radiotherapy in Women With Node Negative Early Breast Cancer Phase NAn=1022 · primary completion 2028-12 · PMRT in pT1-2N0 with adverse prognostic factors
- Do modern systemic therapy and receptor subtype lower these LRR estimates?
- Can biomarkers refine LRR risk beyond clinicopathologic factors?
📚 Sources · 📄 1 paper
NSABP B-15/B-16/B-18/B-22/B-25 IBTR and LRR prognosis
ForNode-positive breast, lumpectomy + WBI + adjuvant chemo and/or tamoxifen
TL;DRAfter lumpectomy + WBI in node-positive pts, IBTR (HR 2.58) and other LRR (HR 5.85) predicted death; 5-yr OS 59.9% vs 24.1%.
Supraclavicular failure is the RT-relevant read: it made up 81 of 165 oLRRs and carried 5-yr DDFS 12.1% vs 31.5% after axillary recurrence. oLRR reached 14.6% at 10 yrs with ≥10 positive nodes, so nodal burden frames the regional-field question after BCS; field design was not reported in source.
In a node-positive pt with an isolated in-breast or regional recurrence after lumpectomy and WBI, this supports treating the event as a marker of high distant risk when weighing restaging and systemic options; it does not describe recurrence risk under taxane or HER2-directed therapy. The longer read
Supraclavicular failure dominated oLRR (81 of 165) and had 5-yr DDFS 12.1%, while oLRR hit 14.6% at 10 yrs with ≥10 nodes. This frames the regional-field question after BCS in node-positive disease, though WBI technique and nodal coverage were not reported in source.
An oLRR carried mortality HR 5.85 and an IBTR 2.58, with 5-yr DDFS 18.8% and 51.4% after each, so a locoregional relapse signals high distant risk. Whether chemotherapy at relapse helps was unresolved; regimens predate taxanes and HER2-directed therapy.
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Pooled secondary analysis of 5 NSABP node-positive adjuvant trials (B-15, B-16, B-18, B-22, B-25). Cumulative incidence for IBTR and oLRR; IBTR and oLRR entered Cox models as time-varying covariates. Median time on study 13.3 yrs.
Of 10,010 women entered, 2,669 had breast-conserving surgery and were eligible. Negative margins were required; about two thirds had 1-3 positive nodes. B-18 contributed only its postoperative chemotherapy arm.
AC, CMF, PF/PAF and tamoxifen-based adjuvant regimens from 1984-1994, including AC cyclophosphamide intensification in B-22 and B-25. Pts aged >50 received tamoxifen in several protocols; premenopausal women did not receive tamoxifen irrespective of ER status.
All pts received whole-breast irradiation after lumpectomy. Dose, fractionation, boost and any regional nodal coverage are not reported in source.
Cumulative incidence of IBTR and oLRR; DDFS and OS after each event; mortality modeled with clinical factors plus IBTR or oLRR.
oLRR carried roughly double the mortality hazard of IBTR (HR 5.85 vs 2.58), and supraclavicular recurrence had the poorest DDFS. Arm-level values are in the detail table.
| Endpoint | IBTR | oLRR |
|---|---|---|
| Pts with event | 259 (9.7%) | 165 (6.2%) |
| 10-yr cumulative incidence | 8.7% | 6.0% |
| Events within 5 yrs | 62.2% | 80.6% |
| 5-yr DDFS after event | 51.4% | 18.8% |
| 5-yr OS after event | 59.9% | 24.1% |
| Mortality HR (time-varying Cox) | 2.58 (95% CI 2.11-3.15) | 5.85 (95% CI 4.80-7.13) |
| Adjusted HR, distant disease | 2.72 | 6.68 |
| Protocol | Pts at risk | 10-yr IBTR % | 10-yr oLRR % |
|---|---|---|---|
| B-15 | 624 | 10.0 | 7.6 |
| B-16 | 340 | 4.8 | 5.4 |
| B-18 | 210 | 9.1 | 8.7 |
| B-22 | 596 | 10.1 | 6.1 |
| B-25 | 899 | 8.3 | 4.5 |
| Total | 2,669 | 8.7 | 6.0 |
Consistent with the NSABP B-06 IBTR literature the authors cite and with the EBCTCG overview linking local failure to breast cancer mortality. The supraclavicular-dominant oLRR pattern is the population later addressed by randomized RNI trials such as MA.20 and EORTC 22922.
Lumpectomy was not the randomized variable, so the 2,669-pt subset is self-selected. Site-specific DDFS estimates rest on small numbers with wide CIs, and no HER2 or RT technique data are available.
oLRR clusters with nodal burden and receptor negativity, the same drivers of distant failure, so it may flag disseminated disease rather than cause it. Later IBTRs fared better, consistent with the authors' view that many are new primaries. The role of chemotherapy at recurrence was unresolved at publication.
Post-hoc pooled analysis of a non-randomized lumpectomy subset; LRR is a prognostic marker here, not a tested intervention target. Pre-taxane, pre-HER2 era therapy.
- Does regional nodal RT reduce supraclavicular failure in this population?
- Does chemotherapy at isolated locoregional recurrence improve survival?
- Can molecular profiling separate true IBTR from new ipsilateral primaries?
📚 Sources · 📄 1 paper
Abstract
T1-2N1 mastectomy without PMRT (MSKCC)
ForT1-2N1 breast, mastectomy + ALND, no neoadjuvant chemo
TL;DR10y LRR 7.0% without PMRT vs 4.0% with it (p=0.32) in T1-2N1 after mastectomy; age <40 + LVI reached 28% without PMRT.
The RT read is the no-PMRT stratification: 10y LRR 28% for age <40 with LVI vs 2% for ≥40 without LVI. Supraclavicular nodes carried 27% of LRRs and the axilla only 15.9%, so where PMRT is chosen for the high-risk stratum, the regional field targets where these pts actually failed.
In a woman ≥40 with T1-2N1, no LVI, after mastectomy with completion ALND and no neoadjuvant chemo, this supports omitting PMRT; it does not extend to a positive-sentinel axilla left undissected or to post-NAC pts. The longer read
Without PMRT, 10y LRR spans 2% (≥40, no LVI) to 28% (<40, LVI), defining whom to offer RT. Supraclavicular nodes carried 27% of LRRs versus 15.9% axillary involvement, supporting chest wall plus SCV coverage when PMRT is chosen.
The low LRR without PMRT rests on ALND in 94.2% with a median 18 nodes removed; the authors state omission does not apply to positive sentinel nodes without completion ALND. For women <40 with LVI, they suggest axillary RT may replace completion ALND.
13 details 4 trials watching
Single-institution retrospective cohort from a prospectively maintained database, mastectomy 1995-2006. PMRT given at physician discretion. Median follow-up 10.8 yr.
T1-2N1 (1-3 positive nodes), N=1087. Excluded T3/T4, neoadjuvant chemotherapy, and isolated tumor cells. Median age 51, median tumor 1.8 cm; 58% had one positive node.
All PMRT pts received chest wall RT; supraclavicular field in 137/163 (84%), axilla 7 (4%), IMN 6 (4%). Dose and fractionation not reported in source.
Systemic therapy in 98%; chemo 88%, mostly anthracycline and/or taxane. All ER+ pts received hormone therapy; trastuzumab in 51/123 HER2-amplified.
Without PMRT, age <40 (HR 4.15) and LVI (HR 3.47) independently predicted LRR. Chest wall (51%) and supraclavicular nodes (27%) dominated failure sites.
| Endpoint | PMRT (n=163) | No PMRT (n=924) | p |
|---|---|---|---|
| LRR | 4.0% | 7.0% | 0.32 |
| RFS | 75% (95% CI 69-82) | 73% (95% CI 69-76) | 0.46 |
| OS | 81% (95% CI 73-86) | 80% (95% CI 77-82) | 0.44 |
| Subgroup | 5-yr LRR | 10-yr LRR |
|---|---|---|
| <40, LVI | 15% | 28% |
| <40, no LVI | 6% | 11% |
| ≥40, LVI | 6% | 8% |
| ≥40, no LVI | 1% | 2% |
The EBCTCG 1-3 node subset showed 20.3% 10-yr LRR without PMRT, versus 7.0% here, a gap the authors attribute to modern systemic therapy and thorough ALND (median 18 nodes). EORTC 22922 included lumpectomy and stage I-III pts, limiting direct comparison.
Dose and target-volume data absent, so the 4.0% PMRT LRR cannot be tied to a technique. Pathology not re-reviewed, and HER2-directed therapy was incomplete in the cohort. The 10-yr LRR 28% subgroup CI as printed (11.0-22.1) excludes its own estimate.
The useful product is a risk filter for omission, not a PMRT efficacy estimate. It shows age and LVI separating a 2% from a 28% 10-yr LRR in unirradiated pts, which is the decision a T1-2N1 consult turns on.
Retrospective, non-randomized; PMRT selected for higher-risk pts, so null LRR/RFS/OS difference cannot estimate PMRT effect. Risk-stratification value lies in the no-PMRT cohort only.
- Does age/LVI risk stratification hold after SLNB without completion ALND? n=82 · primary completion 2024-12 · upfront mastectomy, 1-2 SN macromets, LRC with RTn=1900 · primary completion 2026-07 · 1-2 SN macromets, no axillary tx, age-stratified, incl…recruiting The T-REX Trial: Tailored Regional External Beam Radiotherapy in Clinically Node-negative Breast Cancer Patients With 1-2 Sentinel Node Macrometastases. Phase NAn=1350 · primary completion 2028-12 · randomised omission of regional RT, cN0 1-2 SN macromets
- Should intermediate-risk T1-2N1 pts (one of age <40 or LVI) receive PMRT? n=1106 · primary completion 2026-12 · phase 3 PMRT vs no PMRT in pN1, 7y DFS non-inferiority
- Does modern HER2-directed therapy lower LRR further without PMRT?