Part IX · Early-stage disease: in situ, locally advanced, residual, and the neoadjuvant platform · Chapter 51

Locoregional recurrence

A potentially curable event whose biology has to be re-measured before anything is prescribed.

1 · Diagnostic confirmation and restaging

Biopsy before treating. A new nodule in a treated breast or on a chest wall has several possible explanations and only one of them is recurrence. Fat necrosis, post-radiation change, a suture granuloma, a new primary and a non-breast malignancy all present in similar ways on imaging.

The distinction between a true recurrence and a new ipsilateral primary is made on location relative to the original tumour bed, on histology and on receptor profile. It is frequently not resolvable. It matters less for the immediate treatment decision than the literature implies, and more for the prognosis that should be quoted to the patient.

Restaging is justified here for the same reason as in Definitions, presentation, and staging. The probability of concurrent distant disease at locoregional recurrence is high enough that finding it changes intent from curative to palliative. That is the criterion for ordering the investigation.

Circulating tumour DNA adds something at this point and what it adds is asymmetric. A positive plasma result raises the probability of occult distant disease substantially. A negative result does not exclude it, because shedding depends on burden and on site Biology of circulating tumor DNA, shedding, half-life, and detectability. The analogous experience in the residual disease setting is instructive. In c-TRAK TN, most patients with detectable circulating tumour DNA already had radiologically evident metastases by the time the result could be acted on1.

2 · Reassessment of tumor biology at recurrence

This is where receptor discordance stops being a conceptual problem and becomes a prescription.

Re-test oestrogen receptor, progesterone receptor and HER2 on the recurrence. The result governs systemic selection, and there are three separate reasons why it may differ from the primary. It may be true biological change. It may be assay variation, including different antibody clones, platforms and fixation. It may be sampling, because the primary and the recurrence are different pieces of tissue. Only the first is biology, and Receptor discordance and conversion sets out how the three are told apart.

The published discordance literature is dominated by distant metastases rather than by locoregional recurrence2. Rates taken from it should be applied here with that caveat attached rather than quoted as though the settings were equivalent.

HER2-low is the least stable of the routinely reported categories and it now determines eligibility. Among 547 patients with matched primary and relapse samples, overall HER2 discordance was 38.0%. Tumours scored HER2-0 became HER2-low in 15% of cases, and HER2-low became HER2-0 in 14%3. Two movements of similar size in opposite directions are the signature of measurement variation as much as of biology, and the design cannot separate the two components.

The practical consequence holds whichever explanation applies. The result on the recurrence is the result that determines what the patient can be offered. Repeating the test is justified by the decision it feeds, not by a claim about what changed Expression and alteration-defined treatment across subtypes.

3 · Salvage surgery

Complete excision with clear margins is the objective, and achieving it is the strongest modifiable predictor of subsequent local control.

Axillary restaging at recurrence is possible. Repeat sentinel node mapping succeeded in 80.4% of patients in one series, sparing most of them a completion dissection4. A systematic review put its feasibility at 64% and its negative predictive value at 96.5%5.

After breast-conserving surgery the standard salvage is mastectomy. A second breast conservation is possible in selected patients. In NRG Oncology/RTOG 1014, a single-arm phase 2 trial, 58 evaluable patients underwent a second lumpectomy followed by three-dimensional conformal partial breast reirradiation6. The five-year cumulative incidence of a further recurrence in the ipsilateral breast was 5%, with a 95% confidence interval of 1% to 13%. Seven patients subsequently underwent ipsilateral mastectomy, a five-year cumulative incidence of 10%. Distant metastasis-free survival and overall survival were both 95%. Grade 3 late adverse events occurred in four patients, which is 7%, with none of grade 4 or higher.

The selection should be read alongside those numbers. Eligibility required a unifocal recurrence under 3 cm, at least one year after the original breast-conserving therapy, clinically node negative, excised with negative margins. In 53 of the 58 patients the tumour was 2 cm or smaller. The result describes what is achievable in that population rather than in every in-breast recurrence.

After mastectomy the operation is excision of the chest wall recurrence, with a flap where primary closure is not achievable.

The axilla needs a plan in both situations. If it was never dissected, stage it. If it was dissected, imaging-directed sampling of an abnormal node is more useful than a repeat dissection.

4 · Radiation and reirradiation

If the field was never irradiated, irradiate it. That is the simple case and it applies to chest wall recurrence after a mastectomy given without radiation.

If the field was irradiated, reirradiation is possible and the constraints are cumulative. Skin and subcutaneous tissue, brachial plexus, heart, lung and any reconstruction all carry dose from the first course. The question is therefore not whether the patient has had radiation but how much, where, when and with what technique Reirradiation and metastatic applications.

Partial breast reirradiation after a second lumpectomy has prospective evidence behind it, with the control and toxicity figures given in Salvage surgery6. It is the only reirradiation strategy in this disease supported by a trial rather than by case series.

Hyperthermia is used as a radiosensitiser for chest wall recurrence. The supporting evidence is old and largely non-randomised, and availability of the technique varies widely between centres. Both of those facts belong in the discussion rather than only the first.

The case for treating local disease hard rests on a relationship measured elsewhere. After breast-conserving surgery, radiotherapy halved the ten-year recurrence rate and reduced the breast cancer death rate by about a sixth7. Roughly one death was avoided by year 15 for every four recurrences avoided by year 10. That was the primary setting. It supports taking local control seriously at recurrence. It is not evidence that salvage radiation delivers the same ratio.

Hyperthermia is the one adjunct to radiation with randomised support in superficial tumours of 3 cm depth or less, the category into which a chest wall recurrence usually falls. A thermal dose above a defined threshold improved local control, without an overall survival benefit8.

5 · Systemic therapy selection after locoregional recurrence

One randomised trial addresses whether chemotherapy helps after a completely excised isolated locoregional recurrence, and its final analysis is more useful than its first.

CALOR randomised 162 patients with completely excised isolated locoregional recurrence to chemotherapy or to no chemotherapy9. At a median follow-up of 4.9 years, five-year disease-free survival was 69% with chemotherapy against 57% without, with a hazard ratio of 0.59 and a 95% confidence interval of 0.35 to 0.99.

The final analysis at nine years of median follow-up separated the population10. Among 58 patients with oestrogen receptor negative recurrence, the hazard ratio for a disease-free survival event was 0.29, with a 95% confidence interval of 0.13 to 0.67, and ten-year disease-free survival was 70% against 34%. Among 104 patients with oestrogen receptor positive recurrence, the hazard ratio was 1.07, with an interval of 0.57 to 2.00, and ten-year disease-free survival was 50% against 59%. The interaction test gave P equal to 0.013.

Two things about that pattern are unusual. The subgroup effect strengthened with longer follow-up rather than regressing, which is the opposite of what usually happens to subgroup findings. And the direction is directly actionable, because it separates the patients for whom chemotherapy is worth its toxicity from those for whom it is not.

The limits are the denominators. Fifty-eight patients carry the positive result. Overall survival did not separate significantly in either group, with hazard ratios of 0.48 and 0.70 and intervals crossing one10.

In practice

For an oestrogen receptor negative isolated locoregional recurrence, offer chemotherapy10.

For an oestrogen receptor positive recurrence, endocrine therapy is the backbone and chemotherapy is not supported by this trial.

Select the endocrine agent on what the patient received before and how long ago, not on what is conventionally first.

For a HER2-positive recurrence, HER2-directed therapy is given by extrapolation from the adjuvant setting rather than from a trial conducted in this position. Say that it is an extrapolation.

Base every one of these decisions on the receptor result from the recurrence rather than from the primary Reassessment of tumor biology at recurrence.

6 · Curative intent, prognosis, and aligning with patient goals

An isolated locoregional recurrence is potentially curable and frequently is not cured. Both halves of that sentence belong in the conversation, and omitting either one produces a predictable failure.

The variables carrying prognosis are the interval since the primary, the receptor status of the recurrence, whether complete excision was achieved, and what systemic therapy the patient received the first time. In two randomised trials of mastectomy against breast conservation, an early locoregional recurrence marked a biologically aggressive tumour after either operation, and salvage cured only a limited number11. A recurrence during adjuvant treatment says something different from one appearing eight years after completing it De novo and recurrent metastatic disease as different populations.

Two failure modes recur. The first is treating a curable recurrence as palliative, on an unstated assumption that recurrence means incurable. The second is putting a patient with occult distant disease through salvage surgery, reirradiation and chemotherapy, when the distant disease will declare itself within months.

The second is harder to avoid, because the information that would prevent it does not exist at the time of the decision. Restaging lowers the probability and does not eliminate it Diagnostic confirmation and restaging.

In practice

Say the word curable if it applies, and say what the probability is rather than leaving it implied.

Say what the treatment will cost in time and in function before it starts, in weeks and in named losses.

Agree in advance what finding would end the curative attempt. New distant disease during salvage is the obvious one, and naming it beforehand makes it much easier to act on.

Ask what the patient is trying to protect. Six months of planned locoregional treatment is something they are spending, and what they are spending it for is theirs to say Communication and shared decision-making.

Interplay

Locoregional recurrence is temporal heterogeneity presenting as a lump. The tumour that recurs is the population that survived the first treatment, so its receptor profile is a measurement of what selection left rather than a re-measurement of what was originally there Therapy as selective pressure, the central premise. That is why the result from the recurrence governs and the result from the primary does not, and it is why HER2-low status moves in both directions between the two samples3. The specimen is new. The tumour is the old one, filtered.

See Integrative biological interplay

References

All 11 references
  1. Turner NC, Swift C, Jenkins B, et al. Results of the c-TRAK TN trial: ctDNA mutation tracking to detect molecular residual disease and trigger intervention in moderate- and high-risk early-stage triple-negative breast cancer. Ann Oncol 2023 34:200-211. PMID 36423745
  2. Schrijver WAME, Suijkerbuijk KPM, van Gils CH, et al. Receptor conversion in distant breast cancer metastases: a systematic review and meta-analysis. J Natl Cancer Inst 2018 110:568-580. PMID 29315431
  3. Miglietta F, Griguolo G, Bottosso M, et al. Evolution of HER2-low expression from primary to recurrent breast cancer. NPJ Breast Cancer 2021 7:137. PMID 34642348
  4. Cox CE, Furman BT, Kiluk JV, et al. Use of reoperative sentinel lymph node biopsy in breast cancer patients. J Am Coll Surg 2008 207:57-61. PMID 18589362
  5. Poodt IGM, Vugts G, Schipper RJ, Nieuwenhuijzen GAP. Repeat Sentinel Lymph Node Biopsy for Ipsilateral Breast Tumor Recurrence: A Systematic Review of the Results and Impact on Prognosis. Ann Surg Oncol 2018 25:1329-1339. PMID 29468606
  6. Arthur DW, Winter KA, Kuerer HM, et al. Effectiveness of breast-conserving surgery and 3-dimensional conformal partial breast reirradiation for recurrence of breast cancer in the ipsilateral breast: the NRG Oncology/RTOG 1014 phase 2 clinical trial. JAMA Oncol 2020 6:75-82. PMID 31750868
  7. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). 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. PMID 22019144
  8. Jones EL, Oleson JR, Prosnitz LR, et al. Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol 2005 23:3079-85. PMID 15860867
  9. Aebi S, Gelber S, Anderson SJ, et al. Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol 2014 15:156-163. PMID 24439313
  10. Wapnir IL, Price KN, Anderson SJ, et al. Efficacy of chemotherapy for ER-negative and ER-positive isolated locoregional recurrence of breast cancer: final analysis of the CALOR trial. J Clin Oncol 2018 36:1073-1079. PMID 29443653
  11. van Tienhoven G, Voogd AC, Peterse JL, et al. Prognosis after treatment for loco-regional recurrence after mastectomy or breast conserving therapy in two randomised trials (EORTC 10801 and DBCG-82TM). EORTC Breast Cancer Cooperative Group and the Danish Breast Cancer Cooperative Group. Eur J Cancer 1999 35:32-8. PMID 10211085