Part IX · Early-stage disease: in situ, locally advanced, residual, and the neoadjuvant platform · Chapter 50

Locally advanced and inflammatory breast cancer

A category defined by anatomy at presentation, and the group that four decades of progress reached last.

1 · Definitions, presentation, and staging

Locally advanced breast cancer is an administrative grouping rather than a biological one. It collects tumours defined by anatomical extent at the moment of presentation. Large primaries, matted or fixed nodal disease, direct extension to skin or chest wall, and inflammatory carcinoma all fall inside it.

What the category records is the relationship between the tumour and what surgery could achieve on the day it was assessed. That is a statement about anatomy and about a surgical judgement. It is not a statement about growth rate, receptor subtype or metastatic potential.

Two different populations are merged by this definition. One arrived late because the tumour grew slowly over a long unobserved interval. The other arrived late because it grew quickly. They share a stage and they do not share a natural history. Nothing in the T and N categories separates them. The only variable that does is the reported duration of symptoms, which is recalled rather than measured.

Staging practice differs from early disease for a defensible reason. The probability of occult distant disease rises steeply with nodal burden, so systemic imaging is justified here where it is not justified in a small node-negative tumour Systemic staging, when it helps and when it harms. In a retrospective series of 41 women with inflammatory disease, FDG PET/CT at diagnosis showed locoregional and distant disease that informed staging1. A review of locally advanced and inflammatory disease sets out the same staging logic2. Finding distant disease changes intent completely, and that is the criterion which should govern any staging investigation.

The measurement problem in this chapter begins at the clinical examination. Skin oedema, erythema, fixation and nodal matting are all assessed by eye and hand. No reproducibility study supports any of them, and the categories they feed are the ones that define the group.

2 · Inflammatory breast cancer biology

Inflammatory breast cancer is diagnosed clinically. The requirements are rapid onset over weeks to a few months, erythema and oedema involving a substantial proportion of the breast, and pathological confirmation of invasive carcinoma3. Dermal lymphatic tumour emboli support the diagnosis. Their absence does not exclude it, because a punch biopsy samples a small area of skin.

The name is a misnomer that has survived for a century. There is no infection and the erythema is not primarily inflammatory. It is the surface appearance of obstructed dermal lymphatics, and the obstruction is produced by tumour emboli sitting inside them.

The biology of those emboli runs against the standard account of dissemination. In a transplantable human xenograft that reproduces the phenotype, the emboli carried an intact and overexpressed E-cadherin and alpha,beta-catenin adhesion axis rather than a disrupted one4. The cells grew as compact spheroids at high density. Antibodies against E-cadherin dissolved the pulmonary emboli, and a dominant-negative E-cadherin construct abolished embolus formation altogether. Increased membrane E-cadherin and catenin staining was present in 90% of the human inflammatory carcinomas examined in the same study.

That makes this a cohesion phenotype rather than a dissociation phenotype. Most of Metastatic dissemination and organ tropism describes spread in terms of loosened adhesion and mesenchymal transition. Here the cells travel as adherent aggregates, which is closer to the circulating cluster biology in5 than to single-cell invasion.

Expression profiling finds the same intrinsic subtypes in inflammatory disease as in other breast cancers6,7. The subtypes do not explain the phenotype, because the genes that separate inflammatory from non-inflammatory disease are different from those that define the subtypes. A hyperproliferative phenotype was found in one of the largest molecular analyses8. HER2 positivity is common, at 52% in one series9. In a registry of 2,014 inflammatory cancers, HER2 positivity was associated with advanced stage and was not an independent adverse factor for survival10. Before trastuzumab, HER2 status carried prognostic weight, and trastuzumab at recurrence improved survival in the HER2-positive group11.

Incidence is low, it rose across the 1990s, and it is not evenly distributed. Between 1988 to 1990 and 1997 to 1999, United States registry incidence rose from 2.0 to 2.5 per 100,000 woman-years, while rates for non-inflammatory locally advanced disease fell from 2.5 to 2.012. Incidence over that period was higher in Black women than in White women, at 3.1 against 2.2 per 100,000 woman-years.

3 · Multimodality sequencing

The standard sequence is systemic therapy, then surgery, then radiation. All three, in that order, for almost everyone in this group.

The reason for putting systemic therapy first is not mainly to shrink the tumour. It is that a large fraction of these patients already carry disseminated disease below the resolution of imaging. Operating first treats the visible problem and leaves the invisible one growing. Response also yields information that is otherwise unavailable, which is the argument developed in The neoadjuvant setting as a scientific platform.

The case for combined modality treatment is historical. Treated with local therapy alone, most women died within two years, and combined chemotherapy, surgery and radiation left 35% to 55% alive and disease-free at five years13. Over 20 years at one centre, 178 patients were treated with chemotherapy, mastectomy, further chemotherapy and radiotherapy, and an estimated 28% were free of disease beyond 15 years14. A population analysis of 485 patients found that mastectomy improved locoregional control and modern chemotherapy improved breast cancer-specific survival15. Adding paclitaxel to anthracycline regimens improved outcome in ER-negative disease in an institutional series16.

Response decides how much the operation contributes. Mastectomy gave no survival or local-control benefit to patients with no significant response to induction chemotherapy17. Patients whose axillary nodes were cleared by chemotherapy had better long-term survival than those with residual nodal disease18. A systematic review found that the lack of uniform diagnostic criteria limits comparison of treatment outcomes across studies19.

Outcome remains worse than for other locally advanced cancers. In 1,071 patients from ten trials, inflammatory disease carried a worse prognosis and an early, distinctive pattern of recurrence20. In a population-based comparison of the modern era, the hazard ratio for death against non-inflammatory stage III disease was 1.4321. About a third of women become long-term survivors22.

HER2-directed therapy entered the preoperative regimen through small phase II studies in locally advanced disease, some of which enrolled inflammatory cancers. They combined trastuzumab with paclitaxel, with docetaxel, with docetaxel and cisplatin, or with docetaxel and vinorelbine23,24,25,26. Lapatinib was tested the same way in inflammatory disease itself. In 42 women with HER2-expressing tumours, lapatinib was given alone for 14 days and then with weekly paclitaxel for 12 weeks27. The pathological complete response rate was 18.2%, and the combined clinical response rate was 78.6%. Grade 3 diarrhoea occurred in 55%. The current HER2 regimens are in Neoadjuvant therapy.

Trimodality treatment is associated with better survival and it is not delivered to everyone. In a National Cancer Database analysis of 10,197 patients who underwent surgery for non-metastatic inflammatory breast cancer between 1998 and 2010, the proportion receiving all three modalities ranged between 58.4% and 73.4% by year28. Five-year and ten-year survival were highest in the trimodality group, at 55.4% and 37.3%. Patients who were older, treated earlier in the period, on lower incomes, publicly insured or more comorbid were significantly less likely to receive all three.

Two features of the surgery follow from the biology rather than from the trial data.

Surgery for inflammatory disease is modified radical mastectomy. Breast conservation and skin-sparing techniques are not appropriate, because the skin and its lymphatics carry the disease3.

Post-mastectomy radiation is given regardless of the pathological response, including after a complete response. That is a deliberate exception to the response-adapted reasoning of The neoadjuvant setting as a scientific platform, and it rests on observed patterns of failure rather than on a randomised comparison within this population.

Caution

The trimodality survival difference is observational. Patients who receive all three modalities are patients who responded well enough to be operated on and were well enough to complete radiation. Some of the gap is selection and some of it is treatment, and the analysis cannot separate the two28. What the finding supports is not omitting a modality without a stated reason. It does not license quoting the difference as an effect size.

4 · Assessment of operability and response

Operability is a surgical judgement about whether a complete resection can be achieved and the wound closed. It is not a prognosis and it is not a statement about curability. Treating those as interchangeable is the commonest error in this setting.

Response assessment here is harder than in early disease, and each modality fails differently. Clinical measurement of a diffusely infiltrated breast has no reliable edges. Mammography is limited by density and by oedema. Ultrasound underestimates scattered residual disease. Magnetic resonance imaging performs best of the four and still misclassifies in both directions, by overcalling treatment-related enhancement and by undercalling scattered residual cells.

Skin findings are the specific trap in inflammatory disease. Erythema and oedema can persist after the tumour has cleared, because lymphatic drainage recovers slowly. They can also settle while viable emboli remain. The skin is a slow and indirect read-out of the quantity being measured.

The endpoint that carries prognostic weight is pathological, and it is obtained after surgery rather than before it. Residual cancer burden gives more information than a binary complete response and is prognostic across every subtype29,30. What that measurement can and cannot support is developed in The neoadjuvant setting as a scientific platform.

In practice

Record, before the first cycle, what will be used to judge response.

The extent of skin involvement, photographed or drawn rather than described in words.

A named imaging modality with a named baseline date, to be repeated with the same modality.

Which finding would trigger an early surgical opinion rather than completion of the planned regimen.

A tumour that progresses on the first regimen is not a tumour to be pushed through the rest of it.

5 · Management of persistent unresectable disease

Some patients finish planned systemic therapy with a chest wall that still cannot be resected. That is a defined clinical situation and it needs a stated goal before the next decision is made.

Three options exist and they can be combined. Change the systemic class, on the reasoning that the failure was of that class rather than of systemic therapy in general Treatment selection and sequencing principles. Give radiation first, accepting that it complicates any subsequent operation. Or accept that local control rather than resection is now the objective.

Preoperative radiation in this position is a reasonable strategy and the evidence supporting it is not randomised. Dose and fractionation are chosen against a chest wall that will later be operated on or one that will not, and those are different plans. Technique is covered in Reirradiation and metastatic applications.

Local control remains worth pursuing where cure is not available. Uncontrolled chest wall disease produces ulceration, odour, bleeding and pain, and it carries one of the worst symptom burdens in this disease Malignant effusions and chest wall disease. Treatment that prevents that is doing real work whatever the survival curve shows.

Caution

Unresectable frequently means unresectable by the surgeon who assessed the patient on that day. Chest wall resection with myocutaneous reconstruction changes the answer for some patients, and the assessment has to be made by a surgeon who performs it. The opposite failure runs the other way. Pursuing operability through successive regimens can consume the months in which the patient was well, and nothing recovers them.

6 · Locoregional control and reconstruction considerations

Reconstruction decisions in this group are governed by the radiation plan rather than by the mastectomy.

In inflammatory disease immediate reconstruction is generally deferred. There are two reasons and they are separable. The skin is part of the disease, so the tissue that immediate reconstruction preserves is the tissue under suspicion. And an immediate reconstruction constrains the post-mastectomy radiation plan at exactly the point where that plan matters most. Delayed reconstruction after radiation is the usual route3.

The surgical rules for inflammatory disease are stricter than for other locally advanced cancers. Mastectomy alone was followed by local recurrence in 20% and a median survival of two years31. Chemotherapy, mastectomy and radiotherapy together achieve local control in about 80%, and breast-conserving surgery and sentinel node biopsy are contraindicated. The sentinel node is unreliable here for a measurable reason. In a small study of sentinel biopsy after neoadjuvant chemotherapy, the false-negative rate was 14% overall and 6% once inflammatory cancers were excluded32. Combined-modality treatment changed the natural history of the disease, with five-year survival of 35% to 60% reported in older series33.

In non-inflammatory locally advanced disease immediate reconstruction is possible. The condition is that the radiation plan is agreed before the operation rather than negotiated afterwards.

Axillary management also differs from early disease. The trials supporting omission of dissection enrolled populations from which this group was excluded, so ACOSOG Z0011 and AMAROS do not transfer to matted or fixed nodal disease Axillary staging and the long retreat from dissection. Axillary dissection remains standard here.

The reason to take locoregional control seriously is that it carries a mortality consequence and not only a symptom one. The trialists' meta-analysis of radiotherapy after breast-conserving surgery covered 10,801 women in 17 randomised trials34. Radiotherapy reduced the 10-year risk of any first recurrence from 35.0% to 19.3%, and the 15-year risk of breast cancer death from 25.2% to 21.4%. Across the whole dataset, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10.

That relationship was measured in a different population at a different stage. It is the principle behind aggressive local treatment here rather than direct evidence for it, and the distinction is worth keeping in view.

7 · Why outcomes have improved least in this group

Survival in breast cancer has improved substantially across four decades of research35. This group has gained least from it. The reasons are separable rather than a single fact about aggressive biology, and each one points at a different remedy.

The first is the definition itself. A category defined by anatomical extent at presentation selects for whatever produced the delay. Part of that is tumour growth rate. Part of it is the interval between a symptom and a diagnosis, which is patterned by insurance, distance, language and previous experience of medical care36,37. A new drug does not shorten that interval.

The second is that the trials producing the advances largely did not enrol these patients. Adjuvant trials require operable disease. Metastatic trials require measurable metastatic disease. Locally advanced disease falls between the two, and usually appears as a small stratum inside a subtype trial rather than as the population of a trial of its own.

The third is that the trial machinery works less well here. Pathological complete response rates are lower, so a trial powered on that endpoint needs more patients drawn from a smaller population. Response assessment is less reliable Assessment of operability and response, which makes response-adapted designs harder to run.

The fourth is delivery rather than discovery. Trimodality treatment was underused across a decade, and the predictors of underuse were age, income, insurance and comorbidity rather than tumour biology28. An effective treatment that a third of eligible patients do not receive produces a population-level result that looks like treatment failure.

The fifth is that inflammatory disease has no separate development pathway. It is enrolled inside trials organised by receptor subtype, where it forms a small and usually unanalysed stratum.

The arithmetic from the pre-trastuzumab era is worth stating, because it set the expectation that persists. Median survival was 2.9 years for inflammatory carcinoma, 6.4 years for non-inflammatory locally advanced disease and more than ten years for non-T4 disease, in United States registry data covering 1988 to 200012. Those figures predate HER2-directed therapy and understate current outcomes. The ordering between the three groups has not changed.

Interplay

This chapter is where sampling and staging meet. A locally advanced tumour is large, and a large tumour is the situation in which a single core is least representative of the whole Spatial heterogeneity. The receptor result determining the entire treatment plan comes from one needle pass through a mass that may be several centimetres across and subclonally structured. Inflammatory disease adds a second layer, because the compartment defining the disease sits in dermal lymphatics and is not what the core sampled. Heterogeneity here is not an abstraction about tumour evolution. It is the gap between the tumour that was measured and the tumour that is being treated.

See Integrative biological interplay

References

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