Part IX · Early-stage disease: in situ, locally advanced, residual, and the neoadjuvant platform · Chapter 49

Atypia and in situ disease

The one setting in this book where the first question is whether the diagnosis needs treating at all.

1 · Atypical ductal and lobular hyperplasia

Atypical hyperplasia is a diagnosis made at a threshold. Atypical ductal hyperplasia carries the cytology and architecture of low-grade ductal carcinoma in situ below a limit of size or extent that pathologists apply by convention. Move the limit and the same slide changes category. The biology beneath the boundary is developed in Breast carcinogenesis and precursor states and the morphology in Histopathology and the spectrum of breast neoplasia.

Two facts govern management and they point in different directions.

The first is that the risk conferred is bilateral. A lesion found in one breast raises risk in both. That is what a risk marker means and it is not what a precursor means.

The second is that the risk is large enough to act on. In NSABP P-1, tamoxifen reduced invasive breast cancer by 49% across 13,388 women at increased risk. In the subgroup with atypical hyperplasia the reduction was 86%¹. That was the largest subgroup effect reported in the trial. After seven years of follow-up the overall effect held, with the cumulative rate of invasive breast cancer falling from 42.5 to 24.8 per 1,000 women². Tamoxifen also reduced clinically detected benign breast disease and the biopsies it prompts, by 29%, mostly in women younger than 50³.

Management follows. Excision confirms the diagnosis and excludes an adjacent carcinoma that the core missed. Risk reduction is then a systemic decision rather than a local one, and the options are set out in⁴ and in Risk assessment and prevention.

2 · Lobular carcinoma in situ as risk marker and as precursor

Lobular carcinoma in situ is taught as a pure risk marker. The longitudinal data say it is both a marker and, in part, a precursor.

In a single-institution cohort of 1,060 women with lobular carcinoma in situ and no concurrent cancer, 150 women developed 168 breast cancers at a median follow-up of 81 months⁵. The annual incidence was about 2%. The distribution of those cancers is the informative part. Sixty-three per cent were ipsilateral, 25% contralateral and 12% bilateral. A pure risk marker predicts an even split between the two breasts. A two-to-one ipsilateral excess does not.

The histology of the subsequent cancers was mixed, with ductal carcinoma in situ in 35%, invasive ductal carcinoma in 29% and invasive lobular carcinoma in 27%⁵. The lesion therefore does not commit the later tumour to a lobular phenotype.

Two further findings change practice. Chemoprevention was associated with a 10-year cumulative breast cancer risk of 7% against 21% without it, with a hazard ratio of 0.27 and a 95% confidence interval of 0.15 to 0.50. And neither age nor family history was associated with risk in multivariable analysis⁵. The clinical variables normally used to stratify risk do not stratify this population.

Pleomorphic and florid variants are managed more like in situ carcinoma by convention. That convention rests on morphological resemblance to high-grade disease rather than on outcome data.

3 · Ductal carcinoma in situ, risk stratification and genomic assays

Stratification in ductal carcinoma in situ has to answer a narrow question. It is not whether the patient will die of breast cancer, because almost none do. It is whether an ipsilateral event will occur, and whether that event will be invasive.

The clinicopathological variables are grade, lesion size, margin width and age at diagnosis. They separate risk groups and they separate them coarsely.

The first index combined three of them. The Van Nuys Prognostic Index scored tumour size, margin width and pathological classification from 3 to 9⁶. Its authors proposed excision alone for scores of 3 or 4, and mastectomy for 8 or 9, where eight-year local recurrence exceeded 60% even with radiation. Retrospective series have since used it to pick out women at low risk after excision alone^7,8. Prospective selection gave a cleaner answer. ECOG E5194 treated carefully selected patients by excision without radiation⁹. Five-year ipsilateral events were 6.1% in 565 patients with low- or intermediate-grade disease no larger than 2.5 cm, and 15.3% in 105 with high-grade disease no larger than 1 cm.

Single markers have not filled the gap. HER2 expression was not significantly associated with recurrence in one series¹⁰. Nor has HER2 become a target here. NSABP B-43 randomised 2,014 women with HER2-positive in situ disease treated by lumpectomy to whole-breast radiation with or without concurrent trastuzumab¹¹. Ipsilateral recurrence fell by a statistically non-significant 19%, with a hazard ratio of 0.81 and a 95% confidence interval of 0.56 to 1.17. In a population-based cohort, basal-like, triple-negative and high-grade lesions carried no statistically significant excess risk¹². A systematic review concluded that the markers that matter in invasive disease have not been adequately studied in in situ disease¹³. Combinations did better in one population-based cohort treated by lumpectomy alone¹⁴. Eight-year risk of invasive cancer was 19.6% for palpable or p16, COX-2 and Ki67 triple-positive lesions, against 4.1% for screen-detected triple-negative ones. Receptor testing has one settled use. Testing in situ disease for ER is recommended, to judge the benefit of endocrine risk reduction, and PgR testing is optional¹⁵.

Two commercial assays address the same gap from different directions. The 21-gene DCIS Score was measured in 327 patients treated by excision without radiation in ECOG E5194. The continuous score was associated with an ipsilateral breast event, with a hazard ratio of 2.31 and a 95% confidence interval of 1.15 to 4.49 after adjustment for tamoxifen use. Ten-year risks of an ipsilateral event in the prespecified low, intermediate and high groups were 10.6%, 26.7% and 25.9%. The corresponding risks of an invasive ipsilateral event were 3.7%, 12.3% and 19.2%¹⁶.

Read the two rows carefully. For any ipsilateral event the intermediate and high groups are indistinguishable. Only when the endpoint is restricted to invasive disease does the top group separate from the middle. A three-level assay reporting a two-level result is not a failure of the biology. It is a property of the endpoint chosen.

The second assay adds treatment prediction rather than risk alone. A biological signature was developed and cross-validated in 526 patients treated with breast-conserving surgery with or without radiation. Among patients treated without radiation it identified a low-risk group with a 10-year invasive breast cancer risk of 4%, and an elevated-risk group with a risk of 15%. In the elevated group the hazard ratio for radiation benefit was 0.3. The signature reclassified 42% of a clinicopathologically low-risk subset into the elevated group¹⁷.

Neither assay has been tested in a randomised trial of assay-directed management. Both were developed in cohorts assembled for other questions. The distinction between clinical validity and clinical utility is set out in Receptor assessment and the measurement problem, and the evidence bar for adoption in Prognostic and predictive assays and somatic profiling.

4 · Surgery and radiation for in situ disease

The local treatment literature in ductal carcinoma in situ is unusually clean, and its central result is unusually uncomfortable.

Radiation halves invasive local recurrence. Two NSABP trials were analysed at median follow-up of 207 and 163 months. Radiation after lumpectomy reduced invasive ipsilateral recurrence by 52%, with a hazard ratio of 0.48 and a 95% confidence interval of 0.33 to 0.69. The 15-year cumulative incidence of invasive ipsilateral recurrence was 19.4% after lumpectomy alone and 8.9% after lumpectomy with radiation¹⁸. The UK, Australia and New Zealand trial gave the same direction, with a hazard ratio of 0.32 for ipsilateral invasive disease¹⁹.

Each trial had reported the same direction earlier. In NSABP B-17, 818 women were randomised, and at eight years radiation reduced invasive ipsilateral tumours from 13.4% to 3.9% and non-invasive ones from 13.4% to 8.2%²⁰. In EORTC 10853, 1,010 women were randomised, and the 10-year local recurrence-free rate was 74% after excision alone and 85% with radiation, with similar low risks of metastasis and death^21,22. Every subgroup benefited. The UK, Australia and New Zealand trial first reported a hazard ratio of 0.45 for ipsilateral invasive disease with radiation, and little evidence for tamoxifen²³. SweDCIS randomised 1,046 women and found a hazard ratio of 0.33, with seven women treated to prevent one recurrence²⁴. In a subgroup analysis its protective effect was low below age 50 and substantial above 60²⁵. A pooled analysis of the four trials, 3,925 women, gave a hazard ratio of 0.49 for any ipsilateral event, and nine women needed treatment to prevent one²⁶. Deaths from vascular disease, pulmonary toxicity and second cancers were not significantly higher with radiation. A systematic review of the wider literature reached the same conclusions for radiation and tamoxifen²⁷.

This holds even in the lowest-risk disease that has been randomised. NRG/RTOG 9804 enrolled 636 women with mammographically detected disease of low or intermediate nuclear grade, no larger than 2.5 cm, with margins of 3 mm or more. The 15-year cumulative incidence of ipsilateral breast recurrence was 7.1% with radiation and 15.1% with observation. For invasive local recurrence the figures were 5.4% and 9.5%²⁸. At seven years, local failure had been 0.9% and 6.7%²⁹.

Now the uncomfortable part. Across the same NSABP cohorts the 15-year cumulative incidence of breast cancer death was 3.1% after lumpectomy alone and 4.7% after lumpectomy with radiation¹⁸. A registry analysis of 108,196 women found the same dissociation. Radiation after lumpectomy reduced 10-year ipsilateral invasive recurrence from 4.9% to 2.5%, with an adjusted hazard ratio of 0.47. It did not reduce 10-year breast cancer mortality, where the figures were 0.9% and 0.8%, with a hazard ratio of 0.86 and an interval of 0.67 to 1.10³⁰.

Two later analyses of the same registry disagree, and the disagreement is the finding. With propensity weighting across 32,144 women, 10-year breast cancer mortality was 1.8% with radiation and 2.1% without it, a hazard ratio of 0.73³¹. The difference was confined to higher nuclear grade, younger age and larger size. Among 140,366 women, 15-year breast cancer mortality was 1.74% after lumpectomy and radiation and 2.33% after lumpectomy alone³². Its authors attributed the difference to systemic effects of radiation rather than to local control. All three are observational, and none can separate the effect of radiation from the reasons it was given.

Invasive recurrence does carry mortality. In the NSABP analysis an invasive ipsilateral recurrence raised the risk of death, with a hazard ratio of 1.75, while a recurrence that was itself in situ did not¹⁸. Preventing the invasive recurrences has nonetheless not translated into fewer deaths in these datasets.

A boost to the tumour bed was long extrapolated from invasive disease. There, the EORTC trial showed that a boost improved local control at every age without changing survival, at the cost of more fibrosis^33,34. Smaller trials in Lyon and Budapest agreed^35,36. For in situ disease, a pooled analysis of 4,131 patients from ten institutions associated the boost with lower ipsilateral recurrence, with a hazard ratio of 0.73³⁷. BIG 3-07 then randomised 1,608 women with non-low-risk disease³⁸. Five-year freedom from local recurrence was 92.7% without a boost and 97.1% with it, a hazard ratio of 0.47. Grade 2 or higher breast pain and induration were more frequent with the boost. Its two-year quality-of-life report had already found persistent adverse effects of the boost on cosmetic status and on arm and shoulder function³⁹.

Partial-breast irradiation trials included in situ disease. The GEC-ESTRO trial randomised 1,184 women with low-risk invasive or in situ carcinoma to multicatheter brachytherapy or whole-breast irradiation⁴⁰. Five-year local recurrence was 1.44% and 0.92%, within the prespecified margin. The Florence trial found no significant difference in ipsilateral recurrence or survival at five years, with less toxicity⁴¹. The ten-year results and the other partial-breast trials are in Whole-breast, partial-breast, and chest wall irradiation.

Margin width matters most when radiation is omitted. In 469 lesions, margins of 10 mm or more gave an eight-year recurrence probability of 0.04 with no benefit from radiation, while margins under 1 mm did benefit⁴². In 455 patients treated by excision alone, margins under 10 mm carried 5.39 times the recurrence risk of wider ones⁴³. With radiation, a meta-analysis of 4,660 patients found a 2 mm margin as good as a wider one⁴⁴. In 2,996 women, the association between margin width and recurrence was significant without radiation and absent with it⁴⁵. The consensus guideline adopted 2 mm as the standard margin with whole-breast irradiation⁴⁶.

Preoperative MRI adds sensitivity without clearly improving surgery. In a prospective series, MRI diagnosed 92% of pure in situ carcinoma against 56% for mammography, and 98% of high-grade lesions⁴⁷. It can also misjudge extent, and a decision for mastectomy should not rest on MRI alone⁴⁸. Studies of its effect disagree. Some found no reduction in re-excision, conversion to mastectomy or locoregional recurrence^49,50. One multidisciplinary centre found fewer operations and more single successful excisions⁵¹. In ECOG-ACRIN E4112, MRI found additional cancer in 6.2%, but its features did not predict pathological or genomic outcome⁵².

A core biopsy showing in situ disease may be wrong about invasion. Across 52 studies and 7,350 lesions, the pooled rate of invasive cancer at excision was 25.9%⁵³. A systematic review for a National Institutes of Health conference put it at about 15%²⁷. That underestimate is the argument for sentinel node biopsy when mastectomy is planned, because the axilla cannot be mapped afterwards. A published debate set the case for it⁵⁴ against the case that it remained investigational⁵⁵. ASCO's guideline judged sentinel node biopsy less morbid than axillary dissection, with its comparative effect on recurrence and survival still unknown⁵⁶.

Surgical extent follows the same logic. Mastectomy lowers local recurrence further than lumpectomy with radiation and has not been shown to lower mortality. The reconstruction questions belong to Surgery and reconstruction and the fractionation and omission questions to Radiation oncology.

5 · Endocrine risk reduction

Endocrine therapy in in situ disease is prevention rather than treatment. It acts on the tissue at risk in both breasts, not on a tumour that has been removed.

Tamoxifen added to lumpectomy and radiation reduced invasive ipsilateral recurrence by 32%, with a hazard ratio of 0.68 and a 95% confidence interval of 0.49 to 0.95. The 15-year cumulative incidence of any contralateral breast cancer was 10.8% with placebo and 7.3% with tamoxifen¹⁸. The benefit is confined to ER-positive disease. In a retrospective receptor analysis of B-24, tamoxifen reduced subsequent breast cancer at 10 years in ER-positive in situ disease, with a hazard ratio of 0.49, and showed no significant benefit when ER was negative⁵⁷.

The second randomised trial of tamoxifen in this setting reported a different pattern. Tamoxifen reduced all new breast events, with a hazard ratio of 0.71 and an interval of 0.58 to 0.88. It reduced ipsilateral in situ recurrence and contralateral tumours. It had no effect on ipsilateral invasive disease, where the hazard ratio was 0.95 with an interval of 0.66 to 1.38¹⁹. The two trials differ in design, in the use of radiation and in whether either treatment could be withheld electively, so the discrepancy is not evidence that one result is wrong.

Aromatase inhibition has been compared with tamoxifen twice in postmenopausal women, with two answers. In IBIS-II DCIS, 2,980 women were randomised after local excision and 144 recurrences were recorded at a median follow-up of 7.2 years. Anastrozole was non-inferior to tamoxifen and not superior, with a hazard ratio for all recurrence of 0.89 and an interval of 0.64 to 1.23⁵⁸. In NSABP B-35, 3,104 women who had all received lumpectomy and whole-breast irradiation were randomised, and 212 breast cancer-free interval events occurred at a median follow-up of 9.0 years. Anastrozole was superior, with a hazard ratio of 0.73 and an interval of 0.56 to 0.96. A treatment-by-age interaction was significant, and the advantage was confined to women younger than 60⁵⁹.

Dose is a separate axis from agent. In TAM-01, 500 women with breast intraepithelial neoplasia received tamoxifen 5 mg daily for three years or placebo. At a median follow-up of 9.7 years there were 25 breast events against 41. The annual rate was 11.3 against 19.5 per 1,000 person-years, with a hazard ratio of 0.58 and an interval of 0.35 to 0.95. Contralateral events were 6 against 16. The number needed to treat to prevent one breast event was 22 at five years and 14 at ten years⁶⁰.

6 · Active surveillance trials and what they will and will not answer

Three randomised trials ask whether some ductal carcinoma in situ can be left alone. They are the direct experimental form of the question posed in Breast carcinogenesis and precursor states.

COMET has reported. It enrolled 995 women aged 40 or older with hormone receptor-positive grade 1 or grade 2 disease and no invasive cancer, and analysed 957. Active monitoring meant six-monthly imaging and examination. Median follow-up was 36.9 months. The two-year cumulative rate of ipsilateral invasive cancer was 4.2% with active monitoring and 5.9% with guideline-concordant care. That difference of minus 1.7 percentage points carried an upper 95% confidence limit of 0.95, against a prespecified non-inferiority bound of 5 percentage points⁶¹. Forty-six invasive cancers occurred, 19 in the monitoring group and 27 in the surgery group.

LORIS randomises surgery against active monitoring in screen-detected or asymptomatic low-grade disease, and in intermediate-grade disease with low-grade features⁶². LORD randomises 1,240 women aged 45 or older with pure low-grade disease diagnosed on vacuum-assisted biopsy of microcalcifications. Its primary endpoint is the 10-year ipsilateral invasive breast cancer free percentage, with annual mammography in both arms⁶³.

What these trials can answer is whether a defined low-risk group has a similar short-term rate of invasive diagnosis under monitoring. What they cannot answer is set by three features of their design.

The first is the endpoint. A diagnosis of invasive cancer is not a death. Surveillance that converts an operation now into an operation later, for the same eventual outcome, changes when treatment happens rather than whether it is needed.

The second is the non-inferiority margin. A 5-point bound on a two-year risk is wide relative to the event rates being compared, and the general problem is developed in Clinical trials and evidence interpretation.

The third is the timescale. In a retrospective series of 45 women whose low-grade in situ disease was treated by biopsy alone, 16 women, which is 36%, later developed invasive carcinoma. Every one occurred in the same breast and the same quadrant. Eleven appeared within ten years. The rest appeared at 12, 23, 25, 29 and 42 years, and seven of the 16 women died of metastatic disease⁶⁴. A natural history that runs for four decades cannot be characterised by a two-year or a ten-year endpoint.

7 · Recurrence risk, follow-up, and communicating a diagnosis that may not need treating

The numbers that matter in this conversation are absolute and long.

In a registry cohort of 108,196 women, breast cancer specific mortality 20 years after a diagnosis of ductal carcinoma in situ was 3.3%, with a 95% confidence interval of 3.0 to 3.6. It was 7.8% for women diagnosed before age 35 against 3.2% for older women. It was 7.0% in Black women against 3.0% in non-Hispanic White women, with a hazard ratio of 2.55 and an interval of 2.17 to 3.01³⁰. The disparity is larger than most treatment effects in this chapter, and the structural drivers are developed in Disparities across the breast cancer continuum.

One finding in that cohort deserves separating out. Of the women who died of breast cancer, 517 did so without ever having had an in-breast invasive recurrence³⁰. Their disease was either disseminated before the in situ lesion was found, or arose from tissue that was never sampled. No local treatment addresses either possibility.

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