Breast cancer in situ

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Patients with breast cancer in situ are best managed by a multidisciplinary team of breast cancer consultants, including medical oncologists, surgeons, radiation oncologists, radiologists, pathologists, and nurses. Patients should be involved in decision making and treatment planning throughout the course of treatment.

The main goal of primary treatment for patients with breast cancer in situ is to prevent progression to invasive breast cancer.

The treatment approach differs for low-risk and high-risk ductal carcinoma in situ (DCIS), and for lobular carcinoma in situ (LCIS).

Low-risk ductal carcinoma in situ (DCIS): primary treatment

The primary treatment options for patients with low-risk DCIS (e.g., DCIS that is screen detected, unifocal, unicentric, low to intermediate grade, and ≤2.5 cm) are:[66]

breast-conserving therapy (involving wide local surgical excision of the tumour [lumpectomy] followed by adjuvant radiotherapy), or
total mastectomy (with or without breast reconstruction).

Both approaches have demonstrated equivalent outcomes in terms of overall survival.[66][106][107]

Guidelines generally recommend breast-conserving surgery plus adjuvant whole breast radiotherapy (WBRT) as the primary treatment for most patients with low-risk DCIS.[66][108] The preferred post-surgical margin following breast-conserving surgery for DCIS is ≥2 mm if WBRT is planned.[108][109] The risk of relapse increases with margins ≤2 mm.[66]

Breast reconstruction should be discussed with all patients who plan to undergo mastectomy. It can be performed at the time of mastectomy (immediate reconstruction) or at a later date (delayed reconstruction).

Breast-conserving surgery alone

Select patients with low-risk DCIS may be considered for breast-conserving surgery alone without adjuvant radiotherapy (e.g., those with clear margins ≥3 mm).[66][110][111] However, this approach is controversial because adjuvant radiotherapy decreases the risk of disease recurrence (local and distant) in various sub-groups of women with DCIS.[111][112] [ ] Research is ongoing to identify patients with low-risk DCIS for whom adjuvant radiotherapy may confer little benefit or potentially constitute over-treatment.[113][114][115][116]

Guidelines advise that breast-conserving surgery alone should be considered only for patients with a low risk of recurrence, and following a discussion between the physician and patient on the risks and benefits.[66] If breast-conserving surgery alone is undertaken, then frequent follow-up should be performed during the first 3-5 years in order to detect disease recurrence early.

Axillary lymph node surgical staging

Axillary lymph node surgical staging is controversial in patients with DCIS.[117][118]

Sentinel lymph node biopsy (SLNB) may be considered in the setting of:[66]

mastectomy for DCIS,
excision in an anatomical location compromising the performance of a future SLNB procedure, or
oncoplastic breast-conserving surgery.

SLNB should not be routinely performed in women with preoperative (biopsy-determined) pure DCIS who are undergoing breast-conserving surgery, but it may be considered if there is high suspicion for invasive disease or axillary metastasis (e.g., palpable mass, extensive microcalcifications).[66][95][96]

Low-risk DCIS: adjuvant (post-operative) radiotherapy

Options include WBRT, radiotherapy boost to the tumour bed, accelerated partial breast irradiation/partial breast irradiation (APBI/PBI).

Whole breast radiotherapy

Adjuvant WBRT following lumpectomy is recommended in order to treat microscopic disease, and to reduce the risk of ipsilateral recurrence.[66] Systematic reviews and meta-analyses report reduced risk for ipsilateral recurrence in women with DCIS who received adjuvant radiotherapy following breast-conserving surgery compared with those who did not receive radiotherapy.[119][120] In patients with DCIS, treatment with lumpectomy and radiotherapy is associated with a significant reduction in 15-year breast cancer mortality rate compared with lumpectomy alone or mastectomy alone.[121]

Radiotherapy boost to the tumour bed

May be offered along with adjuvant WBRT, depending on individual patient factors and patient preference.[66][108] In one multi-centre phase 3 randomised study, tumour bed boost after WBRT reduced local recurrence in women with resected non-low-risk DCIS (5-year free-from-local-recurrence rate 92.7% in the no-boost group compared with 97.1% in the boost group).[122] The boost group experienced higher rates of breast pain and induration.

Accelerated partial breast irradiation/partial breast irradiation

APBI/PBI may be an alternative to adjuvant WBRT in patients with low-risk DCIS and all of the following factors:[123]

BRCA negative
Age ≥40 years
Low to intermediate grade DCIS
Tumour size ≤2 cm
Negative margins

Guidelines suggest that APBI/PBI may also be considered with caution in some patients with high grade (grade 3) disease or tumour size >2 to 3 cm; however, there may be an increased risk of recurrence, especially when both of these factors are present.[123]

External beam radiotherapy (EBRT) techniques, such as 3-D conformal radiotherapy (3-D CRT) or intensity modulated radiotherapy (IMRT), and multicatheter brachytherapy are recommended for APBI/PBI.[123] Single-entry catheter brachytherapy may be considered, although evidence from randomised controlled trials (RCTs) is lacking.

PBI delivers radiation specifically to the tumour or tumour bed and surrounding breast tissue; APBI involves larger than standard doses of radiation over a shorter time period. APBI/PBI spares healthy breast tissue, and reduces treatment time and some treatment-related adverse effects (e.g., acute skin toxicity).[123][124]

RCTs with long-term follow-up, and one systematic review and meta-analysis, suggest that APBI/PBI using EBRT or brachytherapy techniques has a similar recurrence rate to WBRT in patients with early stage breast cancer.[125][126][127][128][129][130][131] Sub-group analyses of patients with DCIS from two RCTs suggest little difference in recurrence rates up to 10 years.[125][132]

APBI/PBI using intraoperative radiotherapy may allow radiotherapy to be completed at the same time as surgery, but studies suggest it may be associated with a higher rate of recurrence compared with WBRT (with comparable overall mortality). It should therefore be used only as part of a clinical trial.[123][131][133][134][135]

No studies have directly compared APBI/PBI techniques and regimens. APBI/PBI using EBRT (3-D CRT or IMRT) given once daily or on alternate days is associated with improved cosmesis and reduced acute and late toxicities compared with WBRT.[126][129][136] Twice-daily EBRT regimens are associated with worse late toxicity and cosmesis.[124][125] APBI/PBI using multicatheter brachytherapy has shown similar late toxicity outcomes to WBRT, with comparable or improved cosmesis.[124][127][130][137]

Radiotherapy toxicity

Adverse effects of radiotherapy are localised to the area(s) through which the radiation passes. The most common acute adverse effects are skin changes (similar to sunburn) and fatigue. The skin may tan, either temporarily or permanently. The irradiated breast may appear smaller due to both surgical therapy and radiotherapy.

In patients receiving WBRT, a small portion of the lung and ribs receive radiation, which can induce lung scarring and slightly increase the risk of rib fracture. Furthermore, the heart is incidentally exposed to small doses of radiation when treating left-sided breast cancers, which may increase the risk of ischaemic heart disease.[138] Risk of ischaemic heart disease may increase with increasing doses of radiation to the heart.[138] Hypofractionated and ultra-hypofractionated WBRT regimens and APBI/PBI minimise the dose and, therefore, sequelae.[139]

High-risk DCIS: primary treatment

Mastectomy is generally recommended for women with high-risk DCIS, and for men with DCIS.[16][72][140] High-risk patients include those with:[66][141]

Multicentric disease (DCIS in two or more quadrants)
Multifocal disease (two or more sites of disease in the same quadrant); mastectomy should be considered because it may not be feasible to surgically clear the disease and achieve a good cosmetic outcome with breast-conserving therapy
A palpable mass and/or imaging showing a formed lesion on presentation
Histologically high-grade DCIS (should be considered for mastectomy)

SLNB should be considered in patients undergoing mastectomy.[66] Performing an SLNB after mastectomy is impractical. The likelihood that an initial diagnosis of DCIS will be upgraded to invasive breast cancer is greater if the disease is high grade, and/or the tumour is large (>2.5 cm based on imaging) or palpable.[142][143][144][145][146]

Disease recurrence is low following total mastectomy for DCIS.[147][148] Adjuvant radiotherapy is not required for DCIS treated with mastectomy unless disease is present near or at the chest wall, or if there is a substantial positive surgical margin.[149]

Adjuvant (post-operative) systemic treatment for DCIS

Hormone (oestrogen) receptor status can guide decisions regarding use of adjuvant endocrine therapy to reduce the risk of ipsilateral recurrence and contralateral breast cancer. Improved survival has not been shown, therefore the risks and benefits of adjuvant endocrine therapy should be discussed with the patient.[66][108]

For premenopausal women with oestrogen receptor (ER)-positive DCIS, tamoxifen for 5 years is considered first-line therapy for risk reduction of the ipsilateral breast after breast-conserving therapy (i.e., lumpectomy followed by adjuvant radiotherapy), and for risk reduction of the contralateral breast after either mastectomy or breast-conserving therapy has been completed.[66][108] Tamoxifen is effective in preventing recurrence in patients with ER-positive breast cancer (both invasive and non-invasive), as well as in decreasing the risk of ER-positive breast cancer developing in the contralateral breast.[150] [ ]

For postmenopausal women with ER-positive DCIS, either tamoxifen or an aromatase inhibitor (e.g., anastrozole or exemestane) for 5 years is considered first-line therapy for risk reduction after surgery.[66][108] Aromatase inhibitors may be preferred for postmenopausal women who are aged <60 years or who have an increased risk of thromboembolism.[66][108][151] Bisphosphonates or denosumab should be considered to maintain or improve bone mineral density and to reduce the risk of fractures in postmenopausal women receiving aromatase inhibitors.[66]

The efficacy of adjuvant endocrine therapy is independent of age.[152][153] Guidelines from the European Society of Breast Cancer Specialists suggest that aromatase inhibitors are slightly more beneficial than tamoxifen for women aged >70 years and preferred for high-risk patients, although choice of drug should take into account multimorbidity and recurrence risk.[152]

Lobular carcinoma in situ (LCIS)

Pleomorphic and florid LCIS should be managed like DCIS.

Treatment for classic LCIS includes endocrine therapy (chemoprevention) and counselling; close monitoring can be considered for patients not desiring chemoprevention.[52]

If there is concern for progression of LCIS in patients undergoing close monitoring, the management approach may be revised (based on clinical, imaging, and pathology results).

Endocrine therapy (chemoprevention) for LCIS

Patients with LCIS have an increased risk for invasive breast cancer and should be offered chemoprevention.

Endocrine therapy for 5 years is recommended for breast cancer risk reduction for patients aged ≥35 years who have a history of LCIS.[52]

Tamoxifen is indicated for premenopausal women. For postmenopausal women, tamoxifen, raloxifene, anastrozole, or exemestane can be considered.

Tamoxifen and raloxifene have been found to reduce the risk of LCIS progression to invasive breast cancer.[61][62] Anastrozole and exemestane reduce the risk of invasive breast cancer in high-risk postmenopausal women.[154][155]

According to the National Comprehensive Cancer Network (NCCN) breast cancer risk reduction expert panel, tamoxifen is a superior choice of risk reduction agent for most postmenopausal women.[52] However, consideration of adverse effects may lead some patients to choose raloxifene in preference to tamoxifen.[61][62]

Bisphosphonates or denosumab should be considered to maintain or improve bone mineral density and to reduce the risk of fractures in postmenopausal women receiving aromatase inhibitors.[52]

Risk-reducing mastectomy may be considered for patients with high-risk LCIS

Preferred management of LCIS comprises endocrine therapy (chemoprevention) and close monitoring.[52] Prophylactic bilateral total mastectomy should, however, be discussed and can be considered for patients with high-risk features, such as:[52][63][64]

Germline pathogenic/likely pathogenic variants in high penetrance breast cancer susceptibility genes (e.g., BRCA1, BRCA2)
Compelling family history
History of chest wall radiation before 30 years of age

Individualising management of these patients is essential.

Local recurrence of DCIS

Treatment options for local recurrence of DCIS are dependent on the initial surgical treatment and whether adjuvant radiotherapy was given.

Local recurrence following prior breast-conserving surgery

Patients with local recurrence following breast-conserving surgery with adjuvant radiotherapy can be treated with mastectomy (and consideration for SLNB, although there is limited data for repeat SLNB in a patient who had a prior SLNB) followed by repeat radiotherapy, if feasible and indicated.[66]

Patients with local recurrence following breast-conserving surgery without adjuvant radiotherapy can be treated with repeat breast-conserving surgery or mastectomy (and consideration for SLNB, although there is limited data for repeat SLNB in a patient who had a prior SLNB), followed by radiotherapy after repeat breast-conserving surgery or, if indicated, after mastectomy.[66]

Local recurrence following prior mastectomy

Patients with local recurrence following mastectomy (with or without adjuvant radiotherapy) can be treated with surgical resection (limited excision) of the local recurrence (if clear margins and acceptable cosmesis can be obtained) and considered for SLNB (although there is limited data for repeat SLNB in a patient who had a prior SLNB), followed by radiotherapy (if not previously given) or repeat radiotherapy (if previously given, and if feasible and indicated).[66]

A decision about adjuvant endocrine therapy is made in the context of the previous treatment the patient has received, the hormone receptor status of the disease (if this information is available), and following discussion about the risks and benefits of the treatment options.

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