Ductal Carcinoma in Situ (Tis, N0, M0)

The recommended workup and staging of DCIS includes:
- History and physical examination
- Bilateral diagnostic mammography
- Pathology review
- Determination of tumor estrogen receptor (ER) status
- MRI as indicated is special situations
For pathology reporting:
- The NCCN panel endorses the College of American Pathologists Protocol:
  - For both invasive and noninvasive carcinomas of the breast
The NCCN panel recommends testing for ER status:
- In order to determine the benefit of adjuvant endocrine therapy or risk reduction
Although the tumor HER2 status is of prognostic significance in invasive cancer, its importance in DCIS has not been elucidated:
- To date, studies have either found unclear or weak evidence of HER2 status as a prognostic indicator in DCIS
- The NCCN Panel has concluded that knowing the HER2 status of DCIS does not alter the management strategy and is not required DCIS
The role of MRI in management of DCIS remains unclear:
- MRI has been prospectively shown to have a sensitivity of up to 98% for high-grade DCIS
- In a prospective, observational study of 193 women with pure DCIS who underwent both mammography and MRI imaging preoperatively:
  - 93 (56%) women were diagnosed by mammography and 153 (92%) were diagnosed by MRI (P < .0001)
  - Of the 89 women with high-grade DCIS:
    - 43 (48%) who were not diagnosed by mammography:
      - Were diagnosed by MRI alone
- However, other studies suggest that MRI can overestimate the extent of disease
- Therefore, surgical decisions should not be not be solely based on MRI results especially when mastectomy is being contemplated
- If MRI findings suggest more extensive disease than is seen on mammography such that a markedly larger resection is required for complete excision:
  - The findings should be verified histologically through MRI-guided biopsy of the more extensive enhancement
- Studies have also been performed to determine whether the use of MRI reduces re-excision rates and decreases local recurrence in women with DCIS:
  - No reduction in re-excision rates was seen in women undergoing lumpectomy following MRI compared with those who did not undergo preoperative MRI
- The NCCN Panel recommends only performing breast MRI for DCIS in select circumstances where additional information is warranted during the initial workup, noting that the use of MRI has not been shown to increase likelihood of negative margins or decrease conversion to mastectomy for DCIS
Primary Treatment for DCIS:
- The goal of primary therapy for DCIS:
  - Is to prevent progression to invasive breast carcinoma
- Management strategies for DCIS treatment include:
  - Surgery:
    - Mastectomy or lumpectomy
  - Radiation therapy
  - Adjuvant endocrine therapy:
    - To reduce risk of recurrence
- Surgery:
  - Excision of DCIS using a breast-conserving approach (lumpectomy) with or without whole breast radiation therapy (WBRT) or alternatively, mastectomy:
    - Are the primary treatment options for individuals with DCIS:
      - The choice of local treatment does not impact overall disease-related survival:
        Therefore, the individual patient’s acceptance of the potential for an increased risk of local recurrence must be considered
Post-excision mammography:
- Is valuable in confirming that an adequate excision of DCIS has been performed particularly for DCIS patients who initially present with microcalcifications
Mastectomy:
- Patients with DCIS and evidence of widespread disease (ie, disease involving two or more quadrants) on diagnostic mammography or other imaging, physical examination, or biopsy:
  - May require mastectomy
Mastectomy permanently alters the lymphatic drainage pattern to the axilla:
- So that future performance of a sentinel lymph node biopsy (SLNB) is not technically feasible
  - Therefore, for DCIS patients who intend on treatment with mastectomy, or alternatively, for local excision in an anatomic location that could compromise the lymphatic drainage pattern to the axilla (eg, tail of the breast):
    - A SLNB procedure should strongly be considered at the time of definitive surgery to avoid necessitating a full axillary lymph node dissection for evaluation of the axilla
Complete axillary lymph node dissection (ALND):
- Is not recommended unless there is pathologically documented invasive cancer or axillary lymph node metastatic disease in patients (by either biopsy or SNLB)
- However, a small proportion of women (about 25%) with seemingly pure DCIS on initial biopsy:
  - Will have invasive breast cancer at the time of the definitive surgical procedure and thus will ultimately require ALN staging
Lumpectomy plus Whole Breast Radiation Therapy (WBRT):
- Breast conserving therapy (BCT) includes lumpectomy to remove the tumor with negative surgical margins followed by WBRT to eradicate any residual microscopic disease
- Several prospective randomized trials of pure DCIS have shown that the addition of WBRT after lumpectomy:
  - Decreases the rate of in-breast disease recurrence, or distant metastasis-free survival
- In the long term follow-up of the RTOG 9804 trial, at 7 years:
  - The local recurrence rate was:
    - 0.9% (95% CI, 0.0%–2.2%) in the radiation therapy arm versus 6.7% (95% CI, 3.2%–9.6%) in the observation arm (HR, 0.11; 95% CI, 0.03– 0.47; P < .001)
  - In the subset of patients with good-risk disease features:
    - The local recurrence rate was low with observation but was decreased significantly with the addition of radiation therapy
  - A meta-analysis of four large multicenter randomized trials:
    - Confirms the results of the individual trials, demonstrating that the addition of WBRT after lumpectomy for DCIS:
      - Provides a statistically and clinically significant reduction in ipsilateral breast events (HR [hazard ratio], 0.49; 95% CI; 0.41–0.58, P < .00001)
      - However, these trials did not show that the addition of RT has an overall survival benefit
  - The long-term follow-up of the NSABP B-17 showed that at 15 years:
    - Radiation therapy resulted in a 52% reduction of ipsilateral invasive recurrence compared with excision alone (HR, 0.48; 95% CI, 0.33–0.69, P < .001)
    - However, overall survival (OS) and cumulative all-cause mortality rates through 15 years were similar between the two groups (HR for death, 1.08; 95% CI, 0.79–1.48)
  - Similar findings were reported by a large observational study of the SEER database that included 108,196 patients with DCIS:
    - In a subgroup analysis at 10 years, of 60,000 women treated with breast-conserving therapy, with or without radiation therapy:
      - Radiation therapy was associated with a 50% reduction in the risk of ipsilateral recurrence (adjusted HR, 0.47 [95% CI, 0.42–0.53]; P < .001), however, breast cancer-specific mortality was found to be similar (HR, 0.86 [95% CI, 0.67–1.10]; P = .22)
- More recently, in a population-based study, the use of WBRT in patients with higher-risk DCIS:
  - Higher nuclear grade, younger age, and larger tumor size:
    - Was demonstrated to be associated with a:
      - Modest, but statistically significant improvement in survival
RT Boost:
- The use of RT boost has been demonstrated to provide a small but statistically significant reduction in IBTR risk (4% at 20 years):
  - In all age groups for invasive breast cancer
- Recently, a pooled analysis of patient-level data from ten academic institutions evaluated outcomes of pure DCIS patients:
  - All treated with lumpectomy and WBRT (n = 4131) who either received RT boost with a median dose of 14 Gy (n = 2661) or received no boost (n = 1470):
    - The median follow-up of patients was nine years
      - A decrease in IBTR was seen in patients who received boost compared with those who did not at:
        5 years 97.1% vs 96.3%
        10 years (94.1% vs 92.5%)
        15 years (91.6% vs 88.0%)
        P = .0389 for all
    - The use of RT boost was associated with significantly decreased IBTR across the entire cohort of patients (hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01)
    - In a multivariate analysis that took into account factors associated with lower IBTR, including grade, ER positive status, use of adjuvant tamoxifen, margin status, and age:
      - The benefit of RT boost still remained statistically significant (hazard ratio, 0.69; 95% confidence interval [CI], 0.53 – 0.91; P < .010)
      - Even in patients considered very low risk based on negative margins status (defined as no ink on tumor as per National Surgical Adjuvant Breast and Bowel Project definition, or margins 10 mm or no tumor on re-excision in 48 % of patients)
      - Although the rate of IBTR were acceptably low for the low-/intermediate grade group at the 5 years, at a median follow-up time of 12.3 years, the rates of developing an IBTR were 14.4% for low/intermediate-grade and 24.6% for high grade DCIS (P = .003)
      - This suggests that IBTR events may be delayed but not prevented in the seemingly low-risk population
      - Therefore, the NCCN panel concluded that for DCIS patients treated with lumpectomy alone (without radiation), irrespective of margin width:
        The risk of IBTR is substantially higher than treatment with excision followed by whole breast radiation therapy (even for predefined low-risk subsets of DCIS patients)