Radiotherapy Versus Low-Dose Tamoxifen Following Breast Conserving Surgery for Low-Risk Breast Ductal Carcinoma in Situ
Radiotherapy Versus Low-Dose Tamoxifen Following Breast Conserving Surgery for Low-Risk Breast Ductal Carcinoma in Situ
Although the results obtained from ECOG E5194 cohort 1 (criteria: mammographically detected
 low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins ≥ 3 mm) and RTOG
 9804 trial (the same enrolled clinicopathological features to cohort 1 of ECOG E5194 trial)
 demonstrated that the 7-year ipsilateral breast tumor recurrence (IBTR) ranged from 5.6% to
 10.5% for low-risk ductal carcinoma in situ (DCIS) patients, the aforementioned two studies
 included a proportional patients who had young age and negative estrogen receptor (ER) status
 tumor. Previous studies and our studies revealed that age < 40 years and ER-negative status
 in tumor were independent prognostic factor for recurrence of breast DCIS irrespective of
 tumor characteristics. The UK/ANZ randomized trial, enrolling high-risk and low-risk
 clinicopathologic features of DCIS, demonstrated that a benefit of tamoxifen in terms of
 reducing the IBTR is observed in the BCS alone group but not found in the BCS plus RT group.
 A recent published randomized trial showed that tamoxifen at the dose of 5 mg/day for 3
 years.

 Based on the aforementioned results, we hypothesized that the administration of tamoxifen is
 not inferior than the prescription of RT in terms of reducing the IBTR for DCIS patients who
 had age more than 40 years, the pathological features meeting the ECOG E5194 cohort 1
 criteria, and positive ER status in tumors. To approve the hypothesis, we will design a
 randomized non-inferiority trial to assess whether the effect of administration of tamoxfien
 (5 mg per day) for 10 years following BCS is not inferior in terms of reducing IBTR when
 comparing RT following BCS for patients who had low-risk clinicopathologic features (age more
 than 40 years and ECOG E5194 cohort 1 criteria) and positive-ER status of breast DCIS.
[Background] Radiotherapy (RT) following breast conserving surgery (BCS) is commonly used in
 ductal carcinoma in situ (DCIS) of breast to decrease local recurrence. Previous
 retrospective studies suggested that a substantial proportional of low-risk DCIS patients who
 underwent BCS alone will not develop a subsequent invasive breast cancer over time.

 To further identify a population of patients with low-risk DCIS in whom adjuvant RT could be
 safely omitted, two prospective trials and one randomized trial have been published the
 ipsilateral breast tumor recurrence (IBTR) rate in patients with low-risk breast DCIS,
 including smaller size, larger margin width, and lower grade. The 5-year IBTR rate in Dana
 Farber/Harvard Cancer Institute (low to intermediate grade disease and a margin width of 10
 mm) was 12% for breast DCIS patients who underwent BCS alone. The Eastern Cooperative
 Oncology Group (ECOG) E5194 reported a 12-year IBTR rate of 14.4% (7-year IBTR rate, 10.5%)
 for patients with low-risk DCIS (cohort 1 criteria: mammographically detected low- or
 intermediate-grade DCIS, measuring less than 2.5 cm with margins ≥ 3 mm) who underwent BCS
 alone. The risk for DCIS and invasive cancer increased steadily over time, without any
 plateau.

 Another randomized trial, Radiation Therapy Oncology Group (RTOG) 9804, showed the IBTR rates
 from that at 5 years (3.5%) to that at 7 years (6.7%) in post-BCS patients with low-risk
 breast DCIS (similar criteria of ECOG E5194 trial, cohort 1) who did not receive RT. In
 contrast, the 7-year IBTR rate was low (0.9%) for patients who underwent BCS and received RT
 in RTOG 9804 trial. Our retrospective study showed that the 7-year IBTR rate was 5.6% in
 breast DCIS patients who had criteria of cohort 1 of ECOG E5194 trial and underwent BCS
 alone. Taken together, two prospective clinical trials and our retrospective study disclosed
 that the 7-year IBTR for BCS alone group (no RT) ranged from 5.6% to 10.5%, even if patients
 whose clinicopathologic features met the criteria of ECOG E5194 cohort 1. These results
 suggest that RT following BCS is indicated for these patients who have low-risk breast DCIS.

 Another randomized trial, UK/ANZ [UK, Australia, and New Zealand] DCIS trial], including
 high-risk and low-risk breast DCIS patients, demonstrated a significant benefit of tamoxifen
 (20 mg every day for 5 years) in terms of reducing the ipsilateral (Hazard ratio [HR], 0·77;
 95% confidence interval [CI], 0·59-0·98; P = 0·04) and contralateral breast events (HR, 0·27;
 95% CI, 0·12-0·59; P = 0·001) in the BCS alone group, and this benefit of tamoxifen was not
 observed in the BCS plus RT group for ipsilateral events (HR, 0·93; 95%, 0·50-1·75; P = 0·8).
 These findings suggest that even if patients with low-risk clinicopatholgical features of
 DCIS (relatively low-risk of IBTR), the addition of tamoxifen in patients who had received RT
 may not reduce IBTR than those receiving RT alone. However, the estrogen receptor (ER) status
 among the patients with DCIS enrolled in the aforementioned three prospective randomized
 trials (ECOG E5194 trial, RT9804 trial, and UK/ANZ trial) was initially unknown.

 In a retrospective analysis of the relationship between ER status and response to tamoxifen
 in 732 patients (41%) who comprised the original NSABP B-24 population (76% positive for ER),
 the significant effect of tamoxifen in reducing ipsilateral and contralateral breast events
 was demonstrated in ER-positive DCIS but not in ER-negative tumors. Our retrospective study
 also showed that age < 40 years and negative ER status in tumors were closely associated with
 the higher IBTR rate. Among our patients with cohort 1 criteria of ECOG E519 study, the
 7-year IBTR rate for ER-positive group and ER-negative group was 5.0% and 8.0%, respectively.

 [Rationale] Although the results obtained from ECOG E5194 (cohort 1) and RTOG 9804 trial (the
 same enrolled clinicopathological features to cohort 1 of ECOG E5194 trial) demonstrated that
 the 7-year IBTR ranged from 5.6% to 10.5% for low-risk DCIS patients, the aforementioned two
 studies included a proportional patients who had young age and negative ER status tumor.
 Previous studies and our studies revealed that age < 40 years and ER-negative status in tumor
 were independent prognostic factor for recurrence of breast DCIS irrespective of tumor
 characteristics.

 The UK/ANZ randomized trial, enrolling high-risk and low-risk clinicopathologic features of
 DCIS, demonstrated that a benefit of tamoxifen in terms of reducing the IBTR is observed in
 the BCS alone group but not found in the BCS plus RT group. In a recent published data of a
 randomized trial of comparing low-dose tamoxifen (5 mg QD) for 3 years with placebo in
 prevention of recurrence of women with hormone-positive DCIS or lobular carcinoma in situ,
 low-dose tamoxifen was demonstrated to significantly decrease local recurrence when compared
 with placebo arm. These findings indicate that tamoxifen at the dose of 5 mg/day can decrease
 the incidence of recurrence in women with operated hormone sensitive DCIS with a limited
 toxicity. However, the effect of the administration of low-dose tamoxifen is similar to the
 RT effect in terms of reducing IBTR for patients who had the criteria of ECOG E5194 cohort 1
 and positive ER status remains unclear.

 [Hypotheses] Based on the aforementioned results, we hypothesized that the administration of
 tamoxifen is not inferior than the prescription of RT in terms of reducing the IBTR for DCIS
 patients who had age more than 40 years, the pathological features meeting the ECOG E5194
 cohort 1 criteria, and positive ER status in tumors.

 To approve the hypothesis, we will design a randomized non-inferiority trial to assess
 whether the effect of administration of tamoxfien (5 mg per day) for 10 years following BCS
 is not inferior in terms of reducing IBTR when comparing RT following BCS for patients who
 had low-risk clinicopathologic features and positive-ER status of breast DCIS.

 [Study Design] We will design a randomized non-inferiority trial to assess whether the effect
 of administration of tamoxfien (5 mg) for 10 years following BCS is not inferior in terms of
 reducing IBTR when comparing RT (in terms of 50 Gy in 25 fractions or 40.05 Gy in 15
 fractions) following BCS for patients who had age more than and equal 40 years, low-risk
 clinicopathological features (ECOG E5194 cohort 1 criteria), and positive-ER status of breast
 DCIS.
Inclusion Criteria:

 1. Women

 2. New histologically diagnosed breast ductal carcinoma in situ (DCIS).

 3. Age ≥ 40 years

 4. Low risks of BRCA (breast cancer)1 and BRCA2: Manchester Score < 10

 5. The DCIS must be detected by mammogram and must be unicentric, and no-mass lesion.

 6. Status post breast conserving surgery

 7. Pathological characteristics (all characteristics) 7.1 Lesions ≤ 2.5 cm in greatest
 dimension on pathologic specimen (use the largest measured size from the pathology
 report to obtain the required measurement of ≤ 2.5 cm).

 7.2 Must be classified as low or intermediate nuclear grade DCIS but without comedo
 necrosis according to Pathologic Guidelines (section 9.2.2) 7.3 Margins as assessed by
 the ink method will be 3 mm or greater. 7.4 Must be estrogen receptor (ER)-positive
 DCIS, ER percentage must be ≥10%

 8. Clinically node negative.

 Exclusion Criteria:

 1. Known BRCA1 or BRCA2 mutation

 2. Age < 40 years

 3. Women whose DCIS is palpable at the time of diagnosis, or multi-centric (mammography),
 or mass (mammography), or who have bloody nipple discharge.

 4. Pathological characteristics 4.1 Lesions measuring greater than 2.5 cm in greatest
 dimension on pathologic specimen.

 4.2.High-grade lesions or low to intermediate grade with comedo necrosis as classified
 by the Guidelines.

 4.3. Margins as assessed by the ink method will be less than 3 mm. 4.4. ER-negative
 DCIS or ER-positive percentage < 10% in tumor cells

 5. Post-mastectomy patients

 6. Prior diagnosis of neoplasm within 5 years, except cervical intraepithelial neoplasia
 type 1 (CIN1) or localized non-melanomatous skin cancer.

 7. Evidence of clinically significant cardiac disease, as defined by cardiac disease (New
 York Cardiac disease grade II), history of myocardial infarction, cerebral stroke,
 unstable arrhythmia, and unstable angina pectoris within 12 months before study entry.

 8. Pregnant or lactating status.