[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.