The past year has produced an embarrassment of riches regarding the value of aromatase inhibitors for women with ductal carcinoma in situ of the breast. The long-awaited NSABP B-35 study matured and was reported by Margolese and colleagues at the 2015 ASCO Annual Meeting this past summer, followed by the publication of both the main results and the patient-reported outcomes analysis in December.^1,2 This coincided with the publication and presentation (at the 2015 San Antonio Breast Cancer Symposium) of the results of the IBIS-II DCIS trial by Forbes et al.³

Thus, for the first time, a large experience (over 6,000 women combined) of randomized comparisons between tamoxifen and anastrozole therapy for patients with ductal carcinoma in situ offers an evidence-based alternative to tamoxifen for this problem. The results are reassuringly concordant in terms of (at least) equivalent efficacy overall, with an observed advantage with anastrozole for women younger than age 60 in NSABP B-35. As the authors of both studies noted, postmenopausal women with ductal carcinoma in situ now have an alternative to tamoxifen, with possibly a gain in efficacy through anastrozole use in younger women, although this is offset by an increase in symptoms, also seen particularly in younger women.

A Closer Look at the Studies

All women in the NSABP B-35 trial underwent ductal carcinoma in situ resection with free surgical margins and whole-breast radiotherapy, whereas in the IBIS-II DCIS trial, radiotherapy “was permitted according to local practice” and was received by 71% of women in each arm. All participants in both studies were required to have estrogen receptor– or progesterone receptor–positive disease.

In the IBIS-II trial, women with atypical hyperplasia or lobular carcinoma in situ were included after 2009, but the number of such patients in the final analysis is not clear. Follow-up was reported at 9 years for NSABP B-35 (with 122 events in the tamoxifen arm and 90 in the anastrozole arm) and at 7 years for IBIS-II DCIS (77 and 67 events, respectively). The breast cancer–event rate diverged in the NSABP B-35 trial after 5 years, with the 10-year rate of breast cancer–free survival being 78% (95% confidence interval [CI] = 75%–81%) in the tamoxifen group and 83% (95% CI = 80%–85%) in the anastrozole group. However, the advantage appeared to be restricted to women younger than age 60, in whom the hazard ratio was 0.50 (95% CI = 0.35–0.80). In contrast, the event rate was essentially equal in the IBIS-II DCIS trial, with a hazard ratio of 0.89 (95% CI = 0.64–1.32), and age-stratified analyses were not reported.

The number of recurrences was small, but among those with estrogen receptor–positive recurrences in the IBIS-II DCIS trial, risk for such recurrence was significantly higher in the tamoxifen vs anastrozole groups (56 vs 30, HR = 0.55, P = .008). Whether this finding implies more efficient suppression of estrogen receptor–positive disease by anastrozole than by tamoxifen is a matter of speculation, but this theory is supported by the advantages of anastrozole seen in adjuvant trials for invasive disease.

In view of the recent spate of publications regarding breast cancer mortality following a ductal carcinoma in situ diagnosis, it is of interest that 11 of 3,104 patients in NSABP B-35 developed distant metastases (0.35%); in IBIS-II DCIS, the number of women with breast cancer metastases was not reported, but there were 4 breast cancer deaths (0.13%).

Thus, full-court treatment of ductal carcinoma in situ (complete excision, radiotherapy, endocrine therapy) results in almost-perfect 10-year breast cancer–specific survival; how these results would be altered with lesser treatment is a pressing question in 2016. Since more than 800 women did not receive radiotherapy in the IBIS-II DCIS trial, information regarding the recurrence experience of this subset would be of considerable interest.

Patient-Reported Outcomes

Compliance was remarkably similar—64% in NSABP B-35 and 67% in IBIS-II DCIS; most women who discontinued therapy did so because of symptoms, the overall frequency of which was similar and consistent across the two trials. The specific symptoms and adverse events differed between arms, however, as would be expected from these agents. Thus, musculoskeletal problems were more frequent in the anastrozole arms, and vasomotor symptoms occurred more commonly in the tamoxifen arms.

In view of the interaction between anastrozole benefit and age under 60 years in the NSABP B-35 trial, the careful analysis of patient-reported outcomes in 1,193 participants by Ganz and colleagues² is particularly illuminating, focusing as they do on the interactions between symptoms and age. Thus, although NSABP B-35 showed a significant efficacy gain in women younger than age 60, this age group also appeared to suffer the most with treatment. Vasomotor symptoms, vaginal symptoms, gynecologic symptoms, and weight problems were all significantly more severe in younger women. For sexually active younger postmenopausal women, the significant increase in vaginal symptoms reported by the anastrozole group may be a particular concern. However, the mean mental health and physical health component scores were identical across the two arms in NSABP B-35.

These results clearly offer a choice for postmenopausal women with ductal carcinoma in situ in terms of endocrine therapy; they also validate the excellent outcomes that result from use of all three modalities of ductal carcinoma in situ therapy. The challenge for the future remains the selection of patients with ductal carcinoma in situ who may do well with less. ■

Disclosure: Dr. Khan reported no potential conflicts of interest.

References

1. Margolese RG, Cecchini RS, Julian TB, et al: Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): A randomised, double-blind, phase 3 clinical trial. Lancet. December 10, 2015 (early release online).
2. Ganz PA, Cecchini RS, Julian TB, et al: Patient-reported outcomes with anastrozole versus tamoxifen for postmenopausal patients with ductal carcinoma in situ treated with lumpectomy plus radiotherapy (NSABP B-35): A randomised, double-blind, phase 3 clinical trial. Lancet. December 10, 2015 (early release online).
3. Forbes JF, Sestak I, Howel A, et al: Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): A double-blind, randomised controlled trial. Lancet. December 11, 2015 (early release online).