Is there a role for adjuvant tamoxifen in progesterone receptor-positive breast cancer? An in silico clinical trial

Purpose: Subset analysis from the Arimidex, Tamoxifen, Alone or in Combination trial, a major adjuvant therapy trial, suggests that progesterone receptor - negative (PR-) cases may derive greater benefit from aromatase inhibitor compared with tamoxifen than PR+ cases. We postulated that estrogen receptor-positive (ER+)/PR+ patients might do as well or better by starting on tamoxifen and later switching to an aromatase inhibitor rather than by starting on an aromatase inhibitor as initial therapy. Experimental Design: We constructed a computer model using retrospective data to approximate exponential failure rates for PR+ and PR- in tamoxifen-treated and tamoxifen-untreated patients, adding the assumptions that about half of patients are cured at surgery and that ∼ 20% of postmenopausal ER+ early breast cancer cases are PR-. This model provided a very good approximation to the published overview data and to the clinical trials. We then used the failure rates to generate relapse times for a large number of cases (n = 50,000) for each treatment scenario. Results: In PR- cases, initial therapy with an aromatase inhibitor is superior to tamoxifen and this advantage can never be made up by switching. In PR+ cases, tamoxifen is only modestly inferior to aromatase inhibitor at the outset, and after switching to an aromatase inhibitor at 3 or 5 years the tamoxifen relapse-free survival curve catches up and then begins to surpass the aromatase inhibitor curve at 7.5 or 12 years, respectively. Discussion: Although our in silico trial is based on many assumptions, it closely approximates results of the published trials and, therefore, suggests that an in vivo comparison in ER+/PR+ patients of aromatase inhibitor versus tamoxifen followed by aromatase inhibitor may be worth considering.