Prediction
of early distant relapses on tamoxifen in early-stage breast cancer
(BC): A potential tool for adjuvant aromatase inhibitor (AI) tailoring.
Loi
S, Piccart M, Haibe-Kains B, Desmedt C, Harris A, Bergh J, Ellis P,
Miller L, Liu E,
Sotiriou C
Background:
The majority of early-stage BC express estrogen receptors (ER) and
receive tamoxifen in the adjuvant setting. Yet up to 40% of these
patients will relapse on tamoxifen and develop incurable metastatic
disease. Recent evidence from three large randomised controlled trials
exploring the role of AI in the adjuvant setting shows a benefit from
the novel strategy, however the optimal sequence and duration of
AI/tamoxifen treatment is unknown. Therefore, it is vital that we learn
to identify those women at higher risk of tamoxifen resistance. Our aim
was to identify genes that could predict for this subset of women.
Methods: We
determined the gene expression profiles from 105 tamoxifen-only treated
ER positive early stage BC (training set) using Affymetrix U133 A and B
chips. Within this group, 30 (29%) patients developed distant
recurrence at a median time to relapse of 3.8 years (yrs) and 75 (71%)
remained disease free at a median of 5.7 yrs of follow-up. The
independent validation set consisted of 64 ER+ tamoxifen only treated
BC patients (17 recurrences) from a different institution (Karolinska,
Sweden).
Results: Cox
proportional hazards regression analysis identified 50 genes that were
significantly associated with distant relapse on tamoxifen. The
probability of selecting these genes by chance was estimated to be
p=0.001 after 1000 random permutations. These genes were powerful
predictors of clinical outcome in the independent validation set,
dividing the cohort into 2 statistically different prognostic groups
(p=0.02) in the poor prognostic group (tamoxifen resistant) the median
time to distant relapse was 2.4yrs compared with 7yrs in the good
prognostic one (tamoxifen sensitive). We are currently validating this
signature in another independent dataset (Guys hospital, UK).
Conclusions:
These results suggest that a group of genes can identify BC patients at
risk of early distant relapse on tamoxifen. These patients could be the
ideal candidates for upfront AIs, while the others would be considered
for sequential tamoxifen/AI. This hypothesis will be tested in an
upcoming prospective clinical trial “MINDACT”.