Central Review of ER, PgR and HER2 in BIG 1-98 Evaluating Letrozole vs. Letrozole Followed by Tamoxifen vs. Tamoxifen Followed by Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women with Hormone Receptor-Positive Breast Cancer.

Abstract

Background: The BIG 1-98 trial, a large international Phase III study, evaluated letrozole (Let) for 5 years (n=1546) vs. Let for 2 years followed by tamoxifen (Tam) for 3 years (L→T; n=1540) and vs. Tam for 2 years followed by Let for 3 years (T→L; n=1548) as initial adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. Patients with HER2-positive disease did not receive trastuzumab. Efficacy results were presented in SABCS 2008 and showed that neither of the sequential therapy arms significantly improved disease-free survival (DFS) compared with letrozole alone. Centrally-assessed ER, PgR and HER2 have now been evaluated as potential predictive factors for treatment selection.Methods: Tumor blocks for 3975 of the 4634 (86%) patients on these three treatment arms were centrally collected and assessed by the IBCSG Central Pathology Laboratory. The tumors were evaluated for ER and PgR content by immunohistochemistry (IHC), and for HER2 immunoreactivity by IHC and by FISH for IHC 1+ or 2+ tumors. DFS according to centrally-assessed ER, PgR and HER2 status was analyzed using multivariable Cox modeling. STEPP methodology was used to explore patterns of DFS differences according to quantitative values of receptor levels (% staining cells).Results: Upon central review, 3885 tumors were confirmed to express ER and are the focus of this analysis. PgR expression did not predict differential treatment effects among the 3 treatment arms. With only 240 (6.2%) HER2-positive tumors, there was a suggestion of differential treatment benefit relative to HER2 status, in particular of a benefit of Let for 5 yrs over Tam→Let in HER2-positive tumors.Discussion: Given the caveat of a low prevalence of HER2-positive tumors and absence of HER2-directed therapy in the BIG 1-98 trial population, there is a suggestion that Let for 5 years may be a better option than a sequence of Tam and Let among women with HER2-positive tumors. Thus it may be better to initiate and continue treatment of endocrine-responsive, HER2+ tumors with Let rather than a sequence of Tam and Let. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 76.

First generation prognostic gene signatures for breast cancer predict both survival and chemotherapy sensitivity and identify overlapping patient populations

“…In particular lymph node status was prognostic but not predictive of chemotherapy response. This confirms findings by other studies that the genomic markers cannot replace but rather compliment prognostic information derived from anatomical pathological variables [3,6,[14][15][16]. Also, even though all of the genomic predictors had statistically similar performance and in multivariate analysis they provided no independent information, when applied to individual patients they frequently yielded discordant risk prediction results.…”

“…In almost all studies, these anatomical pathological variables remain statistically significant independent predictors of prognosis (i.e., probability of survival in the absence of systemic adjuvant therapy) [3,6,[14][15][16]. However, neither tumor size nor nodal status has a strong and consistent association with treatment sensitivity (i.e., probability and extent of response to therapy).…”

Risk of early recurrence among postmenopausal women with estrogen receptor‐positive early breast cancer treated with adjuvant tamoxifen

“…Central subset analyses of tumor blocks of patients enrolled in the ATAC and BIG 1-98 trials 23,24 demonstrated that AIs were superior to tamoxifen irrespective of the degree of positivity of ER, HER-2 status, and progesterone receptor (PgR) status. In the neoadjuvant literature, Ellis et al reported that letrozole was superior to tamoxifen at all levels of ER expression between Allred scores of 3 and 8.…”

HER2/neu in systemic therapy for women with breast cancer: a systematic review

“…As HER2/neu overexpression and amplification are highly correlated with estrogen-receptor positive/progesterone-receptor negative status [71], these results may reflect an interaction between HER2/neu status and anastrozole therapy. However, an abstract from the BIG 1-98 trial [72] reported no obvious difference between estrogenreceptor positive/progesterone-receptor positive (hazard ratio 0.84, 95% confidence interval 0.69 to 1.03) and the estrogen-receptor positive/progesterone-receptor negative (hazard ratio 0.83, 95% confidence interval 0.62 to 1.10) subgroups comparing letrozole versus tamoxifen, so this relationship may not hold across all aromatase inhibitors. If and when HER2/neu subgroup analyses are published from these trials, it may then be possible to make a definitive statement regarding aromatase inhibitor therapy and HER2/neu status.…”