Abstract P3-14-03: Combining or Sequencing Targeted Therapies in ER+/HER2 Amplified Breast Cancer (BC): In Vitro and In Vivo Studies of Letrozole and Lapatinib in an ER+/HER2+ Aromatase-Transfected BC Model
Authors: Leary AF , Martin L-A , Thornhill A , Dowsett M , Johnston SRD. 
Published: April 2011

Rationale: ER+/HER2+ BC may be resistant to endocrine therapies, but sensitive to HER2 inhibitors such as lapatinib. There is evidence that lapatinib may reactivate ERα expression1,2 raising the possibility that lapatinib may sensitize BC to subsequent endocrine therapy. Whether targeting the ER and HER2 in combination or in sequence in ER+/HER2+ BC may enhance anti-tumour effect is unknown. Aims: (1) To determine in ER+/HER2+ aromatase-expressing breast cancer models in vitro and in vivo.whether the combination of lapatinib with letrozole or tamoxifen is synergistic, and (2) to investigate whether using lapatinib and letrozole in sequence rather than in combination may provide a superior strategy.

Methods: ER+/HER2+ BT474 cells were stably transfected with aromatase (BTArom). Combination growth studies, immunoblots and gene expression assays were conducted in BTArom cells. BTArom xenograft studies were performed over 18 weeks under androstenedione support and mice randomized to daily treatment with vehicle, lapatinib, letrozole, or lapatinib and letrozole (L+L). In addition, mice in the lapatinib alone arm, were randomized at 6 weeks to continued lapatinib, vs. switch to letrozole, vs switch to L+L.

Results: Formal combination studies in aromatase-transfected BT474 (BTArom) cells demonstrated synergy between lapatinib and letrozole (combination index, CI=0.4, p&lt;10-5), but antagonism between lapatinib and 4-OH-tamoxifen (CI=1.34, p=0.05). In BTArom cells, lapatinib increased ESR1 2.8-fold (P&lt;0.0001) and ERα protein expression 2- fold. As expected, androstenedione upregulated both ER-controlled genes, PGR and GREB1, however lapatinib treatment increased PGR and GREB1 further, by 4.6- and 1.8—fold over androstenedione alone (p=0.0001 and p=0.045, respectively). In long-term BTArom xenografts the combination of lapatinib and letrozole was no more effective at controlling tumour growth than either treatment alone (Kruskall-Wallis comparing treatment arms, P&gt;0.05). However for the group of mice treated with lapatinib for 6 weeks followed by the combination of lapatinib and letrozole for 12 weeks, tumour volume increased only 2.2-fold, compared to 4.5-fold for those continuing on lapatinib, 5.7-fold for those switching to letrozole and 5.2-fold for those on lapatinib and letrozole from the start. Conclusion: We have demonstrated that HER2 targeted therapy enhanced responsiveness to aromatase inhibition in an ER+/HER2+ breast cancer model in vitro and in vivo. In contrast, the interaction between lapatinib and 4-OH-tamoxifen was antagonistic. Lapatinib increased ER expression and function, and the most effective tumour control was achieved with lapatinib alone followed by the combination of lapatinib and letrozole. Maximizing benefit from ER and HER2 targeted therapies in ER+/HER2+ BC may involve sequential rather than concurrent treatment to exploit lapatinib-induced ER reactivation. 1 Leary et al, Clin Canc Res 2010 2Xia et al, PNAS 2006

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-03.