[chrisy]

Dear Lori,
Thanks for posting this - you may want to also post this under the Clinical Trials area (OOPS, NEVER MIND! I JUST SAW IT THERE, TOO!. It's exciting to see they are seriously studying these combinations that target more pathways - aiming to shut down all the sneaky avenues. I keep the following article - a poster from the 2004 SABCS as a reminder that there may just be the "miracle" combination out there. I hope this trial will be super successful for you. Thanks for posting, and do keep us updated if you can!

Regards
Chris
[23] Complete disappearance of ER+/HER2+ breast cancer xenografts with the combination of gefitinib, trastuzumab, and pertuzumab to block HER2 cross-talk with ER and restore tamoxifen inhibition.

Arpino G, Weiss H, Wakeling AE, Osborne K, Schiff R.. Baylor College of Medicine, Houston, TX; AstraZeneca, Macclesfield, United Kingdom

Background. Tamoxifen (Tam) stimulates growth of ER+, HER2-overexpressing MCF7/HER2-18 breast tumor xenografts as a mechanism of Tam resistance. Anti-EGFR/HER2 treatment with either the tyrosine kinase inhibitor gefitinib ( Iressa , Gef) or the monoclonal antibody trastuzumab ( Herceptin , H) eliminates the ER-EGFR/HER2 cross-talk and temporarily restores Tam growth inhibition. Although the combination of Gef plus H is better than either agent alone, resistance still develops in 2-3 months and tumor growth resumes. Pertuzumab (P) is a new antibody targeting HER2 that inhibits heterodimerization of HER2 with all other HER family members and reduces HER2 signaling. We evaluated P as a single agent and in various combinations with Tam, Gef, and H in this model of in vivo Tam resistance.
Methods. Mice bearing MCF-7/HER2-18 cell xenografts established in the presence of estrogen (E2) were randomized (n 16) to continued E2 (+E2), E2 withdrawal ( E2), or E2 plus Tam alone or with various combinations of Gef, H, and P. Rates of complete disappearance of palpable tumor (CR), and median time to tumor progression (TTP) were determined and compared in the various treatment groups.
Results. In the +E2 group, P, like Gef and H, only minimally inhibited E2-stimulated tumor growth. In the -E2 group, however, the addition of P increased CRs from 0% ( E2 alone) to 56% ( E2+P) and TTP from 74 days to more than 140 days. In the Tam group, the addition of Gef, H, or P alone temporarily blocked Tam-stimulated growth and stabilized tumor volume (TTP=98 days p<0.001; 105 days, p<0.0001; and 84 days, p<0.0001, respectively). CRs were observed with the combination of Tam plus H (33%) or plus P (28%), but not plus Gef (0%). Since P, H, and Gef inhibit HER2 signaling in slightly different ways, combination therapy was investigated. In mice given Tam, the addition of P with H had a more dramatic effect, with 71% (12/17) of mice achieving a CR. The TTP has not yet been reached although 4 tumors are now progressing at 133 days of treatment. Even more remarkable effects were observed when all 3 growth factor inhibitors were combined with Tam: CR was observed in 90% (18/20) of mice and no tumors have progressed at a median follow up 129 days. Drug toxicity was not evident even with the combination regimens.
Conclusion. Growth factor receptor inhibitors cooperate through distinct, yet complementary, mechanisms to convey a potent HER2 signaling blockade. Combination treatment blocks crosstalk with ER to restore Tam antagonist effect on ER, and together with Tam eradicate MCF7/HER218 tumors. Because growth of these tumors seems to depend mainly on ER and EGFR/HER2 pathways, complete targeted disruption of these pathways can achieve remarkable antitumor activity deserving a clinical trial.


Friday, December 10, 2004 10:00 AM

General Session 4 (9:30 AM-12:00 PM)