A phase I/II study of imatinib and docetaxel as neoadjuvant therapy in locally advanced breast cancer

Abstract

11039 Background: Imatinib mestylate(Gleevec,G) is a tyrosine kinase inhibitor of platelet derived growth factor receptor(PDGFR) and KIT(CD117). In breast cancer(BC),PDGFR signaling regulates tumor interstitial fluid pressure(IFP). PDGFR inhibition lowers IFP enhancing tumor drug delivery and chemo effect. KIT’s role in BC growth is unclear.PDGFR and KIT signal pathways regulate proliferation and cell cycle progression.Receptor blockade may enhance anti-tumor activity combined with chemo.This study evaluated tolerability,toxicity and efficacy of imatinib and docetaxel and treatment changes in biomarker expression and downstream mediators. Methods: Eligibility:Total 12 women, invasive LABC(T2–4,No-2,Mo)IHC + for KIT and/or PDGF, ECOG 0–2,bidimensional disease.Treatment:Assigned to 1of 3 G dose levels(400,600,800mg) taken daily 2 weeks then combined with D30mg/m2 IV weekly x3 Q28 days. Three completed G(400mg D) and protocol modified to G600 and 800mg dose for 1 week then combined with D30mg/m2 IV weekly x12. Tumor(T)measured pretreatment and at definitive surgery at conclusion of G+D.T biopsy done preG, postG and at end of G+D for tissue markers. Three treated G400, 5G600 and 4G800mg dose. Results: 12 patients median age 51 (range 39–62), ECOG PS O, 4 pre/8 post menopausal treated. Clinical pretreatment (C-PRx) tumor size (TS)median 6cm (range 3- 12cm).C-PRx node status 7cN0 and 5cN1.PRx x-ray TS median 4.5 cm (range 2.5–8.5cm). Response:OR 25% 1 near CR+2 PR(3/12) at 400 and 600mg dose levels.Two SD(G800mg),3 progressed/off study,2 withdrew/toxicity(G3 rash/edema and G4 N/V), 2 NR.Surgery:5PM and 7MRM. Toxicity:Non- hematologic:nausea(1G4/G400mg),vomiting(1G4/G600mg),diarrhea(1G3/G800mg),fatigue(2G3/G800mg),myalgia(1G3/G800mg),rash(1G3/G600m g) and hypophosphatemia (2G3/G600mg). Hematologic toxicity mild neutropenia/anemia G1/2.One hospitalized for G3 odonophagia/stomatitis,G800mg.Dose Delay:2 missed 1 week of D+G (G600mg),2 missed 2 weeks of D+G (1G600mg and 1G800mg). Conclusion: Imatinib and docetaxel in neoadjuvant LABC is feasible and tolerable with low G3/4 toxicity and acceptable activity.G400mg dose best tolerated. Tissue IHC and molecular profiles to be reported separately.

Potential Role of Platelet-Derived Growth Factor Receptor Inhibition Using Imatinib in Combination with Docetaxel in the Treatment of Recurrent Non-small Cell Lung Cancer

“…neoadjuvant setting of breast cancer, ImD yielded a response rate of 25%. 22 There are several possible explanations for our negative outcome. We postulated that the mechanism of action of Im was predominantly angiogenesis inhibition through PDGF pathway blockade.…”