title: A phase II neoadjuvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer.
abstract: Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining 12 patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (P value = 0.01), with a parallel reduction in the expression of the Cyclin D1 (P value = 0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors.
authors.affiliation: The Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA. massarweh@uky.edu
authors.forename: Suleiman
authors.initials: S
authors.lastname: Massarweh
authors.forename: Yee L
authors.initials: YL
authors.lastname: Tham
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Krystal
authors.initials: K
authors.lastname: Sexton
authors.forename: Heidi
authors.initials: H
authors.lastname: Weiss
authors.forename: Anna
authors.initials: A
authors.lastname: Tsimelzon
authors.forename: Amanda
authors.initials: A
authors.lastname: Beyer
authors.forename: Mothaffar
authors.initials: M
authors.lastname: Rimawi
authors.forename: Wei Yen
authors.initials: WY
authors.lastname: Cai
authors.forename: Susan
authors.initials: S
authors.lastname: Hilsenbeck
authors.forename: Suzanne
authors.initials: S
authors.lastname: Fuqua
authors.forename: Richard
authors.initials: R
authors.lastname: Elledge
mesh_terms: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000628:therapy; D018567:Breast Neoplasms, Male / Q000188:drug therapy; D002453:Cell Cycle / Q000235:genetics; D019938:Cyclin D1 / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D000077267:Fulvestrant; D000077156:Gefitinib; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000008:administration & dosage; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D018931:Antineoplastic Agents, Hormonal; C530104:CCND1 protein, human; D019394:Ki-67 Antigen; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D019938:Cyclin D1; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol; D051058:Oncogene Protein v-akt; D020928:Mitogen-Activated Protein Kinases; D000077156:Gefitinib