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 (EGFR) 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 (AF) 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 twelve 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.

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

“…Indeed, the G2M pathway score of primary tumors was significantly reduced by chemotherapy in patients who achieved a good response (t-test p < 0.001), while the score did not change in those who had an intermediate (p = 0.355) or poor (p = 0.226) response ( Figure 6A). Furthermore, we found that the G2M score significantly decreased (p < 0.001) following successful endocrine therapy with anastrozole and fulvestrant in combination with gefitinib in the GSE33658 cohort [23] ( Figure 6A).…”

ErbB3 downregulation enhances luminal breast tumor response to antiestrogens

“…These results suggest that ErbB3 targeting in combination with fulvestrant may restrain signaling through both the PI3K and the mTOR pathways, as opposed to mTOR inhibitors, which may allow signaling through the PI3K pathway. Because ErbB3 is known to activate PI3K signaling in response to ErbB family RTKS and also in response to heterologous RTKs (e.g., MET, FGFR2, IGF1R), we performed phospho-RTK array analysis tion phase II neoadjuvant trial, in which postmenopausal women with newly diagnosed ER-positive breast cancer were treated for 4 months with anastrozole (Arimidex, an aromatase inhibitor) and fulvestrant (Faslodex) (30,31). After a baseline tumor core biopsy on day 0, patients received anastrozole (1 mg daily), and fulvestrant (250 mg monthly).…”

“…Paraffin sections of human breast tumor biopsies collected as part of a single stage, single institution a phase II neoadjuvant trial testing the combined effects of anastrozole (Arimidex), fulvestrant (Faslodex), and gefitinib (Iressa) in postmenopausal women with newly diagnosed ER-positive breast cancer (30,31) were assessed by immunohistochemical staining with antibodies against ErbB3 as described previously (24). The pathologist reading the results was blinded to the treatment group (day 1 versus 21).…”

Whole exome precision oncology targeting synthetic lethal vulnerabilities across the tumor transcriptome

“…We collected an additional cohort of 17 publicly available datasets from clinical trials of targeted therapies in cancer, each one containing both pre-treatment transcriptomics data and therapy response information. This compendium includes breast cancer patients treated with lapatinib 22 , gefinitib 23 , letrozole 24 , doxorubicin 25 , trastuzumab 26 , everolimus 27 and cetuximab 28 ; ovarian cancer patients treated with dasatinib 29 ; colorectal cancer patients treated with irinotecan 30 , multiple myeloma patients treated with bortezomib 31 and non-small cell lung cancer patients treated with sorafenib 32 . We identified the SL interaction partners of the drug targets in these datasets (Methods) and computed an SL-score for each sample using the SL partners of the corresponding drugs.…”

“…Cancer types are noted on the top of each dataset. (B) ROC curves for breast cancer patients treated with lapatinib (GSE66399) 22 , gefinitib (GSE33658) 23 , letrozole (GSE16391) 24 , doxorubicin (GSE8465) 25 , trastuzumab (GSE76360) 26 , everolimus (GSE119262) 27 and cetuximab (GSE23428) 28 , ovarian cancer patients treated with dasatinib (GSE37180) 29 , non-small cell lung cancer patients treated with sorafenib (GSE33072) 32 , colorectal cancer patients treated with irinotecan (GSE72970) 30 , multiple myeloma patients treated with bortezomib (GSE68871) 31 . (C) Bar graphs show the predictive accuracy in terms of AUCs (Y-axis) of SL-based predictors and a variety of controls specified earlier in Figure 1E (X-axis).…”