Phase I study and biomarker analysis of lapatinib and concurrent radiation for locally advanced breast cancer.

PURPOSE: This phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways. METHODS: Eligibility for this dose-escalation study included unresectable and locally recurrent or chemotherapy-refractory and locally advanced breast cancer, and adequate organ function. Patients underwent three serial biopsies: at baseline, after 1 week of lapatinib alone, and after 1 week of lapatinib and radiation. Endpoints included determination of toxicity, maximum tolerated dose, and analysis of the effect of lapatinib with or without radiation on EGFR and HER2 signaling pathways by immunohistochemistry. RESULTS: Doses of lapatinib up to 1,500 mg/day were well tolerated. Toxicity of grade 3 or more was limited to radiation dermatitis and pain. Out of 19 patients treated, in field responses per response evaluation criteria in solid tumors criteria were complete in four patients and partial in six patients. Serial biopsies were obtained in 16 patients with no complications. Total Her2 was relatively unchanged while phospho-Her2, phospho-Akt, and phospho-ERK showed variable responses to both lapatinib alone and dual therapy with lapatinib and radiation. CONCLUSIONS: The combination of lapatinib and radiation was well tolerated in this patient cohort. Overall local response rates were comparable to those reported in other studies in this patient population. Biopsies were safely performed at all time points. Inhibition of HER2 and downstream signaling pathways was identified, although no strong correlation with response was seen.

Local control following single-dose intraoperative radiotherapy prior to surgical excision of early-stage breast cancer.

BACKGROUND: Multiple partial breast radiotherapy techniques are available. We have previously presented the technical details of our procedure of delivering partial breast irradiation with a single fraction of intraoperative radiotherapy (IORT) targeting the tumor in situ prior to partial mastectomy. This study details our completed, single-institution trial. MATERIALS AND METHODS: An IRB-approved, DSMB-monitored phase II trial was performed with the following inclusion criteria: women age ≥48, ultrasound-visible invasive ductal cancers <3 cm, clinically negative axillary nodes. IORT was delivered using mobile electron irradiator, at least a 1.5-cm radial and 1-cm deep margin; patients received 15 Gy and immediately underwent partial mastectomy. Ipsilateral breast recurrence was classified as true/marginal, elsewhere in the breast or nodal basin. Kaplan-Meier methods were used to estimate survival functions and exact 95% confidence intervals are reported. RESULTS: Between 2003 and 2007, 71 women underwent IORT (median follow-up: 3.5 years). For patients with tumor-involved or close margins, additional therapy was required: 7 patients, total mastectomy; 11, whole breast radiation. Four women experienced invasive ipsilateral breast failures (1 new primary, 3 margin recurrences) for a 3-year local control rate of 49 of 53 (94.8%; 95% confidence interval 92.4% [95% CI] 84.2­98.3%), actuarial three-year in breast recurrence was 8% (95% CI 2­18%), and breast cancer-specific survival was 100%. CONCLUSIONS: Intraoperative radiotherapy delivered to an in situ tumor is feasible, but our local control rate at 3.5 years is concerning. Possible changes to this technique to improve local control rates include better preoperative imaging (MRI), routine intraoperative ultrasound, and improved IORT delivery (larger cone, increased dose).