Kuerer, Henry M.

Abstract Background: Estrogen receptor (ER)-negative tumors and human epidermal growth factor 2-Neu (HER2) positive breast cancers are known to be more clinically aggressive subtypes of breast cancer and account for 30% of all breast cancers. Women with HER2 + breast cancers, whether ER+ or ER -, require cytotoxic chemotherapy with a HER2-targeting agent, and often have adverse outcomes. Thus, preventive agents are needed to reduce the incidence of these subtypes of aggressive breast cancer. Lapatinib, a dual tyrosine kinase inhibitor, inhibits epidermal growth factor receptors (EGFR) and HER2 kinases and has shown to decrease breast cell proliferation in invasive breast cancer and adjacent premalignant lesions. Therefore, we conducted a multi-institutional randomized Phase II clinical trial to study the effects of the signal transduction inhibitor lapatinib in women with HER2-positive or EGFR-positive ductal carcinoma in situ (DCIS). Methods: Randomized participants received either lapatinib (750mg, 1000mg, or 1500mg) or placebo daily for 2-6 weeks prior to their surgery. After minimal accrual, the trial was later amended to lapatinib 1000mg or placebo. Pre-treatment breast tissue was obtained from initial diagnostic core biopsy and post-treatment breast tissue was obtained from surgical excision specimen. Blood was obtained prior to surgery to assess serum lapatinib level. Participants kept a daily symptom assessment log and had a cardiac assessment at baseline and prior to surgery. Patients were instructed to take drug up to and including the day before surgery. The dual primary endpoint for this study was change in proliferation in pre- versus post-treatment biopsies between the two treatment arms, as measured by Ki67 as well as toxicity assessment. Secondary endpoints included incidence of DCIS at surgery and modulation of tissue biomarker expression in growth factor receptors (EGFR, ErbB2); phosphorylated growth factor receptor (phospho-ErbB2); signal transduction markers (MAPK, phospho-MAPK); hormone receptors (ER, PR); and p27. Results:Twenty-two women (mean age: 51; range: 32-66) with HER2+ or EGFR+ DCIS were treated with lapatinib (1,000 or 1,500 mg) or placebo for 2–6 weeks prior to surgical excision. Ki67 expression was significantly decreased in the lapatinib treatment arms compared to placebo (p=0.0122). Diarrhea, fatigue, and skin reactions were notable adverse events that occurred predominately in the lapatinib arm compared to placebo. No grade 3 or 4 events related to the study drug were noted during the study. No changes were noted in cardiac function. DCIS was present in all surgical specimens in both arms. Invasive breast cancer was noted in 1 patient on lapatinib 1000mg and 3 patients on placebo. No statistically significant changes were noted in signal transduction biomarkers Conclusion:These results demonstrate the effectiveness of lapatinib in reducing proliferation in women with EGFR+ or HER2+ DCIS. Even low-grade toxicities can deter use of an agent in the prevention setting. This and the lack of a risk model for HER2+ and triple negative breast cancer make the development of larger scale clinical prevention trials of lapatinib for the prevention a challenge. Citation Format: Thomas PS, Contreras A, Pruthi S, Krontiras H, Rimawi M, Garber J, Wang T, Hilsenbeck SG, Vornik LA, Gilmer T, Friedman R, Heckman-Stoddard BM, Dunn B, Kuerer H, Brown PH. A phase II pre-surgical trial of lapatinib for the treatment of women with HER2 positive or EGFR positive ductal carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-07.

Postmastectomy radiotherapy (PMRT) reduces the risk of locoregional and distant recurrence and improves overall survival in women with lymph node–positive breast cancer. Because of stage migration and improvements in systemic therapy and other aspects of breast cancer care, the absolute benefit of PMRT and regional nodal irradiation may be small in some favorable subsets of patients with very low nodal burden, and newer consensus guidelines do not mandate PMRT in all node-positive cases. The use and need for PMRT may considerably complicate breast reconstruction after mastectomy and therefore mandates multidisciplinary input that takes into account patient choice given potential risk of acute and long-term toxicities, benefits, life expectancy, the biology of the tumor, plans for systemic therapy, and actual tumor burden. Management of axillary lymph node metastases is changing with selective use of axillary lymph node dissection for advanced disease, sentinel lymph node biopsy alone for clinically and pathologic node-negative cases receiving mastectomy, and targeted axillary dissection alone among patients with eradication of initial biopsy-proven nodal metastases with neoadjuvant systemic therapy use. In general, when the need for PMRT is anticipated, autologous reconstruction should be delayed. This comprehensive article reviews the current indications and implications regarding integration of breast cancer surgery and timing of reconstruction with optimum radiation delivery to achieve the best possible patient outcomes.

Learning Objectives After completing this course, the reader will be able to: Discuss the role of radiation therapy in the adjuvant treatment of DCIS.Describe the impact of tamoxifen in the treatment of DCIS.Discuss evolving strategies in neoadjuvant treatment for DCIS. Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com