Molecular effects of lapatinib in patients with HER2 positive ductal carcinoma in situ

Abstract

IntroductionHuman epidermal growth factor receptor 2 (HER2) amplification is frequent in ductal carcinoma in situ (DCIS) of the breast and is associated with poorly differentiated tumors and adverse prognosis features. This study aimed to determine the molecular effects of the HER2 inhibitor lapatinib in patients with HER2 positive DCIS.MethodsPatients with HER2 positive DCIS received 1,500 mg daily of lapatinib for four consecutive weeks prior to surgical resection. Magnetic resonance imaging (MRI) was used to determine changes in tumor volume. The molecular effects of lapatinib on HER2 signaling (PI3K/AKT and RAS/MAPK pathways), cell proliferation (Ki67 and p27) and apoptosis (TUNEL) were determined in pre and post-lapatinib treatment samples.ResultsA total of 20 patients were included. Lapatinib was well tolerated with only minor and transient side effects. The agent effectively modulated HER2 signaling decreasing significantly pHER2 and pERK1 expression, together with a decrease in tumor size evaluated by MRI. There was no evidence of changes in Ki67.ConclusionsFour weeks of neoadjuvant lapatinib in patients with HER2-positive DCIS resulted in inhibition of HER2 and RAS/MAPK signaling pathway.Trial registration2008-004492-21 (Registered June 25th 2008).Electronic supplementary materialThe online version of this article (doi:10.1186/bcr3695) contains supplementary material, which is available to authorized users.

CD8+ tumor‐infiltrating lymphocytes contribute to spontaneous “healing” in HER2‐positive ductal carcinoma in situ

“…The proportion of HER2-positive DCIS (23.2%) was similar to that of HER2-positive invasive breast cancers (15-25%) [21,29]. Interestingly, clinical trials of anti-HER2 therapies have been initiated for HER2 DCIS [9][10][11]. The anti-HER2/neu antibody promotes cooperation between innate and adaptive immunity, warranting the use of combination therapies promoting antibody-initiated anti-tumor immune responses [37].…”

“…While the concept of surrogate subtyping for invasive cancers is well established, surrogate subtyping for DCIS has attracted much less attention, probably as a result of the lower efficacy of targeted therapeutics in DCIS compared with invasive cancers. Currently, clinical trials targeting HER2‐positive DCIS with different anti‐HER2 treatments with or without radiation are underway , and may eventually pave the way for less‐traumatic treatments.…”

The prognostic role of HER2 expression in ductal breast carcinoma in situ (DCIS); a population-based cohort study

“…This has been acknowledged by recently conducted clinical trials testing the efficacy of HER2 targeting therapy with lapatinib in DCIS patients (ClinicalTrials.gov NCT00555152 and NCT00857714, respectively). The results of these trials are currently not published, however the trial results by Estevés et al assessing lapatinib in the pre-surgical setting reported significant inhibition of HER2 signalling and reduced tumor size following 4 weeks of treatment in HER2 positive DCIS patients [ 38 ]. Further, other biomarker trials have assessed the effects of trastuzumab in DCIS patients, among which, one trial has reported the results, showing no significant tumor effects in terms of proliferation and apoptosis after a single-dose monotherapy trastuzumab pre-surgically [ 39 ].…”

Paradigm Shift toward Reducing Overtreatment of Ductal Carcinoma In Situ of Breast

“…A small prospective phase II single-arm study has also demonstrated that lapatinib (a tyrosine kinase inhibitor) interrupts the HER2/neu and epidermal growth factor receptor pathways, and significantly decreases the expressions of pHER2 and pERK1 in patients with HER2-positive DCIS. However, it did not alter the expression of Ki-67 (a proliferation marker) ( 41 ). The National Surgical Adjuvant Breast Project B-43 trial is a large phase III RCT (target recruitment: 2,000 patients) that is evaluating the addition of trastuzumab to standard treatment using surgery and RT (NCT00769379) ( 42 ).…”