Clinical impact of interruption in adjuvant Trastuzumab therapy in patients with operable HER-2 positive breast cancer

Abstract

Background Trastuzumab-induced cardiotoxicity (TIC) can lead to early discontinuation of adjuvant therapy, however there is limited evidence on long-term survival outcomes in patients with operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) experiencing treatment interruption or discontinuation. Methods The primary objective of the study was to evaluate disease-free survival (DFS) in non-metastatic, HER2-positive, female BC patients who experienced treatment interruption or early discontinuation of trastuzumab therapy. Clinical and histopathological data were collected on 400 patients at The Ohio State University, an NCI-designated comprehensive cancer center between January 2005 and December 2015. Treatment interruption was defined as any delay of ≥2 weeks during trastuzumab therapy, including permanent cessation prior to completing planned therapy. TIC was defined as LVEF < 50% or > 15 points decline from baseline as evaluated by 2D echocardiogram after initiation of (neo) adjuvant therapy. DFS was defined as the time from diagnosis to first recurrence (loco-regional or distant recurrence) including second primary BC or death. Overall survival (OS) was defined as the time from diagnosis to death or last known follow up. OS/DFS estimates were generated using Kaplan-Meier methods and compared using Log-rank tests. Cox proportional hazard models were used to calculate adjusted hazard ratios (aHR) for OS/DFS. Results A total of 369 patients received trastuzumab therapy; 106 (29%) patients experienced treatment interruption at least once and 42 (11%) permanently discontinued trastuzumab prior to completing planned therapy. TIC was the most common reason for interruption (66 patients, 62%). The median duration of trastuzumab in patients with treatment interruption was 11.3 months (range: 0.5–16.9) with 24 (23%) patients receiving ≤6 months of therapy. This duration includes the time delay related to treatment interruption. Patients with any treatment interruption had worse DFS (aHR: 4.4, p = 0.001) and OS (aHR: 4.8, p < 0.001) after adjusting for age, stage, grade, ER, node status and TIC. Conclusions Treatment interruption or early discontinuation of trastuzumab therapy in early HER2-positive BC, most often from TIC, is an independent prognostic marker for worse DFS and OS in operable HER2-positive BC. Future prospective studies should consider targeting at-risk populations and optimizing cardiac function to avoid interruption in trastuzumab therapy.

New Insights in the Era of Clinical Biomarkers as Potential Predictors of Systemic Therapy-Induced Cardiotoxicity in Women with Breast Cancer: A Systematic Review

“…Trastuzumab-related cardiotoxicity can be reversible upon discontinuation of treatment [ 5 ], which may, however, be associated with tumor recurrence and worse overall survival [ 68 , 69 ]. Evidence also supports that the recovered LVEF measurements in patients treated with trastuzumab for 12 months (48.53%), never reached the baseline LVEF levels at 30 months after treatment completion [ 70 ].…”

Real-World Data of Cardio-oncologic Interventions for Cardiotoxicity with Oral Oncolytics

“…Furthermore, interruption of anti-HER2 agents because of cardiotoxicity was found to be associated with worse outcomes in patients with breast cancer. (44) The aforementioned observation led to the emergence of the concept of permissive cardiotoxicity, which favors aggressive management of cardiotoxicity to enable the patient to remain on life-prolonging cancer treatment rather than discontinuation of cardiotoxic treatment. ( 45) For example, it is now recommended to continue anti-HER2 agents with close surveillance when CTRCD is asymptomatic and moderate.…”

Real-world data of cardio-oncologic interventions for cardiovascular adverse events with oral oncolytics

“…Oral oncolytics have been associated with high response rates and survival benefit in many instances, and reluctance to immediately withdraw these highly effective medications before attempting to manage their toxicities is justifiable. Furthermore, interruption of anti-HER2 agents because of CV adverse events was found to be associated with worse outcomes in patients with breast cancer [ 55 , 56 ]. The aforementioned observation led to the emergence of the concept of permissive cardiotoxicity, which favors aggressive management of cardiotoxicity to enable the patient to remain on life-prolonging cancer treatment rather than discontinuation of cardiotoxic treatment [ 57 ].…”