Disease outcomes of HER2+ breast cancers have dramatically changed after targeted therapies, such as trastuzumab, came to clinical practice but predictive factors for trastuzumab sensitivity and resistance are frequently unknown. Current work included metastatic breast cancer patients (n = 48), who were treated with trastuzumab and had pre-treatment tumour samples available. The tumours were immunostained for T-cell (CD3, CD8), natural killer (NK)-cell (CD56) and macrophage (CD68) markers and quantitative analysis of the immune cells was carried out using a computer-assisted image analysis in different tumour locations. High number of CD3 and CD8 positive T-cells was associated with significant survival benefit in the center of the tumour (CT) (p = 0.007, p = 0.001) but not in the invasive margin. The number of NK-cells and macrophages in the CT showed non-significant tendency towards improved survival. In subgroup analyses, high density of CD8 CT cells was associated with significant survival benefit in non-bone only disease, in TX or T1-3, and in ER+ tumours (p = 0.006, p = 0.003, p = 0.001). Moreover, high CD8 CT cell density associated significantly with long trastuzumab interruption periods in response. The results suggest important prognostic and predictive role of tumour infiltrating lymphocytes in center of the tumours in metastatic HER2+ breast cancer.

IntroductionHuman epidermal growth factor receptor 2 (HER2)-targeted-therapy regimens can lead to prolonged tumour responses in metastatic HER2+ breast cancer. Clinical trials have concerned use of HER2-targeted agents until disease progression, but it is unknown whether the therapy can be interrupted in cases of a good response.MethodsSingle institute, retrospective collection of data on patients with HER2+ metastatic breast cancer (n=68) was carried out through a pharmacy search for patients who had received trastuzumab in 2006–2014. Clinical and pathological factors, treatment history and survival data were collected from patient records.ResultsMedian survival in metastatic disease (all patients) was 32 months and survival times were dramatically different in patients with and without trastuzumab as adjuvant or primary metastatic disease (median 16, 77 and 35 months, respectively; p=0.0004). More importantly, HER2 therapy was intentionally interrupted in 21 responding patients, and these patients experienced long HER2-therapy-free intervals (median 51 months), with excellent long-term survival. A lack of previous adjuvant trastuzumab was the only statistically significant factor predictive of HER2 therapy interruption.ConclusionsThese results from our retrospective study show that HER2 therapy interruption in patients with metastatic HER2+ breast cancer, who have responded to the therapy, is associated with low risk of rapid disease progression. Study suggests that therapy interruption in cases of response and reinitiation in progression is feasible.

Trastuzumab cardiotoxicity seems to accumulate among patients with underlying cardiac conditions. EF monitoring could be targeted to risk groups without compromising of the cardiac health or survival of HER2-positive breast cancer patients.