Efficacy and safety of trastuzumab emtansine treatment in patients with metastatic HER-2 positive breast cancer: a single center study

Introduction: Trastuzumab emtansine (T-DM1) is one of the effective treatment options in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. In this study, we aimed to find the effect of T-DM1 on survival, its tolerability and prognostic factors of T-DM1 treatment. Material and methods: The study was designed as a single-center, retrospective study that included patients treated in the oncology department of a university hospital in Turkey. HER2-positive patients with metastatic breast cancer who had a progression response to trastuzumab and taxane treatment and received T-DM1 treatment for at least 2 months between 2016-2022 were included in the study. Adverse events were defined according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE). Kaplan-Meier methodology and Cox proportional hazard modelling were used for survival treatment in patients with metastatic HER-2 positive breast cancer: a single center study.

Eficacia y seguridad del tratamiento con trastuzumab emtansina en pacientes con cáncer de mama metastásico HER-2 positivo: estudio de un solo centro INFO

INTRODUCTION
Breast cancer is the most common cancer in women and is one of the leading causes of cancer-related deaths [1]. Breast cancer, which has a heterogeneous structure, has been molecularly subtypes according to its hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Treatment approaches and survival times also vary according to the subtypes [2,3]. One of the subtypes, HER2positive breast cancers, is an aggressive subtype that constitutes 15-20% of breast malignancies and has a high risk of recurrence [4]. In addition to conventional chemotherapies, HER2-targeted therapies significantly improved treatment outcomes of HER2-positive breast cancer patients [5].
HER2 is a transmembrane glycoprotein with tyrosine kinase activity. Its overexpression is associated with poor prognosis, but the presence of trastuzumab, the target treatment for HER2, has improved the prognosis [6]. However, since it is inadequate in metastatic patients, new treatment options were needed. The TH3RESA study conducted in 2017 reported the efficacy of trastuzumab emtansine (T-DM1), a new treatment option in metastatic breast cancer patients [7]. T-DM1 is an antibody-drug conjugate formed by the addition of cytotoxic drug emtansine to the monoclonal antibody trastuzumab [8]. Thanks to this new molecular complex, the effect of trastuzumab on tumor cells has been increased without harming healthy cells [9]. However, very different adverse events, which are thought to be related to DM1 but may also be caused by the structure of trastuzumab, can be observed [10]. In this study, we aimed to investigate the prognostic factors affecting the response time and the effect on survival as well as drug toxicity related to T-DM1 in patients received T-DM1 treatment in our center.

STUDY POPULATION
This study has been designed as a single center and retrospective study. The institutional ethics committee approved this study (approval no: 2022.121.06.11). The study included outpatient metastatic breast cancer patients who received treatment between 2016 and 2022. The study included patients with: 1) HER2 positive breast cancer with pathological diagnosis; 2) 18 years of age or older; 3) patients who completed at least 2 months of T-DM1 therapy; 4) metastasis was confirmed in organs using computed tomography, magnetic resonance imaging scans, or other imaging methods; 5) concomitant or no previous history of malignancy; 6) no active infectious disease, no immunosuppressive drug use. All patients received at least one line of cytotoxic chemotherapy (taxane) and trastuzumab for metastatic disease and progressed on or after the last treatment. The HER2-positive disease was considered as those with positive results by immunohistochemistry (IHC) 3+ or IHC 2+ expression and those with positive results by fluorescent in-situ hybridization (FISH). According to the guide of the American Society of Clinical Oncology/College of American Pathologists, those with estrogen receptor (ER) and progesterone receptor (PgR) above 1% were evaluated as positive [11].

TREATMENT
Patients were treated with T-DM1 at a standard dose of 3.6 mg per kg of body weight intravenously every 21 days. Computed tomography (CT) and positron emission tomography (PET-CT) was used at 3-4 cycle intervals to evaluate the treatment response. Treatment responses were determined according to RECIST (Response Evaluation Criteria In Solid Tumors) 1.1. According to the information obtained from the patient archive files, adverse events were defined according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE).

STATISTICAL ANALYSIS
Progression-free survival (PFS) was defined as the time from the beginning of the T-DM1 treatment to the time of any documented clinical progression, relapse, or death from any cause. Overall survival (OS) was defined as the time from the diagnosis to death for any reason. All statistical analyses were performed using SPSS version 26.0 (IBM Corb, Armonk, NY). Survival analysis was performed using the Kaplan-Meier method and the Log-Rank test was used

SURVIVAL TIMES
The median follow-up period in our study was 21 Figure 2). In the univariate cox regression analysis for OS, only ECOG performance status (HR=2.61, 95% CI: 1.14-5.96, p=0.023) was found to be prognostic ( Table 3). The mOS of patients with poor performance status was 18.4 months (95% CI 11.8-24.9), while mOS was 44.3 months (95% CI 16.7-71.9) in patients with good performance status.

TOXICITY AND SIDE EFFECTS
In the adverse event assessment according to CTCAE v5.0, T-DM1 was found to be well tolerated in most patients. There was no patient who died due to toxicity or whose   Table 4).

DISCUSSION
In this study, we aimed to investigate the survival effect of T-DM1 in patients who received trastuzumab and taxane treatment, the prognostic factors affecting response time of T-DM1 treatment, and T-DM1-related adverse events as a single-center experience with real-life data. In our study, we found that T-DM1 was safe and a tolerable medication in the majority of patients. Our survival analyses found that ECOG performance status, liver metastasis and pre-treatment serum CA 15-3 level were prognostic for T-DM1-related PFS. We found that only the ECOG performance status was prognostic for OS.
In the EMILIA study, which included 991 patients receiving trastuzumab and taxane, mPFS was reported as 9.6 months in advanced breast cancer patients [12]. In a multicenter study including 441 patients, mPFS was reported as 9 months while PFS was reported as 10 months in another study conducted in Italy [13,14]. In our study, mPFS was found to be 10.4 months, similar to previous studies. The relationship between performance status and survival time in breast cancer is known [15,16]. As expected, this important connection was also demonstrated in studies that included patients using only T-DM1 . In this study, ECOG performance status was found to be prognostic, and mPFS was detected as 9 months in patients with poor performance status and 21.1 months in patients with good performance status. Despite its low sensitivity, CA 15-3  levels are one of the most frequently used tumor markers in patient follow-up in daily oncology practice. The American Society of Clinical Oncology (ASCO) has reported CA 15-3 as a useful marker in making treatment decisions [20]. However, there is no consensus in previous studies that included breast cancer patients for its prognostic feature [21][22][23]. Ozyukseller et al. investigated the prognostic feature of CA 15-3 levels in patients using only T-DM1 and found the change in CA 15-3 levels during treatment as prognostic [17]. In our study, on the other hand, the relationship between pretreatment serum CA 15-3 levels and survival was investigated, and a longer survival time was found in patients with high pretreatment serum levels. CA 15-3 level was found to be an independent prognostic factor for patients using T-DM1. The liver is one of the most common visceral organs to which advanced breast cancer metastasizes, and the presence of liver metastases has been reported as a poor prognosis in studies including all breast cancer subtypes [24][25][26][27]. In previous studies that included patients using T-DM1, the prognostic feature of the presence of visceral metastases was investigated, but liver metastasis was not investigated as a subgroup. In the studies of Ozyukseller et al., Fabi et al., and Noda-Narita et al., visceral metastasis was not found to be prognostic, similar to our study [14,17,28]. However, liver metastasis status was also analyzed in our study and this was found to be prognostic for T-DM1 response time.
To the best of our knowledge, this is the first study to detect the presence of liver metastases as prognostic for patients using T-DM1. In our study, it was observed that T-DM1 was well tolerated and although 82.1% of the patients had adverse events, no treatment was changed due to toxicity in any of the patients. The rate of those who experienced grade 3-5 adverse events was 17.9%. This rate was 40% in the TH3RESA study, 25.7% in the KATHERINA study, and 37.5% in the KAMILIA study [7,29,30]. These differences in the incidence of adverse events between studies may be related to many factors, such as the median age of the patients included, performance status, treatment lines, and sites of metastasis [10,31]. The most common serious adverse events were fatigue, nausea, thrombocytopenia, and anemia, consistent with previous studies [10,32]. Further multicenter studies with large patient populations are needed for more generally accepted information on adverse events. Our study has some limitations. The first of these is that the study has a single-centered and retrospective design. Second, even if the patient selection criteria were carefully chosen, various circumstances can influence laboratory markers. However, the strengths of the study are that it includes real-life data and extensive prognostic factor analysis for T-DM1.

CONCLUSIONS
T-DM1 is an important treatment agent that has shown its survival effect in patients with advanced HER2 positive breast cancer. In this study, we found that ECOG performance status, liver metastasis status, and pretreatment serum CA 15-3 levels were prognostic factors associated with the response time of T-DM1 treatment. In addition, our results showed that T-DM1 is a safe and tolerable treatment agent.