Clinical Profile of Carcinoma Breast Patients Treated with Trastuzumab: A Single Centre Study

Introduction: Breast cancer is the most common female cancer in India and accounting for almost 1 in 4 cancer cases in women worldwide. According to GLOBOCAN 2018: breast cancer incidence is increased to 162,468 in 2018 compared to 144,937 in 2012. Biosimilar drugs allow ex-panding access to the therapies in the form of cost savings and leading to better overall health outcomes. Our study evaluates the efficacy and safety of Trastuzumab biosimilars and assesses overall survival in the study population. Materials & Methods: This prospective study was conducted in Healthcare Global Enterprises Ltd., Bengaluru, India, and all female patients diagnosed with Her2 positive, metastatic (mBC) and Locally advanced breast cancer (LABC), between March 2013 and November 2014, with at least 4 years of post-treatment follow up. Results: A total of 65 patients diagnosed with Her2 positive breast cancer and satisfied the selection criteria were included for the study. Partial Response (PR) was observed in 42 (64.6%) patients, Stable Disease (SD) in 11 (16.9%) patients and Progressive Disease (PD) in 12 (18.5%) patients. The overall response rates were 46.1% PR, 30% SD, 23.8% PD in metastatic population and 76% PR, 7.2% SD, 15% PD observed in locally advanced disease. The mean overall survival of the study population was 20.75 ± 15.20 months in metastatic and 29.2 ± 17.06 months in locally advanced patients. Conclusion: This prospective study shows the effectiveness of Trastuzumab for HER2-positive in locally advanced and metastatic breast cancer. The response rates, survival and toxicity correlate with other global studies. The response and survival are as same as either generic or original Trastuzumab.


Introduction
Breast cancer is the most common female cancer in India and accounting for almost 1 in 4 cancer cases in women worldwide. According to GLOBOCAN 2018: breast cancer incidence is increased to 162,468 in 2018 compared to 144,937 in 2012 [1]. HER2/neu overexpressed in 20% -25% of breast cancer patients in Indian population and worldwide [2]. HER2 overexpression is associated with an aggressive clinical phenotype that includes high-grade tumors, increased growth rates, early systemic metastasis, and decreased rates of disease-free and overall survival [3]. Addition of anti-HER2 therapy to chemotherapy, as compared with chemotherapy alone, significantly improves progression-free and overall survival among patients with HER2+ metastatic breast cancer [4]. Trastuzumab is a humanized monoclonal antibody directed to the external domain of HER2 and exerts its antitumor effects by blocking HER2 cleavage, stimulating antibody-dependent, cell-mediated cytotoxicity and inhibiting ligand-independent, HER2-mediated mitogenic signalling [5]. Initially approved by all major regulatory bodies for the treatment of HER2+ metastatic breast cancer (MBC), approved use of Trastuzumab was expanded to HER2+ early breast cancer (EBC) in 2006 [6]. Trastuzumab for 1 year (once in 21 days -17 cycles) administered with an acceptable chemotherapy regimen is the recommended standard of care according to the guidelines [7] [8]. Clinical trials in HER2+ EBC and MBC have established that treatment with Trastuzumab/chemotherapy increases disease-free and overall survival (OS) [4] [9]. As a result, Trastuzumab has become standard of care in the treatment for Her2+ breast cancer patients. A significant side effect with this drug was cardiac dysfunction, including congestive heart failure (1% -3%), especially when Trastuzumab was used in combination with anthracycline-based regimens [10]. Trastuzumab related decreased Left Ventricular Ejection Fraction (LVEF) usually resolves after drug discontinuation [11]. Biosimilars are biologic medicines which are highly similar to the reference biological molecule and they demonstrated no differences in the efficacy, safety and purity [12]. Cost savings from the use of a biosimilar might allow for expanded access to the therapies, indirectly leading to better overall health outcomes. Multiple Trastuzumab biosimilars are available in the market. Our study evaluates the efficacy and safety of Trastuzumab biosimilars and assesses overall survival in the study population.
The Objectives of the study: 1) To assess the response rate to Trastuzumab therapy in metastatic and non-metastatic breast cancer patients.
2) To evaluate overall survival and toxicity in these patients.

Results
A total of 65 patients diagnosed with Her2 positive breast cancer and satisfied the selection criteria were included for the study. Amongst the sample, 26 (40%) patients presented with metastatic disease and 39 (60%) were locally advanced.   Table 3). The p-value was not significant, as the study population number was small.

Discussion
The frequency of breast cancer has increased rapidly over the last decades especially in premenopausal women [13]. Breast cancer in India is known to be characterized by a higher prevalence of aggressive breast cancers with lower rates of estrogen and progesterone receptor expression [14] [15]. In a retrospective study by Ghosh et al., estrogen receptor and progesterone receptor were expressed in 56.3% and 53.1% of cases, respectively [16]. In another study by Kaul et al., estrogen and progesterone receptor positivity was noted in 34.5% and 36.4% cases, respectively [17]. Findings of the current study are in agreement with this data.
It is well known that patients Trastuzumab concurrent with endocrine therapy more effective than HER2 therapy alone [18]. The addition of other anti-HER2 drugs to Trastuzumab improved median survival and overall survival [19]. In this study, patients were not treated with dual anti-HER2 therapies because of unavailability of the drugs.  [15].
Although biosimilar therapies hold a promise of alleviating the cost burden on access to treatment, data on comparative efficacy and safety is relatively scarce.
Results of the current study indicate that overall survival did not differ between patients on Herclone/Biceltis, and Canmab. Even, response rates in original and biosimilar Trastuzumab were not statistically significant because the numbers of patients receiving biosimilar Trastuzumab were less.
According to FDA approval on biosimilars, the response of Trastuzumab with biosimilars was not superior to the generic version Apsangikar et al. [25]., an Indian study supports the statement.
With respect to cardiac safety of Trastuzumab, it may be important to monitor ejection fraction decreases. However, as per the results of the current study overall survival of patients with >10% drop in ejection fraction did not differ from those with <10% drop. No cardiac related mortality is seen in this study. In the median follow-up of 3 years, the incidence of CHF is not increased.
Large cohort studies and clinical trials were established Trastuzumab efficacy; this study explored a single institution experience with small number of patients.

Conclusion
This prospective study shows the effectiveness of Trastuzumab for HER2-positive in locally advanced and metastatic breast cancer. The response rates, survival and toxicity correlate with other global studies. The response and survival are as same as either generic or original Trastuzumab.