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Year : 2021  |  Volume : 5  |  Issue : 3  |  Page : 97-103

A Retrospective analysis of biosimilar and reference trastuzumab in human epidermal growth factor receptor-2 positive early and/or locally advanced breast cancer patients treated with neoadjuvant-adjuvant setting: Safety and event-free survival outcomes

1 Department of Medical Oncology, Sahyadri Hospital, Pune, Maharashtra, India
2 Department of Family Medicine, Sahyadri Hospital, Pune, Maharashtra, India

Date of Submission16-Jun-2021
Date of Decision09-Aug-2021
Date of Acceptance25-Oct-2021
Date of Web Publication14-Dec-2021

Correspondence Address:
Shona Nag
6727, Sahyadri Super Speciality Hospitals, Maharashtra State Electricity Board, Nagar Rd, Hermes Heritage Society Phase 1, Shastrinagar, Yerawada, Pune - 411 006, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/oji.oji_25_21

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Background: There is limited real-world evidence on the treatment outcomes with Trastuzumab, specifically with biosimilars. This analysis aims to evaluate the safety and effectiveness of Trastuzumab in early and/or locally advanced breast cancer patients treated with neoadjuvant-adjuvant treatment in the real world setting and to compare biosimilar with reference trastuzumab. Materials and Methods: We retrospectively analyzed the data of patients with human epidermal growth factor receptor-2 (HER-2)-positive breast cancers, who were treated with trastuzumab-based standard therapies. The survival curves were generated using the Kaplan–Meier method. Event-free survival (EFS) was calculated. All patients were assessed for toxicity as per CTCAE version 4.0. The subgroup analysis was carried out to compare the effectiveness of biosimilar with reference trastuzumab. Results: A total of 88 patients were evaluated from 2008 to 2018. EFS at 1, 2, and 5-year was 89.5%, 78%, and 44.2%, respectively. The median EFS was 43 months. In subgroup analysis, the 1, 2-, and 3-year EFS rates were 86.7%, 86.7%, and 57.8%, respectively, for reference Trastuzumab (n = 29) as compared to 91%, 74.4%, and 56.9%, respectively, for Biosimilar Trastuzumab (n = 59). Similarly, median EFS was 43 months and not reached, respectively. There was no significant difference in EFS between the two groups (P = 0.991). A significant asymptomatic decrease in the left ventricular ejection fraction (LVEF) of ≥10% to below the lower limit of normal was noted in only two patients (2.3%). There was no significant difference observed in reduction of LVEF to below the lower limit of normal between the two groups (P = 0.514). The common grade 3/4 adverse events (AEs) observed such as vomiting, diarrhea, pancytopenia, and anemia were mostly due to chemotherapy. These AEs were comparable in both groups. Conclusions: The EFS in our study is consistent with the historical data. Safety and effectiveness of biosimilars were comparable to the reference transtuzumab.

Keywords: Adjuvant, biosimilar, human epidermal growth factor receptor-2 positive breast cancer, neoadjuvant, trastuzumab

How to cite this article:
Kulkarni R, Kulkarni S, Pathan A, Nag S. A Retrospective analysis of biosimilar and reference trastuzumab in human epidermal growth factor receptor-2 positive early and/or locally advanced breast cancer patients treated with neoadjuvant-adjuvant setting: Safety and event-free survival outcomes. Oncol J India 2021;5:97-103

How to cite this URL:
Kulkarni R, Kulkarni S, Pathan A, Nag S. A Retrospective analysis of biosimilar and reference trastuzumab in human epidermal growth factor receptor-2 positive early and/or locally advanced breast cancer patients treated with neoadjuvant-adjuvant setting: Safety and event-free survival outcomes. Oncol J India [serial online] 2021 [cited 2022 Jul 6];5:97-103. Available from: https://www.ojionline.org/text.asp?2021/5/3/97/332507

  Introduction Top

Globally, breast cancer is the most common female cancer, accounting for almost 24.5% of all cancers in women.[1] India faces a challenging situation due to a rise in cancer-associated morbidity and mortality from breast cancer.[2] Human epidermal growth factor receptor-2 (HER-2) overexpression and gene amplification are present in around 15%–20% of breast cancers and are associated with increased aggressive clinical behavior, early systemic metastasis, poor prognosis, and decreased survival outcomes.[3] The development of novel and effective HER-2 targeted therapies has significantly improved the treatment outcomes of patients with HER-2-positive breast cancer.[4]

The addition of HER-2 targeted therapies significantly improves tumor response and survival function in adjuvant, neoadjuvant, and metastatic settings compared to chemotherapy alone in this subtype of patients.[5] Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of the HER-2 transmembrane growth factor receptor.[4] Several clinical trials have shown that treating HER-2 positive metastatic breast cancer with Trastuzumab, either alone or in combination with chemotherapy, significantly improves treatment outcomes.[6],[7],[8],[9],[10],[11] Similarly, Trastuzumab has been shown to be an effective adjuvant therapy for HER2-positive early stage breast cancer patients.[12],[13],[14],[15],[16] In the neoadjuvant setting, randomized trials have shown that more patients achieved a pathological complete response with the addition of Trastuzumab to chemotherapy.[17],[18],[19],[20] Despite the overall encouraging efficacy and safety profile of Trastuzumab, cardiotoxicity has emerged as an adverse effect that is generally consistent throughout clinical trials.[21],[22] Therefore, the need for long-term data assessment on the safety profile and real-world effectiveness in daily clinical practice is essential.

Owing to the high cost anti-HER2 targeted therapy, only 8.41%−35.85% of eligible patients are able to receive it in the Indian setting.[23],[24],[25] With the advent of different Trastuzumab biosimilars, there has been a rapid increase in the use of Trastuzumab for the treatment of HER-2-positive breast cancer in clinical practice. However, several barriers such as high and differential cost between generics, insufficient evidence on long-term safety and effectiveness of biosimilars remain. The present study retrospectively assessed the real-world patterns of usage and treatment outcomes of Trastuzumab (biosimilars or Reference) in neoadjuvant and adjuvant setting for HER-2-positive breast cancer along with the comparison of biosimilar with reference Trastuzumab.

  Materials and Methods Top

This was a retrospective study carried out at a tertiary oncology hospital in Pune, India. The analysis was based on the data extracted from patient's hospital/medical records treated from 2008 until 2018. The data were retrospectively collected in accordance with good clinical practice principles.

We retrospectively reviewed the records of histopathological confirmed cases of breast cancer patients treated for HER-2-positive breast cancer. The patients included in this analysis were selected based on the following criteria: age ≥18 years; histologically confirmed diagnosis of breast cancer; had early and/or locally advanced; had been diagnosed as HER-2 positive by immunohistochemistry (IHC) and/or positive fluorescence in situ hybridization (FISH) test; and had undergone surgery for breast cancer and received neoadjuvant and/or adjuvant standard chemotherapy therapy with trastuzumab (either biosimilar or reference).

Data of each patient were collected, which included demographic details, clinical details, imaging findings, histopathological reports, IHC and FISH reports, Echocardiography reports, clinical course, surgical/operative details, and details of drug therapies including neoadjuvant-adjuvant chemotherapy and trastuzumab therapy (including biosimilars).

IHC done for the cases to evaluate estrogen receptor, progesterone receptor, HER2 neu receptor, and Ki67 status. In cases of HER2 neu equivocal result (2+) repeat IHC or FISH study was applied for confirmation of HER2 neu status.

Echocardiography data were captured retrospectively at baseline and posttreatment. Left ventricle ejection fraction (LVEF) value was recorded from each echocardiography report.

Transtuzumab was used along with chemotherapy in neoadjuvant and/or adjuvant settings and also used as maintenance therapy. The various chemotherapeutic drugs such as taxane, anthracycline, 5FU, and cyclophosphamide were used in different combination regimens. As per the hospital protocol, majority of patients received trastuzumab on weekly cycle basis and some patients were treated with 3 weekly trastuzumab as per their convenience. Weekly transtuzumab was given as 4 mg/kg body weight (mg/kg) in the first cycle followed by 2 mg/kg in subsequent cycles, whereas 3 weekly transtuzumab was given as 8 mg/kg in first cycle followed by 6 mg/kg in subsequent cycles. All the maintenance transtuzumab was given as 3 weekly cycles.

The outcome of treatment was analyzed as effectiveness of treatment in terms of event-free survival (EFS) and toxicity profile. EFS was defined as time from the date of start of therapy to the date of disease recurrence or progression (local, regional, distant, or contralateral), or last follow-up (censored) or death from any cause, whichever occurred first.

Toxicity data were assessed using the National Cancer Institute Common Terminology Criteria for adverse events (NCI CTCAE) version 4. Change in the LVEF from baseline to posttrastuzumab treatment was evaluated. An absolute asymptomatic decline in LVEF of ≥10% to below the lower limit of normal is considered significant.[26]

Effectiveness in terms of EFS rates and safety was compared between the biosimilar and reference trasrtuzumab.

Statistical analysis

Statistical Package for the Social Sciences IBM SPSS Statistics for Windows, Version 21.0 Armonk, New York (USA): IBM Corp. software version 21.0 was used for the statistical analyses. Descriptive statistics were used to express the data. The survival curves were generated using the Kaplan − Meier method. The probability (P) value for the comparison of survival function between the groups was obtained using the log-rank test. The association between the variables was estimated by the Chi-square test and Fisher's exact test, as appropriate. P < 0.05 was considered statistically significant.

  Results Top

Eighty-eight patients of HER-2 positive early and/or locally advanced breast cancer treated with neoadjuvant and adjuvant standard chemotherapy and Trastuzumab were identified and analyzed. Eleven patient's data were collected from 2008 to 2013, 35 patients from 2014 to 2015, and 42 patients from 2016 to 2018.

The patient's demographic and clinical characteristics are depicted in [Table 1]. The mean age of the patients was 51.3 ± 10.3 years, and all the patients were female. KPS score ≥90 was seen in 96.6% patients. 70.5% patients had IHC 3+ and 46 (52.3%) patients had stage III disease. In the neoadjuvant-adjuvant setting (n = 88), 23 (26.1%) patients received transtuzumab treatment on neoadjuvant setting and 65 (73.9%) received in adjuvant setting. Of these patients in neoadjuvant/adjuvant trastuzumab treatment, 28 patients received <6 cycles, 26 patients received 6−11 cycles, and 34 patients received ≥12 cycles. Thirty-nine out of these 88 patients (40.9%) received maintenance trastuzumab, with an average number of cycles of 5.7 ± 2.9 and 9.6 ± 2.8 for Biosimilar and Reference trastuzumab, respectively.
Table 1: Patient characteristics

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Entire study population

EFS were analyzed using the Kaplan–Meier method. The 1-year, 2-year, and 5-year EFS rates for entire study population were 89.5%, 78% and 44.2%, respectively [Figure 1]. The median EFS was 43 months (95% confidence interval [CI]: 26.7–59.2).
Figure 1: Kaplan–Meier curve for event-free survival in neoadjuvant-adjuvant setting (entire population)

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According to CTCAE version 4, the detailed toxicity and their grades are summarized in [Table 2]. The most common grade 3/4 AEs were vomiting (42%), diarrhea (35.2%), pancytopenia (34.1%), and anemia (30.7%). These toxicities were occurred during neoadjuvant-adjuvant treatment and were mostly due to chemotherapy induced.
Table 2: Adverse events encountered

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A significant asymptomatic decrease in the LVEF of ≥10% to below the lower limit of normal was noted in only two patients (2.3%) after treatment completion, whereas in 15 (17.0%) patients, the decrease in the LVEF was between 5% and 9% post-trastuzumab treatment.

Biosimilar versus reference trastuzumab

Comparison analysis was done between Biosimilars and Reference transtuzumab. In this study, 29 patients received reference Trastuzumab (manufactured by Roche), and remaining 59 patients received Biosimilars. Majority of Biosimilars received were USFDA approved Biocon's Biosimilar Trastuzumab (28 patients; 47.46%) and 31 patients received multiple other Biosimilars. The general characteristics of patients in reference and Biosimilars were similar and are shown in [Table 1].

The 1-year, 2-year, and 3-year EFS rates for Biosimilar Trastuzumab (n = 59) were 91%, 74.4%, and 56.9%, respectively, whereas it was 86.7%, 86.7%, and 57.8%, respectively, for reference Trastuzumab (n = 29) [Figure 2]. The median EFS for Biosimilar Trastuzumab group was not reached as compared to 43 months for reference Trastuzumab group (95% CI: 32.4-53.5). There was no significant difference in EFS between the two groups (P = 0.991).
Figure 2: Kaplan–Meier estimates of event-free survival in reference trastuzumab and biosimilar trastuzumab in neoadjuvant-adjuvant setting

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In both groups, majority of patients post treatment had a decrease in the LVEF of <5% from the lower limit of normal. The reduction in the LVEF to below the lower limit of normal between the groups was not statistically significant (P = 0.514). Grade 3/4 AEs were comparable in both groups (biosimilar vs reference trastuzumab): vomiting (40.7% vs. 44.8%), diarrhea (33.9% vs. 37.9%), pancytopenia (39.0% vs. 24.1%), and anemia (28.8% vs. 34.5%). These toxicities were mainly related to chemotherapy and not due to trastuzumab. The overall safety profile of biosimilar trastuzumab was similar in nature with reference trastuzumab and is summarized in [Table 2].

  Discussion Top

The findings of our retrospective analysis indicate that trastuzumab-based therapies resulted in survival benefit in HER-2-positive breast cancer in neoadjuvant-adjuvant setting.

Treatment of patients with HER-2 positive breast cancer has evolved rapidly since the identification of HER-2 as a potential target for anticancer activity. Reference Trastuzumab was approved in 1998 by the USFDA and first Biosimilar Trastuzumab entered into India market in late 2013.[27] HER-2 targeted therapies have significantly improved the treatment outcomes in HER-2 positive breast cancers.[4] Randomized trials and meta-analysis have shown strong evidence of clinical efficacy in early[12],[13],[15],[16] and metastatic[6],[7],[8],[11] HER2-positive breast cancer.

Although randomized clinical trials (RCT) are the gold standard, they have limitations. The selected population enrolled in a clinical trial is not always true representative of the actual population coming into routine practice where patients have diverse ethnicity, comorbid conditions, poor clinical status, advancing age, complex interactions and financial restraint.

In this retrospective study, an attempt was made to explore the real-world treatment outcomes of Trastuzumab in HER-2-positive breast cancers and to explore the treatment outcomes between Biosimilar and Reference Trastuzumab in neoadjuvant-adjuvant setting.

In our study, the 1-year, 2-year, and 5-year EFS rates were 89.5%, 78%, and 44.2%, respectively and the median EFS was 43 months (95% CI: 26.7-59.2). The 3-year and 5-year EFS rates in NOAH trial for HER2-positive disease were 71% and 58%, respectively, in patients who received 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery).[20],[28] HannaH clinical trial reported a 3-year EFS of 73% in patients treated with neoadjuvant-adjuvant intravenous trastuzumab.[29] In another study by Palmieri C et al., treatment with neoadjuvant chemotherapy plus trastuzumab reported a better 5 year EFS compared to neoadjuvant chemotherapy followed by adjuvant trastuzumab (69.6% vs 59.3%).[30] Thus, the overall results of improved EFS outcomes in our study in the neoadjuvant-adjuvant setting are in agreement with historical data.

The safety profile observed in our study is similar to the safety profile of Trastuzumab containing therapies observed in RCT.[20] The most frequently reported AEs common to both the setting in our study were vomiting, diarrhea, pancytopenia, and anemia.

Cardiac dysfunctions (decrease in LVEF) are relatively common (2-3 times increased risk) during Trastuzumab therapy,[20],[31],[32] but usually are reversible with interruption in or cessation of Trastuzumab therapy.[21],[22] It is mandatory to assess cardiovascular functions before initiation and continuously monitoring during the Trastuzumab therapy. In our study, only two patients (2.3%) had an asymptomatic significant decrease in the LVEF ≥ 10% to below the lower limit of normal with Trastuzumab therapy in the neoadjuvant-adjuvant setting. The cardiac risks are substantially declined with sequential therapy compared to concurrent administration of Trastuzumab with anthracycline-taxane-based chemotherapy.[21],[22]

In the subgroup analysis, we compared biosimilar trastuzumab with reference trastuzumab. The 1, 2, and 3-year EFS rates between the biosimilar and reference trastuzumab groups were comparable. The safety profile and LVEF reduction in both the groups were comparable.

In India, around 70% of the population pay health-care expenses out of their own pockets.[33] Owing to its high cost, cancer treatment usually exceeds per capita income by multiple folds. Gupta et al. showed that price reduction of 15% to 35% would make 1-year Trastuzumab treatment more cost effective.[34] Globally, cost savings of up to 70% have been observed with the introduction of biosimilars, which has increased accessibility and affordability to life-saving biologics.[34],[35]

Various biosimilar trastuzumab drugs are available in the market and have followed diverse pathways in their clinical development, with variations in trial design, patient population, and assessment endpoint.[34],[35] In order to make informed decisions in practice, it is important for the oncologist to view the totality of phase-3 clinical trial evidence and regulatory approval. Biosimilar Trastuzumab offers an alternative option to reference Trastuzumab with equivalent efficacy, safety, and immunogenicity evidence as demonstrated in phase-3 confirmatory clinical trial (Heritage Study)[36] and also with approvals from regulatory licensing authorities, including CDSCO-India, U. S. Food and Drug Administration (US-FDA), European Medicines Agency, Health-Canada, ANVISA-Brazil and TGA-Australia.

Although the findings in our study are comparable with previous studies, there are some limitations of this retrospective analysis. This was a retrospective study performed at a single hospital. There is disparity in the number of cycles of Trastuzumab administered, heterogeneous standard therapies. Overall survival analysis could not be conducted due to inconsistencies in the available data, patients nonreporting and lost to follow-up. Despite these limitations, our retrospective studies provide a real picture of the benefits of HER2-targeted therapy in “real-world” practice.

  Conclusions Top

Trastuzumab is a standard of care in the management of HER-2-positive breast cancer. The findings of this real-world evidence are consistent with historical data, irrespective of reference or biosimilar trastuzumab. In subgroup analysis, safety and effectiveness of biosimilar trastuzumab were comparable to the reference Trastuzumab. Hence, instead of reference trastuzumab, biosimilars because of being cost-effective can be safely practiced in developing countries like India for HER2 positive breast carcinoma patients. Further prospective studies with large sample size and longer duration of follow-up could provide better survival analysis.


We acknowledge the support provided for data cleaning and medical writing by Ramez Ahmed, Medical Affairs, Biocon Biologics Limited and statistical analysis by an independent statistician, Dr. Pradeep Jadhav.

Financial support and sponsorship

The data analysis and medical writing was sponsored by Biocon Biologics Limited.

Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2]


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