Comparison of adverse effects of trastuzumab with other drug combinations for the treatment of breast cancer: A review

INTRODUCTION

Breast cancer (BC) is the most common cancer among women.^[1] In 2017, more than 250,000 new cases of BC were discovered in the United States, and it is estimated that 12% of all women in the US will be diagnosed with BC at some point in their lives. About 62% of BC are restricted to the breast at the time of diagnosis, while another 31% have progressed to lymph nodes around the breast.^[2]

The BC accounts for 14% of all cancers in Indian women. One woman gets diagnosed with BC every 4 min in India and one woman dies of BC every 13 min, making it the most prevalent cancer among women.^[3] In 2018, about 162,468 new registered cases of BC and 87,090 deaths were recorded in the country. By 2030, BC is expected to cause more deaths among women in India than any other cancer.^[4]

HER-2 is a tyrosine kinase receptor that facilitates signalling pathways of cell growth, division, motility, and repair in normal cells.^[5] Overexpression of HER-2 activates the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) ‘survival pathway’ whose action favours cell proliferation apparently by inhibiting apoptosis.^[6] The ‘survival’ signal is normally coupled to the activation of the mitogenic signal involving mitogen-activated protein kinases (MAPK) pathway recruitment. Increased HER-2 expression in cancer enhances and prolongs signalling from both the PI3K/Akt and MAPK pathways, associating upregulation of HER-2 to the BC.^[7]

Patients with HER-2 Positive BC are given treatment before surgery to reduce the tumor size and the neoadjuvant therapy after surgery to prevent the reoccurance of BC. Various treatments for these are chemotherapy,target therapy like tyrosine kinase inhibitors , hormonal therapy like PI3K/Akt/mTOR inhibitors (everolimus), CDK4/6 inhibitors, antiPD(L)1(programmed cell death protein ligand 1) antibodies, endocrine therapy.^[8] The treatment is recommended to start within 2–6 weeks after the surgery.^[9]

Trastuzumab is a recombinant humanised IgG₁ monoclonal antibody against the extracellular domain of the HER-2 receptor (ErbB-2). The HER-2 receptor consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. Trastuzumab binds to the extracellular domain of HER-2 and prevents cleavage of the extracellular domain of HER-2 and thereby activation of the receptor; blocking the dimerization of HER-2. By binding to the juxta membrane domain of HER-2, trastuzumab triggers the downregulation of HER-2 expression.^[10] It may be administered by a 3-week cycle (i.e., the initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks) or by a weekly cycle (i.e., initial dose of 4 mg/kg, followed by 51 further weekly doses of 2 mg/kg) and sequentially or concurrently with standard chemotherapy of anthracycline-taxane regimens (e.g., doxorubicin and cyclophosphamide [AC] plus paclitaxel/docetaxel or fluorouracil, epirubicin and cyclophosphamide plus docetaxel/paclitaxel), taxane regimen (e.g., docetaxel plus cyclophosphamide) or anthracycline regimen (e.g., AC). Trastuzumab is currently available as 150 mg (single-dose vial) and 440 mg (multidose vial) powder for concentrate solution for intravenous infusion and for subcutaneous injection containing 600 mg/5 mL. Most often, combinations of 2 or 3 of these drugs are used as adjuvant or neoadjuvant therapy.^[11]

There are scattered reports of adverse effects (AEs) with trastuzumab or chemotherapy with or without tyrosine kinase inhibitors and a comparative analysis of the safety of trastuzumab with the different treatment regimens is not available. This is essential as it can assist clinicians to make the rational treatment choice that can improve the quality of life and safety of the patient. Hence, to address this, we have compared the safety profile of chemotherapy drugs and TKi with trastuzumab in a single study present in this systematic review and meta-analysis.

MATERIALS AND METHODS

Study selection flow

There were 275 articles found in the PubMed database after an electronic search. Their titles and abstracts were carefully examined and 207 were eliminated based on the methodology section’s exclusion criteria. The whole text of the remaining 68 papers was reviewed for eligibility, while 43 were excluded due to the usage of trastuzumab in combination with other mAbs. Finally, 32 studies were included in this meta-analysis which was grouped [Figure 1].

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Figure 1:

Flowchart of study.

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RESULTS

General disorders and administration site conditions

Fatigue, asthenia, peripheral oedema, pyrexia, and mucosal inflammation were the most common general disorders.

The mean percentage of patients that reported general disorders and administration site conditions are mentioned [Table 2]. The IQR is shown [Figures 2a-d].

Table 2: Mean % of patient reporting AEs.

Mean% of patients	T+C	Tb	T+TKi+C	T+TKi
General disorders and administration site conditions
Fatigue	18.65	11.08	34.2	28.18
Asthenia	12.3	1.1125	0	2
Pyrexia	3.61	4.5	2.95	2.22
Peripheral oedema	2.6	0	5.875	0
Skin and subcutaneous tissue disorders
Alopecia	25.19	8.0125	6.025	15.37
Rash	13.58	2.9	11.225	7.11
Pruritus	5.07	0	2.95	0
Palmar-plantar erythrodysesthesia	1.2	0	16.175	1.22
Gastrointestinal disorders
Diarrhoea	9.1	43.2	29.21	42.05
Nausea	18.73	25.44	28.61	26.675
Vomiting	12.22	12.26	15.45	8.825
Constipation	8.57	3.11	10.61	6.175
Stomatitis	2	2.33	8.18	7.35
Abdominal pain	2.1	2.97	0.97	2.95
Anorexia	4.16	1.58	10	4.3
Dyspepsia	0	0	2.11	4.4
Oral mucositis	0	0	1.98	6.9
Abdominal pain upper	2.1	2.97	0.97	2.95
Nervous system disorders
Headache	3.9	6.91	7.44	2.95
Neuropathy peripheral	9.93	0	8.43	0
Peripheral sensory neuropathy	12.85	3.46	3.17	0
Dizziness	1.71	0	2.44	0
Musculoskeletal and connective tissue disorders
Muscle spasms	0	0	1.22	2.95
Pain in extremity	1.06	0	2.33	0
Arthralgia	8.57	0	10.3	0
Myalgia	7.99	33.3	4.86	0
Back pain	1.01	0	1.66	0
Infections and infestations
Paronychia	0	0	13.57	3.44
UTI	0	0	5.87	1.64
Injection site pain	0	0	0	0
Upper respiratory tract infection	0	0	1.47	1.33
Nasopharyngitis	4.12	1.11	2.45	0
Infusion-related reaction	2.76	0.4	1.45	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	11.375	2.77	2.64	7.9
Cough	5.83	3.11	6.2	2.95
Metabolism and nutrition disorders
Decreased appetite	5.58	7.625	5.66	8.82
Hypokalaemia	0	6.25	1.58	8.82
Hyponatremia	0	0	0.53	3.45
Hypocalcaemia	0	0	0.53	1.72
Eye disorders
Dry eye	0	0	4.4	0
Psychiatric disorders
Depression	3.81	0	1.775	0
Insomnia	2.9	0	0	1.55
Anxiety	3.81	0	0	0
Blood and lymphatic system disorders
Anaemia	5.92	13.25	33.77	11.2
Leucopenia	0.32	9.75	6.79	10.37
Neutropenia	7.6	14.54	27.47	16.75
Thrombocytopenia	10.18	4.38	12.06	0
Investigational disorder
Raised AST	8.96	13.81	17.25	25.45
Increase WBC	6.81	1.64	0	0
Raised ALT	5.97	9.87	17.6	28.32
ALP increased	1.81	0	9	1
Blood bilirubin increased	8.33	1.08	0	1.51
Increase neutrophil count	1.99	0	1.77	0
Cardiovascular disorders
Cardiac disorder	2.38	1.14	0	0
LSVD increase	0.42	0.48	0	0
Congestive heart failure	0	0	0	0
Left ventricular dysfunction	0	0	0	0
Palpitation	0	0	0	0
Hypertension	0.375	1.01	0	0
Hot flush	0	0	0	0
Palpitations	0	0	0	0
Reference	12–22	23–30	31–34	35–41

n: Total patients, LSVD: Left ventricle systolic dysfunction, UTI: Urinary tract infection, AST: Aspartate transaminase, ALT: Alanine transaminase, WBC: White blood cell, AEs: Adverse effects

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Figure 2:

Box and whisker representation of the range of patients in different groups showing (a) fatigue, (b) asthenia, (c) pyrexia and (d) peripheral oedema.

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Skin and subcutaneous tissue disorders

Alopecia, rash, nail disorder pruritus, palmar-plantar erythrodysesthesia, dry skin, and skin discolouration were the most common skin disorders.

The mean percentage of patients that reported skin and subcutaneous tissue disorders are mentioned [Table 2]. The IQR is shown [Figures 3a-e].

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Figure 3:

Box and whisker representation of the range of patients in different groups showing (a) fatigue, (b) asthenia, (c) pyrexia, (d) peripheral oedema and (e) palmar-plantar erythrodysesthesia.

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Gastrointestinal disorders

Diarrhoea, nausea, vomiting, constipation, anorexia, and abdominal pain were the most common GI disorders.

The mean percentage of patients that reported gastrointestinal disorders are mentioned [Table 2]. The IQR is shown [Figures 4a-h].

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Figure 4:

(a and b) Box and whisker representation of the range of patients in different groups showing (a) diarrhoea, (b) nausea, (c) vomiting, (d) constipation, (e) stomatitis, (f) abdominal pain, (g) anorexia and (h) dyspepsia.

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Nervous system disorders

Headache, neuropathy peripheral, peripheral sensory neuropathy, sensory neuropathy, and dizziness were the most common reported nervous system disorders.

The mean percentage of patients that reported nervous system disorders are mentioned [Table 2]. The IQR is shown [Figures 5a-d].

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Figure 5:

Box and whisker representation of the range of patients in different groups showing (a) headache, (b) peripheral neuropathy, (c) peripheral sensory neuropathy and (d) dizziness.

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Musculoskeletal and connective tissue disorders

Muscle spasms, pain in the extremity, arthralgia, and myalgia were the most common musculoskeletal and connective tissue disorders.

The mean percentage of patients that reported musculoskeletal and connective tissue disorders are mentioned [Table 2]. The IQR is shown [Figures 6a-d].

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Figure 6:

Box and whisker representation of the range of patients in different groups showing (a) muscle and spasm, (b) pain in extremity, (c) arthralgia and (d) myalgia.

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Infections and infestations disorder

Paronychia, urinary tract infection, injection site pain, upper respiratory tract infection, nasopharyngitis, and infusion-related reaction were the most common infections and infestations disorders.

The mean percentage of patients that reported infections and infestations disorders are mentioned [Table 2]. The IQR is shown [Figures 7a-d].

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Figure 7:

Box and whisker representation of the range of patients in different groups showing (a) paronychia, (b) UTI, (d) nasopharyngitis and (d) infusion-related reaction.

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Respiratory, thoracic, and mediastinal disorders

Dyspnoea, epistaxis, and cough were the most common respiratory, thoracic and mediastinal disorders.

The mean percentage of patients that reported respiratory, thoracic, and mediastinal disorders are mentioned [Table 2]. The IQR is shown [Figures 8a-c].

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Figure 8:

Box and whisker representation of the range of patients in different groups showing (a) dyspnoea, (b) epistaxis and (c) cough.

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Metabolism and nutrition disorders

Decreased, hypokalaemia, hyponatremia, hypocalcaemia, and hypomagnesaemia were the most common metabolism and nutrition disorders.

The mean percentage of patients that reported metabolism and nutrition disorders are mentioned [Table 2]. The IQR is shown [Figures 9a-d].

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Figure 9:

Box and whisker representation of the range of patients in different groups showing (a) decreased appetite, (b) hypokalaemia, (c) hyponatremia and (d) hypocalcaemia.

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Eye disorders

Dry eye was a common eye disorder.

The mean percentage of patients that reported these eye disorders are mentioned [Table 2]. The IQR is shown [Figure 10].

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Figure 10:

Box and whisker representation of the range of patients in different groups showing dry eye.

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Psychiatric disorders

Depression and insomnia anxiety were the most common psychiatric disorders. The mean percentage of patients that reported psychiatric disorders are mentioned [Table 2]. The IQR is shown [Figure 11].

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Figure 11:

Box and whisker representation of the range of patients in different groups showing depression.

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Blood and lymphatic system disorders

Anaemia, leucopenia, neutropenia, and thrombocytopaenia were the most common blood and lymphatic system disorders.

The mean percentage of patients that reported blood and lymphatic system disorders are mentioned [Table 2]. The IQR is shown [Figures 12a-d].

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Figure 12:

Box and whisker representation of the range of patients in different groups showing (a) anaemia, (b) leucopenia, (c) neutropenia and (d) thrombocytopenia.

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Investigational disorders

Raised AST, ALT, increase WBC, and decreased platelet count were the most common investigational disorders.

The mean percentage of patients that reported investigational disorders are mentioned [Table 2]. The IQR is shown [Figures 13a-c].

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Figure 13:

Box and whisker representation of the range of patients in different groups showing (a) increase AST, (b) increase WBC and (c) increase ALT.

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Cardiovascular disorders

The mean percentage of patients that reported cardiac disorder, ejection fraction decrease, and palpitation left ventricular dysfunction were the most common cardiovascular disorders. No vascular disorder was reported in T+TKi+C and T+TKi.

The mean percentage of patients that reported investigational disorders are mentioned [Table 2]. The IQR is shown [Figures 14a and b].

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Figure 14:

Box and whisker representation of the range of patients in different groups showing (a) cardiac disorder and (b) LSVD decrease.

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DISCUSSION

The term BC refers to a malignant tumour that has developed from cells in the breast. Usually, BC either begins in the cells of the lobules, which are the milk-producing glands, or the ducts, the passages that drain milk from the lobules to the nipple. The treatment plans for BC are usually classified according to the type of disease, its stage, and any special circumstances. Some treatments are local, which means that they only impact the tumour and not the rest of the body. Most of the women with BC will undergo surgery to remove the tumour. The first-line treatment option for HER-2-positive BC is a combination of pertuzumab, trastuzumab, and a single chemotherapeutic drug.^[44] In the second-line treatment, monotherapy of trastuzumab emtansine (T-DM1) is used which is an antibody-drug conjugate that incorporates the HER2-targeted anti-tumour properties of trastuzumab with the cytotoxic activity of the microtubule inhibitory agent (a derivative of maytansine [DM1]) and allows intracellular drug delivery specifically to HER2-overexpressing cells.^[45]

Beyond trastuzumab, pertuzumab, and T-DM1, a new class of therapy that is, tyrosine kinase inhibitors (neratinib and tucatinib), were approved for the treatment of HER-2-positive BC that had progressed despite routine treatment after trastuzumab. Bottom of FormOther emerging therapies and novel combinations Top of Form Bottom of Formsuch as the immune checkpoint inhibitors (Keytruda), CDK4/6 inhibitors, and alpha-specific PI3K inhibitors (alpelisib) were also approved.^[46]

Trastuzumab therapy prolongs the survival of patients with HER-2 BC when combined with chemotherapy or with tyrosine kinase inhibitors and has been demonstrated to lead a dramatic improvements in disease-free survival.Trastuzumab is a specially made antibody that targets HER-2-positive cancer cells. Trastuzumab attaches to the HER-2 protein on the surface of HER-2-positive cancer cells. Data suggested that both dual HER-2 blockades and mono HER-2 blockade increase AEs risk and huge differences were found among the treatment strategy subgroups.^[47]

In the absence of head-to-head to trial, we have conducted a meta-analysis of various study (original research) articles published during the year from 2016 to 2020. The research was done on 27 January 2021. We found 275 articles on PubMed out of which 111 were screening for analyses. Out of 111, we included 35 articles for our study. Out of 32 studies, maximum studies were of Phases II and III CT, conducted in 2017–2019 on age group 71–80 and mainly conducted in the USA. Our main concern or main objective is to study adverse events.

The reported AEs from each of the groups were categorised according to the SOC. The maximum number of AEs reported are related to digestive after that blood-related disorder. The five most prevalent general disorders were noted, with fatigue and asthenia being the most common. The T+C regimen and T+TKi+C regimen had the largest percentage of subjects reporting overall disorder, while the Tb had the lowest rate. Moreover, percentages, respectively, indicating that overall disorder was prevalent in the T+C and T+TKi+C groups. The four most prevalent skin disorders were identified, with baldness and rash being the most common. The T+C regimen had the largest percentage of subjects reporting skin disorder and the T+TKi+C regimen had the lowest percentage. The 13 most frequent digestive system disorders were reported, including diarrhoea, nausea, vomiting, constipation, stomatitis, anorexia, and stomach pain. The T+TKi+C regimen had the largest percentage of subjects reporting digestive disorders. The five most prevalent nerve system disorders were documented, with headaches and neuropathy being the most common. T+C regimens had the largest percentage of subjects reporting neurological disorders followed by T+TKi+C regimens. In the musculoskeletal system, disorder arthralgia, pain in extremity, and back pain in the most common were reported.

The highest percentage in subject reported musculoskeletal system disorder were of T+TKi+C and T+C regimen. In respiratory system, disorder cough and epistaxis were most commonly reported. The highest percentage of subject reported respiratory system disorder was of T+C and T+TKi regimen. In T+TKi+C, infection and infestation were found at a high rate. Few patients in all treatment regimens experienced a decrease in appetite, which was particularly common in the T+TKi regimen. Anaemia, leucopenia, neutropenia, and thrombocytopenia were found in all groups. T+TKi+C regimens had the highest percentage of subjects reporting blood associated disorders followed by Tb. Out of 32 studies, death is reported with biosimilar and T+C.

Repeated electronic searches did not reveal any previous single meta-analysis that assesses and compares the safety of trastuzumab with the various combination used for the treatment of BC. The previous meta-analysis by Dahabreh et al. found that the use of trastuzumab benefits in disease control and survival came at the cost of serious cardiovascular AEs, particularly heart failure accompanied by LVEF decline.^[48] Furthermore, Abraham J states that the combination of trastuzumab and lapatinib (seems to be a safe treatment option in terms of cardiotoxicity but the lapatinib was associated with two well-documented AEs, diarrhoea and dermatologic toxicity.^[40] Similar results are also shown by Xin et al. and Xu et al. that is, the use of lapatinib and trastuzumab in HER2-positive BC cause skin rash, diarrhoea, neutropenia, and hepatic and other AEs.^[49,50] Gianni L, Dafni U, et al. found that cardiac toxicity was comparable between anti-HER2 combination therapy and anti-HER2 monotherapy.^[51]

As we have seen that the previous studies only reported about cardiovascular AEs related to trastuzumab but our study concluded all the systemic AEs along with cardiovascular, more often cardiotoxicity when TKi is given combined with chemotherapy, other systemic toxicities also occur. Furthermore, when chemotherapy is given in this combination, it causes higher systemic side effects. As a result, this study implies that Tb is preferable to alternative medication combinations but the patients must be monitored for cardiovascular toxicity.

CONCLUSION

This study concluded that biosimilar of trastuzumab (SB-3 and CT-6P) is safest for the treatment of HER-2-positive BC. Cardiovascular disorder is often reported with biosimilar group, but this group has less AEs reported as compared with chemotherapy, tyrosine kinase inhibitors groups related to other systems such as digestive, nervous, and respiratory.

The choice of combination is depending on the type of BC and the condition of patients. The patients must monitor for cardiotoxicity when the biosimilar of trastuzumab is used.