According to the Surveillance, Epidemiology, and End Results (SEER) data, breast cancer (BC) is one of the leading causes of cancer-related mortality in women worldwide. In 2012, BC was responsible for the highest cancer mortality rates in 161 countries (1). By surpassing cervical cancer, BC has become one of the leading causes of mortality among Indian women, with 144,937 new cases reported in 2012. Moreover, it is ranked the most prevalent malignancy among Indian women, with an incidence rate as high as 25.8 per 100,000 women and a mortality rate of 12.7 per 100,000 women (2).
The available treatments for BC include surgery, radiation therapy, chemotherapy, hormone therapy, and targeted therapy. Breast conservation surgery is regarded as the best approach for localized BC. Moreover, neoadjuvant therapy is used before surgery to shrink tumors (2). Monoclonal antibodies (MoAbs), which are generated from a single B-lymphocyte clone, are monovalent antibodies, binding to similar epitopes. Kohler and Milstein first discovered MoAbs in 1975 using the hybridoma technology (1) (3), which revolutionized anti-cancer therapeutics in the 19^th century.
Chemotherapeutic MoAbs have emerged as standard therapeutic agents against hematological and solid cancers, acting as “targeting missiles” toward cancer cells (2). Moreover, chimeric MoAbs (CMoAbs) are composed of antibodies from two different species. They are less immunogenic than other MoAbs and exhibit more efficient interactions with human effector cells (4). On the other hand, humanized CMoAbs, which are collected from human sources (90%), are less immunogenic than CMoAbs (4). The adverse effects of naked MoAbs are mild and involve allergic reactions (16). These adverse effects include fever, chills, weakness, headache, nausea and vomiting, diarrhea, low blood pressure, rashes, and in some cases, leucopoenia, thrombocytopenia, and anemia. Studies suggest that conjugated MoAbs cause more adverse events due to immunosuppression; they are also associated with an increased risk of infection and cancer development (5).
The most common adverse effects of atezolizumab, used alongside nanoparticle albumin-bound paclitaxel (Nab-paclitaxel), are peripheral neuropathy, fatigue, nausea, anemia, cough, hypokalemia, pneumonia, and increased aspartate transaminase (AST) levels. The severe adverse effects of this regimen include pneumonia, urinary tract infection (UTI), dyspnea, and pyrexia (6). On the other hand, the common side effects of bevacizumab include hypertension (HTN), asymptomatic proteinuria, thromboembolic events, and gastrointestinal perforation. Additionally, bevacizumab used in combination with sunitinib can cause microangiopathic hemolytic anemia; accordingly, this regimen is not recommended (7). Generally, the most common adverse events of MoAbs include arthralgia, nasopharyngitis, back pain, headache, extremity pain, upper respiratory infection, sore throat, rash, and asymptomatic hypocalcemia (21).
According to previous research, renal failure, dyspnea, pneumonia, and cellulitis are the most common side effects of pembrolizumab (8). Also, cardiac dysfunction, heart failure, and decreased left ventricular ejection fraction (LVEF) are the most probable side effects of targeted HER2 therapy (9). Moreover, the most common side effects of herceptin include fever, nausea and vomiting, diarrhea, infection, cough, headache, fatigue, shortness of breath, skin rash, neutropenia, anemia, and myalgia. Cardiac side effects are also recognized as the most common side effects of trastuzumab (10). In the present study, we aimed to investigate the incidence and severity of the side effects of MoAbs in BC patients and to assess the causality of these adverse events using the Naranjo scale and the World Health Organization (WHO) scale.
 

During the study, a total of 120 women were admitted to our center with a diagnosis of cancer, 97 of whom were diagnosed with BC. The mean age of the patients was 51±7 years, and their average age was 49 years (Table 1). Overall, 40% of the participants were in the age range of 45-55 years (P<0.03). More than 50% of the patients had stage II BC (both clinically and pathologically) at the time of referral (P<0.05). Approximately 60% of cancers had hormone receptors (P<0.04) (Table 2). Only 4% of the patients were HER2-negative, while 42% were HER2-positive, and 54% were unknown. The majority of the patients showed no metastasis (54%). The most common sites of metastasis were the dorsal spine (23%), lungs (13%), and liver (7%), respectively (P<0.05). Based on the findings, trastuzumab and bevacizumab had more side effects than other MoAbs (P<0.02) (Table 3).
Anemia was the most common side effect of all evaluated drugs (37%±12), except pembrolizumab which did not cause anemia. Nausea and vomiting were attributed to all evaluated drugs (21%±7), except pertuzumab and pembrolizumab. Overall, electrolyte imbalance was detected in 17%±7 of cases, although it was not observed in patients receiving denosumab, atezolizumab, and pertuzumab. Based on the findings, headache and body pain were reported in 11% of the patients. Similarly, fatigue and weakness were reported in 11% of the patients; however, these side effects were not observed in patients receiving trastuzumab. No significant difference was observed in the aggravation of side effects of different regimens and protocols for BC (P>0.06). On the other hand, the prevalence of complications was lower in patients who did not receive trastuzumab (non-exposure group) compared to the exposure group (P<0.003).

Table 1. The age distribution of breast cancer (BC) patients (n=97)

Table 2. The status of hormone receptors in breast cancer (BC) patients (n=97)

ER: Estrogen; PR: Progesterone.
 
Table 3. The monoclonal antibodies (MoAbs) used in this study and the frequency of side effects

The side effects of MoAbs were monitored in patients throughout the study, and a causality assessment was performed using the Naranjo and WHO scales. The assessment of side effects based on the Naranjo scale revealed that most complications were probable (67%) and possible (32%), respectively. According to the WHO scale, the majority of side effects were also under the categories of probable (61.20%) and possible (38.14%), respectively.
Overall, 19 regimens and protocols were used in the current study. The trastuzumab+paclitaxel regimen was the most frequently used regimen (27.19%), followed by trastuzumab maintenance therapy (18.42%). In all 19 regimens, the most common side effects were anemia, nausea and vomiting, elevated serum globulin levels, and hypocalcemia. On the other hand, the least common side effects were HTN, hypotension, acute kidney injury (AKI), electrolyte imbalance, and body aches. Only one severe adverse event, that is, dilated cardiomyopathy, was detected in one of the patients, due to which trastuzumab was discontinued. According to this finding, the regimens were well tolerated by the patients, with few manageable side effects (Table 4). Moreover, the analysis of the null hypothesis of this study indicated that the side effects depended on the amount and composition of drugs. This finding refutes our assumption and suggests that the frequency of side effects is lower when the amount of drugs is low or when the constituents are few.
 

Discussion

In the present study, we evaluated the causality of the side effects of MoAbs in patients with BC and gynecologic cancers. The most common side effects were identified, and their severity was examined using the WHO and Naranjo scales. We also discussed the treatment regimens for these side effects (8, 11). According to the present findings regarding the clinical stage of BC, out of 97 patients, 10.30% had stage I BC, 52.57% had stage II BC, 28.86% had stage III BC, and 8.24% had stage IV BC, which indicates the predominance of stage II BC, followed by stage III BC. In this regard, a study by Iago Dillion Lima Cavalcanti et al. in 2017 showed the predominance of stage III BC, while no stage IV cases were detected (9, 10).
Moreover, in the present study, the hormone receptor status was evaluated in all 97 BC patients. Based on the results, 30.92% of the patients were ER-positive, 13.40% were ER-negative, 27.83% were PR-positive, 16.49% were PR-negative, and the remaining 11 cases were unknown. In a study by Huszno et al. in 2013, ER expression was identified in 66 (55%) patients, while PR expression was found in 55 (45%) patients (10, 12, 13).
Regarding the clinical tumor (T) stage of BC in our study, 3.098% of the patients were in T₁ stage, 21.64% were in T₂ stage, 2.06% were in T₃ stage, 4.12% were in T₄ stage, 3.09% were in T₄d stage, and 69.07% were unknown. In a study by Hussain et al. in 2018, clinical T staging was compared between the docetaxel /carboplatin/trastuzumab/pertuzumab (TCHP) and docetaxel/carboplatin/trastuzumab (TCP) regimens. The results showed that T₂ stage was the most common stage in both regimen groups. In this study, there were only two patients with T₂ stage receiving the TCHP regimen, while there were nine T₂ stage patients receiving the TCP regimen; the rest of the patients were above T₂ stage (10, 14, 15).
In the present study, the metastasis status of 97 BC patients was investigated. Based on the results, bone metastasis occurred in 8.24% of the patients, brain and bone metastasis in 3.09% of the patients, liver metastasis in 6.18% of the patients, liver, lung, and bone metastasis in 10.30% of the patients (n=10), liver and lymph node metastasis in 1.03% of the patients, lung metastasis in 6.18% of the patients, lung and bone metastasis in 3.09% of the patients, and lymph node and bone metastasis in 4.12% of the patients; also, 57.73% of the patients were non-metastatic. The findings indicated that the incidence of liver, lung, and bone metastasis was the highest, followed by bone metastasis, liver and lung metastasis, lymph node and bone metastasis, lung and bone metastasis, brain and bone metastasis, and finally, liver and lymph node metastasis. In a study by Esin et al. in 2018, the frequency of liver and lymph node metastasis was the highest (23.1%), followed by lung and bone metastasis (19.2%), lung and lymph node metastasis and liver and bone metastasis (15.4%), brain, liver, and lung metastasis, lung metastasis, and liver and lung metastasis (7.7%), and finally, liver metastasis (3.8%) (14, 16).
In the current study, we evaluated the side effects of trastuzumab in BC patients. According to the results, trastuzumab was well tolerated by the majority of the patients. Overall, 21 side effects were detected, among which anemia was the most common (49.26%), followed by nausea and vomiting (17.64%), hypocalcemia (7.35%), and elevated serum globulin levels (4.41%). However, some of the side effects were less frequent and required further attention. Dilated cardiomyopathy was detected in one of the patients, after which trastuzumab was discontinued due to cardiomyopathy. In this regard, Kistler (2014) reported that trastuzumab carries a black box warning for cardiomyopathy/heart failure; these patients may be either symptomatic or asymptomatic. Also, the less common side effects were abnormal liver function tests, odynophagia, AKI, alopecia, bronchiectasis, electrolyte imbalance, HTN, hypermagnesemia, hypocalcemia, hypotension, insomnia, lymphedema, mucositis, myalgia, polyuria, pyelonephritis, and ulcer (15, 17).

 

Conclusion

In this study, most side effects of MoAbs were under the categories of probable (61.20%) and possible (38.14%), respectively. However, none of the side effects were severe; in other words, MoAbs were well tolerated by the patients. The side effects were manageable via supportive care. Based on the results, anemia was the most common adverse effect. No potential adverse cardiovascular events were detected in patients on trastuzumab, expect one case of dilated cardiomyopathy. Further research is required to obtain more accurate results.

 

Author's Contributions

All authors equally contributed to the preparation of this article.

 

Acknowledgements

We would like to express our deepest respect and gratitude to Dr. Thomas. P. John (Chairman of T. John Group of Institutions), Dr. Vineeth Chandy (Principal of T. John College of Pharmacy), Dr. E. Gopinath (Dept. of Pharmacy Practice, T. John College of Pharmacy), Ms. Sunitha. M (Pharm, Dept. of Pharmacy Practice, T. John College of Pharmacy), Dr. Ganesh N.S. (M. Pharm, PhD, Professor and HoD of T. John College of Pharmacy), Dr. Annmary Pious (Pharm D), Mr. Anupam Bag (Dept. of Pharmacology), Dr. Krupanidhi, Dr. Ranajith Damador Tijaree, and Mrs. Khalida Khanum for their valuable assistance and helpful comments throughout the research.

 

Funding

This research received no specific grant from any funding agencies in the public, commercial, or non-profit sectors.

 

Conflicts of Interest

The authors declare no conflicts of interest.