|Ahead of print publication
A case of trastuzumab-induced dermatomyositis
Ioannis Panagiotis Trontzas, Nikolaos Konstantinos Syrigos, Elias Alexandros Kotteas
3rd Department of Internal Medicine, Oncology Unit, Athens School of Medicine, Sotiria General Hospital, Athens, Greece
|Date of Submission||25-Mar-2019|
|Date of Acceptance||22-Oct-2019|
|Date of Web Publication||07-Jul-2020|
Elias Alexandros Kotteas,
3rd Department of Internal Medicine, Oncology Unit, Athens School of Medicine, Sotiria General Hospital, 152 Mesogeion Avenue, Athens 11527
Source of Support: None, Conflict of Interest: None
Human epidermal growth factor receptor 2 (HER-2) is a checkpoint, controlling cell proliferation and differentiation. Trastuzumab, a humanized monoclonal antibody directed against HER-2, is nowadays standard treatment for breast cancer patients whose tumors express HER-2. It is generally well tolerated, with a small number of patients developing mild adverse reactions. Dermatomyositis is a rare adverse event of trastuzumab therapy not well described in the literature. We herein present a case of a patient treated for hormone-sensitive invasive ductal carcinoma, who presented with symptoms of proximal muscle weakness, arthralgias, skin rash, and generalized fatigue. The symptoms started after the sixth cycle of trastuzumab and progressively deteriorated. The patient's medical and family history was unremarkable. Disease progression as a possible cause of dermatomyositis had been ruled out, and laboratory evaluation revealed moderate elevation of serum muscle proteins and acute-phase reactants. Trastuzumab treatment was discontinued, and 3 months later, the patient was free of symptoms without any further intervention.
Keywords: Anti-human epidermal growth factor receptor 2, breast cancer, dermatomyositis, drug-induced myopathies, trastuzumab
| > Introduction|| |
Trastuzumab is a humanized monoclonal antibody directed against the extracellular domain of human epidermal growth factor receptor 2 (HER-2), a checkpoint controlling cell proliferation and differentiation., It is widely used both in cases of early and advanced breast cancer (BC)., We herein present a case of a patient treated with trastuzumab, who presented with clinical symptoms and laboratory findings of dermatomyositis. Although trastuzumab is widely used, to date, there is only one case in the literature describing a flare of preexisting anti-synthetase syndrome in a trastuzumab-treated patient and one case of newly developing myositis., In our patient, timely discontinuation of trastuzumab was adequate to restore her clinical symptoms and laboratory findings, yet clinicians should be aware that more severe myositis symptoms could require aggressive treatment.
| > Case Report|| |
Our patient, a 54-year-old postmenopausal woman with a family history of BC had been diagnosed 2 years before with invasive ductal carcinoma Grade III of the right breast. The tumor was characterized positive by immunohistochemistry for estrogen and progesterone receptors, as well as for HER2. At that time, contrast-enhanced computed tomography (CECT) scans of the chest and abdomen as well as magnetic resonance imaging (MRI) of the brain did not reveal any metastatic disease.
The patient received neoadjuvant chemotherapy with epirubicin and cyclophosphamide followed by quadrectomy of the right breast and resection of the right axillary lymph nodes. The resection margins were R0, and her subsequent treatment regimen consisted of adjuvant chemotherapy, anti-HER2 treatment, radiotherapy, and hormonal therapy. Three cycles of chemotherapy with epirubicin and cyclophosphamide were initially administered, followed by four cycles of docetaxel. Anti-HER2 therapy with trastuzumab was thereafter initiated every 3 weeks, in combination with hormonal therapy with an aromatase inhibitor (letrozole). In addition to the above mentioned, the patient also received radiotherapy and osteoporosis therapy. The patient's scheduled regular follow-ups with CECT of the chest and abdomen, MRI of the brain, breast ultrasonography, and digital mammograms did not show any recurrent disease.
Overall treatment was well tolerated by the patient with performance status 0. After 6 months of trastuzumab injections, she complained of progressively worsening fatigue, arthralgias of small hand joints and knees, as well as proximal lower limb muscle weakness. Physical examination revealed periorbital edema and erythema, intense Raynaud's phenomenon of the hands and feet, muscle wasting, especially of lower limbs and Gottron's signs of the knees and elbows. Muscle strength of all muscles of the lower limbs was diminished (3–4/5) while it was normal in all upper limb muscle groups. The rest of the physical examination was unremarkable. Laboratory examination revealed moderately elevated serum muscle enzymes (creatine phosphokinase value: 391 IU/L with normal laboratory range: 38–176 IU/L) while testing for myositis-specific and myositis-associated autoantibodies showed only anti-Ro52 positivity. Considering her recent negative screening for disease recurrence, dermatomyositis symptoms were attributed to trastuzumab, which was therefore immediately discontinued, and she only remained on letrozole. Her moderate, nonprogressing clinical symptoms and laboratory tests allowed us to closely follow the patient without any further therapeutical intervention. Week by week, the patient's symptoms were ameliorating, and 3 months later, she was symptom-free with serum muscle enzymes within the normal range.
| > Discussion|| |
With BC being the most common malignancy among women worldwide, the need for the development of more sophisticated and effective treatments is increasing. New developments in immunotherapy have enabled the use of targeted cancer treatment against specific molecules/biomarkers. HER2 is overexpressed in about 25%–30% of patients with BC and indicates worse prognosis. Nowadays, it is used as a biomarker and treatment target, with trastuzumab, a monoclonal antibody against HER2 molecules, being the gold-standard in the therapy of this tumor subtype.
Although trastuzumab is considered a relatively safe agent, its use does not come without related adverse events. HER2 participates in signaling pathways of both cancer and healthy cells. Trastuzumab interferes with the homeostasis and function of normal cells as well. Infusion-induced adverse reactions (e.g., fever and chills) are considered the most common side effects, manifesting as frequent as 40% of the cases; however, most of the times are mild to moderate., Gastrointestinal side effects, such as nausea, vomiting, diarrhea, and constipation, and hematological involvement, such as neutropenia, are also frequently met., Hepatotoxicity, cardiotoxicity, and pulmonary toxicity are the most clinically significant adverse events, with the latter two being potentially fatal., Adverse events mimicking myositis, such as muscle weakness, myalgia, arthralgia, fatigue, and cutaneous manifestations are rare., However, the positive association of inflammatory myopathy syndromes with the use of trastuzumab is at times very difficult to be made with certainty as these may manifest as part of paraneoplastic syndromes. It is well-known that drug-induced myopathy can occur after exposure to several drugs such as statins, interferon-a, antimalarials, colchicine, cyclosporine, tacrolimus, corticosteroids, and anti-nucleoside analogs. The causal relation between trastuzumab and myopathy has not yet been established; however, adverse reactions of the agent, such as muscle weakness, arthralgias, and myalgias, are common with some myositis manifestations. Discontinuation of the muscle toxic agent, early on the course of myopathy, usually prevents irreversible muscle damage and leads to the resolution of symptoms, a characteristic of drug-induced myopathies.
Trastuzumab demonstrates three established modes of action against BC. The most well-known effect is the interference of the agent with the cell cycle by binding to the extracellular domains of HER2. The binding to HER2 leads to the suppression of PI3K/Akt and Ras/MAPK pathways, thus inhibiting the growth and proliferation of cancer cells. The second mechanism of action is through the degradation of HER2. How the degradation of HER2 is promoted remains unclear; however, it has been proposed that trastuzumab triggers the internalization of HER2, and in this process, the recruiting of tyrosine kinase ubiquitin ligase c-Cbl is implicated. The third mechanism is attributed to its action as an antibody; trastuzumab coats the cancer cells overexpressing HER2 and through a CD16-mediated antibody-dependent cellular cytotoxicity (ADCC) stimulates their elimination by natural killer (NK) cells. Studies have demonstrated that monoclonal antibodies with clinical efficacy, such as trastuzumab, bind to Fc antibody receptors of immune cells, thus regulating the immune response. After the opsonization of tumor cells, trastuzumab engages with antibody receptors; its therapeutic efficacy depends on its ability to engage preferentially on activation receptors (Fc-gamma-RIII, CD16) than inhibitory (Fc-gamma-RIIB) antibody receptors on NKs. The engagement of trastuzumab to CD16 of NKs enhances their cytotoxic response against cancer cells. In the case of the patient presented herein, we propose that the dermatomyositis symptoms are triggered by an ADCC mechanism induced by trastuzumab. This would explain the late onset of complaints as well as the resolution of symptoms after trastuzumab discontinuation.
In conclusion, dermatomyositis-like symptoms may emerge from treatment with trastuzumab for BC. The diagnosis is a challenge, as dermatomyositis may manifest as a constellation of symptoms denoting the recurrence of disease in cancer patients. In the era of immunotherapy, clinicians of diverse medical fields should be aware that autoimmune manifestations, such as dermatomyositis, demand early detection, and intervention to avoid irreversible and possibly fatal complications.
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Conflicts of interest
There are no conflicts of interest.
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