Interstitial pneumonitis associated with trastuzumab emtansine

Introduction

Human epidermal growth factor receptor-2 (HER-2) amplification is present in 20% of breast cancers. The combination of anti-HER-2 therapy with standard cytotoxic drugs prolong overall survival both in adjuvant and metastatic disease. ¹ Trastuzumab emtansine (TDM-1) is an antibody–drug conjugate that delivers the microtubule-inhibitory agent DM1 directly to HER-2-expressing tumor cells, where it is internalized by lysosomes and promotes apoptosis upon intracellular release. ² The overall survival advantage of the drug in metastatic disease has been reported and it has been approved in the second and third line of advanced breast cancer.^3,4

TDM-1 is generally well tolerated and grade 3–4 toxicities are rare. The most common adverse effects of TDM-1 are diarrhea, fatigue, nausea and vomiting.^3,4 Pulmonary complications were rarely reported, pulmonary embolism in 2 patients out of 405. Here we present a patient presenting with dyspnea after TDM-1 therapy and treated with a diagnosis of interstitial pneumonitis (IP).

Case

A 71-year-old female patient presented with a mass in her left breast and palpable axillary lymph nodes. After initial workup, she was treated with modified radical mastectomy and axillary nodal dissection. Pathology revealed an invasive ductal carcinoma and 2/14 metastatic lymph nodes. She was treated with four cycles of adriamycin/doxorobucin and four cycles of docetaxel. After radiotherapy, she was followed with letrozole 2.5 mg daily. After three years of follow-up, recurrences at liver and lumbar vertebrates were detected. Liver biopsy showed a metastasis of invasive ductal carcinoma with ER 95%, PR 85% and HER-2 positive. Patient was treated with weekly paclitaxel plus trastuzumab. However, after 12 weeks of treatment, the disease progressed and the regimen changed to TDM-1 3.6 mg/kg every 3 weeks. After two courses of therapy, three days after the second cycle, the patient presented with dyspnea and non-productive cough. There was no fever, hemoptysis, chest pain, history of upper airway infection and trauma. Physical examination showed blood pressure of 130/85 mmHg, respiratory rate of 25 breath/min, fine crackles on both lungs and tachycardia without murmur. Arterial blood gas test revealed ph: 7.48, PCO2: 30 mmHg, HCO3: 20 mmol/L, PO2: 63 mmHg. White blood cell count: 10,200/ml (neutrophil 78%) and C reactive protein: 12.1 mg/dl were detected in laboratory work up. The chest x-ray showed diffuse interstitial infiltrates in both lung fields (Figure 1(a)). Further contract enhanced computerized tomography revealed bilateral ground glass opacities without any vascular pathologies (Figure 1(b) and (c)). Cultures of sputum and blood were negative for infection. PPD was negative (4 mm). Three consecutive acid resistant bacillus tests in sputum were negative. Cardiac evaluation was normal. Pulmonary function tests, with spirometry was normal. After excluding infectious and vascular etiologies, TDM-1 related IP was suspected. The patient was hospitalized and treated with 1 mg/kg methylprednisolone, inhaler salbutamol, Moxifloxacin and supportive care. After one week of therapy, dyspnea gradually disappeared and radiological findings improved (Figure 1(d)). Patient was discharged with a plan of gradual decrease in methylprednisolone dosage. The Naranjo algorithm was used to assess whether there was a causal relationship between the clinical IP and TDM-1. ⁵ The scenario concluded a score of 5 (probable). The patient was not rechallenged with TDM-1 because of the life threatening complication. After evaluation of response, the therapy changed with lapatinib and capecitabine regimen.

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Figure 1.

Diffuse interstitial infiltrates in both lung fields (a). Bilateral ground glass opacities without any vascular pathologies in contrast enhanced CT (b) and (c). Resolution of infiltrates after one week of therapy (d).

Discussion

IP is an interstitial lung disease. Drug-related IP is mostly associated with taxanes and bleomycin. The patients usually present with pulmonary symptoms, such as dyspnea, non-productive cough and rarely hemoptysis. Treatment strategies are avoiding exposure and medical therapy. Steroid drugs are usually used to suppress the inflammation. ⁶

Trastuzumab related IP has been rarely reported in literature. The analysis of adjuvant studies with trastuzumab showed that lung toxicities affect only ∼0.5% of patients receiving trastuzumab in the adjuvant setting and may represent a life-threatening adverse event. ⁷ There are a few case reports with IP associated with trastuzumab. ⁸ However, all the cases reported were generally under taxane plus trastuzumab combination therapy.^9–11 In addition, in some of the cases, IP was experienced under radiotherapy. ¹² It is sometimes difficult to conclude an association between drugs and complications. In our case, the patient had also been treated with trastuzumab/paclitaxel regimen. This combination is also a risk factor for IP. In addition it’s difficult to conclude an association between TDM-1 and IP. However the analysis of cases related with paclitaxel or trastuzumab showed that all the reported cases were under weekly paclitaxel regimens.^10,13 In addition all the cases presented with pulmonary symptoms after few days of infusion, mostly less than three days. We documented IP after 10 weeks after last dose of trastuzumab/ taxanes. And similar with trastuzumab cases, our patients presented with dyspnea after three days of TDM-1. So, we concluded an association with TDM-1, instead of taxane or trastuzumab. The cases in literature usually were managed with steroid therapy and in most of the cases, patients gradually improved.^9,11–13 However, rarely the scenario could be fatal.

There are numerous data reporting IP associated with trastuzumab. However, pulmonary complications of TDM-1 were rarely reported in phase 3 studies.^3,4,14 Kwon et al. reported a breast cancer patient presenting with pulmonary arterial hypertension under TDM-1. ¹⁵ In addition, GATSBY study, 3% of patients in TDM-1 arm experienced pneumonia. The etiologies of these cases were not discussed. In literature, there is not a pneumonitis experience that is directly associated with TDM-1. This case, whether related with trastuzumab or emtamsine part of the drug, presented with acute onset symptoms and improved with corticosteroid therapy.

With the increasing use of TDM-1, we will have more experience about both efficacy and complications of TDM-1. Although, TDM-1 is a well-tolerated drug, clinicians should be aware of rare pulmonary complications of it and prepared to respond appropriately.