Successful treatment of pyrotinib for bone marrow metastasis induced pancytopenia in a patient with non‐small‐cell lung cancer and ERBB2 mutation

Abstract ERBB2 mutations are found in about 2% of patients with non‐small cell lung cancer (NSCLC). A recent study reported that pyrotinib (an irreversible pan ErbB inhibitor) had superior antitumor effect compared to other tyrosine kinase inhibitor therapies in patients with ERBB2 mutations. Bone marrow metastasis is rare in lung adenocarcinoma, and has been reported to be associated with poor prognosis. Here, we report the case of a 62‐year‐old female diagnosed with lung adenocarcinoma and bone marrow metastasis. ERBB2 exon 20 insertion mutation was confirmed by next‐generation sequencing (NGS) of lung tissue as well as bone marrow. The patient achieved stable disease and recovery of pancytopenia after two months of pyrotinib therapy. This is the first report of homogenous mutations of ERBB2 detected in bone marrow, as well as a good response of bone marrow to pyrotinib therapy. Key points This is the first report of a homogenous mutation of ERBB2 detected in the bone marrow of an NSCLC patient with bone marrow metastasis. Our patient with NSCLC ERBB2 mutation and bone marrow metastasis responded well to pyrotinib therapy.


Introduction
Human epidermal growth factor receptor 2 mutations (HER2, ERBB2) have been found in about 2% of patients with non-small cell lung cancer (NSCLC) 1,2 . However, in the past 10 years, effective targeted therapies have not been identified. Recently, Wang et al. 3 reported that pyrotinib, an irreversible pan ErbB inhibitor, provided an overall response rate of 53.5% in a phase 2 study. Bone marrow metastasis is rare in patients with lung adenocarcinoma, and has been reported to be associated with poor prognosis. Here, we present a rare NSCLC case with bone marrow metastasis carrying ERBB2 mutations which responded well to pyrotinib therapy.

Case presentation
A 62-year-old woman (non-smoker) was diagnosed with stage IIIb NSCLC in May 2018. Lung histopathology confirmed adenocarcinoma (Fig 1a). Next-generation sequencing (NGS) showed an ERBB2 exon 20 insertion mutation (p.E770delinsEAYVM 24.34%) and a TP53 mutation (p.S241F 10.98%), with a PD-L1 tumor proportion score less than 1%. The patient received six cycles of chemotherapy (pemetrexed/cisplatin) combined with pembrolizumab, underwent radiotherapy of the right lung lesion (64 Gy/eight fractions, three fractions a week) and received six cycles of pemetrexed afterwards as maintenance therapy. Clinical response was evaluated every two cycles as stable disease. However, after six cycles of maintenance therapy, multiple bone metastatic lesions were detected on bone scan in June 2019 (Fig 2). The patient refused further chemotherapy and received one cycle of anlotinib (a multitargeting tyrosine kinase inhibitor and angiogenesis inhibitor) without any improvement. On 6 August 2019, she was unconscious and was admitted to hospital. Blood tests showed anemia, thrombocytopenia, hypercalcemia, and elevation of creatinine. Coagulation profile suggested disseminated intravascular coagulation (DIC). Several serum tumor markers were significantly elevated (Table 1).
Hepatic metastases was confirmed by computed tomography (CT) scan (Fig 3a-c). Bone marrow biopsy suggested bone marrow metastasis (Fig 1b,c). The NGS of bone marrow biopsy revealed the copy number alteration of ERBB2 gene (n = 3.34) and an ERBB2 exon 20 insertion mutation as previously described (p.Y772_A775dupYVMA 38.45%).
On 18 August 2019, pyrotinib therapy (240 mg q.d.) was initiated, based on ERBB2 exon 20 insertion mutation. One month later, platelet count, renal function and coagulation function of the patient had returned to normal and    pyrotinib dose was subsequently increased to 320 mg q.d. Two months later on 16 October 2019, she was assessed as stable disease (Table 1, Fig 3d-f).

Discussion
With the discovery of driver mutations such as epidermal growth factor receptor (EGFR) and the development of tyrosine kinase inhibitor (TKI) therapies targeting these mutations, the treatment of NSCLC has moved from conventional chemotherapy to targeted therapies. Human epidermal growth factor receptor 2 mutations (HER2, ERBB2) are found in about 2% of NSCLC, with a predominance in women and non-smokers 1, 4, 5 . About 96% of ERBB2 mutations are exon 20 insertions, and 83% of those are a recurrent 12 base-pair insertion causing duplication of amino acids YVMA at codon 775. 2,6 Patients with ERBB2 mutations have previously shown a low response to pemetrexed-based first-line chemotherapy. 7 Immunotherapy achieved limited efficacy in these patients with response rates varying from 7% to 27%. 8,9 Since 2006, several case reports and case series have suggested transtuzumab, afatinib, dacomitinib and neratinib as potential targeted therapies for patients with NSCLC carrying ERBB2 mutations. [10][11][12][13] Early clinical activity has also been seen with the dual EGFR 14 3 In our case, the patient carried an exon 20 insertion leading to duplication of amino acid YVMA at codon 775 in ERBB2, which is the most often seen mutation in NSCLC. 2 She was given pyrotinib 240 mg q.d. first for renal insufficiency, and the dose was adjusted to 320 mg q.d. The patient achieved stable disease and recovered from acute kidney injury and bone marrow depression, which is in accordance with the report by Wang et al. 3 Bone marrow metastasis is rarely reported in NSCLC. Tumor cells invading bone marrow will lead to pancytopenia and hematological disorders such as DIC and microangiopathic hemolytic anemia. In our case, it is first reported that the NGS of bone marrow confirmed homeotic mutations with lung tissue and the patient recovered from severe anemia, thrombocytopenia and DIC after pyrotinib therapy.

Disclosure
The authors declare there are no conflicts of interest.