Anastrozole-induced interstitial lung disease followed by tamoxifen-induced agranulocytosis in a patient with breast cancer

Abstract

A 70-year-old woman with the breast cancer exhibited interstitial lung disease 20 months after the administration with anastrozole, which was performed as the post-operative adjuvant therapy. The drug-induced lymphocyte stimulation test revealed that anastrozole was responsible for the development of interstitial lung disease in this patient. The interstitial lung disease was effectively treated by prednisolone. Then, tamoxifen was used as an alternative therapy, resulting in the occurrence of agranulocytosis 24 days after the administration with tamoxifen. Both anastrozole and tamoxifen are widely used and are highly effective drugs for the treatment of breast cancer. However, the current patient shows that both drugs could cause, albeit very rare, serious side effects in some patients.

Introduction

Anastrozole, an aromatase inhibitor, and tamoxifen, a selective estrogen receptor modulator, are widely used to treat all stages of hormone receptor-positive breast cancer and are shown to be highly effective drugs for the treatment of breast cancer. Both drugs are generally believed to be safely used for most patients without inducing any serious side effects. Among side effects accompanied with the treatment of breast cancer, interstitial lung disease and agranulocytosis associated with aromatase inhibitors or selective estrogen receptor modulators are very rare. However, both pathological conditions could cause the fatal outcome. Here, we report a patient with breast cancer, who exhibited anastrozole-induced interstitial lung disease, which was followed by tamoxifen-induced agranulocytosis in a short period. The current patient shows that both drugs could cause, albeit very rare, serious side effects in some patients.

Case report

A 70-year-old woman presented to our hospital with complaints of a 3 day history of cough and dyspnea. She had the cancer of her left breast, and underwent the breast-conserving surgery and sentinel lymph node biopsy at our hospital 2 years ago. The pathological stage of the cancer was stage I (T1bN0M0), and the molecular subtype was determined as Luminal A as evidenced by positive estrogen receptor, positive progesterone receptor, negative human epidermal growth factor receptor (HER2), and low Ki67 index (11.2%). After completing the radiation therapy over the whole left breast (42.56 Gy in total, 16 fractions), she was treated with anastrozole (1 mg/day), an aromatase inhibitor, as the adjuvant hormone therapy. She experienced cough and dyspnea 20 months after the administration of anastrozole.

The findings of peripheral blood examination were as follows: white blood cells (WBCs) 7,800/µL, C-reactive protein 1.88 mg/dL, aspartate aminotransferase 166 U/L, and alanine aminotransferase 305 U/L. Possible infections of influenza A/B and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were excluded, and the possibility of collagen diseases was also excluded. Bilateral fine crackles were detected on the chest auscultation. Consistent with these findings, the computed tomography (CT) images showed multiple patchy ground-glass opacities in the bilateral lung fields (Fig. 1), leading to the diagnosis of the interstitial lung disease. The histological findings of the trans-bronchial lung biopsy specimens were consistent with the diagnosis of interstitial lung disease (organizing pneumonia). She had been treated with two kinds of drugs; anastrozole for 2 years and Sanmotsuogonto (a Japanese herbal Kampo medicine) for 8 months before the occurrence of interstitial lung disease. After admission, Sanmotsuogonto was withdrawn, as we suspected that this herbal medicine must have been responsible for the development of interstitial lung disease. However, the symptoms were not significantly improved by Sanmotsuogonto withdrawal alone. On the 5th day of hospitalization, she was treated with oral prednisolone (30 mg/day). The respiratory symptoms were somewhat improved by the administration of prednisolone. Then, on the 12th day of hospitalization, she was discharged under the treatment with prednisolone (20 mg/day), anastrozole (1 mg/day), sulfamethoxazole/trimethoprim (400 mg/day and 80 mg/day, respectively) and lansoprazole (15 mg/day). In this case, the clinical symptoms were moderate, requiring oxygen administration. Thus, the starting dose of prednisolone was 30 mg/day according to the JRS (Japanese Respiratory Society) Guidelines for the Management of Drug-induced lung disease [1], in which 0.5–1.0 mg/kg prednisolone is recommended as the starting dose. The tapering of prednisolone also followed the Guidelines, observing the improvement of the clinical symptoms.

Fig. 1.

The computed tomography (CT) images (a and b) showed multiple patchy ground-glass opacities in the bilateral lung fields

We initially thought that Sanmotsuogonto must have been responsible for the development of interstitial lung disease in this patient. Unexpectedly, the data from the drug-induced lymphocyte stimulation test (DLST), which we got after her discharge, showed 182 cpm (counts per minutes) for the control, 859 cpm for anastrozole, and 323 cpm for Sanmotsuogonto, respectively. Thus, the stimulation indexes were 471% for anastrozole and 177% for Sanmotsuogonto, respectively, whereas the cutoff value of this test was 180%. These findings strongly indicate that anastrozole, but not Sanmotsuogonto, may be responsible for the development of interstitial lung disease in this patient. Then, anastrozole was withdrawn on the 5th day after her discharge. On the 10th day after her discharge, prednisolone was tapered to 10 mg/day, and, in place of anastrozole, oral tamoxifen (20 mg/day) was used for the treatment of breast cancer.

Twenty-four days after taking tamoxifen, remarkable decrease in WBC (920/µL) and neutrophil counts (27/µL) was found, whereas the counts of red blood cells (382 × 10⁴/µL) and platelets (22.3 × 10⁴/µL) were unaffected. The diagnosis of agranulocytosis was made, and it was highly possible that tamoxifen was responsible for the development of agranulocytosis, since she took no other additional drugs. Then, tamoxifen was withdrawn, and she was admitted, receiving subcutaneous injection of granulocyte-colony stimulating factor (G-CSF) (75 µg/day) for 3 days. The neutrophil counts were recovered to the normal levels without any complications of bacterial infections, and she was discharged on the 6th day of hospitalization. She took sulfamethoxazole/trimethoprim and lansoprazole throughout this clinical course. Sulfamethoxazole/trimethoprim was withdrawn, and prednisolone was tapered to 5 mg/day at the discharge as the interstitial lung disease was improved. One month after her discharge, prednisolone was withdrawn and she was completely free from any signs of interstitial lung disease. The clinical course and the major medications are summarized in Fig. 2.

Fig. 2.

(Upper panel) The clinical course and the major medications are shown in chronological order. (Lower panel) The changes in WBC and neutrophil counts in the peripheral blood during the clinical course are shown. ANA anastrozole, DIILD drug-induced interstitial lung disease, G-CSF granulocyte-colony stimulating factor, IDIA idiosyncratic drug-induced agranulocytosis, PSL prednisolone, TAM tamoxifen

Discussion

The incidence rates of drug-induced interstitial lung disease ranged from 4.1 to 12.4 cases/million/year according to the literature, and it accounts for 3–5% of prevalent interstitial lung disease [2]. Drug-induced interstitial lung disease could be caused by a variety of drugs, including chemotherapeutic agents, immune-suppressive agents, anti-rheumatic drugs, anti-arrhythmic drugs and antibiotics [3, 4]. The disease onset is unpredictable, and varies from days to even years after the administration of the causative drugs. No typical radiological patterns specific to the drug-induced interstitial lung disease were identified. Severity at the presentation was the most reliable predictor of the outcome. The causative drugs should be immediately withdrawn, and the systemic treatment with glucocorticoids is sometimes required for the patients with progressive or disabling diseases. The Japanese herbal Kampo medicines are widely used in Japan for the treatment of various complaints, and could cause serious side effects such as liver damage and interstitial lung disease in some patients [5, 6]. The previous literature shows that the herbal medicines are often responsible for the drug-induced interstitial lung disease. In particular, the herbal medicines, which contain Ogon and Kanzo as constituents, have been reported to be able to cause the interstitial lung disease [7]. Based on these previous reports, we initially suspected that Sanmotsuogonto, which contains Ogon as a constituent, was responsible for the interstitial lung disease in the current patient. However, DLST revealed that anastrozole, but not Sanmotsuogonto, was primarily responsible for the development of interstitial lung disease in this patient, indicating that this test is useful for determination of the causative drug.

DLST is a bioassay based on the measurements of ³H-thymidine incorporation into DNA on exposure of lymphocytes to an antigen (in this case, a drug) in vitro. The positive results may imply the presence of drug-sensitized T-lymphocytes. This test has the advantages such as the absolute safety, but also has its own limitations in its sensitivity and specificity. The accumulated evidences reveal that the sensitivity ranges from 58 to 89% for mild and moderate allergic reactions and from 25 to 75% for severe reactions, and that the specificity ranges from 93 to 100% for mild and moderate reactions and from 63 to 100% for severe reactions [1, 8, 9]. Thus, it appears that the specificity of DLST is high although the sensitivity is not high, implying that the positive results could verify the drug as the causative agent if this conclusion would be also supported by the clinical findings. In the current case, the stimulation index was remarkably high for anastrozole (471%) as compared with that of Sanmotsuogonto (177%) while the cutoff value of the test was 180%. Based on these data and the clinical and laboratory findings, we suggested that anastrozole, but not Sanmotsuogonto, was the causative drug for the interstitial lung disease in this patient. In this regard, it is of interest that all reported cases showed the positive results for anastrozole in DLST when this test was performed (Table 1).

Table 1.

Reported cases of anastrozole-induced interstitial lung disease

Authors	Reported year	Age (years old)	Drugs	Time to onset	Others
Tomitaa	2010	62	Anastrozole	4 months	DLST positive
		55	Anastrozole	9 months	DLST positive
Horiuchi [12]	2011	60	Anastrozole	12 days	DLST positive
Hirohashi [11]	2015	72	Anastrozole	15 months	Diedb
Fujiia	2017	56	Anastrozole	3 months	DLST positive
Fujimori [10]	2019	68	Anastrozole	11 months	Diedc

^aThe cases were just presented in the abstract forms of the proceedings in Japanese, and the abstracts in English were not available and could not be cited in the references. The abstracts presented in Japanese were as follows: Tomita S (2010) Allergy 59(3/4): 447, Fujii K (2017) Nihon Rinsho Geka Gakkai Zassi 78:688

^bThe other aromatase inhibitors (letrozole and exemestane) were administered after anastrozole withdrawal, resulting in the recurrence of interstitial lung disease after administration of each drug. She died of aspiration pneumonia

^cShe died of respiratory failure (interstitial pneumonia) possibly caused by anastrozole

DLST, drug-induced lymphocyte stimulation test

We found out only 6 cases of anastrozole-induced interstitial lung disease in the literature that were summarized in Table 1. Among them, only 3 cases were found in the publications, and the other 3 cases were just presented in the abstract forms of the proceedings in Japanese [10–12]. Intriguingly, all cases were reported from the institutions in Japan. According to these previous reports, the drug-induced interstitial lung disease developed at 12 days to 15 months after the administration of anastrozole. In the current case, the interstitial lung disease developed 20 months after the administration of anastrozole. Treatment with another aromatase inhibitor (letrozole or exemestane) should be avoided for these patients as these patients may be also susceptible to other aromatase inhibitors [11]. Among 6 cases, one case died of respiratory failure (interstitial pneumonia) possibly caused by anastrozole, and another case died of aspiration pneumonia (Table 1).

In considering that aromatase inhibitors have been widely used for the treatment of breast cancer, it is surprising that there are only a few case reports associated with interstitial lung disease as the side effect of aromatase inhibitors. Prior to the development of interstitial lung disease, most patients are likely to have been already exposed to irradiation or treated with various drugs, including molecularly targeted drugs (such as mTOR inhibitors and anti-HER2 antibodies), selective estrogen receptor modulators, and aromatase inhibitors. In these situations, it seems to be hard to determine definitely the drug that was primarily or solely involved in the development of interstitial lung disease in the particular patient. These complicated situations may partly explain why there are only a few case reports showing that aromatase inhibitors are primarily responsible for the development of interstitial lung disease [10–12]. Another explanation is that there are no established methods to determine definitely the drug that is primarily responsible for the development of interstitial lung disease. Nonetheless, the current case and the reported cases taken together indicate that DLST may be useful for the determination of anastrozole as the causative drug for interstitial lung disease. It is also possible that the interstitial lung disease may occur as a result of the combined effects of various agents.

In the current case, the interstitial lung disease might be also caused by the radiation-induced lung injury, because she had received the irradiation over her left breast. Most symptoms of radiation pneumonitis, such as malaise, non-productive cough, low-grade fever, dyspnea, and chest pain, are generally observed in 3–12 weeks after the initiation of radiation therapy, although some symptoms may often occur in the first year of the radiation therapy [13–16]. In the current case, the interstitial lung disease occurred 21 months after the radiation therapy, and the computed tomography (CT) images showed multiple patchy ground-glass opacities in the bilateral lung fields (Fig. 1). The histological findings of the lung biopsy specimens were consistent with the diagnosis of interstitial lung disease. In addition, the interstitial lung disease was effectively treated with anastrozole withdrawal and prednisolone administration. Furthermore, DLST showed the positive results for anastrozole. These findings taken together strongly indicate that anastrozole may be responsible for the interstitial lung disease in this patient, in accordance with the previous reports [10–12, see Table 1].

Idiosyncratic drug-induced agranulocytosis is also a rare, but potentially fatal, disorder that occurs in susceptible individuals, with the incidence rate ranging from 2.3 to 15.4 cases/million/year [17]. Drug-induced agranulocytosis is caused by decreased production and/or increased destruction of neutrophils. Decreased production is frequently a consequence of chemotherapeutic drugs that cause suppression of bone marrow myeloid progenitor cells. Drug-induced agranulocytosis due to increased neutrophil destruction is sometimes induced by adverse idiosyncratic reactions to non-chemotherapeutic drugs. The possible causative drugs include antibiotics, anti-thyroid drugs, neuroleptic and anti-epileptic agents, anti-viral agents, and platelet aggregation inhibitors [18]. Increasing age and female sex have been considered as the risk factors for the development of drug-induced agranulocytosis [19]. The incidence of this disorder rising with age probably reflects the increased use of medications and some disturbance of the immunological states in this population. Drug-induced agranulocytosis has been classically defined by the neutrophil count below 500/µL, but other cell types such as red blood cells and platelets are usually at the normal levels. The most important treatment of drug-induced agranulocytosis is withdrawal of the causative drugs. The mean duration required for the hematological recovery was 7.8 days (range: 2–20 days) after withdrawal of the causative drugs. This mean duration may be reduced to 2.1 days (range: 2–16 days) by administration of G-CSF [20].

The mechanisms explaining the drug-induced agranulocytosis may include the drug-dependent immune-mediated destruction of circulating neutrophils and/or the toxic effects upon granulocytic precursors. The causative agent could be the drug itself or one of its metabolites [19]. Affected patients typically exhibit severe neutropenia within several weeks to several months after exposure to the causative drugs. The onset is often delayed and can even appear 30 days after the drug is withdrawn. At present, there are no established methods to determine the individuals susceptible to drug-induced agranulocytosis. Early detection of drug-induced agranulocytosis is sometimes difficult, as patients with drug-induced agranulocytosis are often asymptomatic unless bacterial infections occur. The early detection and the proper recovery of neutrophil counts to the normal levels are critically important to prevent serious bacterial infections.

The current patient received prednisolone for the treatment of interstitial lung disease. At the same time, she also received sulfamethoxazole/trimethoprim and lansoprazole, both of which were given throughout the clinical course of the occurrence of agranulocytosis and its recovery by G-CSF, and no other additional drugs than tamoxifen were not given (Fig. 2). Based on these clinical findings, we suggested that, among the drugs employed, tamoxifen was the causative drug for agranulocytosis in this patient, although sulfamethoxazole/trimethoprim and lansoprazole have been reported to be able to induce agranulocytosis and agranulocytosis may be more commonly caused by both drugs as compared with tamoxifen [17, 18]. In fact, there are very few reported cases associated with tamoxifen-induced hematological toxicity [21–25]. The long-term use of tamoxifen was reported to be associated with fatal neutropenia or severe myelosuppression [22, 24, 25]. In another case, tamoxifen was associated with agranulocytosis and hepatocellular damage [23]. More recently, a case of agranulocytosis induced by tamoxifen was reported in a 33-year-old woman with breast cancer [21]. In this case, agranulocytosis was found 10 days after the start of tamoxifen treatment, and agranulocytosis was effectively treated by G-CSF. After the recovery of agranulocytosis, she was safely treated with anastrozole [21] in contrast to the current case. The current patient exhibited anastrozole-induced interstitial lung disease, which was followed by tamoxifen-induced agranulocytosis in a short period, suggesting possible existence of the underlying immunological disturbance in this patient.

It is of interest that all reported cases as well as the current case showed the positive results for anastrozole in DLST when this test was performed (Table 1), suggesting that DLST may be a favorable tool for verifying the causative drug when anastrozole is suspected. The precise mechanisms for anastrozole-induced interstitial lung disease and tamoxifen-induced agranulocytosis remain to be elucidated. The direct toxic effect is unlikely, and the injury through the immunological mechanisms may be likely as evidenced by the positive DLST results [1]. In order to avoid the side effects associated with the treatment, careful observation of the clinical course may be critically important.

In conclusion, both anastrozole and tamoxifen are widely used and are highly effective drugs for the treatment of breast cancer. However, it should be kept in mind that both drugs could cause, albeit very rare, serious side effects (interstitial lung disease and agranulocytosis) in some patients.

Abbreviations

CT

Computed tomography

DLST

Drug-induced lymphocyte stimulation test

G-CSF

Granulocyte-colony stimulating factor

WBC

White blood cell

Author contribution

MJ and TI were the surgeons in charge of this case and MJ wrote the manuscript. MH was a radiologist and reviewed the radiological images. KS was a physician and was engaged in the treatment of interstitial lung disease.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request to protect the patient privacy. The data are stored in the Okayama Central Hospital.

Declarations

Conflict of interest

All authors have no conflict of interest.

Ethical approval

This is a case report, and then approval of our institution’s ethical board was not required.

Informed consent

Informed consent was obtained from the patient.