Drug-induced Interstitial Lung Disease in Breast Cancer Patients: A Lesson We Should Learn From Multi-Disciplinary Integration

Systemic therapy is an indispensable part of the treatment for breast cancer, including chemotherapy, endocrine therapy, and targeted therapy [1]. Systemic therapy is commonly used in human epidermal growth factor receptor-2 (HER-2)-positive breast cancer, which is one of the four subtypes of breast cancer. This subtype accounts for about 20% of all types of breast carcinoma [2]. And it is characterized by a high mortality rate in early stage, a short interval to relapse, and a predisposition to metastasis until HER-2-targeted therapies were invented [3, 4]. As a representative of targeted therapy, trastuzumab (Herceptin®) is a monoclonal antibody that targets the HER-2 molecule, inhibits HER-2 expression, and blocks ligand-independent HER-2 signaling [5, 6]. Paclitaxel, a chemotherapy drug belonging to the group of taxanes is a regular treatment for HER-2-positive patients [7]. The combination of paclitaxel and trastuzumab can reduce the relapse rate and drastically improve pathological complete response rate and prognosis of early-stage or advanced HER-2-positive breast cancer [8–11]. Nevertheless, we cannot neglect their toxicity and interstitial lung diseases (ILD) is one of them. ILDs include a class of non-malignant respiratory diseases [12]. ILDs are marked by pathologic changes such as inflammation and fibrosis in the lung parenchyma [13]. According to the latest classification, interstitial pneumonia is a major form of ILDs [14, 15]. Drug toxicity is one of the causes of interstitial pneumonia (IP) [15] and this condition is usually named as a drug-induced interstitial lung disease (DILD). Medications disposed to cause DILD include chemotherapy agents such as taxanes (docetaxel and paclitaxel) [16–19], or monoclonal antibodies such as trastuzumab, adalimumab, bevacizumab, etc. [19, 20]. The frequency of paclitaxel-induced ILDs was 0.73–12% while the incidence of trastuzumab was estimated to be 0.4%–0.6% [21, 22]. This complication is perilous and difficult to be firmly diagnosed due to its atypical clinical presentation. Also, the medical imaging of ILD are indistinguishable from other common pulmonary diseases [15, 23, 24]. In this article, we discuss a case that was encountered on a ward and review previous studies with similar drug-induced pulmonary injury. We 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou 510120, P.R. China


Introduction
Systemic therapy is an indispensable part of the treatment for breast cancer, including chemotherapy, endocrine therapy, and targeted therapy [1]. Systemic therapy is commonly used in human epidermal growth factor receptor-2 (HER-2)-positive breast cancer, which is one of the four subtypes of breast cancer. This subtype accounts for about 20% of all types of breast carcinoma [2]. And it is characterized by a high mortality rate in early stage, a short interval to relapse, and a predisposition to metastasis until HER-2-targeted therapies were invented [3,4]. As a representative of targeted therapy, trastuzumab (Herceptin ® ) is a monoclonal antibody that targets the HER-2 molecule, inhibits HER-2 expression, and blocks ligand-independent HER-2 signaling [5,6]. Paclitaxel, a chemotherapy drug belonging to the group of taxanes is a regular treatment for HER-2-positive patients [7]. The combination of paclitaxel and trastuzumab can reduce the relapse rate and drastically improve pathological complete response rate and prognosis of early-stage or advanced HER-2-positive breast cancer [8][9][10][11]. Nevertheless, we cannot neglect their toxicity and interstitial lung diseases (ILD) is one of them.
ILDs include a class of non-malignant respiratory diseases [12]. ILDs are marked by pathologic changes such as inflammation and fibrosis in the lung parenchyma [13]. According to the latest classification, interstitial pneumonia is a major form of ILDs [14,15]. Drug toxicity is one of the causes of interstitial pneumonia (IP) [15] and this condition is usually named as a drug-induced interstitial lung disease (DILD). Medications disposed to cause DILD include chemotherapy agents such as taxanes (docetaxel and paclitaxel) [16][17][18][19], or monoclonal antibodies such as trastuzumab, adalimumab, bevacizumab, etc. [19,20]. The frequency of paclitaxel-induced ILDs was 0.73-12% while the incidence of trastuzumab was estimated to be 0.4%-0.6% [21,22]. This complication is perilous and difficult to be firmly diagnosed due to its atypical clinical presentation. Also, the medical imaging of ILD are indistinguishable from other common pulmonary diseases [15,23,24]. In this article, we discuss a case that was encountered on a ward and review previous studies with similar drug-induced pulmonary injury. We

Case studies
Nearly 2 years ago, a 55-year-old female was admitted to hospital with a complaint of "a lump in the right breast for 10 months and bilateral hip pain for 2 months". She was finally diagnosed as having invasive breast carcinoma with bone metastasis, (level III, clinical staging: stage IV, T3N3M1). Immunohistochemistry showed estrogen receptor (ER)positive (10%), progesterone receptor (PR)-negative, HER-2-positive (3+), Ki67-positive (about 90%). Subsequently, a rescue treatment plan was decided: Anzatax (paclitaxel injection, Hospira Australia Pte Ltd, Melbourne, Australia) 110 mg (once per week) + Herceptin (trastuzumab injection, Genetech Inc., San Francisco, USA) 390 mg (the first dose)/290 mg (once per 3 weeks and maintaining for a year) + Zometa (zoledronic acid for injection, Novartis Pharma Stein AG, Switzerland, Basel, Switzerland) 4 mg (1 dose per 28 days). Shortly after the first cycle of therapy, the patient had a fever and chill followed by a headache, dizziness and palpitation. The highest body temperature reached was 39.4 °C; fever subsided after antipyretic analgesics were given several times. Physical examination did not find any crackles during lung auscultation. Laboratory tests including blood routine analysis showed a white blood cell count of 6.14 × 10 9 /L, hemoglobin 108 g/L, neutrophil count 5.72 × 10 9 /L; both results of blood cultivation of bacteria and anaerobes were negative. Two more cycles with a subsequently switched plan: Anzatax 110 mg (once per week) + Herceptin 90 mg (once per week and maintained for a year), were completed on October 19 th , 2018 and October 26 th , 2018, respectively, after subclavian venous access device implantation. A chest X-ray was taken on October 19 th and the result showed interstitial pneumonia (bilateral inferior lungs) with rightside pleural effusion (Figure 1). Another six rounds of rescue therapy consisting of Anzatax 110 mg (once per week) + Herceptin 90 mg was given to the patient from November 2 nd to December 8 th in 2018. Series of coughs began after November 9 th with yellow sputum, a slight headache and a stuffy nose. The sputum turned white but cannot be expectorated readily. The condition did not remit after treatment of several expectorants. The cough worsened 2 weeks prior to November 29 th , the day of the next scheduled rescue therapy. An X-ray examined on November 29 th still suggested bilateral pneumonia with slight pleural effusion, the same as that of October 19 th   (terbutaline sulphate solution for nebulization, AstraZeneca AB, Sodertalje, Sweden) and Pulmicort Respules (budesonide suspension for inhalation, AstraZeneca Pty Co., Ltd, Sydney, Australia). No apparent abnormality was found in routine blood tests and a negative sputum cultivation before each therapy session. A re-examination of the CT scan on the December 13 th indicated signs of lung disease with scattered inflammation in the whole lung ( Figure 2A). Throughout the whole treatment, the pain of the patient's bilateral hips was not relieved.
As the patient's condition worsened, the patient had to be transferred to the Department of Respiratory Medicine. Her vital signs were monitored while a physical examination and various blood tests were carried out. Her initial vital signs were normal. Rough breathing sounds and bilateral crackle in the lungs could be heard. Routine blood test revealed the following abnormalities: C-reaction protein (CRP) was high (28.2 mg/L) whereas procalcitonin (PCT) was normal; erythrocyte sedimentation rate (ESR) was significantly high (73.0 mm/h), suggesting an inflammatory reaction; blood biochemistry showed a low serum albumin (32 g/L); blood gas analysis showed decreased PO 2 (9.54 kpa) but with a normal arterial oxygen saturation (SaO 2 ). Meanwhile, pathogen tests (mycoplasma, chlamydia and virus, etc.) were negative. Blood or sputum culture of bacteria, fungus, and tuberculosis were all reported as negative. A similar result was found for the G/GM tests for fungus. The

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Z. Zhao et al.: Drug-induced Interstitial Lung Disease in Breast Cancer Patients patient denied any other diseases but a past record of serious hyperglycemia was proved by a high glycated hemoglobin (HbA 1C ) (9.9%). Her finger-tip blood sugar was monitored since her transfer to the respiratory ward. The highest daily blood sugar measurement could reach 24.0 mmol/L. A diagnosis of interstitial pneumonia (bilateral lungs) and type-2 diabetes was established. Considering the cause of infection, drug-triggered inflammation and hyperglycemia, the current treatment plans are as follows: anti-infection therapy including Tienam (imipenem and Cilastatin Sodium for Injection, Merck Sharp & Dohme Corp., Kenilworth, USA), Vancocin, (vancomycin, Hydrochloride for intravenous, Vianex S.A., Athens, Greece) and Cancidas (caspofungin acetate for injection, Laboratories Merck Sharp & Dohme Chibret, Clermont-Ferrand, France), coupled with Solu Medrol (methylprednisolone sodium succinate for injection, Pfizer Manufacturing Belgium NV, Puurs, Belgium) as anti-inflammatory agent. Meanwhile, Novorapid (insulin aspart injection, Novo Nordisk, Copenhagen, Denmark) and Solostar (insulin glargine injection, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany) were used to treat the diabetes. After adhering to this regimen for 9 days, a thoracic CT scan (December 1 th , 2018) was taken. The result showed a significant reduction in lung lesions as compared to the last CT imaging (December 13 th , 2018), although a pleural effusion ( Figure 3A and B) was newly-discovered, which probably developed due to the low level of serum albumin (30.2 g/L). The level of CRP jumped to 5.9 mg/L during reexamination, indicating suppressed inflammation.
Therefore, the prescription of Tienum and Vancocin were stopped while Cancidas continued being administered. The dosage of methylprednisolone was lowered to 40 mg/day. The condition of blood sugar decreased from 23.2 mmol/L to 10.4 mmol/L. Two weeks later, the patient got better except for an occasional cough accompanied by white and thin sputum. The lung auscultation turned normal and the corticosteroid was reduced to 20 mg/day. Three days afterwards, the patient was discharged with a stable condition. The whole process of this patient's treatment and the change of her conditions are illustrated in Figure 4.
One week later, the patient returned to our department to get further treatment for primary breast cancer. This time, doctors switched the previous therapy to 1.25 g bid Xeloda (capecitabine tablets, Shanghai Roche Pharmaceuticals, Ltd, Shanghai, China) (first 2 weeks) plus 360 mg trastuzumab (once per 3 weeks) for the purpose of safety concern, effective therapy as well as figuring out the culprit DILDs. To date, the patient still suffers from slight headache and an occasional cough with small amount of white sputum. However, the patient's symptoms have regressed as compared to the time when the patient was admitted to the Department of Respiratory Medicine.
To further explore this complication, we collected cases that were diagnosed as "lung fibrosis" and "interstitial lung disease" in our hospital from 2013 to 2019 and had successfully screened out two qualified cases of systemic therapy with paclitaxel and/or trastuzumab (Table 1). However, these patients had received radiotherapy as well, so the drugs cannot be blamed for the complication alone.

Discussion
In the first case detailed, we can conclude that the lung disease is more likely a non-infectious one because the result of blood/sputum culture and antigens of some common pathogens and their corresponding antibodies were all negative. Anyhow, it should still be determined whether it is just DILDs, or a rare disease of lymphangitic carcinomatosis which may be fatal, as both diseases display similar symptoms such as dyspnea, dry cough, tachypnea, and low arterial oxygen saturation (SaO 2 ). This is crucial because the patient was diagnosed with metastatic breast cancer, so the possibility of lymphangitic carcinomatosis must be considered. The main difference between both diseases is the illustration of lymphangitic carcinomatosis as a diffused reticular and nodular-like pattern on an X-ray or on a CT scan [25]. Additionally, the symptoms of the first patient appeared shortly after treatment and the patient finally had a sensitive response to corticosteroids. Hence, DILDs should be considered for this case. The ultimate diagnosis can be confirmed by bronchoalveolar lavage and biopsy specimens [26,27] although some patients are unable to tolerate these. Other than that, a further follow-up is necessary to determine which drug(s) is(are) the culprit(s): paclitaxel, trastuzumab, or the synergistic effect of them. This can be done by discontinuing one of these two drugs and assessing the response of the patient periodically. Since the time when the paclitaxel was stopped, the condition of the patient's symptom has been relieved to some extent. We primarily extrapolate that paclitaxel may contribute more than trastuzumab for the cause of ILD. Steroids play a major part in the regimen of non-infectious ILDs, especially DILDs, which is confirmed by another (the 49-year-old female) as summarized in Table 1.
We collected case reports of drug-induced ILDs in breast cancer patients which were published between 2000 and 2019 in the PubMed database. There were 39 studies that qualified. The summary of these documents can be found in Table 2. The drugs that were administered vary among these cases: chemotherapy agents including epirubicin, cyclophosphamide, paclitaxel, albumin-bound paclitaxel, doxorubicin, gemcitabine, fluorouracil, and pegylated liposomal doxorubicin; monoclonal antibodies such as trastuzumab, bevacizumab, etc.; immunosuppressive drugs such as Everolimus; and other kinds of medications (Table 2). In these case reports or clinical trials, the frequency of these drugs causing the occurrences of ILDs varies, with docetaxel and trastuzumab being mentioned the most (12 times), followed by paclitaxel/albumin-bound paclitaxel (10 times), cyclophosphamide (9 times), epirubicin (7 times), Everolimus (5 times), and doxorubicin (4 times). According to this survey, it suggests that taxanes (paclitaxel and docetaxel) and trastuzumab tend to cause pulmonary injuries in breast cancer patients. Among patients that were treated by paclitaxel (only analysis results of case reports), 14 people had an ILD and recovered through subsequent treatment [22,[28][29][30][31][32][33][34]. As for the 11 patients who were administered trastuzumab [19,22,27,[35][36][37][38][39][40], only one succumbed to trastuzumab-induced ILD [19]. Overall, the response rate for paclitaxel/trastuzumab-induced ILDs seems to be promising. Nevertheless, the rapid progression of DILDs [fever, respiratory distress including shortness of breath (SOB), severe hypoxemia with a low oxygen saturation] still poses a great challenge to medical professionals. Thus, figuring out the culprit of DILDs is of the utmost importance, especially when multiple drugs are used simultaneously. In our case, the patient had been treated with both paclitaxel and trastuzumab, so the cause of ILD may be both or either one of them. To maintain a relative effective anti-cancer therapy and explore further about ILDs, we discontinued paclitaxel while trastuzumab monotherapy is underway. There was no complain of dry cough, SOB and other discomfort after that. Hence, it is more likely that paclitaxel triggered pulmonary toxicity.
To date, mechanism of drug-induced pulmonary toxicity suggests that drugs directly or indirectly damage the lung tissue via overwhelming inflammatory response. As a cytotoxic agent, paclitaxel causes large amount of reactive oxygen species (ROS) secreted by cancer cells, during which the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in cancer cells is activated by paclitaxel. These extracellular ROS will do harm to normal cells which are not exposed to paclitaxel [41]. This so-called cytotoxic bystander effect is a potential mechanism of lung injury during paclitaxel therapy. In an animal study, Liu et al. found that paclitaxel-induced lung injury was caused by the elevation of cyclooxygenase-2 (Cox-2) and reduction of proteins in tight junctions in lung tissue [42]. The former pro-inflammatory substance is mainly derived from neutrophils. The neutrophils and Cox-2 synergistically exacerbated the inflammatory response and cytotoxicity, which resulted in lung injury [43]. Thus, parecoxib sodium, a kind of Cox-2 specific inhibitor can alleviate this side effect [42]. Moreover, pharmacologists invented a novel hydrogel which originated from meshwork consisting of nanocellulose and hexadecyl amine. This brand-new biomaterial can control the release of paclitaxel and avoid potential side effects [44]. On the other hand, the mechanism of trastuzumab-related ILD is unclear. Bronchoalveolar lavage indicated that this side effect is presented as neutrophilic alveolitis [45]. A normal physiological function of alveolar epithelium is dependent on type II pneumocytes which express epidermal growth receptor factor (EGFR). Accompanied with keratinocyte growth factor, EGFR is a well-known mediator of alveolar epithelial recovery [46]. An EGFR-inhibitor, such as trastuzumab, will thus negatively impact the protective effect of type II pneumocyte in response to lung injury [47].
For treatment, this adverse effect can be ceased by either drug stoppage or high-dose steroid therapy, which can rapidly subside lung injury [32]. According to the "Uptodate" recommendation of "Treatment and prognosis of nonspecific interstitial pneumonia" (https://www.uptodate.cn/contents/ zh-Hans/treatment-and-prognosis-of-nonspecific-interstitial-pneumonia?search=interstitial%20lung%20disease&-source=search_result&selectedTitle=5~150&usage_type=-default&display_rank=5), drug stoppage and systemic glucocorticoids are still the two most effective solutions. Take prednisone, for example, the suggested dose initiates with 0.5 to 1 mg/kg ideal body weight every day. The ceiling dose is 60 mg/day for 1 month followed by 30-40 mg/ day for another 2 months. If patients respond sensitively, the dose of prednisone can be tapered to 5-10 mg per day by the end of 6 to 9 months. The duration of prednisone should last for at least 1 year. During the treatment with corticosteroids, a variety of side effects ought to be monitored closely, especially those with comorbidities (high blood pressure, hyperglycemia, etc.) [47]. If the DILD is refractory or the disease progresses, some other immunosuppressive agents can be added such as azathioprine, mycophenolate mofetil, cyclophosphamide, or calcineurin inhibitors (cyclosporine and tacrolimus), or rituximab (a monoclonal antibody). Because these drugs have different side effects such as opportunistic infection and potential secondary lung injury, usage for cancer patients should be accompanied with great caution [48,49]. Of course, in some lucky individuals, both symptoms and radiographic abnormalities can subside without any medical interference [16]. But there is no evidence proving that DILD is a self-limited disease. For some unfortunate cases, however, physicians failed to make an accurate diagnosis because of a non-specific clinical manifestation such as dyspnea or a nonproductive cough [50]. Instead, they used a wide range of antibiotics even if there was no strong  of an infection (normal body temperature, negative results of routine blood test, culture or antigen quantification of bacteria, virus and fungi), which resulted in a long-term ILDs or even ILD-related death.
Throughout this article, we have emphasized that DILDs are a group of rare but severe respiratory complications during anti-cancer treatment in malignancies. Medical professionals should make a quick judgement when SOB, severe hypoxemia, and other clinical manifestation of respiratory distress occur. It is advisable to selectively discontinue potential drugs and to assure periodical physical examination. Usage of antibiotics should be replaced by other agents such as corticosteroids if no evidence of infection is found in lab tests. Besides, it is worthy for scientists and pharmacologists to find a solution to modify these drugs so that DILD can be avoided at least for those whose prognosis are thought to be optimistic. Through integration of clinical practice and medical research and development, a multidisciplinary platform is necessary to make a more effective medical protocol.

State of significance
Drug-induced interstitial lung diseases (DILD) is a group of rare but life-threatening diseases for cancer patients during systemic therapy. Medical professionals tend to misdiagnose this complication as infection, which causes exaggeration of the disease. To avoid this tragedy, multidisciplinary platform where clinical medicine and pharmacological research should cooperate to prevent from DILD.