Emerging Perspectives on mTOR Inhibitor‐Associated Pneumonitis in Breast Cancer

Abstract

Substantial improvements in the early detection and treatment of breast cancer have led to improvements in survival, but breast cancer remains a significant cause of morbidity and mortality in women. In 2012, the mammalian target of rapamycin (mTOR) inhibitor everolimus was approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer in patients resistant to endocrine therapy. Although everolimus is generally well tolerated, mTOR inhibitor‐associated pneumonitis is one of the most common adverse drug events leading to treatment discontinuation. To date, the underlying pathophysiology of this toxicity is unclear, and this uncertainty may hinder the optimization of management strategies. However, experiences from breast cancer and renal cell carcinoma clinical trials indicate that mTOR inhibitor‐associated pneumonitis can be effectively managed by early detection, accurate diagnosis, and prompt intervention that generally involves everolimus dose reductions, interruptions, or discontinuation. Management can be achieved by a multidisciplinary approach that involves the collaborative efforts of nurses, oncologists, radiologists, infectious disease specialists, pulmonologists, clinical pharmacists, and pathologists. Comprehensive education must be provided to all health care professionals involved in managing patients receiving everolimus therapy. Although general recommendations on the management of mTOR inhibitor‐associated pneumonitis have been published, there is a lack of consensus on the optimal management of this potentially serious complication. This article provides an overview of mTOR inhibitor‐associated pneumonitis, with a focus on the detection, accurate diagnosis, and optimal management of this class‐related complication of mTOR inhibitor therapy.

Implications for Practice

This article summarizes the pathogenesis, clinical presentation, incidence, detection, and optimal management of everolimus‐related noninfectious pneumonitis in breast cancer. In particular, this article provides a detailed overview of the important aspects of the detection, accurate diagnosis, and appropriate management of mammalian target of rapamycin inhibitor‐associated pneumonitis. In addition, this article emphasizes that effective management of this adverse drug event in patients with breast cancer will require a multidisciplinary approach and collaboration among various health care professionals.

Abstract

摘要

在乳腺癌早期检测和治疗中取得的重大改善使生存率有所提高, 但是乳腺癌仍然是导致女性病损和死亡的一个重要原因?2012年, 美国食品药品监督管理局批准将哺乳动物雷帕霉素靶蛋白?mTOR?抑制剂依维莫司用于在内分泌疗法耐药性患者中治疗晚期乳腺癌?尽管依维莫司的耐受性普遍良好, 但是mTOR抑制剂相关性非感染性肺炎是导致治疗停止的最常见不良药物事件之一?迄今为止, 此毒性的基础病理生理学尚不明确, 而此不确定性可能会阻碍管理策略的优化?然而, 从乳腺癌和肾细胞癌临床试验中获得的经验表明, 通过早期检测?准确诊断和及时干预?通常包括减少依维莫司剂量以及中断或停止给药?可有效管理mTOR抑制剂相关性非感染性肺炎?可通过多学科方法管理疾病, 该方法需要护士?肿瘤医师?放射科医师?传染病专科医生?肺病医生?临床药剂师和病理学家的协同努力?必须向接受依维莫司的患者管理中涉及的所有医疗保健专业人士提供全面教育?尽管已发布了对mTOR抑制剂相关性非感染性肺炎管理的一般建议, 但是对于此可能发生的严重并发症的最佳管理, 人们尚未达成共识?本文概述了mTOR抑制剂相关性非感染性肺炎, 重点是针对mTOR抑制剂治疗中此类别相关性并发症的检测?准确诊断和最佳管理?

对临床实践的提示?本文总结了乳腺癌患者中依维莫司相关性非感染性肺炎的发病机理?临床表现?发病率?检测和最佳管理?本文特别概述了哺乳动物雷帕霉素靶蛋白抑制剂相关性非感染性肺炎的检测?准确诊断和恰当管理的重要方面?此外, 本文还着重指明, 在乳腺癌患者中有效管理此不良药物事件需要多学科方法和各种医疗保健专业人士的合作?

Everolimus, Breast cancer, Pneumonitis, Adverse drug event

Introduction

Substantial improvements in the early detection and treatment of breast cancer have contributed to an overall increase in survival rates [1]. Nonetheless, breast cancer is still the most frequently diagnosed cancer and the second most common cause of death among women in the U.S. alone; 231,840 new cases and 40,290 related deaths are estimated for 2015 [2]. The prognosis and treatment of breast cancer depend on tumor histology, clinical staging, and biological characteristics and on the age and health of the patient [1, 3].

In patients with breast cancer with hormone receptor (HR)‐positive tumors, disease progression on endocrine therapies is frequent and represents a common clinical situation [3, 4]. One mechanism of resistance to endocrine therapy involves activation of the phosphatidylinositol 3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, which regulates cellular proliferation, survival, and differentiation [5–7]. This signal transduction pathway is the most frequently mutated and hyperactive pathway in breast cancer [8–10], often contributing to aggressive cancer phenotypes [11] and insensitivity to hormonal therapy [12, 13]. As a result, therapeutic agents inhibiting components of the PI3K/AKT/mTOR signaling pathway represent promising targets for the treatment of breast cancer [9].

Everolimus (Afinitor, Novartis, Basel, Switzerland; previously RAD001) is an oral mTOR inhibitor [14]; the inhibition of mTOR signaling leads to reduced cell proliferation and to enhanced apoptosis and endocrine sensitivity of tumor cells [15, 16]. Everolimus has been approved by the U.S. Food and Drug Administration for the treatment of multiple tumor types, including advanced HR‐positive, human epidermal growth factor receptor 2 (HER2)‐negative breast cancers resistant to endocrine therapy [14].

Studies have confirmed the clinical benefit of everolimus in patients with breast cancer [4, 17, 18]. However, clinicians should be aware that everolimus, like other mTOR inhibitors, has a unique adverse event (AE) profile [17–20]. mTOR inhibitor‐associated pneumonitis is an AE of clinical interest that can result in severe outcomes and represents one of the most common AEs leading to treatment discontinuation [19].

To date, evidence‐based guidelines that assist in the early detection, accurate diagnosis, and effective management of mTOR inhibitor‐associated pneumonitis are limited. This article provides a comprehensive summary of the pathogenesis, clinical presentation, incidence, detection, and optimal management of mTOR inhibitor‐associated pneumonitis in breast cancer.

mTOR Inhibitor‐Associated Pneumonitis

Pathogenesis

mTOR inhibitor‐associated pneumonitis was initially reported in kidney transplant recipients receiving immunosuppressive treatment with the mTOR inhibitor sirolimus [21–23]. Additional reports of mTOR inhibitor‐associated pneumonitis were also observed in clinical studies of new‐generation mTOR inhibitors, such as everolimus [18, 24] and temsirolimus [25, 26], in patients with cancer, including those with breast cancer, renal cell carcinoma (RCC), neuroendocrine tumors (NETs), and endometrial carcinoma. Based on these findings, noninfectious pneumonitis is now considered a class effect of mTOR inhibitors.

The exact pathogenic mechanism of mTOR inhibitor‐associated pneumonitis is unclear. One possible mechanism may involve direct damage to alveolar structures because of the immunogenicity of mTOR inhibitors, such as sirolimus, which can lead to T‐cell‐mediated autoimmune responses or delayed‐type hypersensitivity reactions [21, 23]. Sirolimus becomes immunogenic when the drug binds plasma proteins to form a sirolimus‐protein antigen complex that is processed by antigen‐presenting cells in the lungs and recognized by T cells; this results in cytokine release and the recruitment and activation of macrophages and other inflammatory cells [21, 27]. Autoimmune responses may also cause alveolitis, an initial abnormality in the development of interstitial fibrosis that is characterized by the accumulation of macrophages, neutrophils, and lymphocytes within the lower respiratory tract, a process that may damage the alveolar structures [27].

One possible mechanism may involve direct damage to alveolar structures because of the immunogenicity of mTOR inhibitors, such as sirolimus, which can lead to T‐cell‐mediated autoimmune responses or delayed‐type hypersensitivity reactions.

A second potential mechanism of mTOR inhibitor‐associated pneumonitis may involve damage to the lung as a result of enhanced cell apoptosis. In a murine model of pneumonia, Fielhaber et al. demonstrated that mTOR inhibition by rapamycin augments lipopolysaccharide‐induced lung injury and cell apoptosis through a mechanism that involves the proapoptotic transcription factor STAT1 and the amplification of STAT1‐dependent apoptosis genes [28].

Finally, a third potential mechanism of mTOR inhibitor‐associated pneumonitis may involve the induction of proinflammatory mechanisms by mTOR inhibitor therapy. A recent study by Washino et al. demonstrated the ability of temsirolimus to induce alveolar epithelial injury and the depletion of alveolar macrophages followed by surfactant lipid accumulation in a murine model of mTOR inhibitor‐induced interstitial lung disease, resulting in pulmonary inflammation [29]. mTOR inhibitors such as sirolimus may also affect proinflammatory cytokine signaling and have been shown to destabilize the balance of inflammatory cytokines (interleukin [IL]‐6, IL‐10, tumor necrosis factor [TNF]‐α, and soluble TNF receptors), causing an inflammatory response in patients who have received organ transplant [30]. Furthermore, mTOR inhibition with rapamycin was associated with dysregulation of the innate immune system via activation of the nuclear factor‐kB pathway, resulting in an overproduction of proinflammatory cytokines [31]. In summary, the exact pathophysiological mechanism underlying mTOR inhibitor‐associated pneumonitis remains unclear; however, a large amount of evidence does support the concept that an autoimmune reaction is responsible in the initial phases of development.

Clinical Characteristics

The most comprehensive clinical data describing mTOR inhibitor‐associated pneumonitis were derived from the use of mTOR inhibitors in patients with advanced RCC [32]. The condition is characterized by the presence of nonmalignant, inflammatory infiltrations of the lungs, identified on computed tomography (CT) chest scans (Fig. 1) [33]. At onset, patients with mTOR inhibitor‐associated pneumonitis usually present with cough or dyspnea, especially on exertion, or hypoxemia [34, 35]. Patients may also exhibit occasional systemic symptoms, such as fever and fatigue, making the distinction from infectious causes more difficult [33, 34]. mTOR inhibitor‐associated pneumonitis may also remain asymptomatic in some patients [33, 34]. Pulmonary function tests have revealed that mTOR inhibitor‐associated pneumonitis may be associated with a restrictive pattern or an isolated reduction in diffusing capacity [33, 35].

Figure 1.

mTOR inhibitor‐associated pneumonitis in a computed tomography scan of a 59‐year‐old female patient treated for 1 year with everolimus 10 mg and exemestane tablets 25 mg who presented with the primary complaint of cough with dyspnea on exertion.

The general radiographic changes observed with mTOR inhibitor‐associated pneumonitis include ground‐glass and reticular opacities that predominantly involve the lower lobes of the lungs [32, 35–37]. On occasion, patchy areas of focal parenchymal consolidations and pleural effusions are seen [33, 35]. mTOR inhibitor‐associated pneumonitis most commonly presents as either cryptogenic organizing pneumonia (COP) or nonspecific interstitial pneumonia (NSIP) [38, 39]. COP is characterized by patchy and often migratory consolidation in a subpleural, peribronchial, or bandlike pattern, with ground‐glass opacities a common presentation [40]. Histologic features include inflammatory changes in the alveolar space that can involve the bronchioles. NSIP is characterized by a radiologic pattern of ground‐glass opacification, which is often associated with fibrosis and a reticular pattern with or without bronchiectasis [41]. NSIP presents histologically, with varying degrees of fibrosis and interstitial inflammation [40]. Overlapping features of COP and NSIP have also be observed in patients with mTOR inhibitor‐associated pneumonitis [38].

Incidence of  mTOR Inhibitor‐Associated Pneumonitis in Breast Cancer

Data from clinical trials of everolimus‐treated patients with breast cancer reported variable incidence rates of all‐grade mTOR inhibitor‐associated pneumonitis (0%–42%), with relatively low incidence rates of grade 3 or 4 mTOR inhibitor‐associated pneumonitis (0%–9%) across these studies (Table 1) [4, 17, 18, 20, 42–44]. In the pivotal phase III BOLERO‐2 trial, mTOR inhibitor‐associated pneumonitis was reported in approximately 12% of patients in the everolimus 10 mg per day plus exemestane treatment arm; 3% of all patients had grade 3 and none had grade 4 events [4]. In general, most mTOR inhibitor‐associated pneumonitis events resolved after treatment suspension, dose reduction, or corticosteroid treatment [4, 17, 18, 20, 42–43].

Table 1.

Incidence of mTOR inhibitor‐associated pneumonitis in patients with breast cancer

Study	Treatment	Treatment duration, drug exposure, or follow‐up	Noninfectious pneumonitis
			All grades, %	Grade ≥3, %
BOLERO‐2 phase III randomized trial [4, 20]	Everolimus 10 mg daily + exemestane (n = 482)	Median exposure, 14.6 weeks	12	3
	Placebo + exemestane (n = 238)	Median exposure, 12 weeks	0	0
	Everolimus 10 mg daily + exemestane (n = 482)	18 months of follow‐up	20	4.2
	Placebo + exemestane (n = 238)	18 months of follow‐up	0	≤1
Phase II randomized trial [42]	Neoadjuvant everolimus 10 mg daily + letrozole (n = 137)	Treatment duration, 4 months	2.9	2.2
	Placebo + letrozole (n = 132)	Treatment duration, 4 months	0	0
TAMRAD phase II randomized trial [17]	Everolimus 10 mg daily + tamoxifen (n = 54)	Median treatment duration, 6.2 months (range 0.7–31)	17	2
	Tamoxifen alone (n = 57)	Median treatment duration, 4.8 months (range 0.7–27)	4	4
Phase II randomized trial [18]	Everolimus 10 mg daily (n = 33)	Treatment duration, 18 months	42	9
	Everolimus 70 mg weekly (n = 16)	Treatment duration, 18 months	19	0
Phase I trial (all arms with trastuzumab and paclitaxel) [43]	Everolimus 5 mg daily (n = 6)	Median treatment duration, 28 weeks	0	0
	Everolimus 10 mg daily (n = 17)	Median treatment duration, 28 weeks	6	6
	Everolimus 30 mg weekly (n = 10)	Median treatment duration, 33 weeks	0	0
Phase I trial (all arms with carboplatin weekly; n = 15) [44]	Everolimus 2.5 mg daily	Median treatment duration, 26 weeks	0	0
	Everolimus 5 mg daily	Median treatment duration, 6 weeks	0	0
	Everolimus 7.5 mg daily	Median treatment duration, 22 weeks	0	0
	Everolimus 10 mg daily	Median treatment duration, 11 weeks	0	0
HORIZON Phase III randomized trial [59]	Temsirolimus 30 mg daily + letrozole (n = 550)	Median follow‐up, 9.5 months (range, 0–27.2 months)	<0.5	NR
	Placebo + letrozole (n = 553)	Median follow‐up, 9.5 months (range, 0–27.2 months)	0	NR

Abbreviation: NR, not reported.

The findings of previous studies also indicate that prolonged exposure and frequency of drug administration may influence the risk for mTOR inhibitor‐associated pneumonitis occurrence [18, 20, 43]. In a phase III randomized trial conducted by Rugo et al., prolonged exposure to everolimus increased the risk of mTOR inhibitor‐associated pneumonitis (grade ≥2), with cumulative risks increasing from 5% (approximately 25% of all events) within the first 12 weeks of treatment to 10% at 24 weeks and 16% at 48 weeks [20]. A phase II randomized trial by Ellard et al. demonstrated that the frequency of everolimus administration had an influence on the risk of mTOR inhibitor‐associated pneumonitis [18]. The median time to onset of mTOR inhibitor‐associated pneumonitis was shorter in patients receiving daily everolimus (51 days) versus weekly everolimus (104 days) and correlated with higher incidence rates of pneumonitis (42% vs. 19%; Table 1); the overall median duration of grade ≥2 mTOR inhibitor‐associated pneumonitis was 1.9 months (range, 0.59–4.99 months) [18].

In the BOLERO‐2 trial, 80% of patients with grade 3 mTOR inhibitor‐associated pneumonitis experienced resolution to grade ≤1 after a median duration of 3.8 weeks, typically following dose interruption or reduction [20]. After a median duration of 5.4 weeks, complete resolution of grade ≥3 mTOR inhibitor‐associated pneumonitis was observed in 75% of patients [20]. Similarly, a phase II randomized trial of neoadjuvant everolimus plus letrozole reported complete resolution of symptoms in all three patients with mTOR inhibitor‐associated pneumonitis within 15 days of everolimus discontinuation [42].

A recent meta‐analysis of 3,693 HR‐positive, HER2‐negative patients with breast cancer from six randomized controlled trials evaluated the efficacy and safety of everolimus plus exemestane [45]. The incidence of mTOR inhibitor‐associated pneumonitis, including interstitial lung disease, ranged from 0% to 23% of patients included in the analysis [45]. Furthermore, the relative risk (RR) of developing any‐grade mTOR inhibitor‐associated pneumonitis was 47.36 (95% confidence interval [CI], 17.74–126.39; p < .00001) for everolimus plus exemestane versus placebo plus exemestane, whereas the risk of developing grade 3 or 4 mTOR inhibitor‐associated pneumonitis was 13.34 (95% CI, 3.79–46.91; p < .0001) [45].

Lessons from Clinical Trials in Other Cancers

Everolimus was first approved for the treatment of adults with advanced RCC [14]. As a result, the initial clinical data on mTOR inhibitor‐associated pneumonitis come from clinical studies in patients with advanced RCC and can be compared with data from patients with breast cancer.

The findings of a small, investigator‐initiated, phase II trial reported all‐grade mTOR inhibitor‐associated pneumonitis in 49% of patients; 18% of all patients had grade 3 events [24]. Lower incidence rates of clinically diagnosed mTOR inhibitor‐associated pneumonitis were reported in the pivotal, phase III, randomized RECORD‐1 trial (all‐grade, 13.5%; grade 3, 4%) with a median time‐to‐diagnosis of 108 days (range, 24–257 days); however, 39% of patients who did not have a diagnosis of pneumonitis had radiologic evidence of pneumonitis [33, 46]. Similarly, 30% of patients had mTOR inhibitor‐associated pneumonitis in a retrospective review of clinical data and serial CT chest scans from patients treated with either temsirolimus (n = 21) or everolimus (n = 25) [35]. This study established that radiologic mTOR inhibitor‐associated pneumonitis occurred earlier during treatment than clinical pneumonitis, with a median time to onset of 56 days (range, 31–214 days) versus a mean of 66 days (range, 18–119 days) after treatment initiation of everolimus [35].

Everolimus has also received approval for the treatment of progressive NETs of pancreatic origin and for the treatment of progressive, well‐differentiated, nonfunctional NETs of gastrointestinal or lung origin that are unresectable, locally advanced, or metastatic [14]. In the phase III RADIANT‐2 trial, the incidence of mTOR inhibitor‐associated pneumonitis was 8% in patients with advanced NETs treated with everolimus plus octreotide long‐acting repeatable [47]. A similar incidence was observed in the phase III RADIANT‐3 trial, in which 12% of patients with advanced pancreatic NETs developed mTOR inhibitor‐associated pneumonitis (grade 3–4, 2%) [48]. A slightly higher incidence of 21% was observed in a retrospective study specifically investigating the incidence of mTOR inhibitor‐associated pneumonitis in patients with advanced NETs receiving everolimus [39]. A similar result was observed in a real‐world study of everolimus‐treated patients with advanced progressive NETs, in which all‐grade mTOR inhibitor‐associated pneumonitis was identified in 19% of patients (grade 3–4, 8%) [49]. The lower incidence of mTOR inhibitor‐associated pneumonitis observed in patients with NETs compared with patients with RCC may indicate that patients with different cancer types have different susceptibilities to the development of the condition [39].

A meta‐analysis of 2,233 patients (breast cancer, n = 989; NETs, n = 833; metastatic RCC, n = 411) from five clinical trials was conducted to evaluate the incidence and risk of mTOR inhibitor‐associated pneumonitis (10 mg daily); all‐grade mTOR inhibitor‐associated pneumonitis was seen in 10.4% of patients (compared with none in the control arm) and grade 3 or 4 mTOR inhibitor‐associated pneumonitis was reported in 2.4% (compared with none in the control arm) [50]. The RR of developing any‐grade mTOR inhibitor‐associated pneumonitis was 31.1 (95% CI, 8.9–109.6; p < .001) for everolimus versus control treatment, whereas the risk of developing moderate to severe mTOR inhibitor‐associated pneumonitis was 8.8 (95% CI, 2.4–32.2; p < .001) [50].

Interestingly, the retrospective review by Dabydeen et al. reported a correlation between the incidence of mTOR inhibitor‐associated pneumonitis and beneficial clinical outcomes in patients with RCC [35]. Although no such correlation has so far been reported in breast cancer studies, the results from the study by Ellard et al. indicated that the lower incidence of mTOR inhibitor‐associated pneumonitis seen in patients receiving everolimus on a weekly basis was associated with the lack of efficacy, compared with patients treated with everolimus daily (3% vs. 14%) [18]. As a result, the development of mTOR inhibitor‐associated pneumonitis may serve as a potential early marker of antitumor activity during treatment with mTOR inhibitors. However, this hypothesis is as yet unproven, as mTOR inhibitor‐associated pneumonitis typically occurs at the beginning of treatment. It is also possible that the data suggesting mTOR inhibitor‐associated pneumonitis as a marker of antitumor activity may result from biases associated with the clinical studies. For example, responding patients may receive mTOR inhibitor treatment for a longer duration and thus receive higher cumulative doses, resulting in the development of toxicities (such as pneumonitis), whereas nonresponding patients may discontinue therapy at an earlier stage, before toxicities have time to develop. Further clinical trials specifically designed to evaluate mTOR inhibitor‐associated pneumonitis as a marker of antitumor activity will be required to confirm these preliminary data.

Management

Detection

Given that the etiology of drug‐induced pneumonitis is largely unknown and that affected patients are often symptomatic or present with mild symptoms, mTOR inhibitor‐associated pneumonitis is often misdiagnosed or undetected. Table 2 summarizes the diagnostic steps that should be undertaken for an accurate diagnosis of mTOR inhibitor‐associated pneumonitis to be obtained [51].

Table 2.

Steps in the diagnosis of mammalian target of rapamycin (mTOR) inhibitor‐associated pneumonitis

Diagnostic steps	Comments	Differential diagnosis
Pulmonary function tests	Lung volume   Single breath transfer factora   Arterial oxygen saturation	May be used at screening or baseline and follow‐up examinations to exclude other respiratory disorders
Chest radiography and/or high‐resolution CT scan	Common patterns: Ground‐glass opacities Reticular opacities Focal consolidation   Distinct CT scan patterns: Cryptogenic organizing pneumonia: multifocal areas of airspace consolidation Nonspecific interstitial pneumonia: ground‐glass attenuation and reticular opacity Acute interstitial pneumonia: extensive bilateral ground‐glass attenuation or airspace consolidation with traction bronchiectasis	Used to exclude significant tumor progression or pleural effusionb
Histological tests	BALc   Sputum cultures	Used to exclude infection and assess lung inflammation profile
Other diagnostic tests	Tests to identify opportunistic infectionsd	Used to exclude bacterial pneumonia, viral pneumonia, other bacterial infections, and invasive fungal infections
	Tests to identify other causes of interstitial lung disease	Used to exclude disease progression (i.e., lung metastases), onset of acute pulmonary edema, and drug‐induced hypersensitivity
	Titration of infection biomarkers (e.g., procalcitonin, white blood cell count)	Used to exclude infectious causes of pneumonitis in cases of unexplained fever

^aAlso known as diffusing capacity of the lung for carbon monoxide, or DLCO.

^bA negative chest x‐ray does not rule out a diagnosis of mTOR inhibitor‐associated pneumonitis and should be followed by a chest CT scan, particularly in patients with dyspnea.

^cParticularly useful in patients with radiological signs of everolimus‐related mTOR inhibitor‐associated pneumonitis, fever, and/or suspected infection.

^dThe immunosuppressive properties of mTOR inhibitors such as everolimus may increase the risk of opportunistic infections and reactivation of previous infections.

Abbreviations: BAL, bronchoalveolar lavage; CT, computed tomography.

Source: Adapted from Duran et al., 2014 [51, 56].

To facilitate the identification of mTOR inhibitor‐associated pneumonitis, a CT chest scan and pulmonary function tests should be performed prior to the initiation of everolimus therapy, particularly in patients with respiratory symptoms at initiation or documented lung metastases [52–54]. A diagnosis of mTOR inhibitor‐associated pneumonitis should be considered in patients presenting with nonspecific respiratory signs or symptoms at follow‐up, including cough, dyspnea, and pleural effusion [51]. The initial diagnostic workup should include chest radiography or CT scans to exclude differential diagnoses, such as tumor progression [51]. In general, the three main radiological patterns of mTOR inhibitor‐associated pneumonitis that have been identified are ground‐glass opacities, reticular opacities, and focal consolidation. More specifically, glass opacities comprising a combination of ground‐glass and reticular opacities, ground‐glass opacities with or without diffuse interstitial disease, and lung parenchymal consolidation are the most common patterns of mTOR inhibitor‐associated pneumonitis that have been observed [21, 35, 55]. Importantly, a negative chest x‐ray does not rule out a diagnosis of mTOR inhibitor‐associated pneumonitis and should be followed by serial CT chest scans. For example, a radiological review of serial CT scans during study treatment in the RECORD‐1 trial identified new radiographic findings in a higher percentage of patients treated with everolimus (vs. placebo) who had no clinical evidence of pneumonitis [33]. Several distinct CT patterns have been reported in mTOR inhibitor‐associated pneumonitis (Table 2): multifocal areas of airspace consolidation are characteristic of COP, ground‐glass attenuation and reticular opacity are characteristic of NSIP, and extensive bilateral ground‐glass attenuation or airspace consolidation with traction bronchiectasis is characteristic of acute interstitial pneumonia [40, 51].

Additional diagnostic tests, such as the histological evaluation of lung biopsies, can also be used to establish a diagnosis of mTOR inhibitor‐associated pneumonitis or to exclude other diagnoses, such as sarcoidosis, neoplasm, or infection [56]. A biopsy also allows for confirmation of the clinicopathologic subtype, which aids the clinician in making informed treatment decisions [56]. However, several issues with lung biopsies need to be considered [56]. Most notably, a single biopsy specimen may not be representative of the pathological process occurring in other areas of the lung. Yet, multiple biopsy samples may exhibit different pathologic characteristics, which can make confirmation of the diagnosis difficult. Recently, transbronchial cryo‐biopsy has been introduced as an additional tool in the workup of patients with diffuse lung diseases. With the cryoprobe, biopsies are obtained without risking crush effect compared with traditional transbronchial biopsy using forceps, with the main complications being bleeding and pneumothorax. [57] Technical difficulties can also arise in retrieving a surgical specimen; deflation of the tissue because of clamping is an issue that can complicate histological analysis. Rarely, unexpected changes in clinical course can also occur, thus requiring that a clinicopathologic diagnosis be revised. Bronchoscopy with bronchoalveolar lavage is also routinely used to assess the lung inflammation profile in suspected interstitial pneumonitis, although the technique is not required for a diagnosis [56]. It is important to note that mTOR inhibitor‐associated pneumonitis represents a spectrum of similar clinicopathologic syndromes that can be histologically characterized by the presence of organizing pneumonia, bronchiolitis obliterans, interstitial pneumonitis, focal fibrosis, or alveolar hemorrhage [21]. Indeed, organizing pneumonia and bronchiolitis obliterans have been previously described in patients with mTOR inhibitor‐associated pneumonitis [21]. Finally, because of the immunosuppressive properties of everolimus, patients may be at risk for opportunistic infections or reactivation of previous infections [52]. As a result, it is important that an infectious cause of pneumonitis be excluded in patients with unexplained fever, which may be achieved through the titration of infection biomarkers (e.g., procalcitonin, white blood cell count) [51].

Treatment

Prior to the initiation of treatment with everolimus, it is crucial to obtain patients’ complete medical history, with an emphasis on pulmonary conditions. In patients with respiratory symptoms (e.g., cough, dyspnea during exertion or at rest) or documented multiple lung metastases, a baseline CT chest scan and pulmonary function tests should be performed before starting treatment [52, 54]. Patients with an abnormal predicted single‐breath transfer factor of <40% should not initiate everolimus therapy until pulmonary function test results have normalized [52]. In addition, a pulmonary function test should be considered prior to treatment initiation if patients have a documented preexisting lung condition [51]. Finally, caution and strict follow‐up are recommended in patients with preexisting diffuse interstitial lung disease [51].

It is critical that mTOR inhibitor‐associated pneumonitis be recognized early and appropriately managed with minimal disruption to the treatment, thus maximizing everolimus treatment exposure and clinical benefit. Although no specific management guidelines exist for diagnosed mTOR inhibitor‐associated pneumonitis, several publications have proposed the key steps necessary for mTOR inhibitor‐associated pneumonitis management in clinical trial settings (Table 3) [51, 52, 58]. Effective management of mTOR inhibitor‐associated pneumonitis involves observation and appropriate clinical monitoring, everolimus dose reductions or interruptions, the administration of corticosteroid therapy, or everolimus treatment discontinuation. Everolimus dose adjustments and management recommendations are guided by symptom severity graded according to the Common Terminology Criteria for Adverse Events, version 4.0 (Table 4), which classifies mTOR inhibitor‐associated pneumonitis severity as follows: grade 1 (asymptomatic, radiographic evidence only), grade 2 (symptomatic but not interfering with activities of daily living [ADL]), grade 3 (severe symptoms interfering with self‐care ADL; oxygen requirement), and grade 4 (life‐threatening) [14, 51–54, 58]. Patients with grade 1 mTOR inhibitor‐associated pneumonitis may continue everolimus without dose adjustment, but close observation and appropriate monitoring should be initiated and continued until resolution is confirmed. For grade 2 mTOR inhibitor‐associated pneumonitis, no everolimus dose adjustment is required in patients with mild or moderate symptoms that do not interfere with ADL (grade 2a), but a dose reduction (5 mg daily and then to 5 mg every other day, if needed) or interruption should be considered for patients with severe symptoms that do not interfere with ADL (grade 2b); dose reescalation or restarting everolimus at a reduced dose (approximately 50% lower than the previous dose) may be considered if symptoms resolve to grade ≤1. For grade 3 mTOR inhibitor‐associated pneumonitis, everolimus dose should be interrupted and may be restarted at a lower dose if symptoms resolve to grade ≤1; however, the permanent discontinuation of everolimus should be considered if mTOR inhibitor‐associated pneumonitis recurs at grade 3. Finally, patients with grade 4 mTOR inhibitor‐associated pneumonitis should permanently discontinue everolimus therapy.

Table 3.

Management of mTOR inhibitor‐associated pneumonitis [14, 51, 54, 57]: Pretreatment assessment

Pretreatment assessment (i.e., prior to initiating everolimus therapy)
Obtain history of pulmonary conditions
Obtain recent chest radiographic findings and perform baseline chest HRCT scans
Educate patients and HCPs about the possibility of mTOR inhibitor–associated pneumonitis
Consider PFTs if there is a preexisting lung condition
Caution and strict follow‐up recommended if there is preexisting diffuse interstitial lung disease

Table 4.

Management of mTOR inhibitor‐associated pneumonitis [14, 51, 54, 57]: Grading of symptom severity^a

Grade	Description	Monitoring	Active Intervention
Grade 1	Asymptomatic or incidental abnormal radiographic findings	Initiate appropriate clinical monitoring	Continue full everolimus dose
Grade 2	Symptomatic: symptoms not interfering with ADL
Grade 2a	Slight to moderate cough or shortness of breath	Chest CT scans   Clinical monitoring   Repeat CT scans in 4–8 weeks	Consider everolimus dose reduction if symptoms are worsening
Grade 2b	Severe cough or dyspnea	Chest CT scan   Repeat CT scans in 2–4 weeks   Consider BAL, PFTs	Everolimus dose reduction by 1 levelb or dose interruption if symptoms are clinically significant   Consider corticosteroids if symptoms not improving and infection ruled out   Consider everolimus reescalation if symptoms resolve to grade ≤1
Grade 3	Symptomatic: Severe cough and dyspnea interfering with ADL	Chest CT scan   Consider hospitalization, PFTs, bronchoscopy with BAL, and/or biopsy	Everolimus dose interruption   Consider corticosteroids if infection ruled out   Restart everolimus at lower dosec if symptoms resolve to grade ≤1   Consider antibiotic therapy
Grade 4	Symptomatic: Life‐threatening	Hospitalization   Bronchoscopy with BAL and/or biopsy, PFTs   Chest CT scan	Permanently discontinue everolimus   Consider corticosteroids if infection ruled out   Consider antibiotic therapy

^aAccording to the Common Terminology Criteria for Adverse Events, version 4.0.

^bEverolimus dose can be reduced to 5 mg daily, followed by 5 mg every other day, if needed.

^cApproximately 50% lower than the previous everolimus dose.

Abbreviations: ADL, activities of daily living; BAL, bronchoalveolar lavage; CT, computed tomography; HCP, health care professional; HRCT, high‐resolution CT; PFTs, pulmonary function tests.

Effective management of mTOR inhibitor‐associated pneumonitis involves observation and appropriate clinical monitoring, everolimus dose reductions or interruptions, the administration of corticosteroid therapy, or everolimus treatment discontinuation.

If an infectious cause for pneumonitis has been ruled out, the daily use of corticosteroids, such as oral prednisone (0.75–1.0 mg/kg) or, in severe cases, intravenous methylprednisolone, can be administered to patients with grade ≥2 mTOR inhibitor‐associated pneumonitis and continued until symptoms improve to grade ≤1 [34]. Furthermore, the coadministration of broad‐spectrum antibiotic may also be considered for grade 3 or 4 mTOR inhibitor‐associated pneumonitis because of the potential for everolimus‐induced immunosuppression or for impending respiratory distress [54, 58].

Multidisciplinary Approach to the Management of mTOR Inhibitor‐Associated Pneumonitis

The efficient diagnosis and management of mTOR inhibitor‐associated pneumonitis will require a multidisciplinary approach involving the collaborative efforts of nurses, oncologists, radiologists, infectious diseases specialists, pulmonologists, and pathologists. A patient treated with everolimus should be carefully screened for potential risk factors associated with everolimus, educated on the signs and symptoms of mTOR inhibitor‐associated pneumonitis before starting everolimus therapy, and be advised to promptly report newly developed or worsening respiratory symptoms to his or her health care professional (HCP) [52–54]. Furthermore, it is very important that all HCPs involved in managing patients who are receiving everolimus therapy be provided with comprehensive education on the recognition and appropriate management of mTOR inhibitor‐associated pneumonitis [51]. Taking this into account, a number of key messages have been emphasized in educational strategies for HCPs (Fig. 2), including the frequency and clinical impact of mTOR inhibitor‐associated pneumonitis, the importance of an appropriate diagnostic workup, interventional strategies for mTOR inhibitor‐associated pneumonitis, the importance of a multidisciplinary management approach, consideration of patient quality of life (QOL), and the importance of close monitoring and dose adjustments during long‐term everolimus therapy [51].

Figure 2.

Key messages emphasized in educational strategies for health care professionals managing patients receiving everolimus therapy.

Abbreviations: COPD, chronic obstructive pulmonary disease; HCP, health care professional; QOL, quality of life. Adapted from Duran et al., 2014 [51].

Unmet Needs and New Research Frontiers for Noninfectious Pneumonitis

To date, recommendations on the management of mTOR inhibitor‐associated pneumonitis are not always in agreement or do not comprehensively cover all management aspects. This article highlights the need for establishing detailed and consistent guidelines for the diagnosis and management of mTOR inhibitor‐associated pneumonitis in patients with breast cancer.

There is also an unmet need to identify patient populations that are at higher risk of developing mTOR inhibitor‐associated pneumonitis during everolimus treatment. For example, a history of lung disease or prior chest radiation is likely to increase the risk of mTOR inhibitor‐associated pneumonitis [18]. It has also been suggested that everolimus therapy should be considered with great caution in patients with existing interstitial lung disease, significant pulmonary fibrosis, or severe chronic obstructive pulmonary disease [51, 52]. Additional studies investigating the underlying biological mechanisms of mTOR inhibitor‐associated pneumonitis will also be of great value and may address some outstanding questions. Is the underlying mechanism of mTOR inhibitor‐associated pneumonitis the same for different patient populations? What drives mTOR inhibitor‐associated pneumonitis severity? A better understanding of the molecular basis of this toxicity appears to be a critical aspect of future research in this area and may lead to the identification of genetic markers and other biomarkers of mTOR inhibitor‐associated pneumonitis occurrence; this may have predictive value and further aid in distinguishing at‐risk populations.

Conclusion

Breast cancer remains a significant cause of morbidity and mortality in women. Although a number of endocrine therapies are available for the treatment of HR‐positive advanced breast cancer, most patients eventually become resistant to these therapies. Everolimus is an mTOR inhibitor that has demonstrated anticancer activity and clinical benefit when used in combination with exemestane in postmenopausal patients with HR‐positive, HER2‐negative, advanced breast cancer who are resistant to endocrine therapy. To positively weigh the clinical benefit of everolimus against the occurrence of treatment‐related AEs, such as mTOR inhibitor‐associated pneumonitis, careful evaluation of a patient's medical history prior to treatment initiation, prompt and accurate diagnosis, and appropriate management are critical. Implementation of effective management strategies for mTOR inhibitor‐associated pneumonitis may also result in improved treatment adherence, preservation of patient QOL, and the achievement of maximal overall treatment outcomes. To successfully implement mTOR inhibitor‐associated pneumonitis management strategies, optimized health care services should be based on the multidisciplinary collaboration of oncologists (medical and surgical), radiologists, pathologists, pulmonary specialists, and nurses. Given that respiratory side effects, such as mTOR inhibitor‐associated pneumonitis, can be potentially life‐threatening, it is important to integrate the awareness of these toxicities into risk‐benefit decision‐making prior to starting everolimus therapy. Therefore, detailed guidelines for the diagnosis and management of mTOR inhibitor‐associated pneumonitis must be established to ensure safe, uninterrupted treatment and achievement of optimal treatment outcomes for patients with advanced breast cancer.

Acknowledgments

Editorial support in the preparation of this manuscript was provided by Matthew Grzywacz, Ph.D. (ApotheCom, Yardley, PA). This support was funded by Novartis Pharmaceuticals Corporation.

Author Contributions

Conception/design: Ricardo H. Alvarez

Manuscript writing: Ricardo H. Alvarez, Rabih I. Bechara, Michael J. Naughton, Javier A. Adachi, James M. Reuben

Final approval of manuscript: Ricardo H. Alvarez, Rabih I. Bechara, Michael J. Naughton, Javier A. Adachi, James M. Reuben

Disclosures

Ricardo H. Alvarez: Novartis (C/A), Esai (H); Rabih I. Bechara: Olympus, Covidien/Medtronic (C/A); Michael J. Naughton: Amgen, Celgene, Genentech, Novartis, Pfizer (H); Javier A. Adachi: Novartis (C/A); James M. Reuben: Hitachi Chemical Co., ANGLE plc (C/A); Novartis, Roche (H).

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

Author notes

Disclosures of potential conflicts of interest may be found at the end of this article.