Prospective Study of Drug-induced Interstitial Lung Disease in Advanced Breast Cancer Patients Receiving Everolimus Plus Exemestane

Abstract

Background Everolimus-related interstitial lung disease (ILD) (also: pneumonitis) poses a difficulty for physicians, as it is hard to discriminate ILD from other causes of respiratory symptoms and to decide on safe treatment continuation. Objective We investigated the capability of pulmonary function tests (PFT), plasma biomarkers, everolimus pharmacokinetics, and FDG-PET to discriminate between everolimus-related ILD and other causes of respiratory problems and to predict the severity of ILD. Patients and methods Women starting treatment with everolimus plus exemestane for advanced breast cancer were included. At baseline and during the first 3 months, respiratory symptoms, PFT with diffusion capacity of the lungs for carbon monoxide corrected for hemoglobin (DLCOc) and forced vital capacity, serum plasma biomarkers (including SP-D and YKL-40), everolimus trough concentration, and 18 F-FDG-PET were prospectively recorded. Results Twenty-seven (out of 29 included) patients were evaluable for analysis. Fifteen patients (56%) developed everolimusrelated respiratory signs or symptoms and four patients (15%) needed everolimus discontinuation and received corticosteroids. Change in DLCOc differentiated ILD from alternative diagnoses with 0.91 sensitivity and 0.78 specificity. Decrease in DLCOc (non-significant) was greatest in patients who needed everolimus discontinuation. Serum SP-D and YKL-40 could differentiate ILD from alternative diagnoses with 0.83 and 0.83 sensitivity, and 0.85 and 0.62 specificity, respectively. 18 F-FDG-PET abnormalities did not precede clinical symptoms. No relationship between ILD and everolimus trough concentration was found. Conclusions This study shows that everolimus-related ILD occurs frequently. Prospective monitoring of DLCOc in combination with measurement of serum SP-D and YKL-40 appear useful to discriminate ILD from other causes of respiratory symptoms. Clinicaltrials.gov identifier: NCT01978171.

Real-world pharmacokinetics and pharmacodynamics of everolimus in metastatic breast cancer

“…We also found that the average C trough at steady state did not differ between patients with and without any grade of pneumonitis. This observation is consistent with those in earlier studies demonstrating no correlation between everolimus C trough and the occurrence of pneumonitis [30,31]. Therefore, monitoring of blood everolimus concentrations may not help identify patients at increased risk of pneumonitis.…”

“…Therefore, monitoring of blood everolimus concentrations may not help identify patients at increased risk of pneumonitis. Further development of reliable biomarkers in addition to serum KL-6 levels is necessary to improve the prediction of mTOR inhibitor-induced pneumonitis [31,32].…”

Lack of everolimus diffusion in pleural fluid during pleural progression of breast cancer: A case report

“…The main thoracic toxicity of everolimus is pneumonitis. 6 However, nonspecific pleuritis has been associated with everolimus, 7 while chylothorax has been described in a cardiac transplant treated with everolimus. 8 In the described patient, disease progression was proved by pleural puncture and pathological involvement and was accompanied by CA 15-3 increase.…”

Drug-Related Pneumonitis in Cancer Treatment during the COVID-19 Era

“…Since the mechanism of uptake of 18F-Fluorodeoxyglucose (18F-FDG) is shared by neoplastic cells and inflammatory cells, false positive results interpreted as of oncological significance are frequently caused by underlying infections instead. Therefore, during several antineoplastic treatments, drug-related pneumonitis of any form may be erroneously interpreted as progressive disease by 18F-FDG PET/CT [ 140 , 141 , 142 , 143 , 144 ]. To date, this represents a hard to solve diagnostic dilemma, at least on the basis of the conventional image qualitative analysis.…”