Annelieke E.C.A.B. Willemsen

mTOR inhibitor-induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm

Mammalian target of rapamycin inhibitors (mTORi) have clinically significant activity against various malignancies, such as renal cell carcinoma and breast cancer, but their use can be complicated by several toxicities. Interstitial lung disease (ILD) is an adverse event of particular importance. Mostly, mTORi‐induced ILD remains asymptomatic or mildly symptomatic, but it can also lead to severe morbidity and even mortality. Therefore, careful diagnosis and management of ILD is warranted. The reported incidence of mTORi‐induced ILD varies widely because of a lack of uniform diagnostic criteria and active surveillance. Because of the nonspecific clinical features, a broad differential diagnosis that includes (opportunistic) infections should be considered in case of suspicion of mTORi‐induced ILD. The exact mechanism or interplay of mechanisms leading to the development of ILD remains to be defined. Suggested mechanisms are either a direct toxic effect or immune‐mediated mechanisms, considering mTOR inhibitors have several effects on the immune system. The clinical course of ILD varies widely and is difficult to predict. Consequently, the discrimination between when mTOR inhibitors can be continued safely and when discontinuation is indicated is challenging. In this review, we give a comprehensive review of the incidence, clinical presentation and pathophysiology of mTORi‐induced ILD in cancer patients. We present newly developed diagnostic criteria for ILD, which include clinical symptoms as well as basic pulmonary function tests and radiological abnormalities. In conjunction with these diagnostic criteria, we provide a detailed and easily applicable clinical management algorithm.

Experimental treatment of NRAS-mutated neurocutaneous melanocytosis with MEK162, a MEK-inhibitor

Neurocutaneous melanosis (NCM) is a rare congenital disorder characterized by the association of large and/or multiple congenital melanocytic nevi (CMN) of the skin with melanocytic lesions of the leptomeninges, including melanocytosis. Leptomeningeal melanocytosis carries a poor prognosis once neurological symptoms develop. Despite surgery, which is often not radical, few other treatment options exist. Recently, it was demonstrated that early embryonic, post-zygotic somatic mutations in the NRAS gene are implicated in the pathogenesis of NCM.In this report, we present a 13-year-old boy with NCM and progressive symptomatic leptomeningeal melanocytosis. A somatic NRASQ61K mutation was present in both CMN as well as the melanocytosis. Despite repeated surgery, the patient showed clinical progression. Therefore, treatment with MEK162, a MEK inhibitor, was started on compassionate use base. The patient died only five days later, i.e. too early to expect a clinical effect of MEK162 therapy. We therefore studied the effect of MEK162 at the protein level in the leptomeningeal tumor by immunohistochemical and Western Blot analyses using Ki67 and pERK antibodies. We observed lower MIB-1 expression and lower pERK expression in the post-treatment samples compared to pre-treatment, suggesting a potential effect of MEK inhibiting therapy. Further studies are needed to determine whether MEK inhibitors can effectively target NRAS-mutated symptomatic NCM, a rare but potentially fatal disease.

Effect of food and acid-reducing agents on the absorption of oral targeted therapies in solid tumors

Oral targeted therapies represent an increasingly important group of drugs within modern oncology. With the shift from intravenously to orally administered drugs, drug absorption is a newly introduced factor in drug disposition. The process of absorption can have a large effect on inter- and intrasubject variability in drug exposure and thereby potentially treatment benefit or the severity of toxicities. The intake of oral targeted therapies with food and concomitant use of acid-reducing agents (ARAs) can significantly affect drug absorption. The size and direction of the effect of food and ARAs on drug absorption varies among drugs as a result of different chemical characteristics. Therefore, an awareness and understanding of these effects for each drug is essential to optimize patient outcomes.

Caution for interstitial lung disease as a cause of CA 15-3 rise in advanced breast cancer patients treated with everolimus

Dear Sir, Carbohydrate antigen (CA) 15-3 is a tumor marker commonly used to monitor response to treatment in patients with advanced breast cancer. The American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer states: “For monitoring patients with metastatic disease during active therapy [. . .] CA 15-3 can be used in conjunction with diagnostic imaging, history, and physical examination” and “in the absence of readily measurable disease, an increasing CA 15-3 may be used to indicate treatment failure.” In this guideline, caution is advised for a spurious rise of the CA 15-3 level during the first few weeks of treatment. However, an alternative cause of a spurious rise in CA 15-3, where in the oncology setting hardly any attention has been brought upon, is interstitial lung disease (ILD). The CA 15-3 assay utilizes antibodies directed against a unique epitope of mucin-1. Mucin-1 is a high-molecularweight glycoprotein synthesized by several secretory epithelial tissues, such as glandular breast tissue. In breast tumors mucin-1 is frequently overexpressed. Furthermore, mucin-1 is excreted in pulmonary tissue by epithelial cells of the bronchioles and by bronchial serous glands. Consequently, several pulmonary diseases can lead to a rise in CA 15-3. Numerous studies indeed have demonstrated a strong positive correlation between a rise in CA 15-3 and ILD, such as idiopathic pulmonary fibrosis, different idiopathic interstitial pneumonias and ILD associated with collagen diseases. In these patients, CA 15-3 levels up to 300 U/mL were detected. Recently, based on the BOLERO-2 trial, everolimus in combination with exemestane has been approved for advanced breast cancer. In this trial, ILD occurred in 20% of patients, mostly in the first 6 months of treatment. With dedicated review of chest computed tomography (CT) images, evidence of ILD is found even more frequently, as reported in up to 54% of everolimus-treated renal cell carcinoma patients. These data indicate that the incidence of either clinically apparent or subclinical ILD will increase substantially in breast cancer patients upon treatment with everolimus. To our knowledge, the relationship between everolimus-induced ILD and a rise in CA 15-3 has not been described yet and still has to be proven. Hence, oncologists should be aware that a rise in CA 15-3 does not automatically indicate treatment failure in everolimustreated breast cancer patients, but it can also reflect the presence of drug-induced ILD. Additional investigations, such as highresolution chest CT and a pulmonary function test, then should be performed to make this distinction. With the emerging options of targeted treatments in breast cancer, this caveat should be addressed to prevent premature discontinuation of a valuable treatment regimen. Further research to prospectively evaluate the relationship between everolimus-induced ILD and a rise in CA 15-3 is urgently needed.

Nivolumab-associated Nephrotic Syndrome in a Patient With Renal Cell Carcinoma: A Case Report

Introduction: Immune checkpoint inhibitors have taken an important place in the treatment of different types of malignancies. These drugs are known to have specific immune-mediated adverse events. We describe a case of severe nephrotic syndrome secondary to treatment with nivolumab in a patient with renal cell carcinoma. Case Presentation: A 62-year-old man was treated with nivolumab for papillary renal cell carcinoma type 2 for 8 weeks when he was admitted to the hospital with a severe nephrotic syndrome and acute kidney injury. Renal biopsy showed focal segmental glomerulosclerosis. Treatment with high-dose corticosteroids had insufficient effect, but the addition of mycophenolate mofetil resulted in remission of the nephrotic syndrome and recovery of renal function. Proteinuria subsequently relapsed during corticosteroid tapering. Conclusions: The time course in this patient strongly suggests that the nephrotic syndrome occurred as an adverse drug reaction to nivolumab treatment. If during nivolumab treatment renal insufficiency, hypoalbuminemia, or proteinuria develops, further analysis for a possible nephrotic syndrome is warranted for early detection and treatment of this life-threatening complication.

Diagnostic challenges of respiratory adverse events during everolimus treatment

Everolimus has important clinical activity in various malignancies, but its use can be complicated by respiratory adverse events. Important everolimus-induced respiratory adverse events are interstitial lung disease (ILD) and infections, either typical or opportunistic. Furthermore, non-everolimus-related respiratory events can occur. Due to the non-specific presentation of most of these respiratory disorders, it is often not possible to differentiate between these causes on clinical and radiological grounds only. Considering the potential fatal nature of opportunistic infections, these are especially important to recognize. To be able to distinguish between ILD and (opportunistic) infections as the underlying cause, an aggressive diagnostic workup, including bronchoalveolar lavage, should be performed in patients treated with everolimus who develop respiratory disease. We report three cases of severe opportunistic pulmonary infections during everolimus treatment, concerning two Pneumocystis jirovecii pneumonia infections. These cases illustrate the diagnostic challenges of respiratory adverse events and the importance of a thorough diagnostic workup for correct diagnosis and treatment.

Positron emission tomography response criteria in solid tumours criteria for quantitative analysis of [18F]-fluorodeoxyglucose positron emission tomography with integrated computed tomography for treatment response assessment in metastasised solid tumours: All that glitters is not gold

For solid tumours, quantitative analysis of [(18)F]-fluorodeoxyglucose positron emission tomography with integrated computed tomography potentially can have significant value in early response assessment and thereby discrimination between responders and non-responders at an early stage of treatment. Standardised strategies for this analysis have been proposed, and the positron emission tomography response criteria in solid tumours (PERCIST) criteria can be regarded as the current standard to perform quantitative analysis in a research setting, yet is not implemented in daily practice. However, several exceptions and limitations limit the feasibility of PERCIST criteria. In this article, we point out dilemmas that arise when applying proposed criteria like PERCIST on an expansive set of patients with metastasised solid tumours. Clinicians and scientists should be aware of these limitations to prevent that methodological issues impede successful introduction of research data into clinical practice. Therefore, to deliver on the high potential of quantitative imaging, consensus should be reached on a standardised, feasible and clinically useful analysis methodology. This methodology should be applicable in the majority of patients, tumour types and treatments.

Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

PurposeEverolimus treatment is seriously hampered by its toxicity profile. As a relationship between everolimus exposure and effectiveness and toxicity has been established, early and ongoing concentration measurement can be key to individualize the dose and optimize treatment outcomes. Dried blood spot (DBS) facilitates sampling at a patients’ home and thereby eases dose individualization. The aim of this study is to determine the agreement and predictive performance of DBS compared to whole blood (WB) to measure everolimus concentrations in cancer patients.MethodsPaired DBS and WB samples were collected in 22 cancer patients treated with everolimus and analyzed using UPLC-MS/MS. Bland-Altman and Passing-Bablok analysis were used to determine method agreement. Limits of clinical relevance were set at a difference of ± 25%, as this would lead to a different dosing advice. Using DBS concentration and Passing-Bablok regression analysis, WB concentrations were predicted.ResultsSamples of 20 patients were suitable for analysis. Bland-Altman analysis showed a mean ratio of everolimus WB to DBS concentrations of 0.90, with 95% of data points within limits of clinical relevance. Passing-Bablok regression of DBS compared to WB revealed no constant bias (intercept 0.02; 95% CI 0.93–1.35) and a small proportional bias (slope 0.89; 95% CI 0.76–0.99). Predicted concentrations showed low bias and imprecision and 90% of samples had an absolute percentage prediction error of < 20%.ConclusionsDBS is a valid method to determine everolimus concentrations in cancer patients. This can especially be of value for early recognition of over- or underexposure to enable dose adaptations.