Molecular Tumor Boards: current practice and future needs van der Velden, D.L.; van Herpen, C.M.L.; van Laarhoven, H.W.M. ...
Annals of oncology,
December 2017, 2017-Dec-01, 2017-12-00, 20171201, Volume:
28, Issue:
12
Journal Article
Peer reviewed
Open access
Due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as whole-exome and ...whole-genome sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date.
Based on literature review, a survey among hospitals in The Netherlands, and our own experience with the establishment of a nationally operating MTB, this article evaluates current knowledge and unmet needs and lays out a strategy for successful MTB implementation.
Having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, <50% of hospitals and only 5% of nonacademic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools, and workflow. This may not only lead to variation in quality of care but also hinders data sharing and thus creation of an effective learning community.
This article acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning but also improve general interpretation and application of genomics-guided cancer care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are approved as treatment of non-small-cell lung cancer (NSCLC). Despite an initially impressive ...response to EGFR-TKIs, patients with an activating EGFR mutation invariably relapse. For these patients few treatment options are available after additional progression during or after chemotherapy. The aim of this study is to examine the effect of retreatment with an EGFR-TKI after a drug holiday. Patients and methods We retrospectively reviewed the medical records of 14 patients with stage IV NSCLC who progressed after long-term disease control with EGFR-TKI, who were subsequently treated with standard chemotherapy and at renewed progression retreated with EGFR-TKI. Results Fourteen patients (five male, nine female, median age 55 years (39–70 years) received retreatment with erlotinib. The median interval from the discontinuation of EGFR-TKI to the 2nd episode was 9.5 months (3–36 months). Before starting retreatment 36% ( n = 5) had a T790M mutation. Retreatment resulted in 36% ( n = 5) partial response, 50% stable disease ( n = 7) and 14% progressive disease ( n = 2). Among patients with a T790M mutation this number was two, one and two, respectively. Seven patients are still on therapy without signs of progression. Median follow up is 9 months (1.5–16+ months) and median PFS is 6.5 months (1–16+ months). Conclusion Our findings suggest that retreatment with erlotinib is an option for patients with NSCLC who initially benefited from previous EGFR-TKI treatment and progressed after standard cytotoxic chemotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract A considerable number of patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) develop leptomeningeal metastases. Leptomeningeal metastases are ...associated with deterioration of clinical symptoms and poor survival. Traditionally, treatment of metastases in the central nervous system consists of radiotherapy and less frequently, surgery. The role of systemic therapy is limited due to the blood–brain barrier inhibiting pharmacological doses to be reached in the central nervous system. Several case reports have described high-dose, pulsatile tyrosine kinase inhibitors as an effective treatment of leptomeningeal metastases, based on the hypothesis that higher concentrations in the cerebrospinal fluid can be reached by higher systemic concentrations. Here, we describe two patients with EGFR-mutated non-small cell lung cancer, with both clinical and radiological response to this high-dose, pulsatile regimen. Interestingly, one patient showed a remarkable response of intrathoracic response as well.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•Limited antitumor activity of osimertinib in EGFR exon 20 mutated lung cancer.•Objective response rate was 5 %.•Median progression free survival was 3.6 months.•A subgroup derived durable disease ...stabilization of five months and beyond.
Epidermal growth factor receptor (EGFR) exon 20 insertions comprise 4–10 % of EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to first and second generation EGFR tyrosine kinase inhibitors (TKIs). In vitro and preclinical animal studies have shown that osimertinib exerts antitumor activity against EGFR exon 20 mutation positive NSCLC. We report on a cohort of advanced stage NSCLC patients who harbor an EGFR exon 20 mutation and received osimertinib treatment.
Twenty-one patients were treated with osimertinib 80 or 160 mg once daily from April 2016 to June 2018, in four institutions in the Netherlands. Data were obtained retrospectively. Progression free survival (PFS), disease control rate (DCR), overall survival (OS) and objective response rate (ORR) were assessed using RECIST v1.1.
Thirteen patients received prior platinum-based chemotherapy, and three patients a first – or second generation EGFR TKI. We observed 1 partial response, 17 patients with stable disease and 3 with progressive disease as best response to osimertinib (ORR 5 %). Median PFS was 3.6 (95 % CI, 2.6–4.5) months. PFS did not differ for patients with co-occurring TP53 mutations (p = 0.937). The DCR at three months was 71 %. Median OS was 8.7 (95 % CI, 1.1–16.4) months.
Osimertinib has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5 %.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated with T-DXd.
...Patients who received T-DXd across nine studies were included. Investigator-assessed ILD/pneumonitis events were retrospectively reviewed by an independent adjudication committee; events adjudicated as drug-related ILD/pneumonitis are summarized.
The analysis included 1150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%; other cancer, 3.0%). Median treatment duration was 5.8 (range, 0.7-56.3) months, with a median of 4 (range, 1-27) prior lines of therapy. The overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4% (grade 5, 2.2%). Most patients with ILD/pneumonitis experienced low-grade events (grade 1 or 2, 77.4%); 87.0% had their first event within 12 months median, 5.4 (range, <0.1-46.8) months of their first dose of T-DXd. Based on data review, adjudicated ILD/pneumonitis onset occurred earlier than identified by investigators for 53.2% of events median difference in onset date, 43 (range, 1-499) days. Stepwise Cox regression identified several baseline factors potentially associated with increased risk of adjudicated drug-related ILD/pneumonitis: age <65 years, enrollment in Japan, T-DXd dose >6.4 mg/kg, oxygen saturation <95%, moderate/severe renal impairment, presence of lung comorbidities, and time since initial diagnosis >4 years.
In this pooled analysis of heavily treated patients, the incidence of ILD/pneumonitis was 15.4%, with most being low grade and occurring in the first 12 months of treatment. The benefit–risk of T-DXd treatment is positive; however, some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors. Close monitoring and proactive management of ILD/pneumonitis are warranted for all.
•Interstitial lung disease (ILD)/pneumonitis is a significant adverse event related to trastuzumab deruxtecan (T-DXd).•This pooled analysis of nine T-DXd monotherapy studies evaluated ILD/pneumonitis risk in 1150 heavily pretreated patients.•Overall incidence of adjudicated T-DXd-related ILD/pneumonitis was 15.4% (grade 1 or 2, 77.4%; grade 5, 2.2%).•Within 12 months of their first T-DXd dose, 87.0% of patients had their first event median, 5.4 (range, <0.1-46.8) months.•Proactive monitoring and prompt diagnosis and management are important to improving ILD/pneumonitis event outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In 1–3% of non-small cell lung cancer (NSCLC) human epidermal growth factor 2 (HER2) mutations are identified as a genomic driver. Nevertheless, no HER2-targeted treatment is approved for NSCLC. In ...the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort ‘trastuzumab/pertuzumab for HER2 exon20 mutation positive (HER2m+) NSCLC’.
Patients with treatment refractory, advanced HER2m+ NSCLC with measurable disease (RECISTv1.1) were eligible. Treatment with intravenous trastuzumab combined with pertuzumab every 3 weeks was administered. The primary end-point was clinical benefit (CB: either objective response or stable disease ≥ 16 weeks). Patients were enrolled using a Simon-like 2-stage design, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 patient had CB in stage 1. At baseline, a biopsy for biomarker analysis, including whole genome sequencing, was obtained.
Twenty-four evaluable patients were enrolled and treated between May 2017 and August 2020. CB was observed in 9 patients (38%); including an objective response rate of 8.3% (2 patients had a partial response) and 7 patients with stable disease ≥ 16 weeks. The most frequently observed HER2 mutation was p.Y772_A775dup (71%, n = 20). Median follow-up was 13 months, median progression-free survival and overall survival 4 (95% CI 3–6) and 10 months (95% CI 4 – not reached), respectively. Whole genome sequencing data (available for 67% of patients) confirmed the inclusion mutation in all cases. No unexpected toxicity was observed.
Despite the fact that the study did meet its primary end-point, trastuzumab/pertuzumab was only marginally active in a subset of patients with heavily pre-treated HER2m+ NSCLC.
•In 1–3% of patients with non-small cell lung cancer human epidermal growth factor 2 mutations are identified as genomic driver.•The most frequently observed human epidermal growth factor 2 mutation is p. Y772_A775dup.•Trastuzumab/pertuzumab treatment was beneficial in 38% of the included patients.•Whole genome sequencing data revealed that patients with benefit had less potential drivers detected.•Toxicities were similar to those previously observed in pivotal trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose
Rapid diagnosis and treatment of infectious meningitis and encephalitis (ME) is critical to minimize morbidity and mortality. Recently, Qiagen introduced the CE-IVD QIAstat-Dx ME panel ...(QS-ME) for syndromic diagnostic testing of meningitis and encephalitis. Some data on the performance of the QS-ME in comparison to the BioFire FilmArray ME panel are available. In this study, the performance of the QS-ME is compared to the current diagnostic workflow in two academic medical centers in the Netherlands.
Methods
A total of 110 cerebrospinal fluid samples were retrospectively tested with the QS-ME. The results obtained were compared to the results of laboratory-developed real-time PCR assays (LDTs), IS-pro, bacterial culture, and cryptococcal antigen (CrAg) testing. In addition, the accuracy of the QS-ME was also investigated using an external quality assessment (EQA) panel consisting of ten samples.
Results
Four of the 110 samples tested failed to produce a valid QS-ME result. In the remaining 106 samples, the QS-ME detected 53/53 viral targets, 38/40 bacterial targets, and 7/13
Cryptococcus neoformans
targets. The discrepant bacterial results consisted of two samples that were previously tested positive for
Listeria monocytogenes
(C
T
35.8) and
Streptococcus pneumoniae
(C
T
40), respectively. The QS-ME detected one additional result, consisting of a varicella-zoster virus signal (C
T
35.9), in a sample in which both techniques detected
Streptococcus pyogenes
. Finally, 100% concordance was achieved in testing a blinded bacterial ME EQA panel.
Conclusion
The QS-ME is a relevant addition to the syndromic testing landscape to assist in diagnosing infectious ME.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The metabolic syndrome (MS) might increase the risk of cardiovascular disease in testicular cancer (TC) survivors. We investigated its prevalence, development, vascular implications, and the role of ...gonadal function.
TC survivors treated with chemotherapy and follow-up ≥3 years (N = 370, study I) were retrospectively evaluated for the development of cardiovascular risk factors. A subgroup followed 3–20 years (N = 173, study II) was compared with controls (N = 1085) for MS prevalence and evaluated for vascular function.
In TC survivors (study I), 24% developed overweight, 24% hypercholesterolemia, and 30% hypertension, after median follow-up of 1.7, 0.9, and 5.1 years, respectively. At the median follow-up of 5 years (study II), 25% of survivors have the MS {odds ratio (OR) 2.2, 95% confidence interval (CI) 1.5–3.3 compared with controls}. Survivors with MS have features of inflammation and prothrombotic state, increased carotid artery intima-media thickness. Survivors with testosterone levels <15 nmol/l (22%) have an increased risk of the MS (OR 4.1, 95% CI 1.8–9.3).
The current data suggest that the MS occurs at earlier age in TC survivors treated with chemotherapy compared with controls and is accompanied by early signs of atherosclerosis. As low testosterone may have a causal role, it is a target for interventions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyrosine kinase inhibitors (TKIs) and to study resistance mechanisms in afatinib-resistant tumors.
...Characteristics and survival of patients treated with afatinib after resistance to erlotinib or gefitinib in two large Dutch centers were collected. Whole exome sequencing (WES) and pathway analysis was performed on available pre- and post-afatinib tumor biopsies and normal tissue.
A total of 38 patients were treated with afatinib. T790M mutations were identified in 22/29 (76%) pre-afatinib treatment tumor samples. No difference in median progression-free-survival (2.8 months (95% CI 2.3-3.3) and 2.7 months (95% CI 0.9-4.6), p = 0.55) and median overall-survival (8.8 months (95% CI 4.2-13.4) and 3.6 months (95% CI 2.3-5.0), p = 0.14) were observed in T790M+ patients compared to T790M- mutations. Somatic mutations in TP53, ADAMTS2, CNN2 and multiple genes in the Wnt and PI3K-AKT pathway were observed in post-afatinib tumors of six afatinib-responding and in one non-responding patient. No new EGFR mutations were found in the post-afatinib samples of the six responding patients. Further analyses of post-afatinib progressive tumors revealed 28 resistant specific mutations in six genes (HLA-DRB1, AQP7, FAM198A, SEC31A, CNTLN, and ESX1) in three afatinib responding patients. No known EGFR-TKI resistant-associated copy number gains were acquired in the post-afatinib samples.
No differences in survival were observed in patients with EGFR-T790M treated with afatinib compared to those without T790M. Tumors from patients who had progressive disease during afatinib treatment were enriched for mutations in genes involved in Wnt and PI3K-AKT pathways.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • OS significantly longer in single organ metastatic disease compared to 2 or ⩾3 organs. • Single organ metastases also prognostic in subgroup of18 FDG-PET-staged patients. • Single organ ...metastases also prognostic in patients receiving anticancer treatment. • In single organ metastases, low local disease (i.e. T1–2 and N0–1) best prognosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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