Florian Haller

Background In precision oncology, the accurate and reproducible classification of variant oncogenicity is fundamental for therapy decision making. In 2022, a set of guidelines for the classification of oncogenicity of somatic variants in cancer were defined by the Clinical Genome Resource, the Cancer Genomics Consortium, and the Variant Interpretation for Cancer Consortium. However, to date an implementation that automates the evaluation of these criteria does not exist. Furthermore, for the majority of the criteria, the interpretation of the criterion-associated textual indication and the choice of publicly available resources to gather criterion-supporting information depends on the user. Thus, the risk of a variant being classified differently by independent laboratories is relevant, with implications for the management of patient care. Methods Here, we developed Oncogenicity Variant Interpreter (OncoVI), a fully-automated Python-based implementation of the oncogenicity guidelines. First, each criterion was interpreted and publicly available resources were identified to be utilised as reference. Then, criteria were implemented in OncoVI and the information reported by the associated resources were integrated. OncoVI is part of a broader Python-framework that, starting from the genomic position of the variant, automatically performs functional annotation, collects the available evidence from the reference resources, and provides a classification of oncogenicity. Results On the set of 93 somatic variants provided by the guidelines OncoVI achieved an overall accuracy of 80%, with a sensitivity of 88% in the classification of Oncogenic/Likely Oncogenic variants. On a real-world data set of 7,802 variants from 557 patients previously evaluated within the Molecular Tumour Board (MTB) Erlangen, an agreement of 79% was observed between OncoVI’s oncogenicity classification and the MTB pathogenicity assessment. In addition, the pathogenicity classification of 135 variants of the MTB data set was re-assessed by expert biologists adhering solely to the oncogenicity guidelines. This re-evaluation confirmed the validity of OncoVI’s interpretation of the resources chosen as reference, but it also underlined the ability of experts in solving conflicting evidence. Conclusions Taken together, OncoVI provides an effective implementation of the oncogenicity guidelines, thus facilitating their adoption and supporting the reproducible and harmonised oncogenicity classification of somatic variants between institutions.

Molecular Tumor Boards (MTBs) converge state-of-the-art next-generation sequencing (NGS) methods with the expertise of an interdisciplinary team consisting of clinicians, pathologists, human geneticists, and molecular biologists to provide molecularly informed guidance in clinical decision making to the treating physician. In the present study, we particularly focused on elucidating the factors impacting on the clinical translation of MTB recommendations, utilizing data generated from gene panel mediated comprehensive genomic profiling (CGP) of 554 patients at the MTB of the Comprehensive Cancer Center Erlangen, Germany, during the years 2016 to 2020. A subgroup analysis of cases with available follow-up data (n = 332) revealed 139 cases with a molecularly informed MTB recommendation, which was successfully implemented in the clinic in 44 (31.7%) of these cases. Here, the molecularly matched treatment was applied in 45.4% (n = 20/44) of cases for ≥6 months and in 25% (n = 11/44) of cases for 12 months or longer (median time to treatment failure, TTF: 5 months, min: 1 month, max: 38 months, ongoing at data cut-off). In general, recommendations were preferentially implemented in the clinic when of high (i.e., tier 1) clinical evidence level. In particular, this was the case for MTB recommendations suggesting the application of PARP, PIK3CA, and IDH1/2 inhibitors. The main reason for non-compliance to the MTB recommendation was either the application of non-matched treatment modalities (n = 30)/stable disease (n = 7), or deteriorating patient condition (n = 22)/death of patient (n = 9). In summary, this study provides an insight into the factors affecting the clinical implementation of molecularly informed MTB recommendations, and careful considerations of these factors may guide future processes of clinical decision making.

(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.

Background Current risk models in solitary fibrous tumour (SFT) were developed using cohorts with short follow-up and cannot reliably identify low-risk patients. We recently developed a novel risk model (G-score) to account for both early and late recurrences. Here, we aimed to validate the G-score in a large international cohort with long-term follow-up. Methods Data were collected from nine sarcoma referral centres worldwide. Recurrence-free interval (RFi) was the primary endpoint. Results The cohort comprised 318 patients with localised extrameningeal SFTs. Disease recurrence occurred in 96 patients (33%). The estimated 5-year RFi rate was 72%, and the 10-year RFi rate was 52%. G-score precisely predicted recurrence risk with estimated 10-year RFi rate of 84% in low risk, 54% in intermediate risk and 36% in high risk (p < 0.001; C-index 0.691). The mDemicco (p < 0.001; C-index 0.749) and Salas^OS (p < 0.001; C-index 0.674) models also predicted RFi but identified low-risk patients less accurate with 10-year RFi rates of 72% and 70%, respectively. Conclusions G-score is a highly significant predictor of early and late recurrence in SFT and is superior to other models to predict patients at low risk of relapse. A less intensive follow-up schedule could be considered for patients at low recurrence risk according to G-score.

Export BACKGROUND: Pancreatic duct diameter and pancreatic texture are important predictive factors for a postoperative pancreatic fistula (POPF) and are assessed intraoperatively by the surgeon. However, surgical evaluation is arbitrary and difficult to objectify, especially in minimally invasive approaches in pancreatic surgery. STUDY DESIGN: We conducted a retrospective analysis of 275 patients that underwent pancreatoduodenectomy from 2012 to 2019 at our institution. Pancreatic duct diameter and pancreatic fibrosis were assessed by histopathologic examination of the pancreatic resection margin using intraoperative frozen sections and correlated with the occurrence of POPF and clinically relevant POPF (CR-POPF). RESULTS: The POPF and CR-POPF rates were 27% and 19%, respectively. Univariate analysis indicated that the indication for surgery, the surgically determined pancreatic duct diameter, and pancreatic texture, as well as the histopathologically determined pancreatic duct diameter and pancreatic fibrosis were significant predictive factors for POPF and CR-POPF. A multivariate analysis revealed histopathologically determined pancreatic duct diameter and pancreatic fibrosis as independent risk factors for POPF (OR [odds ratio] 2.3 [1.1 to 4.5], p = 0.022 and OR 2.4 [1.1 to 5.1], p = 0.023, respectively) and CR-POPF (OR 2.2 [1.1 to 4.8], p = 0.037 and OR 2.6 [1.1 to 6.1], p = 0.036). CONCLUSIONS: Histopathologically determined pancreatic duct diameter and pancreatic fibrosis are quantitatively measurable independent risk factors for POPF and CR-POPF. An intraoperative objective histopathologic evaluation of these parameters using frozen sections could support the surgical assessment of the pancreatic duct diameter and the pancreatic texture.

Surgical resection remains the first line treatment for salivary gland cancer (SGC). In the case of locally advanced disease, surgery is followed by adjuvant radiotherapy. Surgical resection should be favored in resectable locoregional recurrent disease as well, and even the complete resection of all distant oligometastases has clinical benefit for the patients. For inoperable and disseminated metastatic disease, a multitude of systemic therapies including chemotherapy, targeted therapy, and immunotherapy are available. In this review, the current therapeutic options for inoperable recurrent or metastatic SGCs are summarized. Systemic treatment can achieve prolonged progression-free and overall survival, while the overall prognosis remains poor. Current clinical trials include only a limited number of patients and mostly combine different histologic subtypes. Additionally, no randomized controlled trial comparing different therapeutic options has been performed. In the future, further studies with a larger patient cohort and ideally only one histologic subtype are needed in order to improve the outcome for SGC patients. However, this may be difficult to accomplish due to the rarity and diversity of the disease. Additionally, molecular analyses need to be performed routinely in order to individualize treatment and to go one step further towards precision medicine.

In non-small cell lung cancer (NSCLC), approximately 1–3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of MET is fluorescence in situ hybridization (FISH). However, next-generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable n = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of MET GCN status. Out of the 205 evaluable cases, only n = 9 cases (43.7%) of n = 16 high-level MET amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a MET GCN > 10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon-based NGS assessment of the MET GCN detects high-level MET amplified cases harboring a MET GCN > 10 but fails to detect the various facets of MET gene amplification in the context of a therapy-induced resistance mechanism.