Molecular Tumor Board as a Clinical Tool for Converting Molecular Data Into Real-World Patient Care

Abstract

Purpose: The investigation of multiple molecular targets with next-generation sequencing (NGS) has entered clinical practice in oncology, yielding to a paradigm shift from the histology-centric approach to the mutational model for personalized treatment. Accordingly, most of the drugs recently approved in oncology are coupled to specific biomarkers. One potential tool for implementing the mutational model of precision oncology in daily practice is represented by the Molecular Tumor Board (MTB), a multidisciplinary team whereby molecular pathologists, biologists, bioinformaticians, geneticists, medical oncologists, and pharmacists cooperate to generate, interpret, and match molecular data with personalized treatments.

Patients and methods: Since May 2020, the institutional MTB set at Fondazione IRCCS Istituto Nazionale Tumori of Milan met weekly via teleconference to discuss molecular data and potential therapeutic options for patients with advanced/metastatic solid tumors.

Results: Up to October 2021, among 1,996 patients evaluated, we identified >10,000 variants, 43.2% of which were functionally relevant (pathogenic or likely pathogenic). On the basis of functionally relevant variants, 711 patients (35.6%) were potentially eligible to targeted therapy according to European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets tiers, and 9.4% received a personalized treatment. Overall, larger NGS panels (containing >50 genes) significantly outperformed small panels (up to 50 genes) in detecting actionable gene targets across different tumor types.

Conclusion: Our real-world data provide evidence that MTB is a valuable tool for matching NGS data with targeted treatments, eventually implementing precision oncology in clinical practice.

FIG 1.

(A) Distribution of patients included in the study cohort by primary tumor localization. (B) Prevalence of the NGS assays used in the study cohort. Most (77.4%) tests were performed in house, and the remaining (22.6%) were outsourced and profiled by FoundationOne CDx (550 cases) or OncotypeMAP (two cases). AFP-Lun, Archer FusionPlex Lung panel; AFP-Sar, Archer FusionPlex Sarcoma panel; BRCA, Oncomine BRCA Research Assay; CHP, Ion AmpliSeq Cancer Hotspot Panel v2; FOneCDX-CGP, FoundationOne CDX; LKB1 custom, custom lung LKB1 v.2 panel; OCAplusDNA, Oncomine Comprehensive Assay Plus, DNA.

FIG 2.

Oncoprint plot visualizing pathogenic genomic alterations in patients of the study cohort (in columns), including SNVs, indels, CNVs, and fusions, ranked according to their prevalence (right bars). MSI status, TMB, whenever available (upper panel), and the level of clinical actionability according to ESCAT classification (right panel) are also provided. As expected, TP53 and KRAS mutations were largely represented, with a prevalence of 47% and 27.1%, respectively. Among 566 (28.4%) patients evaluated with CGP panels (FoundationOne CDx, Oncomine Comprehensive Assay Plus, and OncotypeMap), we were able to obtain TMB and MSI status in 493 and 482 cases, respectively. High MSI was detected in 27 patients (5.6%), with the highest prevalence in patients with gastroesophageal carcinoma (10 of 64 patients, 15.6%) and in patients with CRC (11 of 75 patients, 14.7%). TMB ranged from 0 to 252 mutations/Mbp (median, 3.78). Sixty-three (12.8%) patients had a TMB >10 mutation/Mbp, including a case with a POLE mutation and a TMB of 252 mutation/Mbp. Highest percentages of TMB >10 were detected in patients with neuroendocrine carcinoma (5/19; 26.3%), CRC (16/75; 21.3%), gastroesophageal carcinoma (11/61; 18%), and breast carcinoma (5/32; 15.6%). Overall, 149 gene fusions (80) or rearrangements (69) were detected in 135 patients of 1,014 patients (13.3%) tested with Archer lung (29 cases of 296 tests; 9.8%), Archer sarcoma (8/29; 27.5%), FoundationOne CDx (103/550; 18.7%), and Oncomine Comprehensive Assay RNA Plus (9/151; 5.9%) panels, for a total amount of 1,026 tests. Of the 135 patients bearing gene fusions/rearrangements, 56 (41.4%, corresponding to 5.4% of the whole series) had actionable alterations, and targeted treatment was administered to 22 of them (24%, 2.1%), while eight patients were lost at follow-up. CGP, comprehensive genomic profiling; CNVs, copy number variations; CRC, colorectal cancer; ESCAT, European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets; MSI, microsatellite instability; SNVs, single-nucleotide variations; TMB, tumor mutational burden.

FIG 3.

(A) ESCAT classification of pathogenic variants across different tumor types. The high prevalence of targetable genes found in SCLC and carcinosarcoma (ie, malignant mixed mullerian tumors [2/4, including one ALK fusion and one p.L858R EGFR mutation; and 1/4, MSI-high, respectively]) was reasonably due to the small number of patients evaluated. (B) Venn plot describing the prevalences of gene alterations, MTB recommendation, and therapeutic interventions in the whole cohort. Pathogenic or likely pathogenic: patients harboring at least one functionally significant gene variant; actionable: patients with at least one ESCAT 1-4 alteration; eligible: patients for whom MTB gave a therapeutic recommendation; actioned: patients actually receiving the recommended therapy. CT, computed tomography; ESCAT, European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets; GIST, gastro-intestinal stromal tumor; MTB, Molecular Tumor Board; NET, neuro-endocrine tumor; NOS, not otherwise specified; NSCLC, non–small-cell lung cancer; SCLC, small-cell lung cancer; VUS, variant of unknown significance.

FIG 4.

The top-20 actioned genes in our data set. For any gene, (A) absolute and (B) relative values of pathogenic, actionable (eligibility to targeted therapy), and actioned (patients actually receiving a targeted therapy) variants are shown.

FIG 5.

Prevalence of pathogenic (blue), actionable (eligibility to targeted therapy; red), and actioned (patients actually receiving a targeted therapy; teal) variants in the commonest tumor types included in our cohort according to the extent of the NGS panel used. Specifically, FoundationOne CDx (324 genes), Oncomine Comprehensive Plus Assays (501 genes investigated for DNA alterations, and 49 for RNA fusions), and OncotypeMAP panel (290 genes), which are able to detect gene mutations, CNVs, gene fusions, MSI, and TMB, were defined as large panels; however, the Ion AmpliSeq Cancer Hotspot Panel v2 (50 genes), the Oncomine BRCA Research Assay (two BRCA genes), the LKB1 v.2 panel (seven genes), the GIST panel (14 genes), the FusionPlex Sarcoma panel (26 genes), and the FusionPlex Lung panel (14 genes) were classified as small panels. In patients with lung adenocarcinoma, for an unbiased evaluation of the putative added value of large panels over standard diagnostic procedures, the output of large panels was compared with that of small DNA panels (Hotspot and LKB1.v2 panels) plus RNA panels (Archer FusionPlex Lung and Oncomine Comprehensive Assay RNA Plus, which assess ALK, ROS1, and RET fusions). P values refer to the prevalence of actionable targets in large panels compared with small panels. *P < .05 in actioned targets in large versus small panel. ^aFor an unbiased evaluation, in NSCLC only cases with available paired DNA and RNA tests in small panels have been included in the chart. BC, breast cancer; CCA, cholangiocarcinoma; CNVs, copy number variations; CRC, colorectal carcinoma; GEC, gastroesophageal adenocarcinoma; GIST, gastro-intestinal stromal tumor; MM, malignant melanoma; MSI, microsatellite instability; NEN, neuroendocrine neoplasm (including 21 gastroenteropancreatic tumors, 14 lung tumors, and 10 rarer tumors from different districts); NGS, next-generation sequencing; NSCLC, non–small-cell lung cancer; OC, ovarian carcinoma; PC, pancreatic carcinoma; TMB, tumor mutational burden.