Molecular Tumor Board Research Articles

Impact of artificial intelligence (AI) decision support on clinical trial participation: A before-after implementation study on a nationwide molecular tumor board.

1557 Background: Molecular Tumor Boards (MTB) have become the standard for deriving consensus therapy (Rx) recommendations (rec) for patients (pts) with advanced cancer undergoing comprehensive genomic profiling (CGP). However, finding matched Rx and trial options remains laborious, needing informatics strategies. Methods: We examined the outcomes before and after implementation of a decision support system (DSS) at the MTB of the Australian Molecular Screening & Therapeutics program (MoST, ACTRN12616000908437), enrolling pts with refractory solid tumors and linking CGP results to Rx and trials through rec on clinical reports. The DSS comprises a variant interpretation pipeline, a symbolic AI system integrating the TOPOGRAPH database and an annotated trials registry, and a web platform used by the MTB for producing reports shortlisting matching Rx and therapeutic trials. The primary endpoint is the cumulative participation rate (CPR) in genomic matched trials (excluding MoST-related trials) in pts who received Rx after CGP. The secondary endpoints are the CPR in any trial, and overall survival (OS) from MTB. The Fine-Gray model was used to estimate the subdistribution hazard ratios (sHR) for between-group differences in participation. Kaplan-Meier and Cox regression were used for OS analysis. The time-to-event analyses were adjusted for age, ECOG, cancer type, lines of prior rx, and lead-time bias (OS only). Results: In 2203 of 5186 pts (42.5%) received ≥ 1 Rx after CGP, 971 pts were reviewed at MTB before and 1272 after DSS implementation in Sep 2020. At 3, 6 and 12 months (m) after enrolment, CPR in matched trials were 3.2%, 5.0%, and 6.8% before implementation and 3.6%, 5.8%, and 8.9% afterwards (sHR 1.19, 95% CI 0.90–1.57, p=0.23). Pts who received an MTB rec were more likely to participate in a matched trial (sHR 4.75, 3.13–7.23, p<0.001). Notably, DSS specifically increased the likelihood of trial participation following MTB rec (interaction sHR 2.69, 1.02–7.07, p=0.045), with 12m CPR increasing from 10.0% to 12.2% after implementation of the DSS in pts with a MTB rec, whilst for pts without a MTB rec, the CPR fell from 3.1% to 1.6% after implementation. No association was seen between participation in any trials and MTB recs (sHR 1.12, 0.95–1.32) or implementation (sHR 0.95, 0.81–1.11; CPR pre 21.6% v post 23.7% at 12m). No OS difference was seen comparing before with after implementation of the DSS (median 16.7 v 15.3m, adjusted HR 0.97, 0.87–1.08). However, pts receiving genomic matched Rx had a longer OS (median 20.1 v 15.0m unmatched, HR 0.76, p=0.002). Conclusions: The observed interaction between the implementation of DSS and MTB rec suggests there is effect modification in participation rates of pts in genomic matched trials, warranting exploration into how AI might enhance trial participation among pts with incurable cancers undergoing CGP.

CUPCOMP: A multi-site UK trial in carcinoma of unknown primary: A comparison across tissue and liquid biomarkers.

3059 Background: Cancer of Unknown Primary (CUP) is a difficult to treat cancer entity for which the tumour origins remain elusive. There is emerging evidence to support a precision medicine approach to aid treatment decisions, however scarcity of tumour tissue for molecular profiling remains a challenge. CUPCOMP sought to compare the feasibility of molecular profiling from both tissue and blood in patients (pts) diagnosed with CUP. Methods: A non-randomised prospective feasibility clinical trial conducted across 7 UK sites between 06/2021-02/2023. Eligible pts had a histological confirmed diagnosis of favourable/unfavourable CUP based on clinical, radiological, and pathological review at a CUP Multi-Disciplinary Team meeting and ESMO Guidelines for CUP. Pts had mutation profiling performed from circulating tumour DNA (ctDNA) (FoundationOne Liquid CDx) and tumour tissue (FoundationOne CDX or whole genome sequencing (WGS)). All results were discussed at a dedicated Molecular Tumour Board (MTB) to evaluate the activation state of oncogenic pathways. Results: Baseline characteristics of the 117 pts recruited are shown (Table). 114/117 (97%) pts had successful blood (109/117; 93% pts) or tissue (69/117; 59% pts) molecular profiling; both methods were performed in 64/117 (55%) pts. WGS was only successful in 15/21 pts where repeat biopsy was obtained. Where targeted tissue and blood profiling was performed using the same panel (49/117; 42%): 421/550 (77%) Single Nucleotide Variants (SNVs) found in tissue were concordant in ctDNA. ctDNA tumour fraction was ≥10% in 41/109 (35%) pts. In ctDNA, 1556 SNVs, across 271 genes, and 42 rearrangements were identified. 73/114 (64%) of cases carried an actionable alteration in blood or tissue, as determined by MTB. The most frequently reported actionable gene alterations were: KRAS (n=11; 10%); ATM (n=9; 8%); ARID1A (n=9; 8%); PIK3CA (n=10; 9%); NF2 (n=7; 6%); BRAF (n=7; 6%); FGFR2-fusion (n=7; 6%). A tumour mutational burden (TMB) of ≥10 mutations/Mb was detected in 25/117 (22%) of pts. Potential germline variants were found in 8% of pts. 80/114 (70%) pts were alive 6 months after consent to trial. Conclusions: Successful tissue-based molecular profiling is challenging in pts with CUP; achieved in only 59% of pts in this cohort. ctDNA analysis was feasible (93% successful) and reliably concordant with tissue. Potentially actionable alterations were found in 64% of pts. ctDNA molecular profiling should be considered as a reliable alternative to tissue-based testing in pts diagnosed with CUP. Clinical trial information: NCT04750109 . [Table: see text]

Nationwide real-world usage of blood-based (liquid) biomarker testing in Japan.

e23311 Background: Despite the advances in precision oncology with biomarker testing including CGP (comprehensive genomic profiling), not all patients are able to benefit from tissue-guided treatment decisions, underscoring a significant demand for advancements in liquid-based biomarker testing for such patients. However, the treatment landscape based on the application and integration of liquid biopsy in clinical practice has yet to be fully characterized in Japan. Methods: Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national datacenter in Japan, was established by the Ministry of Health, Labour and Welfare (MHLW) with the start of cancer genome medicine since June 2019. The database collects the clinical and genomic data from 68,242 patients who underwent CGP by the end of 2023. This study included all patient records who underwent liquid CGP testing using FoundationOne Liquid test from the C-CAT database up to June 2023. Results: We analyzed data from 7,461 records, where the patients had an average age of 65.1 (±12.0) years; 58.8% were male. A majority (51.3%) exhibited an ECOG performance status of 0, and 66.5% reported a family history of carcinoma. Predominant cancer types included pancreatic (1,825; 24.5%), prostate (1,182; 15.8%) and biliary tract cancers (838; 11.2%). Following review by an MTB (molecular tumor board), new treatments were initiated in 5.8% (434) of cases, with targeted therapy (181; 41.7%) and chemotherapy (174; 40.9%) being the primary interventions. Separately, 9 (2.1%) of new treatments post-MTB occurred as part of clinical trials. Median (IQR) durations from specimen collection to MTB, MTB to treatment initiation, and specimen collection to post-MTB treatment were 28 (24-34), 35 (13-64), and 63 (42-94) days, respectively. The largest proportion of biomarker testing occurred after the start of second line of therapy (1,720; 23.1%) Pancreatic and biliary tract cancer patients tend to have biomarker testing at the earlier line, whereas prostate and ovarian cancer patients tend to have at the later line. Conclusions: Although the positioning of liquid CGP testing may differ among cancer types, it is important for patients to select appropriate tissue- and liquid-based biomarker testing at the right timing. Understanding this descriptive landscape of biomarker tests utilized in real-world settings will aid decision-making for addressing unmet needs (e.g., low accessibility to treatment) in cancer genome medicine and its positioning in improving the standard of cancer care.

Large language models for precision oncology: Clinical decision support through expert-guided learning.

e13609 Background: Precision oncology revolutionized cancer treatment by identifying molecular biomarkers to guide personalized care. The ever-growing body of medical literature presents a challenge for oncologists researching targeted therapies. While recent studies investigated large language models (LLMs) to streamline this process, LLM reliance on general rather than medical knowledge limits clinical relevance and trustworthiness. To address these limitations, we developed a retrieval augmented generation (RAG) system that integrates PubMed clinical studies, trial databases and oncological guidelines with LLMs to support targeted treatment recommendations. The Molecular Tumor Board (MTB) at the Center of Personalized Medicine (ZPMTUM) guided and evaluated treatment options proposed by the LLM to assess their applicability for clinical decision support. Methods: We used 10 publicly accessible fictional patient cases with 7 tumor types and 59 distinct molecular alterations. Our LLM system MEREDITH (Medical Evidence Retrieval and Data Integration for Tailored Healthcare) consists of Google's Gemini Pro, enhanced with RAG and Chain-of-Thought (CoT) prompting. To establish a benchmark, clinical experts at ZPMTUM manually annotated the cases. Informed by MTB expert feedback, we iteratively improved our LLM system from a draft system relying on PubMed-indexed data to an enhanced system, which replicated expert annotation processes by incorporating oncology guidelines, drug availability and trial databases (ClinicalTrials.gov, QuickQueck.de). ZPMTUM assessed credibility and clinical relevance of manually annotated and LLM-generated recommendations. Patient-level data on (likely) pathogenic molecular alterations and recommended treatment options were summarized using median and interquartile range (IQR). Semantic similarity between LLM and clinician responses was assessed using cosine similarity of text vector embeddings; paired t-test evaluated significance. Results: The median of (likely) pathogenic molecular alterations per patient was 2.5 (IQR: 2-3). ZPMTUM identified a median of 2 treatment options per patient (IQR: 1-3), while the enhanced LLM identified a median of 4 (IQR: 3-5). MEREDITH proposed multiple relevant treatment suggestions, including therapies based on preclinical studies, and molecular interactions, for further assessment by the MTB. ZPMTUM prioritized the most suitable clinical option. The mean semantic textual similarity of LLM responses increased significantly from 0.69 in the draft system to 0.76 in the enhanced system (p <0.001). Thus, feedback from ZPMTUM enhanced the model's ability to align its responses with clinician thought processes. Conclusions: Leveraging expert thought processes to instruct LLMs holds promise as a novel decision support tool for precision oncology.

Real-world performance of the digital drug-assignment system for precision oncology in lung cancer.

e13590 Background: Precision medicine has profoundly transformed lung cancer treatment, an array of molecularly targeted agents (MTAs) are approved and used in clinical practice. Comprehensive molecular testing is key in treatment decisions, nevertheless, interpretation of complex molecular profiles can be challenging and subjective. Previously we demonstrated that digital drug assignment (DDA), an algorithmic computational reasoning model that ranks associated targeted therapies based on the totality of individual tumor genomic data, rather than matching one drug to one biomarker, was predictive of relative benefit of the agents as used in the SHIVA01 trial (1). Here, we collected real-world clinical outcome data from lung cancer patients who received decision support where DDA was integrated to aid a molecular tumor board (MTB) and investigated the effectiveness of administered therapies. Methods: Between 2018 and 2022, 111 lung cancer patients were involved in our precision oncology program. Following molecular diagnostic tests, analysis of the individual molecular profiles and scoring of associated drugs (DDA score) was performed by the DDA system as previously described. The output was assessed by the MTB that provided a strategy to the clinicians who made the final therapy decisions. Treatment courses and outcomes were collected from hospital health records and analyzed. Treatment lines were categorized as the following: high-score MTA (1000≤DDA score), low-score MTA (DDA score<1000), and standard of care (SOC). Results: Overall response rate (ORR) of high-score MTA lines administered following DDA-based decision support (n=13) was 69%, whereas of other treatment lines (low-score MTAs and SOC; n=55) it was 16% (p<0.001); and 26% in low-score MTA lines (n=34; p=0.017). Median progression-free survival (mPFS) of high-score MTA lines administered following DDA-based decision support (n=13) was 63 months (95% CI: 12.0 – 66.0), whereas it was 9 months both for any other treatment lines (low-score MTAs and SOC; n=44; 95% CI: 5.0 – 66.0; p<0.001) and for low-score MTA lines only (n=27; 95% CI: 5.0 – 66.0; p<0.001). Median overall survival (mOS) of patients who received at least one line of high-score MTA after decision support (n=13) was significantly longer than of those who only received non-high score treatments after decision support (patients only treated with low-score MTAs and/or SOC, n=34): not reached vs. 32 months (95% CI 24.0 – not reached), respectively (p=0.012). Conclusions: This study revealed that the DDA system is predictive of relative benefit of the various agents as used in lung cancer care, in line with our previous clinical validation. Validated algorithmic AI-guided drug assignment methods represent a new class of tools that can potentially address challenges in utilizing the results of complex molecular profiles in routine clinical setting. 1. Petak et al., 2021, npj Precis. Onc. 5, 59.

Nivolumab plus ipilimumab (N+I) in patients (pts) with solid tumors with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

3130 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with advanced solid tumors with HTMB treated with N+I are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options or prior immune checkpoint inhibitor tx. PD-L1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. HTMB was defined a priorias ≥9 mutations/megabase (Muts/Mb) via a qualifying test for TAPUR or approved by the Molecular Tumor Board. Pts received I at 3 mg/kg every 3 weeks (wks) for 4 doses with N at 1 mg/kg IV every 3 wks for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Low accruing histology-specific cohorts with HTMB were collapsed into 1 cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (α= 0.10; 86% power based on alternative DC rate of 35%). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR), duration of SD, and safety. DOR is time from documented OR to progressive disease (PD); duration of SD is time from tx start to PD. Results: 26 pts with 13 tumor types with HTMB were enrolled. Table shows demographics and outcomes. Tissue tumor mutational burden (TMB) ranged from 8 to 374 Muts/Mb (median= 16). 1 CR (small intestine; TMB= 48 Muts/Mb; DOR= 36 wks), 7 PR (biliary tract, site unspecified [3], soft tissue sarcoma, uterus, vagina; median TMB= 17 Muts/Mb; median DOR= 20 wks [range, 5-231]) and 1 SD16+ (pancreas; TMB= 26 Muts/Mb; duration of SD= 26 wks) were observed for a DC rate of 35% (1-sided 90% CI: 22 to 100) and OR rate of 31% (95% CI: 14 to 52). The null hypothesis was rejected (p=0.011). Notably, 1 pt (uterus, 374 Muts/Mb) is still on tx with an ongoing 66-wk PR as of Jan 2024. Most pts, including 8/9 with DC, were microsatellite stable. 10 pts had ≥1 grade 3 tx-related adverse event (AE) or serious AE. Conclusions: N+I showed antitumor activity in pts with advanced solid tumors with HTMB. Additional study is warranted to confirm the efficacy of N+I in pts with HTMB. Clinical trial information: NCT02693535 . [Table: see text]

Clinical impact of molecular profiling in the national prospective cohort Solving Unknown Primary Cancer (SUPER) study.

3056 Background: Cancer of unknown primary (CUP) is a common cause of cancer death, with a median survival < 12 months. SUPER is a prospective cohort study designed to create a national information and biobank of patients (pts) with no confirmed primary site following diagnostic work-up. We aimed to determine the impact of tumour molecular profiling on treatment decisions. Methods: 449 pts were recruited (2013-2021) over 3 phases from 12 Australian sites. Clinical information collected over 12 months included: demographics, treatments, investigations and clinico-pathological characteristics. Molecular tests were centrally performed and included comprehensive panel (CCP) sequencing and gene-expression tissue of origin (TOO) assays in Phase 1&2 and CCP and whole genome sequencing (WGS) in Phase 3. The number of genes reported on increased over the 3 phases. Molecular results were discussed in a molecular tumour board. Clinicians completed clinical management questionnaires before and after receiving molecular results. A combined retrospective evaluation of therapeutic actionability was applied to all DNA sequencing data using the TOPOGRAPH database. Results: Median age 63 years [19-86], with 81% ECOG 0-1 and 87% classified as unfavourable CUP subtype. Reporting timelines and rates of successful sequencing improved over time (Table). Clinically actionable genomic abnormalities were detected in 95/331 (29%) pts. Moderate or high match results on TOO assay were consistent with a suspected or later confirmed TOO as reported by clinicians in 81/195 (42%) pts in phase 1 + 2. Germline pathogenic mutations were detected in 34/331 (10%) pts. Molecular tests confirmed clinician’s treatment (started while awaiting results) was consistent with the most likely TOO in 170/331 (51%) pts. Clinicians reported that molecular tests resulted in a change in management in 11/118 pts (9%) in phase 1 and 40/213 (19%) pts in phases 2+3, with 17/51 (33%) pts changed treatment based on potential TOO determination. 11/51 (22%) pts could access treatment via standard pathways given a more specific tumour-type diagnosis and 15/51 (29%) pts were potentially eligible for clinical trials; however, only 7 pts were well enough for referral. Conclusions: The clinical impact of molecular testing in CUP improved over time as testing became more sophisticated and turnaround times improved. Clinicians suspected TOO pre-profiling was consistent with molecular results in half of the pts. Routine access to novel therapies in CUP remains a challenge. [Table: see text]

Gene fusions: A retrospective analysis of therapies and treatments of MTB patients over 7 years.

e15183 Background: Gene fusions (GF) are less common than single nucleotide variants, amplifications, and deletions, but have been suggested to be more predictive of responses to specific molecularly targeted therapies than other types of molecular alterations. We reviewed our institutional trends for overall survival in our molecular tumor board database based on the receipt of molecularly targeted therapy. Methods: We identified patients with non-hematologic malignancies and gene fusions (GF) identified by DNA based next generation sequencing (NGS) and reviewed by the Inova Schar Cancer Institute Molecular Tumor Board (ISCI MTB) between March 1, 2016 and March 1, 2023. GFs were confirmed by re-evaluation of next generation sequencing, and we determined the number of patients who received molecularly targeted therapy (RTT) specific for the GF. We evaluated overall survival (OS) in the RTT cohort and in the cohort that did not receive targeted therapy (NTT). TMPRSS fusions in prostate cancer were excluded from this analysis. Results: There were 93 patients with gene fusions in advanced staged cancers that met study criteria. Twenty-three were lost to follow up, transferred care outside ISCI, or enrolled in hospice. Of 70 stage IV patients reviewed, thirty-seven were found to have received GF targeted therapy. OS for all patients was 28.5 months. Patients in the RTT cohort had a median OS of 45 months and patients in the NTT cohort had an OS of 26.8 months (p-value = 0.16, Log-rank test). Conclusions: Targeted therapy in solid tumors with gene fusions is associated with prolonged overall survival. It is critical for MTBs to use NGS platforms that identify GF. Further studies examining OS and GF are warranted. [Table: see text]

Therapeutic implications of phosphoproteomics in molecular cancer diagnostics.

3068 Background: Precision oncology approaches employing genomics-guided targeted therapies for individual patients have provided significant survival benefits in several cancer types. However, varying response rates in solid malignancies, many patients without actionable genomic lesions, and increasing evidence that non-genomic mechanisms may play an important role in tumors indicate that genomics alone is often insufficient to inform and guide the clinical care of patients. Since most targeted anti-cancer drugs inhibit the activity of protein kinases, measuring the tumor phosphoproteome as a direct readout of oncogenic pathway activity is poised to enhance molecular stratification. Methods: We established a clinical (phospho)proteomic workflow for integration into the molecular tumor board (MTB) workflow of the Germany-wide INFORM (for children with relapsed cancers) and MASTER (for young adults with refractory cancers and patients with rare tumors) registry studies and profiled > 1000 tumor tissue specimen from patients enrolled in the DKFZ/NCT/DKTK MASTER study or the INFORM registry trial. To assess the aberrant activity of druggable signaling pathways, we developed a new tumor pathway activity (TUPAC) scoring methodology using expression data of > 8,000 proteins and > 20,000 phospho-sites per patient in a heterogeneous pan-cancer cohort. TUPAC scores integrate protein expression and phosphopeptide abundance data at several levels to detect aberrant signaling pathway activities of several interdependent oncogenic signaling pathways within one tumor specimen. Results: We show for the first time that comprehensive (phospho)proteome profiling is feasible and informative in a real-world prospective precision oncology setting. Discussion of (phospho)proteomic data of > 500 prospective patients in weekly MTB meetings revealed that adding a (phospho)proteomic layer can supply critical information for personalized therapies that is not discernible from genomic and transcriptomic data. In an independent value evaluation (329 target recommendations in 104 patients), the phosphoproteome layer was decisive in 22% of all recommended targets. Based on anecdotal cases with available clinical follow-up, we provide evidence that (phospho)proteome profiling carries important diagnostic value by detecting actionable tumor-driving kinase signaling in patients without actionable genomic lesions or by functionalizing genomic variants of unknown significance. Conclusions: Measuring the tumor phosphoproteome as a direct readout of oncogenic pathway activity is feasible and adds complementary, therapy-relevant information in a real-world prospective precision oncology setting.

Molecularly matched therapies identified by comprehensive genomic profiling before the first-line setting to provide alternative treatment outcomes in patients with solid tumors: 1-year follow-up of the prospective FIRST-Dx study.

3137 Background: Comprehensive genomic profiling (CGP) test by next-generation sequencing has been reimbursed in Japan since 2019. However, only 9.4% of patients (pts) had received molecularly-matched treatment because CGP test in Japan is only indicated after standard of care (SoC). To determine the clinical utility of a CGP test (FoundationOne CDx) in the first-line setting for pts with advanced solid tumors, we previously reported the results of the FIRST-Dx study, in which the molecular tumor board identified molecular-based recommended therapy (MBRT) for 61% of pts (105/172) (Matsubara J, et al. JAMA Netw Open 2023). In this 1-year follow-up of the FIRST-Dx study, we investigated the clinical benefits provided by the upfront CGP test. Methods: The FIRST-Dx study was a multi-institutional, prospective study in 6 hospitals in Japan. Chemotherapy-naïve adult pts with advanced solid tumor (GI, Lung, Breast, GYN, Melanoma) and ECOG performance status of 0-1 were enrolled. This follow-up study was planned for 3 years and an interim analysis was prespecified at 1 year after the final patient enrollment in the FIRST-Dx study. Primary endpoint was overall survival (OS). Secondary endpoints were the proportion of pts who received MBRT, overall response rate, progression-free survival (PFS), and a PFS ratio (PFS on MBRT/PFS on prior therapy). Results: Data from 172 pts with a median follow-up of 15.1 months were available. Median OS was not reached (95% CI: 18.4 months to not reached). Thirty-nine pts (22.7%) had received MBRT. The total number of pts treated with MBRT were 21 in 1st-line, 20 in 2nd-line, 4 in 3rd-line, and 1 in 4th-line, respectively. Overall response rate was 56.3% [95% CI: 29.9-80.2%] in 1st-line MBRT group vs 42.3% [95% CI: 33.9-51.1%] in 1st-line SoC (N=137), and 26.3% [95% CI: 9.1-51.2%] in 2nd-line MBRT group vs 17.1% [95% CI: 9.7-27.0%] in 2nd-line SoC (N=82), respectively. Median PFS was 12.9 months [95% CI: 7.4 months to not reached] in 1st-line MBRT group vs 11.3 months [95% CI: 8.6-14.1 months] in 1st-line SoC, and 6.9 months [95% CI: 2.8 months to not reached] in 2nd-line MBRT group vs 5.7 months [95% CI: 3.7-7.4 months] in 2nd-line SoC, respectively. Regarding the PFS ratio of 2nd-line MBRT (N=15) (PFS on MBRT in 2nd-line/PFS on 1st-line therapy), median PFS ratio was 1.0 (range: 0.1-14.6) and 4 pts (27%) had the PFS ratio of >1.3, indicating that MBRT might be effective in changing the clinical outcome (Von Hoff DD, et al. J Clin Oncol 2010). Conclusions: We showed that MBRT identified by CGP test before the first-line setting provides better treatment outcomes than SoC in pts with solid tumors early in their disease course. Our data suggested that the timing of CGP test in Japan for pts with advanced solid tumors should be indicated before starting SoC. Clinical trial information: jRCT1050220041 .

Results of IMPACT 2, a randomized study evaluating molecular profiling and targeted agents in metastatic cancer at MD Anderson Cancer Center.

3153 Background: To address the limitations of exploratory studies, we conducted IMPACT2. The primary endpoint was to compare the progression-free survival (PFS) between patients treated with matched targeted therapies (MTT) selected on the basis of tumor molecular alterations and those whose treatment was not selected on the basis of alteration analysis (non-targeted therapy, NTT). Methods: Patients with metastatic cancer and targetable alterations were randomized between the 2 arms when eligibility criteria were met (Part A, 5/2014-4/2017; sponsor, Foundation Medicine). In Part B (3/2019-9/2023; sponsor, Tempus), patients who declined randomization selected the treatment arm ( NCT02152254 ). PFS/OS analysis (Kaplan Meier, Cox model; reference group, comparison, NTT). All cases were presented at weekly Molecular Tumor Board meetings; initial plan, to randomize 300 of 1,362 enrolled patients. Results: Overall, 829 patients (Parts A, 391; B, 438); were enrolled (med. age 59.5 yrs, range 18-84; men 50%; med. No. of prior therapies 3, range 0-17; most common cancers: gastrointestinal 34%, head/neck 13.5%, gynecologic 10%, sarcoma 9.53%; most common genomic alterations RAS 38%, PI3K 31%, FGFR 28%). In Part A, 69 were randomized (MTT, n=35; NTT, n=34); Part B (MTT, n=11, NTT=13; Selected arm: n=16: MTT, n=13; NTT, n=3). Results are shown (Table). MTT group: median PFS by therapy type: FDA approved/off-label, 4.7 months (95% CI, 2.93, 7.1); investigational, 2.6 months (95% CI, 2.27,4.87), combined FDA approved/investigational, 1.7 months (1.7, NR) (p=0.22). Conclusions: Considering the challenges to randomize patients (doi: 10.1038/s41698-022-00317-0), and that the study was underpowered for its original goal, no differences in response, PFS (primary endpoint), or OS was noted between the 2 arms, possibly because of the advanced stage disease and the complexity of tumor biology that cannot be addressed by randomization. Clinical trial information: NCT02152254 . [Table: see text]

Utility of circulating tumor DNA (ctDNA) to inform treatment of patients with metastatic breast cancer.

1042 Background: Circulating tumor DNA (ctDNA) can overcome limitations of tissue biopsy (tbx) in patients with metastatic breast cancer (mBC). While tbx provides a snapshot of a tumor’s molecular profile from one site and time, ctDNA provides a more comprehensive landscape of the tumor genome. Serial liquid biopsies (lbx) can be easily obtained for monitoring clinical response and resistance over time. The Individualized Molecular Analyses Guide Efforts in Breast Cancer (IMAGE) II study evaluates tbx and serial lbx methods for tumor genomic profiling in mBC. Methods: IMAGE II (NCT02965755) is a prospective, multi-center trial to evaluate the clinical utility of lbx versus tbx. Eligible individuals had mBC of any subtype, with progression requiring therapy change. Tbx sequencing per standard of care was required unless biopsy was not technically feasible. Upon enrollment, we collected baseline plasma for tissue-agnostic comprehensive genomic profiling (CGP) by Foundation Medicine. Both lbx and tbx sequencing results were reviewed in real time by the Johns Hopkins Molecular Tumor Board to provide treatment recommendations. Clinical data was recorded. We collected serial lbx samples 1-2 weeks post initiation of next line of therapy, at first restaging, and at progression. Here we present the analysis of data collected at enrollment, and serial lbx results will be reported at a later date. Results: Total enrollment was 199 pts, of whom 194 were women (median age = 57 years, range 27-86 years). There were 140 HR+HER2-, 4 HR-HER2+, 20 HR+HER2+ and 35 triple negative (TNBC) cases. Metastases were found in bone only in 19 pts, or included lung in 99 pts, liver in 97 pts, and brain in 14 pts. Median prior lines of metastatic therapy was 2, with 44 pts (22.1%) having been on 4 or more, including antibody-drug conjugates (14 pts), immunotherapy (2), cytotoxic chemotherapy (74), endocrine (88), and targeted therapy (12). 9 pts were newly diagnosed with mBC at the time of enrollment. 110 pts (55%) had tbx sequencing. In lbx-based CGP results from 190 patients, the genes most frequently altered were TP53(90 patients), PIK3CA (63), ESR1 (54). Copy number amplifications were found in FGFR1 (21 patients) and FGFR3 (12), and copy number losses were found in PTEN in 3 patients. Of the 87 patients whose baseline lbx was profiled using FoundationOne Liquid CDx which allows calculation of ctDNA tumor fraction (TF), 69 (79.3%) pts had detectable ctDNA TF. 60 patients (69.0%) had ctDNA TF at least 1%. We will present the frequency of clinically actionable mutations detected via lbx vs tbx genomic profiling, accounting for sites of metastases, receptor subtype and prior therapy exposure, as well as the association between ctDNA TF and sites of disease. Conclusions: A high rate of ctDNA TF detection in pts with mBC highlights the value of lbx for CGP in this setting for detecting multiple alteration classes across mBC subtypes and metastatic sites. Clinical trial information: NCT02965755 .

Genomic landscape and therapeutic implications in advanced solid cancers: KOSMOS-II (KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors, KCSG AL-22-09).

11161 Background: Despite advances in genomic diagnosis and therapeutics, providing precision medicine remains a challenge in the real-world practical application, especially in nations with diverse next-generation sequencing (NGS) cancer panels and a shortage of available targeted agents due to lack of approval or reimbursement. Methods: The KOSMOS-II is an ongoing prospective, nationwide, master observational study with multiple cohorts undergoing molecular-guided treatment (MGT) recommended by a central molecular tumor board based on local NGS cancer panel results for advanced cancer patients (pts) (J Clin Oncol 2023;41:16 suppl TPS 1608). Key genomic features were integrated with clinical data to construct a Clinico-Genomic Database (CGDB). To minimize inter-panel variations, all variant calling format (VCF) data on single nucleotide variants, insertions, and deletions were normalized by lifting over to the same reference genome (hg19). Re-annotation was performed using a consistent pipeline incorporating public databases. This preliminary analysis outlines the genomic landscapes and therapeutic implications in the first half of enrolled patients out of a targeted accrual of 1,000. Results: From September 2022 to December 2023, 489 pts were enrolled with a median age of 60 years (19 - 87), male 56.9%, and a median of 4 lines (1-15) of prior systemic therapy. The most common primary cancer sites were colorectum (n = 96, 19.6%), biliary tract (n = 63, 12.9%), and breast (n=40, 8.2%). CGDB was constructed for 360 pts, employing 20 different panels from 31 participating centers. The most common genomic alterations were TP53 mutation (Mut) (n=183, 50.8%), APC Mut (n=124, 34.4%), and ERBB2 amplification (AMP) (n=90, 25%). MGT was assigned to 59.5% of pts, 45.2% were allocated to investigational drugs targeting genetic alterations approved for other indications (Tier 1), and 12.6 % to clinical trials matching their genetic alterations (Tier 3). The concordance rate between pre-submitted physician choices and the MTB recommendation was 54.6% (Tier 1, 55%; Tier 2 (alternative treatments including palliative care), 46%; Tier 3, 86%). ERBB2 alterations were most frequently led to MGT; trastuzumab emtansine (n = 75, 20.8%; ERBB2 AMP n=36; ERBB2 Mut n=20; ERBB2 AMP & Mut n=17; NA n=2), or trastuzumab plus pertuzumab (n = 17, 7.5%), followed by EGFR gain to bevacizumab plus erlotinib (n = 18, 5%) and high TMB (≥20 mut/Mb) to atezolizumab (n= 46, 12.8%). Response evaluation of Tier 1 treatment was available in 158 patients, with a 16-week clinical benefit rate of 34.8%. Conclusions: The KOSMOS-II study demonstrated the feasibility of a pragmatic, nationwide precision medicine approach using diverse real-world NGS panels and favorable clinical outcomes.

Precision oncology for rare gynecologic malignancies: Integrating molecular tumor boards and real-time treatment matching.

Precision oncology for rare gynecologic malignancies: Integrating molecular tumor boards and real-time treatment matching.

The WERA cancer center matrix: Strategic management of patient access to precision oncology in a large and mostly rural area of Germany

PurposeProviding patient access to precision oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center. MethodsAs members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA´s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care by WERA. Clustering our catchment area along these two dimensions set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria. ResultsThe WERA matrix overlooked an active screening area of 821 postal code areas – representing about 50 % of Bavaria´s spatial expansion and more than six million inhabitants. The WERA matrix identified regions successfully connected to our outreach structures in terms of subsidiarity – with general cancer care mainly performed locally but PO performed in collaboration with WERA. We also detected postal code areas with a potential PO backlog – characterized by high levels of cancer care performed by WERA and low levels or no MTB representation. ConclusionsThe WERA matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers.

Incidental Germline Findings During Comprehensive Genomic Profiling of Pancreatic and Colorectal Cancer: Single-center, Molecular Tumor Board Experience.

Abstract Multidisciplinary molecular tumor boards (MTB) are already well established in many comprehensive cancer centers and play an important role in the individual treatment planning for cancer patients. Comprehensive genomic profiling of tumor tissue based on next-generation sequencing is currently performed for diagnostic and mainly predictive testing. If somatic genomic variants are identified, which are suspected to be pathogenic germline variants (PGVs), MTB propose genetic counseling and germline DNA testing. Commonly used comprehensive genomic profiling approaches of tumor tissue do not include a matched germline DNA control. Therefore, the detection of PGVs could be only predicted based on the content of tumor cells (CTC) in selected tumor area (%) and variant allele frequency score (%). For conclusion, the role of a medical geneticist is essential in these cases. The overall prevalence of PGVs in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) is approximately 10%. In this single-center study, we present 37 patients with PDAC and 48 patients with CRC who were presented at MTB and tested using the large combined DNA/RNA sequencing panel. Content of tumor cells and variant allele frequency scores were evaluated in all tested patients. In case of suspicion of PGV and no previous genetic testing based on the standard guidelines, genetic counseling was recommended regardless of age, sex, and family history. In the PDAC subgroup, five patients were recommended by MTB for genetic counseling based on suspicious genetic findings. Based on a medical geneticist’s decision, germline DNA sequencing was performed in four of these cases, and all of them tested positive for PGV in the following genes: ATM, ATM, BRCA1, and BRCA2. In the CRC subgroup, no PGV was confirmed in the two patients genetically tested based on the MTB recommendations. Furthermore, we present data from our center’s registry of patients with PDAC and CRC who underwent genetic counseling and germline DNA testing based on the standard screening criteria. Our data confirm that comprehensive genomic profiling of tumor tissue can identify patients with hereditary forms of PDAC, who could remain unidentified by standard screening for hereditary forms of cancer.

SNO Pediatric Molecular Tumor Board Series: Successful Beginnings and Future Directions

SNO Pediatric Molecular Tumor Board Series: Successful Beginnings and Future Directions

Liquid profiling for patients with advanced cancer is ready for clinical integration

SummaryMolecular profiling of circulating tumor DNA (ctDNA) to guide treatment decisions has found its way into routine management of patients with advanced cancer. This represents a pivotal advancement in precision oncology, offering a non-invasive and fast-tracked method to detecting clinically relevant biomarkers. With the backing of international oncology guidelines, ctDNA analysis is now a standard approach to consider in molecular diagnostics. Despite the promise of ctDNA in refining treatment strategies through the detection of genomic alterations and treatment-relevant biomarkers with high concordance to tissue biopsies, challenges persist. These include the interpretation of discordances due to tumor heterogeneity, sampling biases, and technical limitations, alongside the differentiation of tumor-derived mutations from clonal hematopoiesis. The current consensus supports the utility of comprehensive genomic profiling (CGP) panels for a broad spectrum of actionable targets, while acknowledging the limitations and advocating for a balanced application of “tissue-first” and “plasma-first” approaches tailored to individual patient scenarios. The essential role of molecular tumor boards (MTBs) is in navigating the complexities of ctDNA data interpretation, thereby ensuring the effective incorporation of liquid biopsy into personalized cancer treatment regimens.

Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22–09

BackgroundNext-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform.MethodsThe KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment.DiscussionThis pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers.Trial registrationNCT05525858.

Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis.

Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered. uLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations.