Precision Oncology Program Research Articles

Implementing precision oncology for sarcoma patients: the CCCLMUmolecular tumor board experience

PurposeDue to poor outcomes and limited treatment options, patients with advanced bone and soft tissue sarcomas (BS/STS) may undergo comprehensive molecular profiling of tumor samples to identify possible therapeutic targets. The aim of this study was to determine the impact of routine molecular profiling in the setting of a dedicated precision oncology program in patients with BS/STS in a German large-volume sarcoma center.Methods92 BS/STS patients who received comprehensive genomic profiling (CGP) and were subsequently discussed in our molecular tumor board (MTB) between 2016 and 2022 were included. Patient records were retrospectively reviewed, and the clinical impact of NGS-related findings was analyzed.Results89.1% of patients had received at least one treatment line before NGS testing. At least one molecular alteration was found in 71 patients (82.6%). The most common alterations were mutations in TP53 (23.3% of patients), followed by PIK3CA and MDM2 mutations (9.3% each). Druggable alterations were identified, and treatment recommended in 32 patients (37.2%). Of those patients with actionable alterations, ten patients (31.2%) received personalized treatment and six patients did benefit from molecular-based therapy in terms of a progression-free survival ratio (PFSr) > 1.3.ConclusionOur single-center experience shows an increasing uptake of next-generation sequencing (NGS) and highlights current challenges of implementing precision oncology in the management of patients with BS/STS. A relevant number of patients were diagnosed with clinically actionable alterations. Our results highlight the potential benefit of NGS in patients with rare cancers and currently limited therapeutic options.

Tumour mutational burden and survival with molecularly matched therapy

BackgroundThe impact of tumour mutational burden (TMB) on outcome with molecularly matched therapy is unknown. Higher TMB could predict resistance to molecularly matched therapy through co-occurring driver mutations. MethodsOne hundred and four patients with advanced cancers underwent molecular profiling in the DKTK-MASTER program. Fifty-five patients received systemic therapy excluding immunotherapy. Patients with molecularly matched (n = 35) or non-molecularly informed therapy (n = 20) were analysed for TMB and survival. Results were validated in an independent cohort of patients receiving molecularly matched (n = 68) or non-molecularly informed therapy (n = 40). Co-occurring driver mutations and TMB were analysed in the exploratory cohort and The Cancer Genome Atlas (TCGA) datasets. ResultsPatients were stratified by the median TMB of 1.67 mutations per Megabase (mut/Mb) of 35 patients receiving molecularly matched therapy into TMB-high or TMB-low groups. Median overall survival (4 months [95% CI, 3.3–7.6] versus 12.8 months [95% CI, 10-not reached], p < 0.001) and progression-free survival (1.8 months [95% CI, 1.1–3.7] versus 7.9 months [95% CI, 2.8–17.0], p = 0.003) were significantly shorter in the TMB-high group compared to the TMB-low group. In the validation cohort, shorter OS and PFS were identified in the TMB-high group (TMB cut-off of 4 mut/Mb) treated with molecularly matched therapy. No differences were observed in patients receiving non-molecularly informed systemic therapy. A significant correlation between co-occurring driver mutations and TMB (n = 104, r = 0.78 [95% CI, 0.68–0.85], p < 0.001) was found in the exploratory cohort as well as the majority (24/33) of TCGA studies. ConclusionA high TMB was associated with unfavourable outcome in patients receiving molecularly matched therapy, indicating untargeted resistance pathways. Therefore, TMB should be further investigated as a predictive biomarker in precision oncology programs.

OTHR-04. DEVELOPMENT OF A FUNCTIONAL PLATFORM FOR REAL-TIME PERSONALIZED DRUG SENSITIVITY PROFILING OF PATIENT-DERIVED 3D FRESH TUMOR TISSUE CULTURES IN THE PEDIATRIC PRECISION ONCOLOGY PROGRAM INFORM

Abstract The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.

Real-world study to evaluate the clinical performance of a computational method in precision oncology.

e13631 Background: In recent years, precision medicine has increasingly been integrated into routine clinical oncology care. However, interpretation of large amounts of biological information can be challenging in daily clinical practice settings. We previously demonstrated that digital drug assignment (DDA), an artificial intelligence-based computational method that ranks associated targeted therapies based on the totality of available genomic data rather than matching one drug to one biomarker, was predictive of relative benefit of the agents as used in the SHIVA01 trial (Petak et al., 2021, doi: 10.1038/s41698-021-00191-2). Here, we collected real-world clinical outcome data from patients with solid tumors who received decision support where DDA was integrated to aid a molecular tumor board (MTB) and investigated the effectiveness of recommended therapies. Methods: Between 2016 and 2021, 208 patients with solid tumors were involved in our precision oncology program (69% gastrointestinal, 14% gynecological, 9% breast, 8% other tumors). In most cases targeted panel sequencing was carried out (50-gene panel: 51%, 591-gene panel: 45%). Classification of the detected alterations and therapeutic ranking was performed by the DDA software tool as previously described. The output was assessed by the MTB that provided a strategy to the clinicians who made the final therapy decisions. DDA output scores were supportive for all molecularly targeted agents (MTAs) administered. Treatment lines after decision support with MTAs were compared with lines of standard agents (STs) retrospectively and evaluated by best overall response, log-rank test of progression-free survival (PFS), and durable clinical benefit (DCB). Results: Of all 208 patients, 81 were treated with MTAs and 59 with STs after DDA, implying 114 and 97 therapeutic lines, respectively. Disease control rate (DCR) of the suggested MTAs was 40% (0 CR, 9 PR, 37 SD, 43 PD, 25 lost to follow-up), while DCR for STs was 25% (1 CR, 3 PR, 20 SD, 48 PD, 25 lost) ( p=0.025). PFS value was available for 88 MTA and 71 ST lines. Log-rank test revealed a significantly longer median PFS for MTAs than STs: 4 vs. 2.5 months, respectively ( p&lt;0.001). Proportion of patients who reached DCB of 6 months was 32% in the MTA and 11% in the ST group ( p&lt;0.001). DCB at 9 months was 19% and 5% in the MTA and ST cohorts, respectively ( p=0.003). Conclusions: This study revealed clear clinical benefit for targeted therapies over conventional treatments used in daily practice, where MTB was aided by a computational tool to interpret complex molecular data. After the previous clinical validation, here we show that integration of DDA into real-world clinical setting is feasible and safe. The results fit well into the trend of targeted therapies becoming a routine procedure and underscore the importance of precision oncology decision support by advanced computational tools.

Tumor mutational burden as a predictive biomarker for molecularly matched therapy in two independent pan-cancer cohorts.

3066 Background: Personalized cancer therapy based on molecular tumor aberrations has shown efficacy in a subset of tumors. Novel biomarkers are warranted to help extend this benefit to a larger patient population. Tumor mutational burden (TMB) is an established predictive biomarker for immune checkpoint inhibition. Its role for molecularly matched therapy is unknown. Methods: Comprehensive molecular profiling including whole-exome and RNA-sequencing was performed in 104 patients with advanced cancer within the DKTK MASTER program. 55 patients received a systemic therapy excluding immunotherapy. TMB and survival were analyzed in patients receiving molecularly matched therapy (n=34) or non-molecularly matched therapy (n=21) as well as in an independent published cohort of patients receiving molecularly matched (n=68) or non-molecularly matched (n=40) therapy (excluding immunotherapy). TMB and co-occurring driver mutations were analyzed in the DKTK MASTER cohort. Results: The median TMB of 1.68 mutations per megabase (mut/Mb) in the 34 patients receiving molecularly matched therapy was used to stratify patients into TMB-high and -low groups. Median overall survival (OS) and progression-free survival (PFS) were significantly shorter in the TMB-high than in the TMB-low group (OS: 4 months [95% CI, 3.3 to 7.6] versus 19 months [95%CI, 10.0 to not reached] p &lt; 0.001, Hazard Ratio (HR) 4.4 [95%CI, 1.9 to 10.2], p&lt;0.001; PFS 1.8 months [95%CI, 1.1 to 3.6] versus 8.5 months [95% CI, 2.8 to 17.0] p = 0.004, HR 2.9 [95%CI, 1.4 to 6.2], p=0.005). No significant differences were observed in patients receiving non-molecularly informed systemic therapy (OS HR 0.7 [95%CI, 0.2 to 2.6], p=0.635 and PFS HR 1.2 [95%CI, 0.4 to 3.5] p=0.701). In the validation cohort, shorter progression-free survival was also identified in the TMB-high group (median TMB cut-off of 4 mut/Mb; HR 2.2 [95%CI, 1.3 to 3.7] p=0.005) treated with molecularly matched therapy but not with non-molecularly informed therapy (HR 1.1 [95%CI, 0.5 to 2.2] p=0.848). TMB was associated with co-occurring driver mutations (n=104, r = 0.78 [95%CI, 0.68 to 0.85], p&lt;0.001). Conclusions: High TMB was previously established as a positive predictive biomarker associated with efficacy of immune checkpoint inhibitor treatments. Our study reveals high TMB as a negative predictive biomarker associated with low efficacy of molecularly informed systemic therapy, potentially due to co-occurring driver mutations. Thus, TMB is a candidate predictive pan-cancer biomarker for combined precision oncology and immunotherapy programs.

Genomic alterations associated with response to immune checkpoint inhibitors in rare cancers: A biomarker exploration study from the Australian Molecular Screening and Therapeutics (MoST) Program.

2594 Background: Despite immune checkpoint inhibitors (ICI) demonstrating efficacy in over 15 cancer types, evidence in most rare cancers remain scarce, reflecting the challenges of conducting prospective trials. This Australia-wide study reports real-world (RW) objective responses to ICIs targeting the programmed death-(ligand)1 (PD-1/PD-L1) pathway in a large precision oncology program, and associations between response and genomic alterations in rare cancers. Methods: This study was conducted within the framework of the MoST Program (ACTRN12616000908437), where adult patients (pts) with advanced solid tumors were screened using comprehensive genomic profiling (CGP). Only pts who received ICI after CGP were included in this analysis. The best overall response (BOR) to ICI was reported by the treating oncologist during the follow-up period. Best response was categorized as complete (CR), partial (PR), stable (SD), or progressive (PD). Two categories were defined: responders were individuals reported to have experienced CR or PR, while non-progressors were those with CR, PR, or SD. The association between tumor mutational burden (TMB) and response categories was assessed by area under the receiver operator characteristic curve (AUC). Odds ratios (OR) of specific genomic alterations associated with each category were also estimated. Results: Between Dec 2016 and Aug 2022, 4343 pts were screened; 3471 (80%) rare cancer pts, of whom 556 went on to 90 different ICI trials after undergoing CGP. In 273 pts treated with ICI where BOR was reported by the treating oncologist, the median survival was 17.3 months (95% CI 15.0 to 20.4). 13 pts (4.8%) had CR reported, including 8 pts with unapproved indications: 3 sarcomas, and 1 each, small cell carcinoma of unknown primary, adenoid cystic carcinoma, pituitary adenoma, thymoma, and pancreatic adenocarcinoma. 45 (16.5%) and 112 (41.0%) had PR and SD reported, respectively. High TMB, defined as ≥10 non-synonymous tumor mutations/megabase, was identified in 39 (14.3%) pts. TMB was associated with response (AUC 0.715, 0.630 to 0.800) and non-PD (AUC 0.600, 0.528 to 0.671) to ICI. Further exploratory analyses identified that alterations in EP300 (n = 7, OR, 9.8, 1.9 to 52), PTCH1 (n = 6, OR, 15.5, 1.7 to 141) , MSH6 and KMT2D (n = 6 each, OR, 7.7, 1.4 to 43) , and NF1 (n = 10, OR, 3.89, 1.1 to 13.9) were associated with CR/PR. Genomic ARID1A alterations (n = 18) were associated with non-PD (OR 5.16, 1.2 to 22.9), as were alterations in the SWI/SNF complex (n = 20, OR 3.64, 95% CI 1.0 to 12.8) . Conclusions: Notwithstanding their limitations, these real-world data suggest that rare cancer patients may also benefit from ICI. Further prospective investigations into pan-cancer genomic biomarkers of response are warranted. Clinical trial information: ACTRN12616000908437 .

National lung cancer screening rates among women veterans within the Veterans’ Health Administration.

1543 Background: Lung cancer is the number one cause of cancer related death among women in the United States. United States Preventive Services Task Force (USPTF) lung cancer screening (LCS) guidelines recommend annual low dose computed tomography (LDCT) among high-risk populations. The data specifically on women veterans is sparse so we retrospectively examined LCS rates among women veterans within the VHA. Methods: Women veterans ages 50-80, current or former (quit within 15 years) smokers from 2013- 2021 were identified through the VA corporate data warehouse (CDW). Captured characteristics included: demographics, smoking history, and cancer screening history (lung, breast, cervical). Data was analyzed using R Studio software. Results: Women veterans with a history of smoking (n=40,299) tended to be aged ≥60, white (66%), single (69%), unemployed (64%), urban dwelling (67%), and residing in Southeast U.S. (31%). Overall, cancer screening rates among women veterans was low (9% lung; 27% breast; 21% cervical). Of the women not screened for lung cancer (91%; n=36,837), 11% (n=4, 016) had a personal history of cancer. While pack-year history was not documented for the vast majority (92%), 7% (n= 2, 729) reported a &gt;30 pack-year smoking history (guideline at the time). Of these &gt;30 pack-year smokers, 88% (n=2,418) were not screened for lung cancer. Other significant demographic predictors of increased LCS rates included Southeast Veterans Integrated Service Network (VISN region) and comorbidities such as bipolar disorder and diabetes likely due to increased exposure to healthcare. Conclusions: LCS rates, as well as breast and cervical, among women veterans within the VHA is low. The lack of documented pack-year history among women veterans with a history of smoking is concerning. Increased documentation of pack-year history may aid in identifying women for LCS. Efforts are ongoing nationally to implement an equitable centralized LCS program for all veterans and as part of that effort the Birmingham VA Health Care System has utilized their Lung precision Oncology program (LPOP) funding to pilot a structured lung cancer screening program within our Women’s Health Clinic in 2022.

Clinical factors associated with successful liquid tumor biopsy in men with prostate cancer.

e13567 Background: Liquid biopsies using cell-free DNA (cfDNA) can be used in prostate cancer (PrCa) patients when tissue is unavailable and repeat biopsy is not feasible. Given the older age of PrCa patients, liquid biopsy may detect alterations related to clonal hematopoiesis of indeterminate potential (CHIP), generating uncertainty in the clinical utility of the results. We sought to identify clinical predictors of successful cfDNA biopsy, where the reported alterations are more likely to reflect the individual’s prostate cancer cfDNA instead of CHIP in a large cohort of United States Veterans with PrCa. Methods: Next-generation sequencing of cfDNA biopsy specimens was performed through the VA National Precision Oncology Program (NPOP) from February 2019 to November 2022. Successful identification of PrCa cfDNA testing was defined as the identification of an alteration in one or more PrCa-related genes included on the panel ( AR, CDK12, SPOP, MED12, CCND1, BRAF, AKT1, TMPRSS2, ERG, ETV1, and ETV4). Student’s t-tests, univariate, and multivariate logistic regression estimated significant patient and disease-specific factors at the time of cfDNA biopsy and the likelihood of obtaining a successful cfDNA biopsy result. Results: Among 5611 total cfDNA tests performed, 2066 cfDNA tests from 1985 Veterans listed PrCa as the clinical indication, passed quality control measures, and could be linked to patient-level demographics. 814 (39%) tests were deemed successful based upon identification of at least one PrCa related gene alteration. The most frequently encountered PrCa alterations were in AR (76.5%) and TMPRSS2 (22.4%). PSA was significantly higher (IQR 209.1 ng/ml) and PSA doubling time (PSADT) was significantly shorter (IQR 2.4 months) in the cohort of Veterans with successful cfDNA testing (p&lt;0.001). Among 1581 tests that reported tumor fraction, an elevated tumor fraction &gt;10 was also significantly associated with success (46.3% vs 8.1%, p&lt;0.001). On multivariate analysis, PSA elevation above 4.8 ng/ml (p&lt;0.001) and PSADT &lt;6 months (p&lt;0.001) were significantly associated with successful cfDNA testing. Actionable DDR mutations, including ATM (15.2% vs 11.7%, p=0.02), BRCA1 (1.7% vs 0.6%, p=0.03), and BRCA2 (7.4% vs 4.4%, p=0.01) were significantly more likely to be detected in a successful test compared to an unsuccessful test. Conclusions: High PSA and short PSADT are significant predictors of a cfDNA test identifying PrCa-related gene alterations in Veterans with metastatic disease instead of alterations due solely to CHIP. Liquid biopsy in PrCa should be reserved for patients with relatively higher disease burden or more aggressive growth rate, reflected by PSA values &gt; 4.8 and PSADT &lt; 6 months, to increase the likelihood of identifying actionable alterations and improve interpretation of testing.

Genomic targetability and survival outcomes of biliary tract cancers (BTC): A retrospective cohort study of the Australian Molecular Screening and Therapeutics (MoST) program.

4093 Background: Despite advances in therapeutic strategies, advanced BTC continue to have poor outcomes. We examined the genomic composition of these cancers and differences in clinical outcomes based on therapies (tx) received. Methods: This study included all BTC patients (pts) undergoing comprehensive genomic profiling (CGP) through an Australia-wide precision oncology program, MoST (ACTRN12616000908437). The primary outcome was overall survival (OS) measured from start of first line (1L) systemic tx. The TOPOGRAPH knowledge base was used to determine genomic actionability of alterations identified, tiered by the strength of supportive clinical evidence. Tier 1/2 are regulatory body (TGA or FDA/EMA) approved therapies in BTC; tier 3A is supported by BTC-specific clinical evidence; 3B by clinical evidence inferred from another cancer type; tier 4, pre-clinical evidence. As targeted therapies are only approved in the subsequent-line setting, a further OS analysis was performed from start of second line tx (2L). Results: Between December 2016 and August 2022, 223 pts had CGP results available: 170 cholangiocarcinoma (99 intrahepatic, 46 extrahepatic, 25 unspecified primary site) and 53 gallbladder carcinomas. Of 211 (95%) pts who received any systemic tx, median OS (mOS) was 14.6 (95% CI: 12.2—15.4) months (mo) from the start of 1L tx. Pts having received immunotherapy had a mOS of 20.7 vs 13.9 mo (HR 0.67, 0.44—1.04; p=0.07). For 198 pts with actionable findings across TOPOGRAPH tiers, receipt of matched tx (n=37) was associated with a significantly longer mOS of 21.4 (15.0—31.8) compared with receipt of unmatched tx (n=161), mOS 12.6 mo (11.5C15.2, hazard ratio for death, HR 0.46, p&lt;0.001). Pts with tier 1-3 actionable alterations who received matched tx had a median OS of 30.5 mo (95% CI: 18.8 - not reached, NR) compared with 12.1 mo (9.8—16.1, HR 0.39, p=0.02) if only unmatched tx received. Receipt of tier 3B/4 matched tx (n=13) only showed a trend towards longer survival, 15.6 mo vs unmatched 14.0 mo (HR 0.60, p=0.16). For 149 pts who received &gt;1 line of systemic tx: 35 matched and 103 unmatched alone, mOS (measured from 2L tx) was 11.3 (5.7-28.4) compared with 8.3 mo (6.1-10.6) respectively (HR 0.67, p=0.10). A significantly longer OS was seen for matched vs unmatched, in pts receiving tier 1-3 tx: mOS 19.0 mo vs 8.3 mo (HR 0.43, p=0.04), but not for tier 3B/4, mOS 5.6 vs 6.7 mo HR 1.31, p=0.48. The most common genomic alterations were in TP53 (86, 39%), KRAS (59, 26%), CDKN2A (43, 19%), and ARID1A (29, 13%), while actionable findings commonly involved IDH1 (26, 12%), FGFR2 (20, 9%), ERBB2 (14, 6%), and BRAF (11, 5%). Conclusions: Receipt of genomically matched tx, particularly those supported by TOPOGRAPH tiers 1-3 evidence was associated with longer OS for pts with advanced BTC. Our results support the greater use of CGP in the management of these pts.

Molecular tumor profiling and therapy selection in advanced gynecological cancers: A retrospective cohort analysis from the Australian Molecular Screening and Therapeutics (MoST) Program.

5526 Background: Gynecological (gyne) cancers are highly diverse with distinct sites of origin and histological subtypes that can limit development of evidence-based therapies. Comprehensive genomic profiling (CGP) has an increasing role in characterizing clinically relevant molecular subsets and in identifying actionable biomarkers with potential to guide therapy selection. Methods: MoST (ACTRN12616000908437) is an Australia-wide precision oncology program for adult patients (pts) with advanced cancers and limited treatment options. Tumor specimens are analysed by CGP and genomic results tiered by the level of evidence supporting matched therapies (https://topograph.info). Pts are followed for subsequent treatment and survival. Here, we present data for the MoST gyne cancer cohort. Results: Between Sept 2016 and Oct 2022, 533 gyne tumors were sequenced, with included pts having a minimum 4 months (mo) follow-up. Key histotypes included: ovarian serous (n=162) and non-serous (n=46) epithelial tumors; uterine carcinomas (n=99) and sarcomas (n=108); cervical carcinomas (n=51); germ cell and sex-cord stromal tumors (n=18); carcinosarcomas (n=33); and vulva/vaginal tumors (n=16). The median number of reported variants was 3 (IQR 2-5) and tumor mutational burden 3.1 mut/Mb (IQR 1.3—5.5, Range 0—284); 9 (2%) tumors were microsatellite unstable; and 22 (4%) had high level loss-of-heterozygosity (confirmed on validated genome-wide assays). The most common pathways involved in this pan-gyne cohort were: p53 (n=287, 54%), PI3K/AKT (n=227, 43%), cell cycle (n=182, 34%), and mitogen-activated protein kinase (n=91, 17%). Pathogenic mutations in BRCA1/2 were identified in 29 tumors (5%; 18 in ovarian serous cancers), whereas 81 tumors (15%) had alterations in other homologous recombination genes, most commonly uterine sarcomas (n=32, 30%). Actionable genomic biomarkers matched to a clinically active treatment (TOPOGRAPH tier 1-3) were identified in 207 (39%) tumors. In 19 pts (3.5%) who received Tier 1-3 matched therapy after CGP, a trend towards longer survival was observed (median OS 22.3 mo, 95% CI 17.3 to not reached) compared to those receiving unmatched therapy (n=65, median OS 14.9 mo, 10.2 to 22.1, p=0.052) following CGP. No OS difference was seen in pts who received matched investigational therapy (Tier 3B/4, n=31, median OS 17.0 mo, 8.1 to NR) versus only unmatched therapy (n=118, median OS 14.0 mo, 11.3 to 22.5; HR 0.97, 0.57 to 1.64; p=0.91). Conclusions: CGP identified actionable genomic results in nearly half of advanced gyne cancers, with enrichment in particular histotypes that supports testing above current standard of care. Trends in prolonged OS with subsequent matched therapies may be better realized with earlier testing and improved drug/clinical trial access.

Real-world rates of FDA-approved targeted therapy and immunotherapy prescriptions for patients with metastatic colorectal cancer in the VA’s National Precision Oncology Program (NPOP).

3602 Background: Colorectal cancer is the fourth most common cancer among Veterans and the third leading cause of cancer-related death in the USA. Use of comprehensive genomic profiling (CGP) to guide administration of FDA-approved biomarker directed therapies can improve outcomes among metastatic CRC (mCRC) patients. We sought to compute the rates of actionable biomarkers and prescriptions of associated FDA-approved therapies among Veterans in NPOP. Methods: The NPOP database was queried to identify mCRC patients who had undergone CGP via tissue or liquid biopsy between February 2019 and July 2022 and had one of the following 5 actionable biomarker profiles: NRAS/ KRAS/ BRAF wildtype, BRAF V600E, MSI-H, TMB-H, or NTRK fusion or rearrangement. The VA’s Corporate Data Warehouse (CDW) was queried to extract prescription data for seven FDA-approved biomarker-directed therapies (targeted agents and immune checkpoint inhibitors (ICIs)). Rates of CGP-directed therapy prescriptions were assessed based upon biomarker and patient characteristics (sex, race, ethnicity, and rurality). Results: A total of 908 mCRC patients underwent CGP, with 81.4% bearing colon adenocarcinoma (COAD) and 18.6% rectal adenocarcinoma (READ). Rates of actionable biomarkers associated with FDA-approved therapies were as follows: NRAS/ KRAS/ BRAF wildtype (34.4%), TMB-H (9.6%), BRAF V600E (7.7%), MSI-H (5.6%), TMB-H and MSI-H (5.6%), and NTRK Fusion or rearrangement (0.3%). The combined rates of any actionable variant were 47.4% for COAD and 44.4% for READ patients. Relative to patients without actionable biomarkers, patients with BRAF V600E mutations were more likely to be older and white; patients with NRAS/ KRAS/ BRAF wildtype were more likely to be younger (all p &lt; 0.001). Among the 424 eligible patients, the frequencies of FDA-approved CGP-directed therapy prescriptions were as follows: MSI-H (70.7%), TMB-H (47.4%), NRAS/ KRAS/ BRAF wildtype (38.5%), and BRAF V600E (17.1%). Across all included biomarkers, African Americans (53.4%) were more likely to receive these therapies than whites (36.8%); and patients with prescriptions were more likely to be younger that those without (all p &lt; 0.01). Conclusions: Nearly 30% of patients with MSI-H mCRC did not receive efficacious ICIs, and though disease laterality data was not readily available, a substantial number of eligible patients also did not receive EGFR inhibitors. This underuse of EGFR inhibitors has been reported previously [1].There were racial and age differences in prescription rates. Further studies should evaluate the barriers to prescribing CGP-directed therapies in the care of mCRC patients. Keywords: molecular testing, metastatic colorectal cancer, comprehensive genomic profiling, actionable biomarkers, FDA approved therapies, veterans. [1] Becker et al. 2021 PMID 34250412.

Genomic therapy matching in rare and refractory cancers: Updated results from a retrospective cohort study in the Molecular Screening and Therapeutic (MoST) program.

1540 Background: Biomarker actionability and therapy matching are two central concepts in precision oncology. However, the best strategy to align therapy with genomic alterations remains unclear. Here we report the updated results from a cohort study conducted in an Australian precision oncology program (MoST, ACTRN12616000908437), examining a therapy matching strategy based on comprehensive genomic profiling (CGP) results. Methods: All patients (pts) with rare or advanced solid tumours undergoing CGP from 2016 to 2021 after exhausting standard treatments were included. The primary outcome was overall survival (OS) from the date of CGP result, estimated using the Kaplan-Meier method. Pts were grouped according to tiers of actionability determined by matching against the TOPOGRAPH knowledge base ( https://topograph.info ) and stratified into clinically active (Tier 1-3, therapies with evidence from prospective trials), investigational (Tier 3B and 4, therapies with evidence from another cancer type, preclinical, or retrospective studies), or unmatched tier groups. To assess between-group differences in OS, hazard ratios (HR) were estimated in a time-varying Cox regression model adjusting for time to initiation of subsequent therapy. Results: This updated analysis included 3,383 pts (79% rare and less common). The median follow-up was 22.6 months (mo). For 2,065 pts who did not receive treatment after CGP, the median OS (mOS) was 8.2 mo (95% CI 7.4 to 9.0). For 1,318 pts who received ≥1 line of therapy after CGP, the mOS was 14.1 mo (13.4 to 15.2). 1,270 pts (38%) carried a genomic alteration linked to clinically active therapies (Tier 1-3). Of these, 116 (3.4%) received matched treatment after CGP, experiencing longer survival compared with 410 (32.2%) that received only unmatched therapy (mOS 21.2 v 12.8 mo, HR 0.58, 0.45 to 0.76, P&lt;0.001). Whilst receiving a matched therapy in the investigational tier group (n=133, T3B/4) did not show significant differences in outcomes (mOS 14.5 v unmatched 12.8 mo, n=536, HR 0.88, 0.72 to 1.08, p=0.24), exploratory analyses identified differences in survival for a subset of 41 pts with Switch/Sucrose Non-Fermentable complex mutations receiving matched Tier 4 therapies (mOS 30.1 v 9.6 mo, HR 0.29, 0.17 to 0.51, P&lt;0.0001). Pts receiving repurposed drugs that matched solely on biomarkers in non-cognate cancer types (Tier 3B) showed no survival difference over unmatched therapy (n=35 v 469, mOS 13.6 v 12.5 mo, HR 0.96, 0.65 to 1.41, p=0.83). Conclusions: This study provides insight into how biomarker-linked therapies can be rationally prioritised in rare and advanced cancer populations. Addressing the barriers of access to Tier 1-3 therapies may broaden the utility of genomic biomarker testing. Off-label drug repurposing without direct supporting evidence should only be undertaken in a clinical trial setting.

Pattern of molecular testing among US veterans with gastrointestinal cancers: A single center experience.

e13663 Background: In response to the rising global burden of cancers, the Veterans Health Administration's (VHA) National Precision Oncology Program (NPOP) supports the use of molecular testing (MT) among veterans. The Oklahoma City (OKC) VHA is serving patients with cancer in both rural and urban areas by implementing the standard practice of precision oncology testing across our diverse patient population. Identification of molecular biomarkers can facilitate treatment selection and trial access for veterans. Here we report real-world practices of physicians caring for veterans with gastrointestinal (GI) cancers namely gastroesophageal (GE), pancreatobiliary (PB) and colon cancers at OKC VHA and determine the degree to which molecular data is being utilized to prognosticate or alter clinical management. Methods: Patients presenting to the OKC VHA with metastatic GE, PB and colon cancer from June 2020 to September 2022 were included in the study. Data was collected retrospectively, including patient demographics, clinical characteristics, mutational data, actionability (OncoKB), and treatment recommendations. The primary outcome was the percentage of tumor sequencing performed, and actionable alteration annotated by the OncoKB database therapeutic evidence level. Results: 101 veterans were diagnosed with metastatic GI cancers (GE 18.8%, PB 28.7% and colon 52.4%), of which 82 samples (81.2%) were submitted for MT. The cohort was male-dominant (98%) with a median age of 69.5 years, and 46.5% of the veterans were from rural Oklahoma. Time from test order date to test result availability was 11.7 days. 25.7% (n=26) had at least one likely oncogenic mutation according to the OncoKB database, and 12.8% of them (n=13) were changed to FDA-approved targeted medications. The most common aberrant genes were TP53, KRAS, HER2, and MSI-H. Statistically significant differences were seen in the level of evidence by cancer group. In multivariate logistic regression, patients with colon cancer were most likely to receive MT (OR, 45.5 95% CI 2.27, 27.0 for colon over PB; OR 14.7 95% CI 2.27, 29.6 for GE over PB). Provider level (fellow vs faculty) and distance from the VHA (urban vs rural) were not associated with MT. Conclusions: Our study indicates clinical implementation of precision oncology is feasible across the VHA healthcare system, including rural veterans. Further analysis of this large cohort of patients will help to address gaps in MT for veterans with GE and PB cancers. The study also highlights the importance of MT to guide clinical trial enrollment and identify investigational drug opportunities among veterans.[Table: see text]

The Maine Cancer Genomics Initiative: Implementing a Community Cancer Genomics Program Across an Entire Rural State.

The Maine Cancer Genomics Initiative (MCGI) aimed to overcome patient- and provider-level barriers to using genomic tumor testing (GTT) in rural practices by providing genomic tumor boards (GTBs), clinician education, and access to comprehensive large-panel next-generation sequencing to all patients with cancer in Maine. This paper describes the successful implementation of the initiative and three key services made operative between 2016 and 2020. A community-inclusive, hub-and-spoke approach was taken to implement the three program components: (1) a centralized GTB program; (2) a modular online education program, designed using an iterative approach with broad clinical stakeholders; and (3) GTT free of charge to clinicians and patients. Implementation timelines, participation metrics, and survey data were used to describe the rollout. The MCGI was launched over an 18-month period at all 19 oncology practices in the State. Seventy-nine physicians (66 medical oncologists, 5 gynecologic oncologists, 1 neuro-oncologist, and 7 pediatric oncologists) enrolled on the study, representing 100% of all practicing oncologists in Maine. Between July 2017 and September 2020, 1610 patients were enrolled. A total of 515 cases were discussed by 47 (73%) clinicians in 196 GTBs. Clinicians who participated in the GTBs enrolled significantly more patients on the study, stayed in Maine, and reported less time spent in clinical patient care. The MCGI was able to engage geographically and culturally disparate cancer care practices in a precision oncology program using a hub-and-spoke model. By facilitating access to GTT, structured education, and GTBs, we narrowed the gap in the implementation of precision oncology in one of the most rural states in the country.

HOPE (SOLTI-1903) breast cancer study: real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer.

Metastatic breast cancer (mBC) causes nearly all BC-related deaths. Next-generation sequencing (NGS) technologies allow for the application of personalized medicine using targeted therapies that could improve patients' outcomes. However, NGS is not routinely used in the clinical practice and its cost induces access-inequity among patients. We hypothesized that promoting active patient participation in the management of their disease offering access to NGS testing and to the subsequent medical interpretation and recommendations provided by a multidisciplinary molecular advisory board (MAB) could contribute to progressively overcome this challenge. We designed HOPE (SOLTI-1903) breast cancer trial, a study where patients voluntarily lead their inclusion through a digital tool (DT). The main objectives of HOPE study are to empower mBC patients, gather real-world data on the use of molecular information in the management of mBC and to generate evidence to assess the clinical utility for healthcare systems. After self-registration through the DT, the study team validates eligibility criteria and assists patients with mBC in the subsequent steps. Patients get access to the information sheet and sign the informed consent form through an advanced digital signature. Afterwards, they provide the most recent (preferably) metastatic archival tumor sample for DNA-sequencing and a blood sample obtained at the time of disease progression for ctDNA analysis. Paired results are reviewed by the MAB, considering patient's medical history. The MAB provides a further interpretation of molecular results and potential treatment recommendations, including ongoing clinical trials and further (germline) genetic testing. Participants self-document their treatment and disease evolution for the next 2 years. Patients are encouraged to involve their physicians in the study. HOPE also includes a patient empowerment program with educational workshops and videos about mBC and precision medicine in oncology. The primary endpoint of the study was to describe the feasibility of a patient-centric precision oncology program in mBC patients when a comprehensive genomic profile is available to decide on a subsequent line of treatment. www.soltihope.com, identifier NCT04497285.

Actionable Genomic Alterations in Prostate Cancer Among Black and White United States Veterans.

Black Veterans have higher a incidence of localized and metastatic prostate cancer compared to White Veterans yet are underrepresented in reports of frequencies of somatic and germline alterations. This retrospective analysis of somatic and putative germline alterations was conducted in a large cohort of Veterans with prostate cancer (N = 835 Black, 1613 White) who underwent next generation sequencing through the VA Precision Oncology Program, which facilitates molecular testing for Veterans with metastatic cancer. No differences were observed in gene alterations for FDA approved targetable therapies (13.5% in Black Veterans vs. 15.5% in White Veterans, P = .21), nor in any potentially actionable alterations (25.5% vs. 28.7%, P =.1). Black Veterans had higher rates of BRAF (5.5% vs. 2.6%, P < .001) alterations, White Veterans TMPRSS2 fusions (27.2% vs. 11.7%, P < .0001). Putative germline alteration rates were higher in White Veterans (12.0% vs. 6.1%, P < .0001). Racial disparities in outcome are unlikely attributable to acquired somatic alterations in actionable pathways.

Abstract 938: Outcomes of molecular tumor board recommendations for cancer patients with progression on standard of care therapies in Saudi Arabia

Abstract Introduction: Molecular Tumor Boards (MTB) are essential in Precision Oncology Programs. Gaps, however, remain in interpreting comprehensive genomic profiling (CGP) results, and determining their actionability. Our MTB, established in October 2020 and conducted at a tertiary cancer center in Saudi Arabia, focused on discussing patients with complex CGP results and recommending genomic based therapies. Meetings occurred virtually, every month, with oncologists, pathologists and genomicists attending. Methods: This is a retrospective cohort study of patients discussed in our MTB from October 2020 till October 2022. We report the outcomes of these patients who had progressive disease on standard of care (SOC) therapies, and have had non Tier 1 alterations (ESCAT classification) in their CGP reports. We chose an FDA approved, commercially available CGP, which tests 324 genes (FoundationOne CDX). We present the demographics, clinical characteristics, CGP results, recommendations of the MTB, and patient outcomes. Results: Sixty patients fitting the criteria above have been discussed. Median number of prior systemic therapy lines was 2 (range 0-8). The most common primary diagnosis was soft tissue sarcoma (25%), followed by liver and pancreato-biliary cancers (20%), followed by head and neck cancers (15%) and skin cancers (8%). Of the 60 patients, 48 patients had response evaluations. Thirty five patients (out of 48, 73%) have had recommendations for genomic based therapies based on their CGP results. Only 16 patients (out of 35, 46%) received MTB recommended therapies. Eight patients (out of 16, 50%) have remained progression free and on MTB recommended genomic therapy for 6 months and above. The commonest reasons for not receiving MTB recommended therapy were patient clinical deterioration or death (9 patients, 47%) followed by patients responding on current line of therapy (7 patients, 37%). Most common pathogenic targetable alterations were CDKN2A/B mutations (6 patients), followed by alterations in FGFR (5 patients), PTEN (4 patients), BRAF (4 patients), PIK3CA (2 patients) and ERBB2 (2 patients) followed by others (will be presented). Conclusion: Following recommendations, of the first MTB in Saudi Arabia, resulted in improved outcomes of cancer patients who had progressive disease on SOC therapies. Consideration of performing CGP and discussing patients early in their cancer journey may allow them to receive, and benefit from recommended genomic therapies earlier. Citation Format: Kanan Alshammari, Fouad Sabatin, Mehlika Hazar-Rethinam, Faizah Alotaibi, Reham Ajina, Hussam Shehata, Mohammad Alkhayyat, Abdullah Alsaleh, Mohammed Algarni. Outcomes of molecular tumor board recommendations for cancer patients with progression on standard of care therapies in Saudi Arabia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 938.

Abstract 4509: A pan-Canadian precision oncology program for children, adolescents and young adults with hard-to-cure cancer: The PRecision Oncology For Young peopLE (PROFYLE) Program

Abstract Background: Over 4,300 children, adolescents, and young adults (CAYA) are diagnosed with cancer each year in Canada, 1/3 of whom have refractory/metastatic disease or will relapse. The PRecision Oncology For Young peopLE (PROFYLE) national, collaborative program, was created to provide equitable access to molecular profiling to identify novel targeted treatment options in a clinically relevant timeframe for all CAYA with hard-to-cure cancers in Canada. Design: Building upon 3 pre-existing regional precision oncology programs, PROFYLE now includes &amp;gt;20 institutions and has united an interdisciplinary team of experts, leaders, research teams, end-users and advocates from across Canada. The program has 14 domain specific nodes that are unified by a shared governance structure, and has harmonized biobanking, genomics, bioinformatics and reporting procedures. PROFYLE includes genomic and transcriptomic sequencing of paired germline and cancer fresh/frozen samples, proteomic analysis, and cancer modelling. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-cure cancer. Profiling results are reviewed by multidisciplinary Molecular Tumor Boards. A report including a results/recommendations summary of actionable findings (therapeutic, diagnostic, prognostic, cancer predisposition), potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling recommendations is provided to the treating oncologist. Results: &amp;gt;1,000 CAYA are included from all of the provinces. Cancer diagnoses: 34% sarcoma, 16% leukemia/lymphoma, 16% CNS tumor, 11% neuroblastoma, 23% other. 17% of participants had a cancer-predisposing pathogenic/likely pathogenic germline variant, 45% had ≥1 potentially actionable somatic alteration, 22.6% had a therapeutically targetable somatic alteration. The most frequent classes of therapeutic alterations were RAS/MAPK (15%), cell cycle (14%), epigenetic (13%), RTK (12%), PI3K/AKT/mTOR (11%), DNA repair (9%), immune checkpoint (8%). Of clinicians who reported the utility of results, 55% indicated the findings were useful for clinical management. Future Directions: Collaborations with other national and international initiatives and data from this interdisciplinary, multi-institutional research program will inform the development of a framework to innovatively link research, clinical and system considerations with Canadian values relevant to multi-omic profiling and drug access for CAYA. In addition, we believe that with a comprehensive molecular view of cancer, PROFYLE will transform our understanding of underlying disease mechanisms, facilitate and improve diagnostic and prognostic indicators, and identify new therapeutic strategies and targets for CAYA patients with cancer. Citation Format: Stephanie A. Grover, Lesleigh Abbott, Jason N. Berman, Guillaume Bourque, Jennifer A. Chan, Avram E. Denburg, Rebecca J. Deyell, Conrad V. Fernandez, Cynthia Hawkins, Jan-Willem Henning, Meredith S. Irwin, Nada Jabado, Steven J. Jones, Philipp F. Lange, Paul Moorehead, Michael F. Moran, Daniel A. Morgenstern, Sapna Oberoi, Antonia Palmer, Shahrad R. Rassekh, Donna L. Senger, Adam Shlien, Daniel Sinnett, Caron Strahlendorf, Patrick J. Sullivan, Michael D. Taylor, Suzanne Vercauteren, Anita Villani, Stephanie Villeneuve, James A. Whitlock, David Malkin, on behalf of the PROFYLE Consortium. A pan-Canadian precision oncology program for children, adolescents and young adults with hard-to-cure cancer: The PRecision Oncology For Young peopLE (PROFYLE) Program. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4509.

Real-world performance analysis of a novel computational method in the precision oncology of pediatric tumors.

The utility of routine extensive molecular profiling of pediatric tumors is a matter of debate due to the high number of genetic alterations of unknown significance or low evidence and the lack of standardized and personalized decision support methods. Digital drug assignment (DDA) is a novel computational method to prioritize treatment options by aggregating numerous evidence-based associations between multiple drivers, targets, and targeted agents. DDA has been validated to improve personalized treatment decisions based on the outcome data of adult patients treated in the SHIVA01 clinical trial. The aim of this study was to evaluate the utility of DDA in pediatric oncology. Between 2017 and 2020, 103 high-risk pediatric cancer patients (< 21years) were involved in our precision oncology program, and samples from 100 patients were eligible for further analysis. Tissue or blood samples were analyzed by whole-exome (WES) or targeted panel sequencing and other molecular diagnostic modalities and processed by a software system using the DDA algorithm for therapeutic decision support. Finally, a molecular tumor board (MTB) evaluated the results to provide therapy recommendations. Of the 100 cases with comprehensive molecular diagnostic data, 88 yielded WES and 12 panel sequencing results. DDA identified matching off-label targeted treatment options (actionability) in 72/100 cases (72%), while 57/100 (57%) showed potential drug resistance. Actionability reached 88% (29/33) by 2020 due to the continuous updates of the evidence database. MTB approved the clinical use of a DDA-top-listed treatment in 56 of 72 actionable cases (78%). The approved therapies had significantly higher aggregated evidence levels (AELs) than dismissed therapies. Filtering of WES results for targeted panels missed important mutations affecting therapy selection. DDA is a promising approach to overcome challenges associated with the interpretation of extensive molecular profiling in the routine care of high-risk pediatric cancers. Knowledgebase updates enable automatic interpretation of a continuously expanding gene set, a "virtual" panel, filtered out from genome-wide analysis to always maximize the performance of precision treatment planning.

Real-world Experience With Neurotrophic Tyrosine Receptor Kinase Fusion-positive Tumors and Tropomyosin Receptor Kinase Inhibitors in Veterans.

Neurotrophic tyrosine receptor kinase 1-3 (NTRK1-3) gene fusions are found in a broad range of tumor types. Clinical trials demonstrated high response rates to tropomyosin receptor kinase (TRK) inhibitors in NTRK fusion-positive cancers, but few reports have described real-world experience with these targeted agents. We evaluated the prevalence of NTRK fusions and the outcomes with TRK inhibitor therapy in a real-world population of patients in the Veterans Health Administration. Patients with NTRK fusions or rearrangements were identified from the Veterans Affairs (VA) National Precision Oncology Program (NPOP), and patients who were prescribed TRK inhibitors were identified from the Corporate Data Warehouse. Baseline data and clinical outcomes were obtained by retrospective review of medical records. A total of 33 patients with NTRK fusions or rearrangements were identified, including 25 patients comprising 0.12% of all patients with solid tumors sequenced through VA NPOP. Twelve patients with NTRK fusions or rearrangements were treated with TRK inhibitors, none of whom had objective responses. Eight patients experienced toxicities leading to drug interruption, dose reduction, or discontinuation. In this retrospective study of VA patients, NTRK fusions and rearrangements were less common than in previous studies, and objective responses to TRK inhibitors were not observed. Real-world experience with TRK inhibitors differs markedly from clinical trial findings, possibly due to differences in patient demographics, tumor types, and sequencing methods. Our findings highlight the need to study TRK inhibitors in the real-world setting and in populations underrepresented in clinical trials.