3015
Background: The clinical care of oncology patients is routinely informed by tumor and inherited genetic profiles. This is accomplished by molecular pathologists synthesizing the growing body of ...clinical guidelines and scientific evidence that associates cancer genome alterations and therapeutic response, and applying that knowledge during case reviews. Many academic medical centers formalize this process in the form of molecular tumor boards. As the number of cases for review and literature continue to increase, there is opportunity to leverage clinical interpretation algorithms to computationally prioritize molecular features and both enhance and automate the sample contextualization process. Here, we present the Molecular Oncology Almanac (MOAlmanac) to enable the rapid assessment of tumor actionability. Methods: Molecular Oncology Almanac is an open source clinical interpretation algorithm and paired knowledge base for precision cancer medicine. It is used to rapidly characterize and identify genomic features related to therapeutic sensitivity and resistance and of prognostic relevance. This is performed by assessing not only individual genomic features (e.g. somatic variants, copy number alterations, germline variants, and fusions) but also interactions between these events as well as secondary features such as mutational burden, mutational signatures, MSI status, and aneuploidy. MOAlmanac summarizes all clinically relevant findings into a web-based actionability report. The underlying knowledge base can be accessed through our API endpoints and web browser, and entries may be recommended through either Github or our browser extension. In addition, we developed a cloud-based web portal on top of the Terra framework to increase accessibility. Results: A total of 32,108 samples from 30,607 patients across 66 cancer types received targeted sequencing to characterize somatic variants, copy number alterations, and fusions from PROFILE’s Oncopanel and were evaluated with MOAlmanac. Based on Oncopanel’s tier 1 and tier 2 criteria for clinical actionability, we observed that 8,285 samples (26%, 0 - 69% by cancer type) of patients harbored at least one alteration suggesting therapeutic sensitivity based on FDA approvals or clinical guidelines. Actionability increases to 18,117 samples (56%, 0 - 85% by cancer type) when considering an expanded set of evidence to include relationships captured from clinical trials, clinical, preclinical, and inferential evidence; consequently providing at least one therapeutic hypothesis to otherwise variant-negative patients. Conclusions: Clinical actionability of molecular tumor data was increased in individual patients by expanding the set of evidence considered. Source code and a web portal for this project are available at moalmanac.org .
e17002
Background: Radiation therapy (RT) is a backbone of treatment for patients with prostate cancer (PCa). However, locally recurrent disease after definitive RT (i.e. radiorecurrent PCa) is not ...uncommon and is associated with a higher risk of distant metastases and death from PCa. While the genomic landscape of primary PCa is well-characterized, little is known regarding the genomic landscape of radiorecurrent PCa or how this compares to that of primary PCa. We hypothesized that the genomic landscape of radiorecurrent PCa differs significantly from primary PCa and that these differences have clinical relevance. We examined this hypothesis by performing whole exome sequencing (WES) of radiorecurrent PCa. Methods: We identified 25 patients with radiorecurrent PCa with available post-RT tissue obtained from biopsy or radical prostatectomy, as well as germline tissue. The tumor and germline tissue for 19 patients successfully underwent WES. We identified genomic variants including single nucleotide variants (SNVs), insertions/deletions, and copy number alterations. Furthermore, we estimated the tumor mutational burden (TMB; number of nonsynonymous mutations per megabase Mb) and contribution of individual mutational signatures. We compared our samples to a publicly available large cohort of primary PCa (n = 680) to define genomic alterations unique to radiorecurrent PCa. Results: In the overall cohort of 25 patients, the RT modality included external beam RT (56%), brachytherapy (36%), and combination of both (8%). 40% of patients received upfront androgen deprivation therapy with RT. The median time to local recurrence was 6.5 years. For the 19 radiorecurrent patients with WES data, the median TMB was 2.7 mutations/Mb, which was significantly higher than the median TMB of 0.7 mutation/Mb for primary PCa ( P= 0.002 after multivariable adjustment). Radiorecurrent PCa demonstrated an enrichment of short deletions, with a significantly higher deletion/SNV ratio compared to primary PCa ( P= 0.006). TP53 was the most frequently mutated gene in radiorecurrent PCa (n = 6), and the TP53 mutation prevalence was significantly higher compared to primary PCa (32% vs 10%, P= 0.016 by Fisher’s exact test). TP53 was also determined to be recurrently mutated using MutSigCV (Q = 0.0003). Additionally, 3 samples demonstrated evidence of whole genome doubling. Conclusions: Radiorecurrent PCa has a distinct genomic profile compared to primary PCa, characterized by a higher TMB with an enrichment of short deletions as part of the mutational composition, which may be a scar of nonhomologous end joining subsequent to RT-induced DNA double-stranded breaks. In addition, TP53 mutations may be of functional consequence in radiorecurrent PCa. Further efforts are underway to examine other genomic features apparent in WES data, as well as perform whole transcriptome sequencing to provide complementary insights into radiorecurrent PCa.
203
Background: Radium-223 (Ra-223) is a bone-seeking alpha emitter that induces double-stranded DNA breaks, and the homologous recombination (HR) pathway is critical for repairing these breaks. ...While prior studies suggested that metastatic castrate-resistant prostate cancers (mCRPC) patients (pts) with HR-deficient (HRD+) tumors may be more likely to benefit from Ra-223, obtaining tissue for next generation sequencing to identify HRD+ is challenging in pts with bone-predominant disease. We hypothesized that circulating tumor DNA (ctDNA) would allow for broader identification of HRD+ to assess association with clinical outcomes in a real-world cohort. Methods: We identified 135 mCRPC pts treated with Ra-223 at our institution between 2013 and 2021. Pts who initiated another anti-tumor therapy within 60 days of Ra-223 treatment were excluded; pts continuing hormonal agents initiated >60 days prior were included. ctDNA isolated from pre-treatment plasma underwent ultra-low-pass whole genome sequencing to estimate tumor fraction (TF). Additionally, targeted panel sequencing using an institutional prostate cancer-specific panel of 319 genes with duplex sequencing (utilizing unique molecular identifiers) for error suppression was used to identify germline or somatic deleterious alterations in HR pathway genes. The primary outcome was association between HRD status and completion of fewer than 6 cycles (as a proxy for early clinical progression), assessed using logistic regression. Results: The median age was 61 (IQR, 56-67) years, median pretreatment prostate-specific antigen (PSA) level was 26.2 (IQR, 8.1-84.1) ng/mL, and median TF was 4% (IQR, 3-6%). 97% of pts (n=131) previously received a novel antiandrogen, and 63% (n=85) received prior taxane. 17% (n=23) were HRD+, and 59% (n=80) completed 6 cycles of Ra-223. On multivariable analysis, HRD+ was associated with decreased likelihood of completing 6 cycles compared to HRD- (adjusted odds ratio AOR 0.16, 95% confidence interval CI 0.05-0.48, P=0.001). 22% (n=5) of HRD+ pts completed 6 cycles compared to 67% (n=75) of HRD- pts. Additional factors associated with decreased likelihood of completing 6 cycles included a higher pretreatment TF (AOR 0.69, 95% CI, 0.48-0.97, P=0.034) and prior taxane use (AOR 0.41, 95% CI, 0.18-0.91, P=0.028), but not pretreatment PSA ( P=0.574). Conclusions: Targeted panel sequencing with error suppression from ctDNA identified HRD+ in mCRPC pts with bone-predominant disease and low median TF at a similar frequency as reported from tissue. In our cohort, HRD+ was prognostic of early clinical progression with Ra-223. Further work is in progress to understand the association of other ctDNA-derived features, including assessment of genomic signatures and transcriptional binding sites, in the setting of Ra-223 therapy. DF/HCC IRB protocol 18-135.
TPS11588
Background: Osteosarcoma (OS) and Leiomyosarcoma (LMS) are sarcomas with complex genomes for which there has been limited progress in identifying new treatments and improving outcomes. Slow ...progress in OS and LMS is partially due to insufficient characterization of the genomic landscape. Generating large genomic datasets in OS and LMS is challenging because of the rarity of these sarcomas and recruitment barriers such as care fragmentation between institutions and specialties. The OS and LMS Project research studies aim to: 1) establish a network of engaged pediatric and adult participants with OS and LMS who will co-create a shared database of clinical, genomic, molecular, and patient reported data to enable research; 2) define the clinicogenomic landscape of OS and LMS; and 3) optimize the approach to direct patient engagement in cancer research. Methods: Count Me In, a research initiative with prior success in angiosarcoma, working with patients and advocates created websites (OSProject.org and LMSProject.org) where patients register and consent to participation. Projects were launched in September, 2022. After 5 months of accrual, 306 patients age 6-79 from 149 Institutions have consented. Blood and saliva are collected from consented participants, tumor samples are obtained from pathology departments and medical records are requested from treating hospitals. WES and WGS of tumor and normal, and RNASeq of tumor is performed. ctDNA is obtained and sequenced. Results are shared with patient, advocacy, physician and research communities in several ways. Individual participants receive a shared learning report describing the somatic variants identified in their tumor from paired tumor-normal WES and are offered genetic counseling and clinical germline testing. Registered participants receive updates via email and Project websites. There are regular pre-publication data releases to the genomic data commons and to cBioPortal. A physician engagement committee meets regularly to discuss clinical insights and conundrums from shared learning reports and germline testing. Patient accrual over the next 3 years is anticipated to result in sequencing of 750 tumor-normal pairs and 500 ctDNA samples.
Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. ...Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit.
modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. SIGNIFICANCE: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC I
subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection.
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Bag-valve-mask ventilation and endotracheal intubation have been the mainstay of prehospital airway management for over four decades. Recently, supraglottic device use has risen due to various ...factors. The combination of bag-valve-mask ventilation, endotracheal intubation, and supraglottic devices allows for successful airway management in a majority of patients. However, there exists a small portion of patients who are unable to be intubated and cannot be adequately ventilated with either a facemask or a supraglottic airway. These patients require an emergent surgical airway. A surgical airway is an important component of all airway algorithms, and in some cases may be the only viable approach; therefore, it is imperative that EMS agencies that are credentialed to manage airways have the capability to perform surgical airways when appropriate. The National Association of Emergency Medical Services Physicians (NAEMSP) recommends the following for emergency medical services (EMS) agencies that provide advanced airway management.
A surgical airway is reasonable in the prehospital setting when the airway cannot be secured by less invasive means.
When indicated, a surgical airway should be performed without delay.
A surgical airway is not a substitute for other airway management tools and techniques. It should not be the only rescue option available.
Success of an open surgical approach using a scalpel is higher than that of percutaneous Seldinger techniques or needle-jet ventilation in the emergency setting.
Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics ...and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.
Background
The phosphatidyl 3‐inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the ...authors performed a phase 2 study evaluating the efficacy of the pan‐isoform class I PI3K inhibitor buparlisib in patients with platinum‐refractory metastatic UC.
Methods
Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway–altered tumors. The primary endpoint was the 2‐month progression‐free survival rate. A rate of ≥80% was considered promising using a Simon 2‐stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome.
Results
Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA‐activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment‐related toxicities, 2 of whom had to discontinue therapy.
Conclusions
Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform‐selective PI3K inhibitors in genomically selected patients.
Lay Summary
The phosphatidyl 3‐inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway frequently is upregulated in patients with metastatic urothelial carcinoma (UC).
This trial explored buparlisib, an inhibitor of the pathway, in patients with heavily pretreated metastatic UC.
Although the drug was found to have modest efficacy, with 6 patients experiencing stable disease and 1 patient achieving a partial response at 8 weeks on therapy, significant side effects also were observed. Patients with specific genetic alterations responded to treatment.
Further studies of PI3K pathway inhibition are warranted using newer agents that have superior toxicity profiles and are more selective inhibitors of the pathway.
Phosphatidyl 3‐inositol kinase (PI3K) pathway inhibition with buparlisib demonstrates modest activity in patients with metastatic urothelial carcinoma, with significant toxicity. Further studies of PI3K pathway inhibition should focus on patients with select genetic alterations and use isoform‐selective inhibitors.
PI3K pathway inhibition with buparlisib exhibited modest activity in metastatic urothelial carcinoma with significant toxicity. Further studies of PI3K pathway inhibition should focus on patients ...with select genetic alterations and using isoform-selective inhibitors.
Abstract
Background: Despite significant advances, only a subset of patients with advanced melanoma treated with immune checkpoint blockade (ICB) experience durable responses, and biomarkers to ...predict response are limited. Further, while combination ICB has higher response rates and improved progression-free survival compared to single-agent therapy in the front-line setting, there is significantly increased toxicity with combination ICB, and biomarkers to identify patients who would disproportionately benefit from combination therapy vs aPD-1 ICB are poorly characterized. Methods: To understand resistance mechanisms to ICB therapy, we analyzed whole-exome-sequencing (WES) of pre-treatment tumor and matched normal tissue from 4 cohorts of previously ICB-naïve, aPD-1 treated patients (n=140). The SKCM TCGA cohort (from a pre-immuno- and targeted-therapy time period) was used for comparison to understand the prognostic and predictive role of the features identified. We then developed a parsimonious predictive model to identify patients with intrinsic resistance (PD as BOR) on aPD1 treatment with high specificity. Finally, we analyzed two additional independent cohorts to validate the model and to test whether patients predicted to have intrinsic resistance to single-agent aPD-1 may respond to combination ICB. Results: We found that high intratumoral genomic heterogeneity and low ploidy robustly identified patients with intrinsic resistance to aPD-1 within and across each independent cohort. Compared to the TCGA SKCM (“untreated” cohort), genomic heterogeneity specifically predicted response (Mann-Whitney p=0.018) and survival (multivariate Cox log rank p=0.002) in the ICB treated cohorts, but not in the untreated cohort, while ploidy was prognostic of overall survival in the “untreated” (by targeted therapy or ICB) group. (log-rank p=0.01). To establish clinically actionable predictions, we optimized a simple decision tree using genomic ploidy and heterogeneity and identified with high confidence a subset of patients with intrinsic resistance (PPV=90%) and significantly worse survival on aPD1 treatment (optimized decision tree OS log-rank p<0.001; PFS log-rank p<0.001). We then validated this model in a set of independent cohorts, and further demonstrate that these features and predictions of the model are independent of known clinical features and previously reported molecular biomarkers associated with poor-risk disease or poor response to ICB. Finally, in an additional cohort, we found that a significant proportion of patients predicted to have intrinsic resistance to single agent aPD-1 responded to combination aPD1+aCTLA4. Conclusions: These findings nominate the clinical and biological importance of genomic heterogeneity and ploidy, and sets a concrete framework towards clinical actionability, broadly advancing precision medicine in oncology.
Citation Format: Giuseppe Tarantino, Cora A. Ricker, Annette Wang, Will Ge, Amy Y. Huang, Shariq Madha, Jiajia Chen, Yingxiao Shi, Dennie T. Frederick, Samuel Freeman, Marta M. Holovatska, Michael P. Manos, Lisa Zimmer, Alexander Rösch, Anne Zaremba, Brendan Reardon, Jihye Park, Haitham Elmarakeby, Bastian Schilling, Anita Giobbie-Hurder, Natalie Vokes, Elizabeth I. Buchbinder, Keith Flaherty, Rizwan Haq, Catherine Wu, Genevieve Boland, F. Stephen Hodi, Eliezer Van Allen, Dirk Schadendorf, David Liu. Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma 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 965.
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