TEST:

Tempus xF Assay

ctDNA testing may serve as an adjunctive tool to clinical risk assessment models in cancer patients to improve personalized VTE risk stratification and management. The number of pathogenic ctDNA mutations was independently associated with increased VTE risk across cancer types, even after adjusting for clinical factors. While ctDNA analysis provided additive value to clinical risk models, it did not outperform them, highlighting the need for multimodal prediction approaches.

Further research is warranted to elucidate how longitudinal ctDNA analysis can delineate biomarkers of response and resistance at both the mutation and ctDNA fraction levels. Understanding these dynamics could offer valuable insights into disease progression and guide personalized treatment strategies for RCC patients.

"Guardant Health filed a lawsuit...against rival cancer genomics firm Tempus AI, alleging that Tempus has infringed a handful of its patents relating to liquid biopsy sequencing methods...Guardant specifically cited Tempus' Tempus xF, Tempus xF+, and Tempus xM Monitor assays as examples, as well as the firm's recently developed minimal residual disease offering, Tempus xM MRD."

70% of patients received Trastuzumab deruxtecan (T-DXd) and 30% received Sacituzumab govitecan (SG). In HR+ mBC, detection of mutated genes associated with the Ras-MAPK pathway by ctDNA was associated with a more favorable response when treated with ADCs. These findings are exciting because HR+ BCs are being targeted with ADCs regardless of HER2 or TROP2 expression, highlighting the need for new biomarkers to distinguish which HR+ patients to treat. Our retrospective analysis findings are limited by the number of patients with ctDNA testing and also timing of testing.

In this retrospective analysis, Tempus EHR integrations increased ordering of comprehensive NSCLC NGS by 53%. Despite study limitations such as the incomplete resolution into internal alternate sequencing workflows, this large-scale analysis provides further evidence that EHR-based workflow improvements reduce the barrier to appropriate sequencing.

This analysis shows that ctDNA profiling is complementary to tissue based NGS in RCC and can increase the detection of mutations. Concordance between ctDNA and tissue profiling increased in individuals with metastatic disease. Future research is warranted to understand how longitudinal ctDNA analysis can define biomarkers of response and resistance at the mutation and ctDNA fraction levels.

xF monitor can be used as a strategy to identify patients at a high risk of progression who could benefit from early switch or intensifying therapy. Results need to be prospectively validated in a larger cohort.

Patients with ESR1m acquired on AI may retain treatment response if switched to selective estrogen receptor degraders (SERDs) like fulvestrant... xF Monitor is a ctDNA assay that tracks changes in quantitative ctDNA TF and simultaneously monitors for the emergence of ESR1m, providing a diagnostic that identifies resistance to AI therapy and enables early switch to therapies that could improve outcomes in a patient population with poor prognosis. A larger prospective clinical study is needed to validate these findings.

Here we introduce a novel sensitive and specific tumor-informed, non-bespoke approach for estimating ctDNA TF. Linearity improves with increased panel size and increased variant number. These results suggest that a tumor-informed ctDNA TF can be utilized to improve the sensitivity of existing methods for estimating tumor fraction to help in treatment decisions using Tempus' tissue and liquid comprehensive NGS genomic profiling platform.

When treated with palbociclib + fulvestrant or palbociclib + estrogen-free medium (mimicking estrogen suppression in patients treated with aromatase inhibitors), cells harboring the Y537S and D538G mutations displayed an 11.2 to 46.9-fold increase in the IC50 of palbociclib. ESR1 mutations are enriched following treatment with CDK4/6i in a cohort of 3,958 patients with ER+/HER2- metastatic breast cancer. Mutations in ESR1 in ER+ breast cancer cells directly promote resistance to CDK4/6i alone or CDK4/6i + antiestrogens in vitro and in vivo.

Notably, only one patient received sequential ctDNA testing, and in that case, there was a gain of TP53 p.N239S following sacituzumab govitecan administration compared to the baseline ctDNA test, followed by a gain of PIK3CA p.P449_L455del after trastuzumab deruxtecan administration. As we observe changes in subtypes following treatment progression, researchers are actively seeking biomarkers to better characterize real-time changes in tumor biology that can predict response and resistance to treatments. Further studies are needed to identify additional genes present in ctDNA that can provide mechanistic insights into why certain patients respond favorably to ADCs while others do not. We are currently enrolling patients for a prospective study that aims to assess baseline ctDNA levels and monitor changes in variant allele frequency following treatment with ADCs and immunotherapy.

"Tempus...announced eight abstracts were accepted for presentation at the Society for Immunotherapy of Cancer’s (SITC) 38th Annual Meeting, which convenes in San Diego, California, from November 1-5, 2023."

These data suggest that liquid biopsy ctDNA detection represents a powerful pre-RT biomarker to risk-stratify oligometastatic NSCLC patients and potentially enable personalized decision-making for local consolidative RT.

Overall, these data suggest that in patients with oligometastatic NSCLC, pre-RT ctDNA can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged PFS and OS. Similarly, ctDNA may be useful to identify undiagnosed micrometastatic disease where it may be appropriate to prioritize systemic therapies.

Conclusions xF Monitor is a novel serial quantitative cTFE algorithm off the Tempus xF assay that has the potential to be used clinically as a predictive biomarker to stratify patients who are likely to benefit from ICI therapy, sparing ineffective therapeutic approaches. The xF Monitor biomarker needs to be prospectively validated in a larger cohort.

These data suggest that liquid biopsy ctDNA detection represents a powerful pre-RT biomarker to risk-stratify oligometastatic NSCLC patients and potentially enable personalized decision-making for local consolidative RT.

"Tempus...announces its GEMINI Non-small Cell Lung Cancer (NSCLC) study (NCT05236114). The Tempus-sponsored study, being run in collaboration with AstraZeneca, aims to create a robust multi-omic dataset for patients with NSCLC to facilitate future novel research related to precision medicine, diagnostic development, and biomarker discovery....Patients enrolled in the trial will be studied for up to three years to assess the impact of their underlying tumor biology on disease progression and therapy efficacy. The results of this study will be used for biomarker discovery, including potential use of circulating tumor DNA (ctDNA) testing to measure MRD."

In this proof-of-concept study, O did not show clinically nor statistically significant antitumor activity in pretreated aTNBC pts with BRCA1/2-meth. Clinical trial information: NCT03205761. >*7 pts had ≥3 CT lines.

AR mutations have implications for clinical decision making and drug development in patients treated with abiraterone and/or enzalutamide. >1n (%).

These data suggest that a ctDNA-informed approach may be a powerful pre-RT biomarker to help risk-stratify oligometastatic NSCLC patients and potentially enable personalized decision-making for RT versus systemic therapy.

"In this large RW dataset, plasma ctDNA-based analysis of BRCA1, BRCA2, and ATM mut showed greater concordance between LB and MT than LB and PT, and may be used as an initial tool for HRR mut detection. When LB results are negative, further exploration with tissue-based testing may identify HRR mut to guide clinical decisions. >"

In SPOPMT PCs, inactivation of APC is a common event and associated with more aggressive disease (higher metastatic potential and faster progression to castration resistance). This observation may help identify SPOPMT PC patients who are at higher risk for early castration resistance and could benefit from more intensive treatment.

This study presents the first large-scale genomic characterization of BRAF mutations in patients with prostate cancer using both tissue and ctDNA NGS analysis. Among thousands of samples from prostate cancer patients, K601E was the most common BRAF mutation. This confirms findings of smaller studies and has implications for developmental therapeutics.

Similarities and differences between the mechanisms of acquired resistance to N+F+T, and those previously reported to be associated with progression on N or N+F, will be discussed.

P2 | "Notably, a complete SMARCB1/INI1 deletion (targetable by tazemetostat) was identified... NGS in conjunction with OGM demonstrated improved detection of clinically actionable alterations for this patient. Thus, both tests should be routinely considered as a part of the diagnostic regimen to better characterize key mutations in rare tumors and uncover actionable targets for treatment. Combining multiple types of molecular analyses uncovered that this patient was eligible for a novel clinical trial."

We show that dual testing in breast cancer patients improves the identification of clinically actionable variants which may be missed by either ctDNA or solid tissue biopsy alone. Adoption of dual testing should be considered as standard practice to provide a comprehensive view of actionable molecular alterations.

Background: CDK4/6 inhibitors (CDK4/6i), like palbociclib, ribociclib, and abemaciclib, along with antiestrogens, have revolutionized treatment for ER+/HER2- metastatic breast cancer (MBC). CCND1, FGF3, FGF4 and FGF19 alterations were copy number amplifications, which may be consistent with 11q13 amplification. Further studies will provide insights into how these trends translate towards our understanding of CDK4/6i related resistance mechanisms.

"We observed high concordances between tissue and cfDNA results that generally decreased with longer durations between tests. Thus, cfDNA NGS reliably measures tissue genomics and is likely beneficial for longitudinal monitoring of molecular changes in mBC."

"In the largest study of its kind, we show that dual tumor tissue and ctDNA testing—with samples collected either concurrently or longitudinally—identified more patients with actionable alterations than single modality testing alone and therefore should be considered as part of routine NGS testing. Additional studies to explore the genetic and intra-patient tumor heterogeneity of these variants as well as the impact of time between tissue and plasma sampling assessments and implications for timing of therapeutic recommendations are underway."

ctDNA testing is a reliable method to detect DNA damage repair LOF alterations but is limited to alterations and genes/exons covered by the ctDNA test. CH alterations are frequent, especially for ATM, thus matched normal analysis is preferred. Changes in ctDNA as early as 3 wks were associated with improved outcomes and may be useful for evaluating drug activity in heterogenous tumors outside of traditional efficacy endpoints.

CDH1 mutations, which are associated with familial gastric cancers and more aggressive disease, were present in 33% of Hispanic patients with gastric adenocarcinoma in our study. Nearly half of these identified patients were younger than 50 years old. The high frequency of CDH1 mutations may contribute to the unique pathogenesis of gastric cancers in Hispanic patients.

Background: Sotorasib has shown promising activity in cancer patients (pts) specifically harboring the KRASG12C mutation... Our data suggest that KRAS variants significantly differ by cancer type . Tumors harboring KRASG12C were significantly associated with high TMB and PD-L1 overexpression . KRASG12C mutation appeared to be associated with smoking status .

"Background The KRAS G12C inhibitor sotorasib has shown promising anticancer activity in patients with advanced solid tumors harboring the KRAS G12C mutation, holding the potential for transforming clinical management of KRAS mutated solid tumors...G12C was most frequently observed in patients with appendiceal, colorectal, small bowel, biliary, and pancreatic cancers. G12C was not detected in SCC of the esophagus or anal canal."

"Both alterations restored the open reading frame of the original germline alteration, likely accounting for acquired resistance. This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and demonstrates the value of longitudinal multi-tissue genomic testing for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes in oncology patients."