Here are the key highlights from these studies:

• Performance of cfDNA fragmentonics-based early detection models in gastric cancer and breast cancer populations. The findings shed light on the potential of this approach in improving early diagnosis and subsequent treatment outcomes.
• Novel drug resistance mechanism in ROS1-rearranged non-small cell lung cancer patients. This research provides valuable insights into the development of targeted therapies and the management of treatment resistance in this subset of patients.
• Comprehensive analysis of homologous recombination repair gene reversion mutations. By examining a large pan-cancer population, this study sheds light on the prevalence, clinical implications, and potential therapeutic implications of these mutations.

Abstracts of the studies to be presented:

• Multi-dimensional cell-free DNA-based liquid biopsy for sensitive early detection of gastric cancer.
• Detecting Early Stage Breast Cancer Using Low-Depth Cell-Free DNA Fragmentomics: A Multi-Center Cohort Study.
• Mechanisms of Resistance to Tyrosine Kinase Inhibitor Treatments in ROS1 Fusion-Positive Non-Small Cell Lung Cancer Patients.
• A four-tier classification system of studying homologous recombination repair gene reversion mutations as a mechanism of resistance to PARP inhibitors and platinum-chemotherapy.

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This study enrolled 87 NSCLC patients who underwent curative surgical resections (23 patients experienced relapses during follow-up). A total of 163 plasma samples were collected at 7 days and 6 months post-surgery and were used for both whole-genome sequencing (WGS). The WGS-based cell-free DNA (cfDNA) fragment profile was used to develop regularized Cox regression models, and the models’ performance was evaluated using leave-one-out cross-validation.

The ultra-sensitive and affordable fragmentomic assay has shown promising results in detecting patients who are at high risk of recurrence. The fragmentomic model was able to detect high-risk patients at 7 days and 6 months post-surgery with an increased risk of 4.6 times and 8.3 times, outperforming the targeted sequencing-based circulating mutations. The overall sensitivity for detecting patients with recurrence reached 78.3% while using both fragmentomics and circulating mutation results from 7 days and 6 months postsurgical, which increased from the 43.5% sensitivity by using only the circulating mutations.

“The non-invasive liquid biopsy assay can effectively detect landmark MRD, which could aid in making informed decisions for post-surgery treatment.”, says Dr. Hua Bao, author and director of Geneseeq Research Institute.

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A recent prospective study published in the Drug Resistance Updates, led by Sun Yat-sen University Cancer Center and Geneseeq Technology Inc. demonstrated that the analysis of ctDNA points to drug resistance mechanisms to the combination of vemurafenib, irinotecan, and cetuximab (VIC) in BRAF^V600E mCRC patients, allowing accurate guidance for clinicians in personalized treatment strategies.

This study included 41 BRAF^V600E mCRC patients enrolled in Sun Yat-sen University Cancer Center from July 2018 to June 2020. Tumor tissues and treatment-naïve plasma samples were collected before treatment. Serial blood samples were collected at the end of every four cycles of VIC treatment until disease progression to dissect the resistance mechanisms and to estimate the prognostic potentials. Tissue and plasma samples were profiled using whole-exome sequencing and the 425-gene Geneseeqprime panel sequencing, respectively.

The study shows that baseline ctDNA BRAF^V600E level was related to a poor prognosis. On the other hand, if ctDNA BRAF is undetected at the first scan, patients showed prominent PFS improvement and dynamic ctDNA BRAF^V600E level changes during/after treatment demonstrated a significant correlation with VIC-related response. Conclusively, NGS-based ctDNA profiling helps detect potential molecular alterations correlated with VIC response and resistance. RNF43 mutations were predominant in pre-treatment plasma samples of patients with long-term clinical benefits, with a response rate as high as 80% and significantly longer PFS after VIC treatment. In those tumors harbouring RNF43 mutations, researchers also observed two tumors achieved clinical responses to immunotherapy. Also, the study shows that acquired gene alterations in DNA damage repair pathways occur in 33% of patients post-VIC treatment, and particularly, patients with this pre-treatment resistance subclones developed inferior responses, along with higher tumor mutation burden both at baseline and progression plasma compared to those without. The researchers identified several additional novel resistance mechanisms to VIC therapy such as TGFBR2 and SMAD4 loss-of-function mutations, and copy-number gains in PTK2, MYC, and GATA6.

These findings highlight the potential of ctDNA surveillance in disease monitor and personalized treatment management in mCRC.

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This study recruited 119 LARC patients who were treated with nCRT plus total mesorectal excision (TME) from the year 2016 to 2017, and serial plasma samples at baseline, during nCRT, and after surgery were collected and subjected to deep targeted-panel sequencing of 422 cancer-related genes. As the traditional MRI approach was not sufficient to predict pCR, researchers in this study compared different pCR prediction models that incorporate only ctDNA features, only MRI data, or the combination of ctDNA and MRI data.

Notably, by combining the results of ctDNA and MRI, the prediction model (AUC=0.886) demonstrated a superior capacity to predict pCR and non-pCR patients, compared with the models that only utilized one set of data (AUC=0.818 and 0.729, respectively). As a result, the newly developed combination model could more accurately assess the treatment response of nCRT. This could help patients access personalized subsequent treatment plans and help reach the optimal balance between quality of life and treatment efficacy. Moreover, the researchers discovered certain pathological risk features, as well as the detection of some diver genetic alterations in ctDNA, were highly correlated with disease recurrence, so these ctDNA and pathological features could be potentially used to predict patients’ prognosis for LARC.

“Accurate predictions of response to therapy will direct patients to the most appropriate treatment regimes,” says Dr. Hua Bao, the Director of Research & Development at Geneseeq. Since 2017, Geneseeq continues to work on minimal residual disease (MRD) monitoring through its CALIBRATE^TM (monitoring post-surgery CAncer recurrence by ctDNA LIquid Biopsy RATing) program for colorectal cancer patients.

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Poster Discussion Session: Developmental Therapeutics-Molecularly Targeted Agents and Tumor Biology

Abstract Number: 3011

Circulating tumor DNA to investigate resistance mechanism and clone evolution of ALK TKI treated lung adenocarcinoma.

Study highlights: Using ctDNA to dissect how secondary ALK mutations drive acquired resistance

Sequential treatment with first-, second-generation ALK TKI followed by third-generation TKI (lorlatinib) has been widely applied to ALK-positive lung cancer. However, acquired resistance is often driven by secondary ALK mutations, which are needed to be further explored. Circulating tumor DNA, a non-invasive approach, can detect tumor-derived DNA from multiple metastatic sites and has become a promising strategy for assessing the genetic evolution of tumors and analyzing TKI resistance.

By genotyping the sequential post-progression plasma specimens on Geneseeq’s 425 gene panel GENESEEQPRIME^TM in this study where more than half of the patients are receiving more than one line of ALK TKI treatment, the most frequent ALK fusion type is EML4-ALK and EML4-ALKv3. Frequently identified secondary mutations in patients progressing on ALK inhibitors were ALK mutations L1196M and G1202R. ALK G1202R was more common in patients with v3 fusion than in v1 while ALK L1196M was more common in v1 than in v3. Meanwhile, G1202R was identified at a higher ratio in patients who progressed on second-generation ALK TKI than first- and third-generation ALK TKI whereas L1196M was more found in patients who progressed on first-generation ALK TKI. Other identified secondary mutations were ALK F1174C/V/L, E1210K/Q, D1269A, D1203N, and L1122M/V. Compound ALK mutations (≥2 concurrent ALK mutations) were more common in patients relapsed on third-generation ALK TKI lorlatinib, compared to first- and second-generation ALK TKIs.

The data reveals that treatment with sequential first, second, and third-generation ALK inhibitors can accelerate the accumulations of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations.

Poster Session: Developmental Therapeutics-Molecularly Targeted Agents and Tumor Biology

Abstract Number: 3028

Circulating tumor DNA as markers of dynamic recurrence risk and adjuvant chemotherapy benefit in resected non-small cell lung cancer

 Study highlights: Using ctDNA monitoring to detect MRD and indicate recurrence risks as well as therapy guidance in NSCLC patients.

A significant proportion of non-small cell lung cancer (NSCLC) patients relapse after surgical resection with or without adjuvant therapy. The detection of molecular residual disease (MRD) has great potentials to stratify postoperative risk and facilitate early recurrence diagnosis. This study of 116 patients with NSCLC following surgery and/or adjuvant therapy, aim to evaluate the clinical utility of serial plasma circulating tumor DNA (ctDNA) in MRD detection, adjuvant therapy guidance, and recurrence risk prediction in resected NSCLC patients.

Plasma samples were collected at baseline, after surgery, after adjuvant therapy and every 3 months thereafter and were analyzed by ultradeep next-generation sequencing, using Geneseeq’s ATG-Seq^TM technology at 30,000X depth. The sequencing panel used was Geneseeq’s 139 gene Pulmocan^TM panel. Pre-treatment ctDNA was detected in 69.8% of patients. ctDNA positivity after surgery and after completion of adjuvant chemotherapy (ACT) were significantly associated with worse recurrence-free survival (RFS); during surveillance after definitive therapy, ctDNA positivity was associated with worse RFS. These results indicate that ultradeep ctDNA sequencing could sensitively detect MRD, thus identifying patients with high recurrence risk and guiding the adjuvant therapy decision in resected NSCLC. The study also demonstrates that joint modeling of serial ctDNA levels and time to recurrent can provide an accurate dynamic risk prediction for NSCLC patients during surveillance.

This study unveils the second cancer type in Geneseeq’s MRD monitoring program CALIBRATE^TM after publishing data on using ctDNA to monitor MRD in colorectal cancer patients.

Poster Session: Gastrointestinal Cancer – Colorectal and Anal

Abstract Number: 3544

NTRK fusion positive colorectal cancer is a unique subset of CRC with high tumor mutation burden and microsatellite instability.

Study highlights: Using NGS to sequence a large number of clinical samples to identify the molecular characteristic of rare NTRK gene fusions that drives colorectal cancers.

Neurotrophin receptor tyrosine kinase (NTRK) gene fusions are rare but actionable oncogenic drivers that are present in a wide variety of solid tumors. This study aims to identify the frequency and the clinicopathologic and genetic features of NTRK-driven colorectal cancers (CRC).

A total of 2,519 unique colorectal cancer cases were profiled using Geneseeq’s 425 gene panel GENESEEQPRIME^TM from April 2016 to May 2020, and 17 NTRK+ fusion events were identified. Furthermore, thirteen out of 17 NTRK+ CRC tumors were microsatellite instability-high (MSI-H) tumors, a much higher rate than that of the molecularly unselected CRC population or NTRK+ non-CRC tumors. NTRK+ CRC patients also had increased tumor mutation burden compared to that of non-NTRK+CRC or NTRK+ non-CRC tumors. TPM3, LMNA and TRP are the most common fusion partner of NTRK1.

In addition to the absence of canonical driver mutations, NTRK+ tumors are rare and demonstrated increased tumor mutation burden, higher frequency of microsatellite instability, and enrichment of POLE/POLD1 mutations relative to molecularly unselected CRC population.

Poster Session: Lung Cancer – Non-Small Cell Lung Cancer

Abstract Number: 8090

Identification of recurrence-associated gene signature and tumor immune microenvironment features in resected stage I NSCLC 

Study Highlights: Using WES to identify the tumor gene and immune microenviroenment profile in stage I NSCLC patients

Surgery is the primary treatment for stage I NSCLC, but postoperative recurrence leads to poor prognosis. Alterations of tumor genes and immune microenvironment may be crucial factors for tumor recurrence; however, the detailed mechanisms remain unclear. This study examines a total of 130 resected stage I NSCLC patients where 69 developed recurrence within three years and 61 without recurrence over five years. Whole exome sequencing (WES) was performed to evaluate genomic alterations. Immunohistochemistry was carried out to assess the expression of PD-L1, CD3 and CD8. Lung adenocarcinoma (LUAD) patients showed significantly higher risk of recurrence. There was no statistically significant correlation between recurrence and other clinical factors, including TNM stage. Although driver gene mutations, such as those of EGFR, had no correlation with recurrence, MUC4 mutation and high tumor mutation burden (TMB) were significantly associated with higher risk of recurrence. A refined immunoscore with a high prognostic value for tumor recurrence in stage I NSCLC was established in this study.

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