TORONTO, May 26 – As abstracts submitted for the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (4−8 June 2021) have published, Geneseeq is excited to announce give a first glance at key data presented by the company, ahead of clinical oncology’s biggest conference of the year. Geneseeq has presented at ASCO for six consecutive years (2016−2021), adding to more than a hundred translational research studies. This year we will present three posters and one poster discussion, with a focus on rare gene fusions present in colorectal cancer patients and using circulating tumor DNA to monitor disease progression in lung cancer patients.
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 GENESEEQPRIMETM 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-SeqTM technology at 30,000X depth. The sequencing panel used was Geneseeq’s 139 gene PulmocanTM 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 CALIBRATETM 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 GENESEEQPRIMETM 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.