New results from the UK’s Tracking Cancer Evolution through Therapy (TRACERx) study are providing a close look at the evolution of non-small cell lung cancer including intratumor heterogeneity (ITH), treatment-related tumor adaptations, tumor features influencing disease progression and metastasis, immune interactions, and other tumor evolutionary clues related to clinical outcomes.
The prospective, multicenter TRACERx study, supported by Cancer Research UK, published initial results in 2019. Seven new papers appearing in Nature and Nature Medicine on Wednesday teased out additional tumor features and evolutionary patterns that appear across cancer diagnosis, treatment, recurrence, and metastasis.
Consequently, the latest results “extend our understanding of the evolutionary underpinnings of NSCLC and further investigate the relationship between established and new measures of ITH and clinical outcome,” co-senior and co-corresponding authors Charles Swanton, Nicholas McGranahan, and Mariam Jamal-Hanjani, all of the University College London, and their colleagues wrote in a lead Nature study.
In that paper, the researchers presented findings from an exome sequencing and phylogenetic analysis of 1,644 samples taken from several regions of tumors representing 421 early-stage, yet-to-be-treated NSCLC cases, including lung adenocarcinoma, lung squamous cell carcinoma, and large cell carcinoma subtypes.
“By looking at the tumor in its entirety, we can observe how these cell populations interact and even compete with one another, which is helping us to glean valuable insights into the likelihood that a tumor will return and when this might happen,” Swanton said in a statement. “We can also observe how the tumor is likely to evolve over time, spread, and respond to treatment, offering hope to millions of patients in the future.”
Among other findings, the team got a look at interactions between tumor drivers, mutational signatures, and whole-genome duplication (WGD) events, uncovering ties between shorter disease-free survival times and the presence of relatively recent WGD or tumor subclone expansions. The results also linked elevated somatic copy number changes with disease relapse involving tumors outside the thoracic region within the first year after lung cancer surgery.
“These data demonstrate the importance of clonal expansion, WGD, and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource,” the authors wrote.
Similarly, in another Nature paper, the researchers focused on exome sequencing profiles for a subset of 126 NSCLC patients who progressed to metastasis, comparing them with those found in 144 non-metastatic NSCLC cases.
There, the team saw signs that most metastatic NSCLC tumors stemmed from tumor subclones and subclonal expansions. Even so, a fraction of the metastatic tumors — particularly those in individuals with a history of smoking — appeared to be driven by clones that originated somewhat earlier.
“We find that approximately 75 percent of metastases diverge late, after the last clonal sweep in the primary tumor, and that the majority of primary clonal mutations, and indeed driver mutations, persist in the metastases, consistent with previous results,” the authors reported, adding that “polyclonal dissemination at the case level was associated with extrathoracic disease recurrence.”
In a related Nature study, members of the team turned to circulating tumor DNA (ctDNA) and a bioinformatic approach known as ECLIPSE to get a better look at metastatic tumor dissemination in NSCLC cases involving monoclonal or polyclonal tumors, along with more general prognostic insights from pre- and post-operative ctDNA samples.
Based on ctDNA dynamics in 1,069 blood plasma samples from 197 TRACERx NSCLC patients, for example, the researchers looked at clonal composition in samples with high or low levels of ctDNA while highlighting polyclonal tumor features and clonal expansions linked to less favorable overall survival outcomes.
“ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome,” they wrote. “By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones.”
Still other papers in the new TRACERx collection delved into everything from immune cell and antibody features coinciding with treatment response to tumor transcriptional profiles, lung adenocarcinoma-specific NSCLC evolution, and so-called cancer-associated cachexia complications marked by uncontrolled muscle and fat loss.
“This latest update to the TRACERx studies raises questions over the role of genomic variation in the development of distinct clonal patterns and metastases, the potential for harnessing the results to target metastatic clones that grow after adjuvant therapy, and the benefits of regular assessment of tumors,” Matthew Meyerson and Tikvah Hayes, medical oncologists with the Dana-Farber Cancer Institute, Harvard Medical School, and the Broad Institute, who were not involved in the research, wrote in a News and Views article in Nature.
“Future studies should consider incorporating such strategies to better understand the complexities associated with a tumor and its microenvironment,” Meyerson and Hayes added.