Why Did It Come Back After Surgical Removal? The Secret of Biliary Tract Cancer Recurrence Lies in 'Clones' [Health Check]

[Financial News]  The reason nearly half of patients experience recurrence even after biliary tract cancer is surgically removed has been identified. Recurrent cancer does not result from a single cancer cell hidden in the body and growing again. Instead, multiple cancer-cell clones that made up the primary tumor survive and proliferate together.
A research team led by Professor Kim Ji-won of Hematology-Oncology and Professor Na Hee-young of Pathology at Seoul National University Bundang Hospital, with Professor Kang Min-soo and researcher Lee Joo-hyun of Hematology-Oncology as co-first authors, announced on the 29th that it had identified the evolutionary path of biliary tract cancer from the precancerous stage through recurrence and metastasis. The findings were published in npj Precision Oncology, an international oncology journal affiliated with Nature.
Biliary tract cancer develops in the passages through which bile flows, including the bile ducts, gallbladder, and ampulla of Vater, and its incidence is particularly high in some countries, including South Korea. More than half of patients are diagnosed at an advanced stage when surgery is not possible, resulting in a survival period of just 11 to 15 months. Even among patients who undergo surgery with the goal of a cure, about half experience recurrence, making it a notoriously difficult cancer to treat. However, few studies have tracked the entire process—from onset to recurrence and metastasis—at the genomic level.
The research team analyzed 72 samples collected from 17 patients with biliary tract cancer, including normal tissue, precancerous lesions, primary tumors, and metastatic and recurrent tumors. The samples underwent whole-exome sequencing, an analytical method that reads the entire portion of the genome containing protein-related information to identify mutations. Based on the results, the researchers reconstructed patient-specific phylogenetic trees showing how cancer-cell clones emerged and branched, allowing them to trace the cancer's evolutionary path backward.
The analysis found key biliary tract cancer mutations in genes such as TP53, KRAS, and SMAD4 as early as the precancerous-lesion stage. Although the lesions did not appear to be cancerous, changes toward cancer had already begun at the genetic level.
Among the various cell clones in the precancerous lesions, only some with a survival advantage persisted and developed into primary tumors. The researchers explained that they observed a phenomenon known as a 'selective sweep,' in which clones with a proliferative advantage prevailed over competing clones and took over the lesion, much like Darwinian natural selection.
This selective expansion continued during metastasis. A particular clone that had been a minority in the primary tumor became dominant at the metastatic site. The researchers concluded that clones better suited to survive in each location were selected because the environment differs from one organ to another.
Notably, multiple clones that had made up the primary tumor also remained in cancers that recurred after surgery. Cancer recurrence has traditionally been viewed as the phenomenon in which a single cancer cell hidden somewhere in the body grows again over time. The findings show that recurrence can occur through a 'polyclonal' process, in which multiple clones escape together as a group and establish themselves in a new location.
The study also found that anticancer treatment may have influenced the cancer's evolution. Mutation patterns known to be left by anticancer drugs used to treat biliary tract cancer were more prevalent in metastatic and recurrent lesions. This means that cancer cells that survived the drugs' attack proliferated while retaining those signatures. However, Professor Kang Min-soo cautioned against overinterpreting the findings, saying, "This does not mean that anticancer drugs worsen cancer. Rather, it shows that the treatment process itself can also influence the evolution of cancer cells."
Some characteristics, however, remained unchanged. Alterations targeted by targeted therapies, including ERBB2 gene amplification and KRAS mutations identified at diagnosis, were preserved even after recurrence and metastasis.
Professor Kim Ji-won said, "The fact that the major genetic alterations identified at diagnosis remain even after recurrence and metastasis shows the importance of developing treatment strategies based on precision genomic analysis from the time of diagnosis," adding, "We will improve treatment outcomes for biliary tract cancer with strategies that reflect the principles of cancer evolution."
Professor Na Hee-young stated, "The significance of this study lies in confirming, as one continuous process, the genetic changes through which biliary tract cancer evolves from the precancerous stage to metastasis and recurrence," adding, "The fact that competition and selection among cell clones begin in precancerous lesions will provide an important clue to understanding how biliary tract cancer develops."
The study was conducted with support from the Ministry of Education and the National Research Foundation of Korea (NRF), including the Korean Small Grants for Exploratory Research (SGER) program.
 


[email protected] Jung Myung-jin, medical correspondent Reporter