Innovative Method to Analyze Treatment Resistance in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC), recognized as one of the most prevalent and aggressive forms of ovarian cancer, poses significant challenges in treatment due to its propensity for early microscopic spread within the abdomen. Patients are often diagnosed at advanced stages, making effective treatment difficult. While initial interventions involving surgery and chemotherapy can be successful for many, the majority of advanced ovarian cancers will eventually recur.

A research team from Memorial Sloan Kettering Cancer Center (MSK) has developed a groundbreaking methodology aimed at addressing treatment resistance in HGSOC. This innovative technique utilizes blood tests to track the evolution of treatment-resistant cells, thereby offering insights into cancer recurrence. Their findings, recently published in the journal Nature, may pave the way for novel strategies to identify and target specific subpopulations of cells responsible for cancer recurrence.

According to the first author of the study, the cancer's diverse cellular composition complicates treatment monitoring, as existing methods fail to differentiate between treatment-sensitive and resistant populations. To overcome this limitation, the research team created a new monitoring system.

The team's approach, referred to as CloneSeq-SV, integrates single-cell whole genome sequencing with targeted sequencing of structural variants--significant alterations in DNA. This dual technique enables researchers to observe the evolution of cancer over time, beginning with initial samples collected during surgery and continuing with subsequent blood tests to determine which tumor subpopulations endure treatment.

By employing structural variants as molecular 'bar codes,' researchers can effectively track cancer cell subpopulations in the bloodstream. Blood samples from 18 patients with HGSOC were analyzed from diagnosis through cancer recurrence, revealing that resistant cells were present at diagnosis and proliferated as treatment-sensitive cells were eliminated.

The study highlights that distinct subpopulations of cancer cells emerge during recurrence, displaying unique characteristics such as amplifications of oncogenes, chromothripsis, and whole genome doubling. These features provide new opportunities for developing targeted treatment strategies aimed at exploiting these vulnerabilities.

For instance, one patient demonstrated an exceptional response to trastuzumab deruxtecan, a drug targeting the oncogene ERBB2, remaining disease-free for years. Analysis showed that the tumor initially contained both cells with and without ERBB2 amplification. First-line treatments eliminated the population lacking the amplification, ultimately resulting in a cancer with multiple copies of ERBB2 at recurrence. This evolutionary change rendered the tumor susceptible to targeted therapy.

Looking ahead, the research team plans to expand their study by including more patients to uncover additional patterns that could inform treatment strategies. They also aim to capture a more comprehensive view of tumor cell diversity by gathering more tumor samples during follow-up procedures. Additionally, the CloneSeq-SV method may be applicable to other cancer types characterized by significant genomic variability.