Research has shown that a simple blood draw or other liquid biopsy can yield untold information about tumors. In a recent publication in Cancer Cell, BCRF investigator Dr. Laura van ’t Veer and her colleagues including Dr. Mark Magbanua showed that circulating tumor DNA (ctDNA) present in patients’ blood can be used as a biomarker to predict prognosis and recurrence in early-stage hormone receptor (HR)–positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC).
Her team—including fellow BCRF researchers Drs. Kathy Albain, Rita Nanda, W. Fraser Symmans, Funmi F. Olopade, Laura J. Esserman, Angela M. DeMichele, Lajos Pusztai, and Hope S. Rugo—also identified specific genes that may play a role in why certain breast tumors shed ctDNA and others do not. These results may inform future testing strategies and provide potential insights to inform and improve treatment decisions for patients with breast cancer.
Over a decade ago, researchers discovered that tumor cells can break away from a tumor and enter the blood. This finding blossomed into years of research on these circulating tumor cells and revealed that fragments of tumor DNA, or ctDNA, could also be detected in the blood. Questions about whether ctDNA could predict prognosis and recurrence then quickly emerged, followed by several tests to detect ctDNA in blood samples (also called liquid biopsies)—enabling researchers to probe these questions effectively.
Prior to the advent of liquid biopsies, patients would primarily undergo invasive tissue biopsies. Liquid biopsy provides a distinct advantage over standard tissue biopsy: It is non-invasive and less painful, yet offers a sensitive method to monitor treatment progression and patient outcomes. Dr. Van ‘t Veer and her team are seeking to leverage this non-invasive technique to decipher early predictors of response.
It is unclear why some breast tumors shed high amounts of ctDNA into the blood while for other tumors it’s undetectable. Tumor size and breast cancer subtype contribute to these differences in ctDNA shedding, but do not fully explain them. Dr. van ‘t Veer and her colleagues sought to understand the clinical impact of ctDNA analysis across different tumor subtypes, how ctDNA levels change during chemotherapy that is administered before surgery or other treatments, if ctDNA levels can predict recurrence, and what genes are involved in the shedding process.
Since there are several subtypes of breast cancer, the researchers hypothesized that the predictive and prognostic value of ctDNA varies between those subtypes. They focused on HR-positive/HER2-negative breast cancer and TNBC, which lacks the HER2 protein as well as hormone receptors.
The study included a cohort of 283 patients in these two subgroups who were accrued as part of the I-SPY2 trial, which tests new targeted drugs in combination with standard chemotherapy. All study patients had their drug therapy prior to surgery to observe if a given treatment shrank their tumors; when chemotherapy is given at that stage it’s called neoadjuvant chemotherapy.
The team took a novel approach by assessing ctDNA levels at four time points before, during, and after neoadjuvant chemotherapy. They wanted to determine if ctDNA levels changed during the course of the treatment and if these levels correlated with how a patient’s tumor responded.
In another set of experiments, the team sought to learn if ctDNA shedding is controlled by specific genes. To accomplish this, they sorted patient blood samples by the presence or absence of ctDNA prior to neoadjuvant therapy. They matched the positive and negative samples to corresponding tissue samples derived from the same patients and then compared the genes between the ctDNA-positive and -negative groups to identify those potentially involved in ctDNA shedding.
Dr. van ‘t Veer and her colleagues found that ctDNA levels were higher in patients with TNBC compared to HR-positive/HER2-negative breast cancer at all time points. This may be because TNBCs have rapid growth and cell turnover rates, as these factors have been associated with increased ctDNA. Interestingly, if ctDNA was no longer present in a patient’s blood three weeks after neoadjuvant therapy started, the patient had a favorable response—but this was only observed in TNBC.
For both subtypes studied, the team could correlate longer term outcomes with the presence or absence of ctDNA following neoadjuvant therapy. Patients that were positive for ctDNA after treatment experienced reduced recurrence-free survival while those negative for ctDNA had better outcomes.
The presence of ctDNA before neoadjuvant therapy was also significantly associated with an increased risk for metastatic recurrence or death in both subtypes. Additionally, patients who did not clear their ctDNA after neoadjuvant therapy had the poorest survival outcomes. In contrast, patients who were ctDNA-negative at all time points appeared to have the best survival outcomes. This is the first study to demonstrate the prognostic value of a biomarker pre- and post-treatment and as early as three and 12 weeks after neoadjuvant therapy begins.
While analyzing gene expression on patients’ tumor tissue samples, investigators found that several genes were increased in the ctDNA-positive group compared to the ctDNA-negative group. These include genes that control the tumor cell growth cycle and those that enable normal cell signaling. Ongoing studies will help determine how these genes influence ctDNA shedding and what role they may play in predicting prognosis and recurrence.
The results obtained from these studies—both subtype-specific clinical correlations and potential genes related to ctDNA shedding—may help maximize and fine-tune the use of ctDNA as a biomarker to anticipate treatment response and survival outcomes in patients with high-risk, early-stage breast cancer receiving neoadjuvant chemotherapy. The I-SPY2 trial is testing this concept to see if those patients who do not clear their ctDNA after 12 weeks of initial therapy would benefit from a change to another therapy.
The investigators will expand their analysis to 1,000 patient samples from the I-SPY2 trial and prospectively test this hypothesis.
The investigators hope to show that ctDNA analysis can inform treatment decisions as early as possible in the treatment protocol, allowing clinicians to switch treatments if they are not effective and spare patients the side effects of chemotherapy when possible. If validated, these findings would benefit patients with aggressive HER2-negative breast cancers that can be difficult to treat.
In the long term, researchers plan to evaluate this strategy across all breast cancer subtypes and assess ctDNA trajectories in patients who received immunotherapy. Their research has the potential to shape how treatment decisions are made—ultimately providing clinicians with a valuable tool to maximize positive outcomes for patients.
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