A significant proportion of women with early breast cancer develop late disease recurrence 5 or more years after surgery. Currently, there are no tests available to determine which patients may be at highest risk for having late recurrence.
Joseph Sparano, MD, Vice Chair of the ECOG-ACRIN Cancer Research Group, and Associate Director for Clinical Research at Albert Einstein Cancer Center, New York, N.Y., and colleagues presented data at the 2017 San Antonio Breast Cancer Symposium from an ECOG-ACRIN study that evaluated, for the first time, the use of a blood test that detects the presence of circulating tumor cells (CTCs) as a prognostic biomarker for late recurrence (Abstract GS6-03).
“We found that a positive test for the presence of CTCs was associated with a 35 percent recurrence risk after 2 years, compared with only 2 percent for those with a negative CTC test,” Sparano noted.
“Late recurrence, 5 or more years after surgery, accounts for at least one-half of recurrences of breast cancer and there are no tests that identify who is at highest risk,” Sparano said. In a recent article, the 10-year recurrence risk for breast cancer patients was determined to be 5 percent, 10 percent, and 22 percent for those having 0, 1-3, and 4-9 positive lymph nodes, respectively (N Engl J Med 2017;377;1836-1846).
“We found that in women who were cancer-free 5 years after diagnosis, about 5 percent had a positive CTC test,” Sparano said. When discussing the reasons for initiating this study, Sparano explained: “We wanted to determine the prevalence of CTC positivity in this population, and determine whether the presence of CTCs was associated with late recurrence.”
Three different studies have been performed that showed the presence and/or burden of CTCs had an association with recurrence in early breast cancer patients. The risks of recurrence ranged from 2.1-fold to 4.6-fold higher in those patients showing the presence of CTCs.
CTC Test Details
The CTC test utilized in this study had previously received approval by the FDA for use in cases of metastatic breast cancer in January 2004, metastatic colorectal cancer in November 2007, and metastatic prostate cancer in February 2008.
The approval in 2004 was for use as a diagnostic to count CTCs in a patient's blood sample to better gauge metastatic breast cancer patient overall and progression-free survival.
This diagnostic utilizes a ferrofluid that consists of minute particles of iron which are bound to antibodies specific to epithelial cell adhesion molecule (EpCAM), a transmembrane glycoprotein exclusively expressed on epithelia and epithelial-derived tumor cells.
Once the CTCs from the blood sample (typically 7.5 mL) have been exposed to the ferrofluid, a strong magnetic field is applied to draw off the ferrofluid and any CTCs bound to it. After separation, staining is done to facilitate visualization as well as confirm the cancerous nature of the CTCs.
“In our study, patients from the E5103 trial (NCT00433511) were chosen because all patients had HER2- disease and were at high risk for recurrence, that is they were either lymph node-positive or high-risk, lymph node-negative. These patients received standard adjuvant chemotherapy plus endocrine therapy if ER-positive,” Sparano stated. “Patients were asked to donate a blood sample for our analysis; they were told that we would follow their progress, however, we would not be reporting their results to them.” Patients were deemed to be CTC-positive if one cell was found in a 7.5 mL blood sample.
There were 547 patients (approximately 9% of the patient population in the E5103 trial) who were enrolled in this study, and of these, 56 percent were aged 50 or more. Lymph-node involvement was present in 73 percent of the patients, and 65 percent of the patients were HR-positive.
Of the 330 patients who were HR-positive for which information was known, roughly 88 percent were on endocrine therapy at the time of sampling. The median follow-up for patients was 1.8 years, with a range of 0-3.9 years.
Recurrences were noted in 4 percent (n=14) of the 353 ER-positive patients (95% CI 3.0-7.9%) and in 0.5 percent (n=1) of the 193 ER-negative patients (95% CI: 0-2.9%). The recurrences for the ER-positive patients were all distant recurrences, while the lone ER-negative patient had locoregional recurrence.
There were 26 patients (4.8%; 95% CI: 3.1-6.9%) who were assessed as being CTC-positive in the 546 patients who had confirmed HR status. Of these patients, 18 were ER-positive (5.1%; 95% CI: 3.0-7.9%) and 8 (4.1%) were ER-negative (95% CI: 1.8-9.0%). Since there was only one ER-negative patient who had recurrence, the data from the 353 patients with ER-positive disease were used to generate hazard ratios.
The median time to recurrence for CTC-positive patients was 1.6 years (range: 0.5-2.8 years). The hazard ratio was 21.7 (95% CI: 7.0-67.8), for CTC-positive patients. These results were considered to be very statistically significant (p < 0.001).
A multivariate Cox model was also performed which corrected for clinical covariates such as age, histologic grade, nodal status, and tumor size. When this was done, a hazard ratio of 18.7 was obtained (95% CI: 5.0-65.3).
The recurrence rates per person-year were 24.7 percent for those who were CTC-positive and 1.5 percent for those who were CTC-negative, respectively. For 2-year recurrence, the positive predictive value was 35 percent, while the negative predictive value was 98 percent. “What this last figure means is that, if a person tested CTC-negative, then there was a less than 2 percent chance that they would develop breast cancer over the next 2 years,” Sparano elaborated.
“Our ultimate goal is to use blood tests like this to tailor treatment in a way that minimizes recurrence risk for those at high risk, and spare treatment for those at low risk who may be unlikely to benefit from it,” Sparano said. “The findings of this analysis provide strong evidence to further evaluate this new risk assessment approach using CTC and other blood-based tests in this setting.”
When questioned as to what were the most noteworthy findings in this study, Sparano replied, “About 5 percent of patients with ER-positive breast cancer without clinical evidence of recurrence at an average of about 5 years after diagnosis had a positive CTC test, and those that did had a nearly 20-fold higher recurrence risk, than those who were CTC-negative.
“This high level of risk stratification far surpasses that of other biomarkers,” Sparano observed. “While there was a trend for higher CTC burden to be associated with higher recurrence risk, that relationship was not statistically significant.
“These findings also support the concept of a second decision point about 5 years after the original diagnosis using a clinically validated biomarker,” Sparano continued. “This new approach may help allow more accurate risk stratification for late recurrence than could be achieved at the time of diagnosis.”
Sparano noted: “Although this study provides a high level of evidence supporting the clinical validity of a positive CTC assay with breast cancer recurrence, additional studies are required to determine the clinical utility of using this test in this setting.
“What this means is that with future studies we may be able to show that CTC-negative patients can be spared extended years of adjuvant endocrine therapy. Alternatively, for those who are CTC-positive, we may be able to suggest novel therapeutic strategies, for example, CDK4/6 inhibitors or oral selective estrogen receptor degraders.
“Other studies may also look to evaluate this biomarker in combination with other relevant biomarkers, such as circulating tumor DNA,” Sparano suggested.
Richard Simoneaux is a contributing writer.