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Although circulating tumor cell analysis of patients with HER2-negative metastatic breast cancer identified patients with CTC amplification, the utility of subsequent HER2-directed treatment with trastuzumab plus vinorelbine in this patient population was low.
Although circulating tumor cell (CTC) analysis of patients with HER2-negative metastatic breast cancer identified patients with CTC amplification, the utility of subsequent HER2-directed treatment with trastuzumab (Herceptin) plus vinorelbine in this patient population was low, according to findings from a single-arm, two-stage, phase 2 trial that were published in JCO Precision Oncology.
In the study, investigators prospectively screened CTCs from patients with HER2-negative metastatic breast cancer from January 2013 to June 2014. CTCs were detected in 65% of patients (n = 201/311).
The median number of CTCs was 10 [interquartile range (IQR), 3-57]. Twenty-two percent of patients (n = 69 of 311) had HER2-positive CTCs, with a median of 3 HER2-positive CTCs (range, 1-21). No significant association was found between HER2-positive CTC status and histopathologic characteristics of the patient’s primary tumor.
Twenty patients with HER2-positive CTCs were treated on study. At a data cutoff of January 13, 2017, no patients remained on study treatment. At a median follow-up of 2.7 months, the objective response rate was 5% (95% CI, 0.1%-24.9%), with 1 of 20 patients experiencing a partial response (PR). An additional 3 patients experienced stable disease for more than 24 weeks, translating to a clinical benefit rate of 20% (95% CI, 5.7%-43.7%). The median progression-free survival (PFS) was 2.7 months.
“The ORR of 5% for the combination therapy was low and did not meet the prespecified threshold for further study. Although total CTCs decreased from baseline to cycle 3, day 1 [C3D1] in the overall population, perhaps reflective of early treatment effect, we did not see meaningful changes in HER2-positive CTCs,” wrote Heather A. Parsons, MD, MPH, a physician at Dana-Farber Cancer Institute, and colleagues, in the study publication.
To be eligible for the CTC collection and screening portion of the study, patients had to have HER2-negative metastatic breast cancer, defined as a fluorescence in situ hybridization (FISH) ratio of less than 2.0 or immunohistochemistry (IHC) 0 or 1+ on a primary or metastatic tissue sample. If the tumor was 2+ by IHC, it had to also be FISH negative. Patients must have also received at least 1 prior chemotherapy regimen for metastatic disease.
To be eligible for the treatment portion of the study, patients had to have HER2-negative, progressive metastatic breast cancer with HER2-positive CTCs, defined as a HER2 to CEP17 ratio of at least 2.0 by FISH, and received at least 1 prior treatment for metastatic breast cancer, with the exception of trastuzumab and vinorelbine.
Patients received intravenous trastuzumab in combination with vinorelbine on days 1, 8, and 15 of a 21-day cycle. Trastuzumab was administered at a dose of 8 mg/kg in cycle 1 and 6 mg/kg thereafter, and vinorelbine was given at a flat dose of 25 mg/m2.
The primary end point was ORR. Secondary end points included the safety and tolerability of the combination, PFS, and clinical benefit rate after 24 weeks. Additional end points included the number of CTCs, the CTCs’ characteristics prior to and following treatment and their association with response.
Patients were evaluated every 2 cycles with computed tomography scans of the chest, abdomen, and pelvis.
Patients remained on study treatment until disease progression, unacceptable toxicity, or treatment discontinuation because of physician request, or withdrawal of consent. Treatment holds or discontinuation with trastuzumab were mandated for patients who experienced significant reduction in left ventricular ejection fraction. Treatment holds or dose reductions with vinorelbine were mandated for patients who experienced prolonged grade 2 or greater hematologic, grade 2 or greater hepatic, or any grade 3 or greater toxicity.
The median age of patients enrolled in the treatment phase of the study was 54 years (range, 34-66). Thirteen (65%) patients had estrogen receptor (ER)-positive disease, and seven (35%) patients had ER-negative disease. Patients were relatively heavily pretreated, with a median of 3 prior lines of chemotherapy in the advanced setting.
The study was stopped early under the Simon two-stage design. The median number of cycles received was 4 (range 2-21).
At a median follow-up of 72 months, the median overall survival (OS) was 14.55 months in patients with detectable CTCs vs 21.55 months in patients without detectable CTCs (HR, 1.60; 95% CI, 1.23-2.08; P = .00037). Among the patients with detectable CTCs, the median OS was 10.74 months in patients with HER2-positive CTCs vs 14.95 months in patients with HER2-negative CTCs (HR, 1.11; 95% CI, 0.81-1.50; P = .56).
Baseline CTC counts were available for all 20 patients. Twelve patients had baseline and C3D1 samples assessed. A significant decrease was found in CTCs from baseline (median = 31) to the C3D1 (median 12.5) assessment (P = .03), but no difference was found in HER2-positive CTCs between baseline (median = 2) and C3D1 (median = 2; P = .52). Notably, 4 of 4 CTCs detected at baseline were HER2 positive in the one patient who experienced a PR.
In terms of toxicity, the most common grade 3 event was neutropenia (20%), followed by anemia (10%). No grade 4 or greater adverse events were reported.
“This study confirms previous reports indicating that HER2-positive CTCs are present in a subset of patients with HER2-negative metastatic breast cancer. Nonetheless, the clinical activity of a HER2-directed regimen in this patient population was very low and the functional significance of these HER2-positive CTCs remains uncertain,” concluded the authors.