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Circulating Tumor Cells May Help to Monitor Patients on Trastuzumab

Laino, Charlene

doi: 10.1097/01.COT.0000368895.29383.4e

Levels of circulating tumor cells (CTCs) may be useful in the monitoring of poor-prognosis metastatic breast cancer patients undergoing treatment with trastuzumab. That was the conclusion of an international team of researchers who found that trastuzumab (Herceptin) is highly effective in patients with HER2-positive metastatic breast cancer and a poor prognosis.

“We found it very interesting. Herceptin eliminated all circulating tumor cells in all 11 HER2-positive patients evaluated,” said Maro Giuliano, MD, a visiting scientist in the department of pathology at the University of Texas M. D. Anderson Cancer Center.

The study, which was conducted in conjunction with the Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) in Meldola, Italy, was presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

Dr. Giuliano explained that the work builds on findings showing that the presence of circulating tumor cells before treatment is an independent predictor of progression-free survival and overall survival times in patients with metastatic breast cancer (Cristofanilli et al: NEJM 2004; 351:781–791).

More recently, the IRST research team demonstrated that all but one of 16 patients with HER2-positive tumors who were treated with a trastuzumab-based regimen had fewer than five CTCs per 7.5 mL of blood at disease progression, indicating that trastuzumab could selectively act against circulating tumor cells in HER2-amplified cases (De Giorgi et al Ann Oncol 7/14/ 2009 epub), he said.

“Nevertheless, 30% to 50% of metastatic breast cancer patients did not express CTCs during the clinical history, so we wanted to verify the effects of trastuzumab in patients with circulating tumor cells at baseline. We hypothesized that trastuzumab may selectively act against circulating tumor cells in HER2-positive metastatic breast cancer,” said Dr. Giuliano, who was speaking on behalf of study head Ugo De Giorgi, MD, of IRST and the rest of the research team.

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Trastuzumab Wipes Out CTCs

The retrospective analysis involved 51 patients with metastatic breast cancer that had a poor prognosis, defined as five or more CTCs per 7.5 mL of blood, at baseline.

Eleven HER2-positive patients were treated with a first-line regimen consisting of trastuzumab plus antimitotic agents. The other 40 were HER2-normal and had not received trastuzumab.

At a median follow-up time of 16 months, 24 patients (47%) had died.

All 11 HER2-positive patients treated with trastuzumab plus antimitotic agents had fewer than five CTCs per 7.5 mL of blood—levels considered undetectable during the treatment, Dr. Giuliano said.

In contrast, only 16 patients (67%) with HER2-normal metastatic breast cancer treated with antimitotic agents and 28 (70%) HER2-normal patients treated with other chemotherapeutic regimens had less than five CTCs per 7.5 mL of blood during therapy.

No statistically significant difference in CTC levels was observed between HER2-normal patients treated with antimitotic agents and those treated with other chemotherapeutic agents; however both groups were significantly less likely to have undetectable CTC levels during therapy than patients treated with trastuzumab.

There was also no difference in CTC levels between patients receiving polychemotherapy and monochemotherapy, Dr. Giuliano said.

The median progression-free survival time was 12 months in HER2-positive patients treated with trastuzumab plus antimitotic agents, compared with seven months for HER2-normal patients who did not receive trastuzumab, a result that strongly trended toward significance, he said.

The median progression-free survival time was eight months in HER2-normal patients with five or more CTCs per 7.5 mL of blood versus four months in those with fewer than five CTCs per 7.5 mL of blood, a significant difference.

“Circulating tumors cells would be useful for monitoring patients; they are a good prognostic index after patients are treated with trastuzumab,” Dr. Giuliano said.

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Circulating Epithelial Cells

In a second study presented at the same SABCS poster session, German researchers found that circulating epithelial tumor cells may be a useful tool for monitoring earlier-stage patients receiving neoadjuvant chemotherapy and trastuzumab.

“We have found that when the cells go down, the drugs are working. If they are stable, it is also a good sign,” said Katharina Pachmann, MD, Professor of Experimental Hematology and Oncology at Friedrich Schiller University Jena, in Bayreuth, Germany.

Her team's previous work showed that most of the epithelial cells circulating in peripheral blood (CETCs) in cancer patients are part of the tumor and that the response of these cells reflects the response of the tumor to applied therapies.

In the new study, six of 15 patients who received simultaneous chemotherapy and trastuzumab showed increased levels of circulating epithelial tumor cells during treatment and all suffered a relapse.

In contrast, six of six patients who received trastuzumab sequentially to neoadjuvant chemotherapy all showed decreasing numbers of circulating epithelial tumor cells and had no signs of disease after four years of followup.

“Even if the tumor cells were not eliminated immediately, trastuzumab contributed to prevent them from settling and growing into metastases. CETC monitoring allows evaluation of treatment success in individual patients.”

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Search for Prognostic Markers

Commenting on the studies, Minetta C. Liu, MD, Associate Professor of Medicine in the Division of Hematology/Oncology at Lombardi Comprehensive Cancer Center, said that both sets of researchers are looking for better prognostic markers—one in patients with metastatic disease and the other in patients with early-stage disease.

“We're trying to find better technologies to predict, at the individual level, which patients are responding to therapy and which aren't,” she said.

“Should we be giving these tests to patients getting trastuzumab? We don't know yet. But that's the direction in which this work is taking us,” Dr. Liu said.

© 2010 Lippincott Williams & Wilkins, Inc.
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