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At the Posters: Trastuzumab Roundup

Laino, Charlene

doi: 10.1097/01.COT.0000368896.29383.95

Trastuzumab took center stage at several of the poster sessions at the CTRC-AACR San Antonio Breast Cancer Symposium. The following is a roundup of the highlights.

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Trastuzumab + GM-CSF Stabilizes Disease

The addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to trastuzumab stabilizes disease in patients with trastuzumab-resistant, HER2-positive metastatic breast cancer, reported Yee Chung Cheng, MD, Assistant Professor of Medicine in the Department of Neoplastic Diseases and Related Disorders at Medical College of Wisconsin.

The combination stabilized the disease for a median of 15.8 weeks without causing any significant toxic effects in about one-third of heavily pretreated patients, he said.

“This was a pilot study to see if simply giving a growth factor—GM-CSF—to very heavily pretreated patients who progressed on trastuzumab would change the natural course of the disease. Very interestingly, about 30% will have stable disease for a median duration of four months. One patient was still stable at one year,” he said.

The proposed mechanism of trastuzumab-induced regression of HER2-positive tumors includes inhibition of tumor cell proliferation, potentiation of chemotherapy, and facilitation of immune function through antibody-dependent cell-mediated cytotoxicity, he explained.

Preclinical research suggests that cytokines such as GM-CSF may augment antibody-dependent cell-mediated cytotoxicity by direct activation of tumor cells or by enhancement of tumors-associated antigen on tumor cells.

The study involved 17 patients with HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab with or without chemotherapy. All continued to take trastuzumab alone at 2 mg/kg intravenous weekly.

The median number of metastatic sites was two, with the liver the most common site of metastasis. The median number of prior regimens for metastatic disease was two.

GM-CSF (250 µg/m2 subcutaneous daily) was added until the absolute neutrophil count (ANC) was higher than 10,000/mm3, and was then given every other day while the ANC was maintained below 10,000/mm3.

Treatment with trastuzumab and GM-CSF was continued until the patients had disease progression or experienced intolerable toxicity.

One patient developed rapidly progressive disease two weeks after the start of the study and died soon after. Among the other 16 patients, five (29%) had stable disease with a median duration of 15.8 weeks.

The median time to progression for all 17 patients was eight weeks.

Two patients suffered Grade 3 toxic effects—one case of fatigue and one of muscle aches. The most common toxic effect was rash at the injection site, followed by skin rash, fatigue, and muscle aches. No Grade 4 or irreversible toxic effect was seen.

“Administration of GM-CSF is simple, safe, and feasible. This combination of trastuzumab and GM-CSF needs further evaluation in combination with chemotherapy or other biological agents,” Dr. Cheng said.

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Trastuzumab-Gemcitabine Combo Highly Active

A combination of gemcitabine, carboplatin, and trastuzumab is highly active in the treatment of metastatic breast cancer, 3.5-year follow-up data of a Phase II trial confirm.

The researchers previously reported (Loesch et al: Clin Breast Cancer 2008) the efficacy and safety of gemcitabine and carboplatin with or without trastuzumab in patients with metastatic breast cancer.

The new analysis updated time-to-progression and overall survival rates after up to 3.5 years of extended follow-up.

The study involved 150 patients who were stratified into three groups at registration: Group 1, HER2-positive tumors, regardless of prior taxane use; Group 2, HER2-negative tumors and no taxanes within the past two years; and Group 3, HER2-negative tumors and pretreated with taxanes.

All patients received gemcitabine (1,500 mg/m2 over 30 minutes) followed by carboplatin (AUC=2.5) repeated on Day 1, repeated every 14 days up to Cycle 9.

Group 1 patients also received trastuzumab: 8 mg/kg in Cycle 1 followed by 4 mg/kg in Cycles 2–9, followed thereafter by 6 mg/kg every 21 days until progression or intolerable toxicity.

Six (12%) of the patients in the trastuzumab arm had a complete response, and 26 (52%) showed a partial response. In Group 2, no patient had a complete response, and 13 (28%) had a partial response. In Group 3, one (2%) patient had a complete response, and 15 (32%) had a partial response.

The median time to progression was 7.2 months in the arm group receiving trastuzumab, compared with 5.6 and 4.6 months in Groups 2 and 3, respectively.

The median overall survival time has not been reached for the trastuzumab arm; for Group 2, it was 21.7 months and for Group 3, 11.9 months.

At 24 months, the survival rates were 73%, 41%, and 20.5% in Groups 1, 2, and 3, respectively; at 36 months, survival rates were 61%, 26%, and 8%, respectively.

Three of the responding patients on trastuzumab have been followed for 3.5 years, at which time they were relapse-free, said David M. Loesch, MD, a medical oncologist at US Oncology Research.

“HER2-positive patients receiving trastuzumab had the highest time-to-progression and survival rates of all treatment groups. The combination of gemcitabine, plus carboplatin and trastuzumab resulted in excellent tolerability, with no alopecia.”

Research support was provided by Lilly USA.

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Trastuzumab vs Axillary Metastases

The majority of patients with proven axillary metastases will have a pathological complete response (pCR) and eradication of disease after treatment with trastuzumab-based neoadjuvant chemotherapy, reported Laura S. Dominici, MD, a surgical oncologist at the University of Texas M. D. Anderson Cancer Center.

“This has implications for the surgical management of the axilla in these types of patients. It may be feasible to perform intraoperative lymphatic mapping and sentinel node biopsy in patients with a clinical complete response to trastuzumab-containing chemotherapy.”

The study aimed to determine the incidence of axillary pCR and the effect of axillary pCR on disease-free survival rates in patients with HER2-positive disease and biopsy-proven axillary metastases who received trastuzumab-based neoadjuvant chemotherapy.

The researchers analyzed the records of 109 consecutive pts with HER2-positive breast cancer and ultrasound-guided fine needle aspiration biopsy-confirmed axillary metastases.

All patients received trastuzumab-based neoadjuvant chemotherapy prior to undergoing breast surgery with complete axillary lymph-node dissections. After surgery, patients were subdivided into those with and without residual axillary lymph-node disease.

At a median follow-up of 29.1 months, patients with negative axillary lymph nodes had a projected four-year response rate of 93%, compared with 76% in the group with residual nodal disease, Dr. Dominici reported.

“As better systemic agents are introduced into the breast cancer armamentarium, it will be critically important to develop minimally invasive and less morbid surgical approaches to the axilla in patients treated with neoadjuvant chemotherapy.”

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Pegylated Liposomal Doxorubicin

Concurrent administration of pegylated liposomal doxorubicin plus cyclophosphamide and trastuzumab followed by weekly paclitaxel and trastuzumab is not associated with increased cardiac toxicity, compared with the use of doxorubicin plus cyclophosphamide (AC) followed by weekly paclitaxel plus trastuzumab, according to the results of a planned interim analysis of a Phase II trial.

The study is designed to test the hypothesis that substituting pegylated liposomal doxorubicin for doxorubicin in an adjuvant regimen may minimize the risk of cardiotoxicity and permit earlier integration of adjuvant trastuzumab.

The study involved 90 patients with HER2-positive tumors randomized to AC followed by weekly paclitaxel and trastuzumab or pegylated liposomal doxorubicin, cyclophosphamide, and trastuzumab followed by weekly paclitaxel and trastuzumab.

During the first eight cycles of therapy, no patient suffered cardiac death or severe heart failure with a left ventricular ejection fraction (LVEF) drop of more than10% to less than 50%.

Additionally, no patient had asymptomatic or mildly symptomatic cardiac events during the eight cycles of chemotherapy.

There was a significant reduction in LVEF in the AC arm from baseline to the end of Cycle 8. The change in LVEF in the pegylated liposomal doxorubicin group was not statistically significant.

The final analysis is planned for the middle of this year, according to the researchers, led by Daniel Rayson, MD, Associate Professor in the Division of Medical Oncology at Beatrice Hunter Cancer Research Institute.

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Preclinical Data: Treating ER-, HER-Positive Tumors

The targeted therapy vandetanib can improve the efficacy of combined endocrine and anti-HER trastuzumab therapy in patients whose tumors are positive for both the estrogen receptor (ER) and HER2, preclinical research suggests.

“Compelling evidence suggests that cross-talk between the pathways of ER and HER1/HER2 contributes to endocrine resistance,” said Luca Malorni, MD, a postdoctorate researcher at Lester and Sue Smith Breast Center at Baylor College of Medicine.

Both ER and HER2 are known to promote angiogenesis. Vandetanib is an orally active, VEGFR/HER1 tyrosine kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR) and HER1 that has shown both anti-angiogenic and anti tumor cell activities in different models.

Dose escalation of vandetanib was first studied in estrogen-supplemented, ovariectomized nude mice bearing parental tumor xenografts. Cells were injected subcutaneously and tumors were allowed to grow. Subsequently, the mice were randomized to receive either continued estrogen supplementation only or estrogen supplementation in combination with vandetanib at different dosages.

In a second experiment, mice bearing xenografts were randomized and treated with tamoxifen alone or in combination with trastuzumab and vandetanib.

“By itself estrogen-deprivation therapy didn't work. When we added trastuzumab, we had a delay in tumor growth. And the combination of three drugs worked best against in the ER-positive, HER2-positive tumors,” Dr. Malorni said.

Phase II studies are now in the planning stage, he added.

The study was supported by the Susan G. Komen for the Cure Fellowship and AstraZeneca.

© 2010 Lippincott Williams & Wilkins, Inc.
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