Inflammatory Breast Ca Responds to Lapatinib/Paclitaxel

Oncology NEWS InternationalOncology NEWS International Vol 16 No 2
Volume 16
Issue 2

The investigational agent lapatinib (Tykerb) when added to paclitaxel has significant clinical activity as neoadjuvant treatment of HER2-positive inflammatory breast cancer (IBC)

• SAN ANTONIO—The investigational agent lapatinib (Tykerb) when added to paclitaxel has significant clinical activity as neoadjuvant treatment of HER2-positive inflammatory breast cancer (IBC), Massimo Cristofanilli, MD, of M.D. Anderson Cancer Center, reported at the 29th Annual San Antonio Breast Cancer Symposium (abstract 1).

Inflammatory breast cancer, the most lethal form of breast cancer, tends to express ErbB1 (epidermal growth factor receptor [EGFR]) and overexpress ErbB2 (HER2/neu). The small molecule tyrosine kinase inhibitor lapatinib targets both ErbB1 and B2 tyrosine kinases.

The EGF102580 international phase II trial was initiated "because lapatinib is one of the few drugs that had shown any activity in phase I studies in patients with recurrent IBC," Dr. Cristofanilli said. "It appeared that this agent could be the first to offer hope for women newly diagnosed with the disease."

Dr. Cristofanilli reported on 35 patients with newly diagnosed inflammatory breast cancer who completed the trial and underwent surgery. All patients had advanced disease, and most had hormone-receptor-negative tumors.

Cohort A overexpressed HER2 while cohort B included patients who were ErbB1 positive and HER2 negative. All patients received lapatinib 1,500 mg orally once daily as monotherapy on days 1 to 14, followed by an additional 12 weeks in combination with weekly paclitaxel 80 mg/m2. After 14 weeks of treatment, patients underwent surgery followed by adjuvant chemotherapy, radiotherapy, or hormonal therapy at the treating oncologist's discretion.

In the 30 HER2-positive patients, lapatinib as monotherapy during the first 14 days produced clinical responses in 30% of patients. Functional imaging done for some of the patients after 2 weeks demonstrated evidence of a metabolic response to lapatinib, Dr. Cristofanilli said.

The combination of lapatinib plus paclitaxel produced a response rate of 77% (10% complete responses and 67% partial responses), and stable disease in 10% of patients. Notably, 17% of patients who underwent surgery had a pathological complete response (pCR), ie, no evidence of residual invasive tumor, even in the axillary lymph nodes.

Among the five HER2-negative patients, four (80%) had a partial response at week 14, but there were no complete responses or pCRs, Dr. Cristofanilli said.

Combination lapatinib/paclitaxel yielded "predictable and manageable" toxicity, he said. Diarrhea grade 3 or higher was reported by 60%, with lesser grades reported by 34%. Other common toxicities of grade 3 or higher included fatigue (20%) and asthenia (20%).

Baseline biomarker analysis suggested that many patients expressed genes related to inflammatory breast cancer, including E-cadherin, p53, and RhoC. "This is important in a multicenter trial, because it strongly supports the clinical diagnosis in all the patients," he said.

Response to lapatinib was associated with high expression of the phosphorylated EGF family members, especially HER2, along with insulin growth factor receptor, phosphatase and tensin homolog (PTEN), heregulin gene (HRG), and transforming growth factor alpha (TGF-α). HRG and TGF-α were expressed in both HER2-positive and HER2-negative responders. Further molecular analyses are ongoing. "We strongly believe these preliminary data provide new hope for inflammatory breast cancer patients," Dr. Cristofanilli concluded.

Proof of Principle

"This study is a terrific proof of principle," commented Frankie Holmes, MD, of US Oncology, Houston. She suggested that further analyses look at topoisomerase II expression, since "the overall response wasn't as brisk as we would have expected, given the previous data with paclitaxel upfront and pCRs of 25%." Dr. Cristofanilli responded that those figures were from women with operable primary breast cancer. "There have never been data showing that weekly paclitaxel can achieve that response in inflammatory breast cancer," he noted. "In any case, there are many other molecular studies going on, including TUNEL assay, phosphorylated AKT, and, of course, topoisomerase II."

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