PI3 kinase activation and response to trastuzumab or lapatinib in HER-2 overexpressing locally advanced breast cancer (LABC).

Abstract

#34 Background: Activating mutations of PI3 kinase (PIK3CA) and PTEN loss may be associated with trastuzumab resistance. Trastuzumab, a HER2 humanized monoclonal antibody, and lapatinib, an EGFR/HER2 tyrosine kinase inhibitor are both established treatments. Greater understanding of the cellular response to trastuzumab or lapatinib is needed to tailor targeted therapy for individual patients and identify those less likely to benefit. Material and Methods: We performed two sequential neoadjuvant clinical trials in HER-2 overexpressing LABC: 40 patients received weekly trastuzumab at standard doses given initially as a single agent for the first 3 weeks, then in combination with 3-weekly docetaxel for 12 weeks (T), while 49 patients received lapatinib as a single agent (1,500 mg daily, orally) for 6weeks then the combination of 3-weekly trastuzumab/docetaxel for 12 weeks, before primary surgery (L). Sequential core biopsies of the primary breast tumors were taken at initial, weeks 1 and 3 after the first dose of trastuzumab, and at initial, weeks 2, 4, and 6 after lapatinib. Apoptosis, Ki67 proliferation rate, and PTEN were assessed by immunohistochemistry. Low PTEN was defined as Allred score of <3. Genomic DNA (10-100ng) was sequenced using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems) and an ABI 3730 automated capillary sequencer. Two sample and paired sample comparisons were performed using nonparametric tests. Results: There was a significant decrease in clinical tumor size after three weeks of trastuzumab (n=35, median=-20%), and six weeks of lapatinib (n=49, median=-74%) compared to pre-therapy (p<0.001). At surgery, pathologic complete response was observed in 38% in patients on upfront T and 70% patient on L. There was a significant increase in apoptosis (median=3.5% to 4.7%, p=0.006) within one week after trastuzumab, with no significant change in Ki67 at any of the time point. Lapatinib was associated with a no significant increase in apoptosis but a significant decrease in Ki67 at week 2, 4, and 6 of therapy (p<0.001). Cases with low PTEN or PIK3CA mutations were significantly less likely to have a pathologic complete response to T (p<0.005). Howver, low PTEN or PIK3CA mutations was not significantly associated with pathologic resistance to L. Conclusions: Activation of PI3 kinase pathway is associated with trastuzumab but not lapatinib resistance. Lapatinib may affect signalling through the Ras/Raf/MAPK/ERK pathway, inhibiting cell division. Low PTEN expression was not associated with lapatinib resistance, and may explain the clinical efficacy of lapatinib in trastuzumab-resistant patients, supporting clinical trials for the combination of both agents. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 34.

Lapatinib in Breast Cancer - The Predictive Significance of Her1 (Egfr), Her2, Pten and Pik3ca Genes and Lapatinib Plasma Level Assessment

“…Moreover, different modes of cellular drug resistance have been suggested for trastuzumab and lapatinib and this underlines the rationale of lapatinib administration after trastuzumab failure 56 . However, some BCs do not respond or develop resistance to lapatinib too (e.g.…”

Novel Mechanism of Lapatinib Resistance in HER2-Positive Breast Tumor Cells: Activation of AXL

“…However, lapatinib inhibits growth of trastuzumab-resistant breast cancer cells (5,6) and shows clinical efficacy in patients who have received prior therapy with an anthracycline, a taxane, and trastuzumab (1). Moreover, low PTEN expression or PIK3CA mutations did not preclude response to lapatinib in primary tumors from women with HER2-overexpressing locally advanced breast cancer who received 6 weeks of lapatinib monotherapy before standard neoadjuvant treatment (7). Multiple mechanisms of resistance have been reported for tyrosine kinase inhibitors that selectively target HER1, such as gefitinib and erlotinib.…”

Perioperative therapy in HER2+ patients

“…With regard to changes following anti-HER2 therapy, change in tumour size after 11 days of therapy may provide additional prognostic information that is not available from a pretreatment tumour specimen. Lapatinib has been reported [20] to shrink tumour size by 74% after 6 weeks which interpolates to a 36% shrinkage after 2 weeks. Moshin et al [21] also found early tumour regression with a median decrease of 20% (0-60.4%) after 3 weeks of trastuzumab; changes in apoptosis were also observed over this period.…”

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