New data demonstrate that lapatinib decreases tumourigenic breast cancer stem cells in women receiving neoadjuvant treatment

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Study results suggest a potential new treatment strategy towards achieving long-term eradication of cancer



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GlaxoSmithKline today announced for the first time final results from a prospective study that demonstrated that lapatinib decreases tumourigenic (‘cancer initiating’) stem cells in primary breast cancers of women receiving neoadjuvant treatment.[1] These data were highlighted in an oral presentation at the 6th European Breast Cancer Conference (EBCC-6).

Despite advances in the detection and treatment of metastatic breast cancer, mortality remains high due, in part, to the emergence of therapy-resistant cancer cells.[2],[3] Recent research has identified a specific subset of tumour cells with the unique capacity to proliferate and form new tumours, referred to as tumourigenic stem cells. [4]Therefore, the possibility arises of using anti-stem cell therapy to prevent breast cancer occurring, [5] as opposed to merely treating the symptoms of the disease.

“The results from this study are exciting,” said Jenny Chang, M.D., Medical Director, Breast Care Center, Associate Professor of Medicine, Baylor College of Medicine, Houston, Texas and lead investigator on this study. “Over time, resistance to chemotherapy builds and this is highly problematic in clinical practice. The genes that trigger molecular pathways involved in chemoresistance, tumour formation and malignant cell self-renewal are all linked to this specific group of tumorigenic breast cancer cells. New therapies that decrease or inhibit the action of these stem cells are vitally important – if these precursors to tumour formation are not targeted, in essence any subsequent treatments are of limited value.”

45 patients with locally advanced ErbB2 over-expressing breast cancer, received lapatinib before surgery, initially as a single agent for the first six weeks, followed by a combination of lapatinib plus weekly trastuzumab and three-weekly docetaxel for 12 weeks. Biopsies were taken at time of diagnosis and after six weeks of lapatinib, and assessed for tumourigenic cells.1

Results showed significant tumour regression (median decrease of -60.8%, p=0.001) in primary tumours after only six weeks of single agent lapatinib. Unlike treatment with chemotherapy, lapatinib decreased tumorigenic breast cancer stem cells from 10.6% to 4.7%. The pathologic complete response rate following combination treatment (lapatinib plus trastuzumab and docetaxel) was 63%.1

“These data have gone some way towards answering a number of questions in current breast cancer knowledge,” saidDr Steven Stein, Vice President, Oncology Medicine Development Centre, GlaxoSmithKline. “For example, stem cell research may bring us closer towards understanding why, in some women, breast cancer can return after lying dormant for many years following full remission. We are encouraged by the data from this study and are committed to further investigations.”

In addition, a further two studies from lapatinib early access programmes were presented at EBCC-6 relating to the safety and efficacy of lapatinib, in combination with capecitabine, in patients with advanced or metastatic breast cancer whose tumours overexpress ErbB2 (HER2). Patients should have progressive disease following prior therapy, which must include anthracyclines and taxanes, and therapy with trastuzumab in the metastatic setting.[6]

French Lapatinib Authorization for Temporary Use (ATU): Design, Operation and Initial Safety Data (Abstract# 405 (poster)

Results from the preliminary analysis of 693 patients from the ATU programme receiving lapatinib, in combination with capecitabine, for ErbB2-positive metastatic breast cancer, confirms the safety profile of lapatinib, in combination with capecitabine,[7]is consistent with the safety profile observed in the pivotal trial EGF100151.[8]

A single-institution experience from Sheba Medical Centre, Ramat Gan, Israel: Effect of lapatinib and capecitabine combination therapy on CNS metastases in patients with ErbB2-positive metastatic breast cancer (Abstract #419 (poster)

Preliminary results from a single-institution experience from the Lapatinib Expanded Access Programme (LEAP) support previous data demonstrating that lapatinib, in combination with capecitabine, is active in patients with ErbB2-positive metastatic breast cancer and shows potential in brain metastases. Further investigation of lapatinib, in combination with capecitabine, in patients with ErbB2-postive CNS metastases is warranted.[9]

Lapatinib

Lapatinib is the first oral, small molecule dual targeted therapy that works by getting inside the cancer cell to inhibit both ErbB1 (EGFR) and ErbB2 (HER2), two receptor proteins which are responsible for tumour growth.[10] This novel mechanism of action is a new way to treat breast cancer.

Future for lapatinib - ongoing clinical trials

A comprehensive clinical development programme is evaluating lapatinib both alone and in combination with other therapies (chemotherapy, hormonal therapy, other targeted agents and VEGF inhibitors) across the spectrum of ErbB2-positive breast cancer, from metastatic to early breast cancer. Trials are also ongoing and planned in a range of other solid tumours that overexpress ErbB1 and/or ErbB2.

Lapatinib Marketing Authorisation

On December 13th 2007 EMEA’s CHMP adopted a positive opinion recommending a conditional marketing authorisation for lapatinib in the European Union. Discussions on the content of the label (SmPC) are still ongoing and GSK cannot speculate as to when the European Commission will grant a conditional marketing authorisation. Until the European Commission grants a marketing authorisation, lapatinib is not commercially available in the European Union.

GSK in Oncology

GSK Oncology is dedicated to producing innovations in cancer that will make profound differences in the lives of patients. Through GSK’s revolutionary ‘bench to bedside’ approach, we are transforming the way treatments are discovered and developed, resulting in one of the most robust pipelines in the oncology sector. Our worldwide research in oncology includes partnerships with more than 160 cancer centres. GSK is closing in on cancer from all sides with a new generation of patient focused cancer treatments in prevention, supportive care, chemotherapy and targeted therapies.
References

[1] Decrease in tumorigenic breast cancer stem cells - final results of a neoadjuvant trial in primary breast cancer patients. Jenny C Chang, Xiaoxian Li, Chad Creighton, et al. 6th European Breast Cancer Conference 2008; Oral presentation: abstract# 204

[2] Stockler et al. Systematic reviews of chemotherapy and endocrine therapy in metastatic breast cancer. Cancer Treat. Rev. 2000;26:151-168

[3] Schultz et al. Recent advances in breast cancer biology. Curr Opin Oncol. 1999;11:429-434

[4] Al-Hajj et al. Prospective identification of tumorigenic breast cancer cells. PNAS. 2003;100(7):3983-3988

[5] Smalley and Ashworth. Stem Cells and Breast Cancer: A Field in Transit. Nature Rev Cancer. 2003;3:832-844

[6] Tyverb Summary of Product Characteristics.

[7] M Campone, Dr El-Kouri,V Dieras et al. French Lapatinib (lapatinib) Authorization for Temporary Use (ATU): Design, Operation and Initial Safety Data. 6th European Breast Cancer Conference 2008; Poster: abstract #405

[8] Geyer C, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355; 2733-43

[9] B Kaufman, R Weitzen, A Goldfarb et al. A single-institution experience from the Lapatinib Expanded Access Program: effect of lapatinib and capecitabine combination therapy on CNS metastases in patients with ErbB2+ metastatic breast cancer. 6th European Breast Cancer Conference 2008; Poster: abstract #419

[10] Konecny GE, Pegram MD, Venkatesan N, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 2006;66:1630-9