Multi-pronged approach

The prognosis for women with breast cancer has improved vastly over the years, with a five-year survival rate of approximately 95 per cent. This is largely due to improved screening and the development of targeted therapy options for patients.

The treatment options available to breast cancer sufferers are varied and often consist of a combination of approaches, including surgery, chemotherapy, radiation therapy, hormonal therapy and targeted therapies.

Chemotherapy regimens are used often after surgery in early invasive breast cancer, to 'mop-up' any cancer cells that may remain in the body. Hormonal therapies reduce the tumour-promoting effects of the endogenous hormones oestrogen and progesterone by blocking their respective receptors on tumour cells. Examples of hormonal therapies include anastrozole (Arimidex; AstraZeneca), fulvestrant (Faslodex; AstraZeneca) and tamoxifen (Nolvadex, Istubal, Valodex; AstraZeneca).

Targeted therapies aim specifically at cancer cells, avoiding normal body cells. Approximately 15–30 per cent of breast cancer patients over-express human epidermal growth factor receptor-2/neu (HER2/neu), a tumour growth-promoting receptor associated with aggressive cancers. Two treatments, trastuzumab (Herceptin; Genetech) and lapatinib (Tyverb; GlaxoSmithKline) block the HER2/neu receptor, improving survival in these patients. Additionally, the angiogenesis inhibitor bevacizumab (Avastin; Roche) is used as a first-line treatment to prevent formation of new blood vessels, restricting tumour growth.

However, while these therapies are effective for a variety of breast cancers, there remain populations of breast cancer patients with a poor prognosis: those with advanced metastatic breast cancer refractory to HER2 targeted therapy and patients whose tumours do not express HER2 or hormone receptors, also known as triple receptor negative breast cancer.

Novel targeted therapies
BSI 201 (sanofi-aventis) is a potential first-in-class targeted therapy to inhibit poly-ADP-ribose polymerase (PARP). PARP, an enzyme involved in repairing single strand breaks in DNA during replication, is expressed in intraductal breast cancer cells and its inhibition prevents DNA repair during replication, leading to cancer cell death.

Results from a randomised phase II trial investigating BSI 201 in women with metastatic triple-negative breast cancer, presented at the 45th Annual Meeting of the American Society of Clinical Oncology in 2008, found that the addition of BSI 201 to gemcitabine + carboplatin significantly improved the clinical benefit rate, compared with gemcitabine + carboplatin alone (62 per cent vs 21 per cent). A phase III trial in the same indication was initiated in 420 patients in July 2009 in the US, and a further phase III trial was initiated in Europe in February 2010. The US Food and Drug Administration (FDA) granted BSI 201 fast track status for metastatic triple-negative breast cancer.

Eribulin (Eisai) is a synthetic analogue of halichondrin B, found in marine sponges, which is known to inhibit tubulin polymerisation, arresting cell division leading to cancer cell death. Results from the phase III EMBRACE (Eisai Metastatic BReast cancer study Assessing physician's Choice versus Eribulin mesylate) trial in advanced or local recurrent breast cancer showed significantly improved overall survival compared to the physician's choice in breast cancer chemotherapy. Based on these results, Eisai has submitted applications for regulatory approval for the treatment of locally advanced or metastatic breast cancer in the US, Europe and Japan.

A novel approach to existing therapies
Trastuzumab-DM1 immunoconjugate, a HER2 antibody therapy linked with an antimicrotubule drug (DM1), is being developed by a collaboration between Genentech, Immunogen and Roche.

Results from a phase II trial in trastuzumab-refractory metastatic breast cancer were presented at the 32nd Annual San Antonio Breast Cancer Symposium in December 2009. According to lead investigator, Ian Krop, of the Dana-Farber Cancer Institute: "These results are significant because they demonstrate that T-DM1 was effective at shrinking tumours in women whose cancer had progressed following prior treatment with standard therapies for HER2-positive breast cancer."

Genentech and Roche plan to submit regulatory filings to the FDA in 2010. The EMILIA phase III trial is now underway as second-line therapy in 580 patients with HER2-positive locally advanced or metastatic breast cancer.

New indications for common therapies
Bevacizumab (Avastin; Genentech and Roche) is a humanised IgG1 monoclonal antibody, which acts as a vascular endothelial growth factor (VEGF) antagonist, inhibiting blood vessel formation in cancer cells. It is currently launched for the first-line therapy of advanced breast cancer. The RIBBON-2 study, investigating second-line therapy with bevacizumab in combination with standard chemotherapy for the treatment of metastatic HER2-negative breast cancer, found an increase in progression-free survival compared to chemotherapy alone.

These results have been submitted to the FDA for review. Additionally, a number of trials are underway to assess the efficacy of bevacizumab as adjuvant therapy. Pending positive results, Roche and Genentech intend to apply for regulatory approvals in this indication in 2012.

Lapatinib (Tyverb; GlaxoSmithKline), a dual inhibitor of HER2 and EGFR, is approved in combination with capecitabine for the treatment of advanced or metastatic refractory HER2-positive breast cancer. GlaxoSmithKline submitted regulatory applications to the FDA and the European Medicines Agency (EMEA) in April 2009 for combination therapy with lapatinib and letrozole. These applications were based on a phase III trial, which showed this regimen improved progression-free survival and was well tolerated. The FDA granted the regimen accelerated approval in January 2010, and the Committee for Medicinal Products for Human Use (CHMP) of the EMEA issued a positive opinion in February 2010.

Doxorubicin liposomal (Myocet; Elan Coroporation) is in phase III development as a first-line therapy for HER2-positive breast cancer in Europe and the US, where it has been granted fast track designation by the FDA. Results of an ongoing phase III trial are expected by the end of 2010.

Biomarker potential
There is an unprecedented need for alternative therapies for women with advanced refractory breast cancer and triple receptor negative breast cancer. However, there is hope in the pipeline. A number of drugs in phase II clinical trials are being assessed in the phase II I-SPY-2 trial. This trial, conducted by the Biomarkers Consortium, will screen patients based on genetic factors and biomarkers for their suitability to treatment before they are allocated to a standard chemotherapy regimen or to a phase II drug.

Treatments being assessed include the TRAIL receptor-2 antagonist conatumumab (Amgen), the angiopoietin-1 and -2 inhibitor AMG 386 (Amgen and Takeda), the IGF-1 receptor inhibitor figitumumab (Pfizer), the irreversible HER2 inhibitor neratinib (Pfizer) and the PARP inhibitor veliparib (Abbott Laboratories).

Linking appropriate patients to drugs based on their genetic and biomarker characteristics will further enable the development of personalised medicine and allow more efficient clinical trial design. This is providing great hope for the speed at which breast cancer treatments can move through to the patient, and therefore, add to the options when fighting this disease.

The Author
Pipeline was written by Leanne Summers of Adis International - Wolters Kluwer Pharma Solutions - using data derived from Adis R&D Insight and Clinical Trials Insight.
For further information on Adis services, please contact contact Kuljeet Sohanpal on +44 (0)207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

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