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Triple negative breast cancer

R&D developments in triple negative breast cancer - a relatively new subset of breast cancer diagnosed in around one million women a year

Breast cancer ribbonTriple negative breast cancer (TNBC) is a relatively new subset of breast cancer. Breast cancer is diagnosed in approximately one million women a year worldwide and, of these, TNBC affects around 10-20 per cent. The first mention of TNBC was in 2005 and since then it has been shown to be one of the more aggressive forms of breast cancer; it tends to be higher grade, metastasize more frequently and have a more basal like phenotype.

To complicate matters a little, in the TNBC population, approximately 90 per cent of patients also have a faulty breast cancer susceptibility gene 1 (BRCA1), which correlates with this cancer's higher degree of aggressiveness and basal type histology.

The overall five-year survival for this population is lower than that for other forms of the disease and patients are more likely to relapse. On top of this, TNBC is particularly difficult to treat. Of the currently approved breast cancer therapies, not all are available for TNBC; chemotherapy is the only approved treatment option for TNBC in the adjuvant and metastatic setting. Therefore, researchers are actively pursuing novel therapies for this indication in growing recognition of its importance.

The 'triple negative' refers to the lack of expression of oestrogen and progesterone hormonal receptors, as well as human epidermal growth factor receptor 2 (HER2) on a patient's breast tumour cells. The presence of one or more of these receptors on breast cancer cells can aid physicians in choosing the most appropriate treatment regimen. The usual treatments for breast cancer sufferers are varied and generally involve a combination of methods, including chemotherapy, surgery, radiation therapy, hormonal therapy and targeted therapies.

Due to the absence of hormonal receptors and HER2, hormonal therapies, such as tamoxifen, anastrazole and fulvestrant, and trastuzumab are eliminated as treatment options. On a positive note though, some studies suggest that TNBC tumours are more responsive to chemotherapy than tumour types with one or more of the previously mentioned receptors. Dose intensification of standard chemotherapeutics may yield improved results, but the discovery and development of novel treatments is more promising.

The somewhat limited treatment option pool and the number of women with TNBC (between 110,000 and 200,000 in the US) presents a significant opportunity for novel targeted compounds, such as inhibitors of poly-ADP-ribose polymerase (PARP), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), among others.

'Triple negative' refers to the lack of expression of oestrogen and progesterone hormonal receptors, as well as human epidermal growth factor receptor 2 (HER2) on tumour cells

PARP inhibitors
PARP is a key regulator of DNA repair and cell proliferation. Inhibition of this enzyme sensitises cells to therapies that induce single-stranded DNA break, such as radiotherapy, platinum and other alkylating compounds. Clinical trials of PARP inhibitors, either alone or given in combination with platinum-based drugs, are currently underway. The latest developments in the field of potential first-in-class PARP inhibitors are making this one to watch.

Frontrunner in the PARP inhibitor race is Sanofi's iniparib, formerly known as BSI 20, but how long can it maintain the lead? A recently completed phase III trial of iniparib in combination with gemcitabine and carboplatin in 519 women with metastatic TNBC failed to meet its co-primary endpoints of overall survival and progression-free survival. However, patients treated with the combination in the second- and third-line setting demonstrated improvement in the aforementioned endpoints, which backs up results from an earlier phase II trial.

Presented at the 35th Congress of the European Society for Medical Oncology (ESMO) in 2010, and subsequently published in the New England Journal of Medicine in January 2011, phase II data showed that iniparib combined with gemcitabine plus carboplatin significantly improved the clinical benefit rate, compared with gemcitabine plus carboplatin alone. Sanofi will perform an in-depth analysis of the phase III results, with plans to open discussion with the European and American regulatory authorities. The company had hoped to file a submission with the US Food and Drug Administration (FDA) in early 2011. Iniparib was granted fast track status in the US for metastatic TNBC. Phase II trials of iniparib for TNBC are continuing.

In light of Sanofi's disappointing phase III results, competitors are proceeding cautiously and those with PARP inhibitors poised to enter phase III trials may yet catch up. Olaparib (AstraZeneca [AZ]) was next in line after iniparib. AZ was in discussions with the US FDA regarding the protocol for an anticipated phase III trial of olaparib in patients with BRCA1 and BRCA2 gene mutations. However, in early 2011 following the announcement of iniparib's phase III results, AZ decided to focus development of olaparib in ovarian cancer. The company may revisit development of olaparib for breast cancer after seeing how the phase III ovarian cancer study pans out.

Abbott's contender veliparib (formerly ABT 888), which is a more potent PARP inhibitor than iniparib, is close behind the other two compounds. Veliparib was expected to enter phase III in early 2011, but it appears that Abbott has stalled the trial's initiation. At the 46th American Society for Clinical Oncology (ASCO) in 2010, phase II results of veliparib in combination with temozolomide were presented. The clinical activity seen was attributed to the veliparib plus temozolomide combination rather than veliparib alone. The groundbreaking I-SPY-2 trial, conducted by the Biomarkers Consortium, is ongoing.

There may be room yet for PARP inhibitors in earlier phase development. Rucaparib is Pfizer's PARP inhibitor candidate that is undergoing phase II development for TNBC as a single agent or in combination with cisplatin following preoperative chemotherapy. CEP 9722 (Cephalon) and MK 4827 (Merck) are both compounds in phase I/II trials for solid tumours.

VEGF players
VEGF has a long history as a target for anticancer therapeutics, arising from the growth factors role in angiogenesis, a critical role in the ability of tumours to metastasize and generate a blood supply, which facilitates tumour growth. Roche's bevacizumab, a VEGF antagonist, is approved as a breast cancer treatment and is a viable treatment for TNBC. A subgroup analysis of TNBC patients in the ATHENA study demonstrated that median overall survival was 18.3 months compared with 20.5 months in non-TNBC patients, which supports the compound's ongoing development in this indication.

The phase III BEATRICE trial intends to assess the efficacy of bevacizumab as an adjuvant in combination with standard chemotherapy (anthracycline with or without taxane or taxane only) in over 2,000 patients with TNBC worldwide. Another phase III study, CALGB 40502, is investigating first-line bevacizumab in combination with either paclitaxel, nab-paclitaxel or ixabepilone in patients with locally recurrent or metastatic breast cancer, including TNBC. Regulatory submissions for bevacizumab as an adjuvant chemotherapeutic for breast cancer may be filed in 2013 if positive results are achieved.

Already approved in renal and liver cancers, sorafenib (Onyx Pharmaceuticals and Bayer) may be an option in TNBC. Sorafenib is in an ongoing phase II trial as a neoadjuvant in combination with cisplatin followed by paclitaxel for TNBC patients with early stage disease. The compound is also being evaluated in the phase III RESILIENCE trial for HER2-negative breast cancer; it will be interesting to see if the sponsors run a subset analysis on triple-negative patients when the results are in.

EGFR
A natural target for TNBC is EGFR. However, there is little evidence to support the use of inhibitors of EGFR as a treatment. Two agents that are already approved for the treatment of other cancers, erlotinib and cetuximab, have been examined as potential TNBC therapies. Erlotinib is a small molecule tyrosine kinase inhibitor that Genentech is investigating in two clinical trials for TNBC.

One is a phase II trial of the drug in combination with chemotherapy and the other is a phase I trial of the compound in combination with cisplatin and temsirolimus. The phase II trial is due to be completed in 2011. The monocolonal antibody cetuximab is undergoing evaluation in several phase II studies for TNBC either as a monotherapy or in combination with antineoplastics such as carboplatin, irinotecan, docetaxel and cisplatin. In the BALI-1 trial, cetuximab plus cisplatin therapy for metastatic TNBC failed to meet the primary endpoint of response rate, although investigators noted a trend of improved tumour response. However, a significant reduction in risk of progression was demonstrated by cetuximab plus cisplatin compared with cetuximab alone.

Dasatinib, a small molecule ABL kinase inhibitor … has been investigated in patients with advanced TNBC in a phase II trial


Other targets
Researchers are continuing to explore other targets that show promise in the treatment of TNBC. Tubulin stabilisation and resulting cell cycle arrest can induce apoptosis in tumour cells. One compound that works via this method is ixabepilone, which binds tubulin and promotes tubulin stabilisation whereby cell division cannot be completed. The agent is currently in phase III development for early-stage TNBC.

The TITAN trial is investigating ixabepilone as an adjuvant in combination with doxorubicin and cyclophosphamide compared with paclitaxel plus doxorubicin and cyclophosphamide. Bristol-Myers Squibb is also investigating ixabepilone in combination with cetuximab in the neoadjuvant setting.

Dasatinib, a small molecule ABL kinase inhibitor, and subsequently inhibitor of BCR-ABL, the SRC family, c-kit and platelet-derived growth factor receptorß (PDGFRß), has been investigated in patients with advanced TNBC in a phase II trial.

There is also BMN 673, a small molecule inhibitor under phase I/II development with BioMarin. Although this compound is only in trials for solid tumour types, it has shown efficacy in breast cancer models.

Conclusion
Targeted therapies in combination with more traditional therapies have proved effective for breast cancer so the same must be hoped for TNBC. Which class of targeted therapies will provide a drug candidate that overcomes the phase III/registration hurdle? How does the presence of BRCA1 mutations in the TNBC population affect potential treatments? With the hiccup in the progress of PARP inhibitors, 2011 is a crucial year for this class of therapies.

Time will tell whether the toxicity:efficacy ratios of promising compounds will prove favourable. Should the once promising class of PARP inhibitors fail, how will other targeted therapies fare? More exploration is required to define the role of targeted inhibition in TNBC, and as such many questions are yet to be answered.

The Author

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

To comment on this article, email pme@pmlive.com

4th August 2011

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