It’s all about me: Towards individualised treatment for metastatic breast cancer

Metastatic breast cancer (MBC) poses a major therapeutic challenge for oncologists1 due to its prevalence and variable prognosis.2 Approximately 5–10% of patients present with MBC at diagnosis, while 30% of those with early disease will develop MBC.3,4

Breast cancer is the most common cancer in women in the world⁵ with 1.38 million new cases diagnosed in 2008.² It is also the leading cause of cancer death among women worldwide and in 2008 caused nearly half a million deaths.² On a local scale, breast cancer is the most common cancer in Australian women, with over 12,500 new cases diagnosed in 2007. In this same year 2,680 women died from breast cancer, making it the second most common cause of cancer-related deaths in Australia.⁶ It is estimated that in 2015 there will be in excess of 15,000 new diagnoses of breast cancer in Australian women, 22% more than in 2006.⁷

Despite the rising incidence of breast cancer in Australia, world-wide mortality rates have been decreasing at a rate of 1–2% per year based on 2004 data.⁸ This is thought to reflect earlier detection of breast cancer and advances in adjuvant treatment regimens.⁹ The 5-year survival rate for women diagnosed with breast cancer between 2000 and 2006 was 88% compared with 73% for those diagnosed between 1982 and 1987.⁷ The prognosis of MBC, however, remains poor, with progressive disease developing within 12–24 months of diagnosis.⁸ Those diagnosed with MBC have a median survival of 2–3 years^10,11 and less than 5% of patients are alive at 5 years post diagnosis.⁸  

To date, with the exception of limited or oligometastatic disease, MBC remains incurable.⁸ The focus of treatment is achieving disease control, with palliation of symptoms for as long as possible while minimising toxic side effects.¹⁰ Recent advances in the understanding of signalling pathways responsible for tumour growth, inhibition of apoptosis, cellular invasion, metastasis and angiogenesis have generated several targets for new therapeutic agents.¹²  Although most of these novel drugs are still in early trial phase, results from preliminary studies show that they have the potential to improve survival in patients with MBC.¹⁰

New chemotherapeutic agents

Chemotherapy is considered first-line treatment for MBC patients with tumours that are hormone receptor negative, refractory to hormonal therapy or rapidly progressive.¹¹ Among the large number of chemotherapeutic agents used to treat MBC, the anthracyclines and taxanes have traditionally been the most effective.⁴ The major limitation of conventional chemotherapy is that of drug resistance: a complex phenomenon which then allows rapid proliferation of resistant tumour cells.⁴

Taxanes, developed in the 1990s, are microtubule sensitisers which induce apoptosis of cells. They have demonstrated superiority to non-taxane containing regimens and are the most active agents for the management of MBC.¹  Traditionally, taxanes were administered in conjunction with a solvent to improve solubility. The solvent, however, was associated with potentially fatal hypersensitivity reactions, increased risk of peripheral neuropathy and prolonged administration times. The development of nab-paclitaxel (Abraxane), an albumin bound formulation, overcame these limitations and led to more convenient drug administration, improved toxicity profiles and greater drug delivery to tumour cells. Phase III clinical trials conducted in 2005 demonstrated the improved efficacy and safety of nab-paclitaxel over solvent-containing paclitaxel and led to US FDA approval for MBC. Furthermore, nab-paclitaxel has proven to be superior to docetaxel (e.g. DBL Docetaxel, Taxotere) in the treatment of MBC and is regarded as being the most effective taxane in the treatment of MBC.¹³

The development of novel chemotherapeutic agents which target tumour cell microtubules, and which don’t exhibit cross-resistance with other chemotherapeutic agents, has been a major breakthrough in the treatment of drug-resistant disease.⁴ The US FDA has approved three agents for treatment of MBC after failure of treatment with anthracycline and taxane based regimens – capecitabine (Xeloda), ixabepilone (Ixempra) and eribulin (Halaven).¹⁴ Capecitabine is an oral prodrug of 5-fluorouracil and has shown clinical response and tolerability rates comparable to that of more complex regimens.¹³ Ixabepilone is an epothilone analogue which binds tubulin, resulting in apoptotic cell death. Despite promising results in clinical trials this agent failed to demonstrate a significant survival benefit and was associated with significant toxicity.¹⁴ A new anti-microtubule, eribulin (E7289), which is a naturally occurring halichondrin,¹⁰ has shown promising results in clinical trials. The phase III EMBRACE trial compared single agent eribulin to other chemotherapy regimens and found that it had an overall survival benefit of 2.5 months in heavily pre-treated MBC patients in addition to a tolerable side effect profile.¹⁰

New targeted therapy

Targeted therapies aim to interrupt pathways involved in tumourigenesis, including those responsible for cell invasion, cell metastasis, apoptosis, the cell cycle and angiogenesis.¹⁵ Among the most common targets are the endothelial growth factor receptors including ErbB1, ErbB2, the angiogenic pathway and inhibitors of the poly (ADP-ribose) polymerase (PARP) enzyme.^10,15  

Anti-ErbB2 based therapies

Patients with MBC and tumours that show overexpression of ErbB2 receptors or amplification of the ErbB2 gene on fluorescent in situ hybridisation (FISH) testing benefit from anti-ErbB2 targeted therapy.¹⁰ These agents are proposed to reduce resistance to endocrinological and cytotoxic agents when administered in combination with them.¹⁵

Trastuzumab

Trastuzumab (Herceptin) is a monoclonal antibody that binds to the ErbB2 receptor and prevents downstream signalling and activation of tumourigenic pathways. Trastuzumab has been successfully combined with chemotherapeutic agents including vinorelbine and the taxanes to improve overall survival, but should not be used in combination with anthracyclines due to excessive cardiac toxicity. Additionally, trastuzumab has shown promising results when added to a regimen of lapatinib, pertuzumab and neratinib.¹⁰  As with chemotherapy, the major limitation of trastuzumab is that of drug resistance, with most MBC patients developing resistance within one year.⁴

T-DM1 is an antibody-drug conjugate made up of trastuzumab and an anti-microtubule agent known as DM1. This combination allows for ErbB2 inhibition via trastuzumab and targeted delivery of DMI to tumour cells, thus reducing toxicity.^10,15 Following binding to the ErbB2 receptor, the T-DM1 conjugate is internalised, resulting in intracellular release of T-DM1. A phase II trial of this drug combination yielded a response rate of 40% in patients who had received prior trastuzumab and chemotherapy.¹⁰

Lapatinib

Lapatinib (e.g. Tykerb) is a reversible tyrosine kinase inhibitor that targets both ErbB1 and ErbB2 receptors in addition to their downstream pathways. It has the ability to cross the blood–brain barrier and has demonstrated an ability to reduce CNS metastases. This agent has been shown to reduce disease progression when combined with both trastuzumab and capecitabine.¹⁰

Pertuzumab

Pertuzumab is a monoclonal antibody which binds to HER2, inhibiting its ability to form dimers with other HER receptors.¹⁵ Its use is limited to the treatment of trastuzumab resistant ErbB2-positive MBC and, when combined with trastuzumab, it has demonstrated significant clinical benefit with a favourable safety profile in early clinical trials.¹⁰

Neratinib

Neratinib is a dual inhibitor of both ErbB2 receptors and EGFR kinase, thereby limiting the proliferation of EGFR dependent cells.^10,15 This agent has demonstrated significant activity in ErbB2 positive patients pre-treated with trastuzumab in addition to trastuzumab naive patients. Trials examining the effect of neratinib combined with paclitaxel, vinorelbine and capecitabine have shown early promising results.¹⁰

Hsp90 inhibitor

Hsp90 is a heat shock protein which, when combined with trastuzumab, has demonstrated the ability to inhibit tumour growth. A small study of this agent combined with trastuzumab has demonstrated promising anti-tumour activity in patients with ErbB2-positive MBC whose tumours have progressed during treatment with trastuzumab.¹⁰

Anti-angiogenic therapy

Angiogenesis plays an essential role in breast cancer development, invasion and metastasis and this process is therefore the target of novel therapeutic agents.¹⁵ The majority of trials examining agents which inhibit angiogenesis have concentrated on patients with ErbB2-negative breast cancer. Several new agents exist, including bevacizumab (e.g. Avastin), axitinib, sunitinib (Sutent), and sorafenib.^10,15

Bevacizumab

Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF). To date there are four randomised controlled trials in which bevacizumab has been combined with chemotherapy. Despite promising effects on response rates and progression free survival, this combination failed to demonstrate an overall survival benefit. Indeed, the combination of bevacizumab with chemotherapy has probably had more clinical trials than any other targeted therapy. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) initially approved bevacizumab in MBC after a single phase II trial (ECOG E2100) where the drug was used in combination with paclitaxel. However, both the FDA²¹ and EMA²² later repealed their approval in light of results of two phase III trials (AVADO and RIBBON1) which failed to replicate the magnitude of benefit seen in the ECOG E2100 trial.²² In Australia, the TGA and PBA resisted the call to make bevacizumab available for this indication. The combination of bevacizumab with other targeted therapies is currently being investigated in clinical trials.¹⁰

Axitinib

Axitinib is an oral inhibitor of the VEGF, platelet derived growth factor (PDGF) and tyrosine kinase receptor. Phase II trials of this agent administered alone and in combination with chemotherapy have shown activity in a range of malignancies including breast cancer. Reported side effects include fatigue, hypertension, diarrhoea, hand-foot syndrome and proteinuria.¹⁰

Sunitinib

Sunitinib is a similar multi-targeted tyrosine kinase inhibitor which also inhibits VEGF receptors, PDGF receptors, stem cell factor receptors and colony stimulating factor-1 receptors. Early clinical trials have failed to demonstrate significant results in undefined patient groups. Those who responded best to treatment included those with triple negative and ErbB2-positive tumours.¹⁰

Sorafenib

Sorafenib is another oral agent which has been studied in patients with ErbB2 negative MBC. Sorafenib administered twice daily in combination with oral capecitabine showed a 42% reduction in the risk of disease progression or death and even better results when used as a first-line agent. The main limitation of this combination was a significant increase in the risk of hand-foot syndrome which needs to be addressed in future trials.¹⁰

PARP inhibitors

Polyadenosine diphosphate ribose polymerase (PARP) is an enzyme involved in the repair of damaged DNA which results in chromosomal instability and apoptosis.¹⁶ Inhibitors of this enzyme are proposed to have a role in the treatment of triple negative breast cancers and those involving BRCA gene mutations, as these cancers are suspected to harbour a DNA-repair deficit.¹⁵ Olaparib and BSI-201 are oral and intravenous PARP inhibitors respectively, which have demonstrated promising results in the treatment of women who carry the BRCA mutation and in those with triple negative disease. Despite promising results, the best application of PARP inhibitors in the setting of MBC remains to be elucidated.^10,17

Advances in radiotherapy

To date, the aim of radiotherapy (RT) in the setting of MBC has been largely palliative. Radiation therapy in MBC is used to relieve symptoms and prevent or improve functional limitations. A recent review of radiotherapy in patients with MBC concluded that local radiotherapy targeting the primary tumour with or without regional treatment has a survival benefit. New data indicate a potential anti-tumoural immune response as a result of radiation-induced necrosis. Where distant metastases are concerned, clinical trials to date have failed to demonstrate an overall survival benefit from the use of targeted radiotherapy.¹⁸

Conclusion

Recent advances in the understanding of molecular pathways involved in MBC have led to the development of an array of promising therapeutic agents, broadening the armamentarium available for the treating oncologist. These agents have already demonstrated promising improvements in response rates and overall survival. The future management of MBC needs to be tailored to the individual and based on patient and tumour characteristics as well as molecular subtypes.^10,18 It is hoped that the combination of novel agents tailored specifically to individual characteristics will one day result in a cure for MBC.¹⁰

Article kindly reviewed by:

Andrew Dean MBChB MRCP(UK) FRACP
Medical Oncologist and Palliative Care Consultant
Medical Director
Virtual Medical Centre

References

1. Mariani G. New developments in the treatment of metastatic breast cancer: From chemotherapy to biological therapy. Ann Oncol. 2005;16(Suppl 2):191-4. [Full text]
2. Cardaso F, Fallowfield L, Costa A, et al. Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011;22(Suppl 6):25-30. [Abstract | Full text]
3. Iwata H. Future treatment strategies for metastatic breast cancer: curable or incurable? Breast Cancer. 2011. [Abstract]
4. Rivera E, Gomez H. Chemotherapy resistance in metastatic breast cancer: The evolving role of ixabepilone. Breast Cancer Res. 2010;12(Suppl 2):S2. [Abstract | Full text]
5. Perez E, Spano J. Current and emerging targeted therapies for metastatic breast cancer. Cancer. 2011. [Abstract]
6. Cancer in Australia: An overview 2010 [online]. Canberra, ACT: Australian Imstitute of Health and Welfare; 16 December 2010 [cited 27 February 2012]. Available from: URL link
7. Breast cancer in Australia: An overview, 2009 [online]. Canberra, ACT: Australian Imstitute of Health and Welfare; 26 October 2009 [cited 27 Februaty 2012]. Available from: URL link
8. Pagani O, Senkus E, Wood W, et al. International guidelines for management of metastatic breast cancer: Can metastatic breast cancer be cured? J Natl Cancer Inst. 2010;102(7):456-63. [Abstract | Full text]
9. Cheng Y, Ueno N. Improvement of survival and prospect in patients with metastatic breast cancer. Breast Cancer. 2011. [Abstract]
10. El Saghir N, Tfayli A, Hatoum H, et al. Treatment of metastatic breast cancer: State-of-the-art, subtypes and perspectives. Crit Rev Oncol Hematol. 2011;80(3):433-49. [Abstract]
11. Coleman R, Bertelli G, Beaumount T, et al. UK Guidance Document: Treatment of metastatic breast cancer. Clin Oncol (R Coll Radiol). 2011. [Abstract]
12. Higgins M, Baselga J. Targeted therapies for breast cancer. J Clin Invest. 2011;121(10):3797-803. [Abstract | Full text]
13. Montero AJ, Adams B, Diaz-Montero CM, Glück S. Nab-paclitaxel in the treatment of metastatic breast cancer: A comprehensive review. Expert Rev Clin Pharmacol. 2011;4(3):329-34. [Abstract]
14. Fornier M. Approved agents for metastatic breast cancer. Semin Oncol. 2011;38(Suppl 2):S3-10. [Abstract]
15. Alvarez R. Present and future evolution of advanced breast cancer therapy. Breast Cancer Res. 2010;12(Suppl 2):S1. [Abstract | Full text]
16. Jurado J, Aznar P, Mata J, et al. Management of patients with metastatic breast cancer. Adv Ther. 2011;28(Suppl 6):50-65. [Abstract]
17. Rios J, Puhalla S. PARP inhibitors in breast cancer: BRCA and beyond. Oncology. 2011;25(11):1014-25. [Abstract]
18. Budach W. Radiotherapy in patients with metastatic breast cancer. Eur J Cancer. 2011;47(Suppl 3):S23-7. [Abstract]
19. Barton S, Swanston C. Recent developments in treatment stratification for metastatic breast cancer. Drugs. 2011;71(16):2099-113. [Abstract]
20. Thomssen C, Scharl A, Harbeck N. AGO Recommendations for diagnosis and treatment of patients with primary and metastatic breast cancer: Update 2011. Breast Care. 2011;6(4):299-313. [Abstract | Full text]
21. Decision of the commissioner: Proposal to withdraw approval for the breast cancer indication for Avastin (bevacizumab) [online]. Silver Spring, MD: Food and Drug Administration; 18 November 2011 [cited 27 February 2012]. Available from: URL link
22. Burstein HJ. Bevacizumab for advanced breast cancer: All tied up with a RIBBON? J Clin Oncol. 2011;29(10):1232-5. [Full text]