Using Multiple Targeted Therapies in Oncology: Considerations for Use, and Progress to Date in Breast Cancer
- 738 Downloads
There has been significant progress in our basic understanding of drugs and targets in the management of breast cancer. Recent breast cancer clinical trials have examined whether combinations of drugs targeting transmembrane receptors or their downstream effectors involved in cell signal transduction can increase response rates and overcome acquired and/or de novo drug resistance compared to a single targeted agent with or without systemic chemotherapy. We reviewed published clinical trials and conference proceedings examining combinations of targeted therapies across different breast cancer subtypes. Improvements in pathological complete response (pCR) rates and progression free survival (PFS) in preoperatively treated and metastatic human epidermal growth factor 2 (HER2)-positive breast cancer, respectively, have been observed with combinations of anti-HER2 therapies given concomitantly. Promising results were also observed in estrogen receptor (ER)-positive, HER2-negative breast cancer using a mammalian target of rapamycin inhibitor with tamoxifen or an aromatase inhibitor (AI) in the preoperative setting and for patients with metastatic breast cancer that had previously progressed on endocrine therapy alone. A recent phase II trial reported a statistically significant improvement in PFS with the addition of an oral inhibitor of cyclin-dependent kinase 4/6 to letrozole compared to letrozole alone (26.1 versus 7.5 months). A phase III study is planned for early 2013. On the basis of preclinical data, clinical trials have examined combinations of hormonal agents such as fulvestrant with an AI. However, the results are conflicting. Early data indicated that poly (ADP–ribose) polymerase (PARP) inhibitors exploiting the concept of synthetic lethality would offer improved outcomes for patients with ER-negative, progesterone receptor (PR)-negative, HER2-negative breast cancer often referred to as triple negative breast cancer (TNBC); however, data in the phase III setting failed to confirm these findings but this may be because the drug was not a true PARP inhibitor. Chemotherapy continues to be the mainstay of treatment for TNBC until specific drugs and their associated targets are identified. As advances in medical technologies continue to identify multiple molecularly distinct breast cancer subgroups that are predicted to respond to combinations of targeted agents new challenges have arisen. In particular, how do we evaluate the safety and efficacy of these new drug combinations in relatively small subgroups of patients? Novel clinical trial designs will be required and increasingly regulatory agencies will require companion diagnostic tests that can identify the subgroups likely to respond to these therapies. The US Food and Drug Administration is assessing the role of pCR in breast cancer studies as a surrogate endpoint to predict clinical benefit in the accelerated drug approval process.
KeywordsBreast Cancer Tamoxifen Trastuzumab Everolimus Aromatase Inhibitor
No sources of funding were used to assist in the preparation of this review. Drs Buzdar and Kelly have no conflicts of interest that are directly relevant to the content of this review.
- 3.Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717.Google Scholar
- 13.Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25–32.PubMedCrossRefGoogle Scholar
- 15.Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N Engl J Med. 2012;366(26):2438–41. doi: 10.1056/NEJmp1205737.
- 20.Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30:2718–24.PubMedCrossRefGoogle Scholar
- 24.Finn RS, Crown JP, Lang I. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2-advanced breast cancer. (BC)CTRC-AACR San Antonio Breast Cancer Symposium 4–8 2012, San Antonio, TX. Abstract S1-6.Google Scholar
- 26.Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005;23:5108–16.PubMedCrossRefGoogle Scholar
- 28.Bergh J, Jonsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30:1919–25.PubMedCrossRefGoogle Scholar
- 31.Di Leo A, Jerusalem G, Petruzelka L. Final analysis of overall survival for the phase III CONFIRM trial: Fulvestrant 500 mg versus 250 mg. San Antonio Breast Cancer Symposium Dec 4–8, San Antonio, TX. Abstract S1-4.Google Scholar
- 32.Johnston S, Kilburn LS, Ellis P, Cameron D, Dodwell D, Howell A, Im YH, Coombes G, Dowsett M, Bliss JM. Fulvestrant alone or with concomitant anastrozole vs exemestane following progression on non-steroidal aromatase inhibitor—first results of the SoFEa trial (CRUKE/03/021 & CRUK/09/007) (ISRCTN44195747). Eur J Cancer. 2012;48(Suppl 3):S2 (Late breaking abstract).Google Scholar
- 33.International Breast Cancer Study Group. Suppression of ovarian function and either tamoxifen or exemestane with or without chemotherapy in treating premenopausal women with resected breast cancer. In: ClinicalTrials.gov: National Library of Medicine (US). http://clinicaltrials.gov/ct2/show/NCT00066807?term=The+Suppression+of+Ovarian+Function+Trial&rank=2. NLM Identifier:NCT00066807. Accessed 18 June 2012.
- 40.Robidoux A, Tang G, Rastogi P, Geyer CE, Azar CA. Evaluation of lapatinib as a component of neoadjuvant therapy for HER21 operable breast cancer: NSABP protocol B-41. Presented at the American Society of Clinical Oncology Annual Meeting, Chicago, June 1–5. 2012. J Clin Oncol. 2012;30 (suppl; abstr LBA506).Google Scholar