Despite advances in the early diagnosis and treatment of breast cancer it still remains a significant public health concern with more than one million new cases diagnosed annually, resulting in more than 450,000 deaths worldwide.1 Worldwide the incidence of breast cancer is estimated at 23% based upon 2008 statistics.2 In the United States over 40,000 women die from breast cancer annually.3
Approximately 25% to 30% of breast cancers are the result of the overexpression of the human epidural growth factor receptor 2 (HER2) gene, a potent mediator of cell growth and proliferation, and the corresponding overexpression of the HER2 receptor.4 In a case-only incidence analysis of female breast cancer patient cases, HER2 was found present in 35% of both locally advanced and metastatic tumors, and 40%-43% of inflammatory breast cancer.5 Women with HER2-receptor positive breast cancer have an aggressive form of the disease and are more likely to have shortened disease-free survival and overall survival resulting in a poor outcome. 4
The dual targeting of HER2-receptor positive tumors by both trastuzumab (Herceptin®, Genentech) and lapatinib (Tykerb®, GSK) is being explored because of primary and acquired resistance to both drugs, their slightly different mechanisms of action, and the established synergistic interactions between both drugs in HER2-positive breast cancer models.6 Trastuzumab works by inhibiting the ligand-independent HER2 and HER3 signaling and by triggering antibody-dependent cellular cytotoxicity.7,8 Lapatinib, in contrast, works by blocking ligand-induced heterodimer signaling and preventing signaling by a frequently expressed truncated version of the HER2 receptor that could make cells resistant to trastuzumab. Also, lapatinib causes an accumulation of HER2 at the cell surface that can enhance immune-mediated trastuzumab-dependent cellular toxicity.8 Trastuzumab primarily induces a proapoptotic effect, and lapatinib inhibits cell proliferation thus allowing the tumor to be targeted from two fronts.9,10 Evidence supports the use of dual HER2-receptor blockade. Blackwell and colleagues reported that the use of trastuzumab plus lapatinib in women with trastuzumab-refractory metastatic breast cancer demonstrated significant improvement in progression free-survival when compared to lapatinib alone (HR=0.73; 95% CI, 0.57-0.93; P=0.008).11
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The use of neoadjuvant systemic therapy for the treatment of breast cancer provides the patient with disease-free survival and overall-survival rates similar to adjuvant systemic therapy and improves breast conservation because of tumor response to therapy. The preoperative setting is unique in that it allows the clinician to monitor response to therapy in previously untreated patients. In patients with HER2-positive breast tumors, pathological complete response (pCR) at the time of surgery appears to be associated with improved disease outcome in several clinical trials.12 Results from the NeOAdjuvant Herceptin (NOAH) trial demonstrated that the addition of trastuzumab to neoadjuvant chemotherapy almost doubled the pathologic complete response, improved overall response rates, and reduced the risk of relapse, disease progression or death in women with locally advanced or inflammatory breast cancer.13 Similar results were found in the the Taxol Epirubicin Cyclophosphamide Herceptin NeOadjuvant (TECHNO) trial.14
Most recently, the NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) study evaluated the efficacy of lapatinib, trastuzumab, and their combination as neoadjuvant therapy in women with HER2-positive early breast cancer.12 In this randomized, parallel-group, open-label, Phase 3 trial, women from 23 countries with HER2-positive primary breast cancer with tumors greater than 2 cm in diameter were randomly assigned to either lapatinib 1500 mg PO daily (N=154), or trastuzumab with a loading dose of 4 mg/m2 IV and subsequent doses of 2 mg/kg IV every week (N=149) or lapatinib 1000 mg PO daily plus trastuzumab (loading dose of 4 mg/m2 IV and subsequent doses of 2 mg/kg IV every week) (N=152). Each drug treatment regimen was given for the first 6 weeks and then paclitaxel 80 mg/m2 IV weekly was added to each regimen for an additional 12 weeks prior to definitive surgery. Patients underwent breast surgery within 4 weeks after the last dose of paclitaxel. After surgery, the patients received adjuvant therapy followed by the same targeted therapy in the neoadjuvant phase to 52 weeks. The primary end point, which was pCR rate with the absence of tumor cells at the time of surgery, was significantly higher in patients receiving combination lapatinib/trastuzumab therapy (51.3%) compared to patients receiving trastuzumab alone (29.5%) or lapatinib alone (24.7%). There was no significant difference in the pCR between the lapatinib group (24.7%) and the trastuzumab group (29.5%). Clinical response rates at the end of the first 6 weeks for combination therapy and lapatinib therapy were superior to trastuzumab alone. This may have been a result of the time for trastuzumab to reach steady-state. All three treatment regimens appeared to be well tolerated with diarrhea (23.4%) and liver enzyme alterations (17.5%) reported more frequently with lapatinib.
Dual HER2 receptor blockade therapy may be an improved approach to treating patients with HER2-positive tumors. The combination of lapatinib plus trastuzumab with paclitaxel has resulted in better study outcomes than either agent alone in the neoadjuvant setting. The NeoALTTO study supports the continued investigation of dual HER2-receptor blockade in the neoadjuvant setting. Results through Week 52 of this study are still pending.
REFERENCES
1. World Health Organization. Cancer Fact Sheet. Published February 2012. http://www.who.int/mediacentre/factsheets/fs297/en/index.html. Accessed February 10, 2012.
2. IARC. Globocan 2008. Section of Cancer Information. Lyon, France. http://globocan.iarc.fr/factsheets/populations/factsheet.asp?uno=900. Accessed February 10, 2012.
3. Breast Cancer Statistics. Atlanta, GA: Department of Health and Human Services. Centers for Disease Control and Prevention. http://www.cdc.gov/cancer/breast/statistics/index.htm. Accessed February 10, 2012.
4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–792.
5. Zell JA, Tsang WY, Taylor TH, et al. Prognostic impact of human epidermal growth factor-like receptor 2 and hormone receptor status in inflammatory breast cancer (IBC): analysis of 2,014 IBC patient cases from the California Cancer Registry. Breast Cancer Res. 2009;11(1):R9 [published February 19, 2009]. doi:10.1186/bcr2225.
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7. Hudis CA. Trastuzumab–mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39–51.
8. Scaltriti M, Verma C, Guzman M, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity [published online ahead of print December 8, 2008]. Oncogene. 2009;28(6):803–814. doi:10.1038/onc.2008.432.
9. Mohsin SK, Weiss HL, Gutierrez MC, et al. Neoadjuvant trastuzumab induces apoptosis in primary breast cancers. J Clin Oncol. 2005;23(11):2460–2468.
10. Dave B, Migliaccio I, Gutierrez MC, et al. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2–overexpressing locally advanced breast cancers [published online ahead of print December 6, 2011]. J Clin Oncol. 2011;29(2):166–173.
11. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28(7):1124–1130.
12. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet [published online ahead of print January 17, 2012]. 2012;(2):135-144. doi:10.1016/S0140-6736(11)61847-3.
13. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375(9712):377–384.
14. Untch M, Fasching PA, Konecny GE, et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study [published online ahead of print July 25, 2011].Clin Oncol. 2011;29(25):3351-3357. http://www.jco.org. Accessed February 15, 2012.
