Trastuzumab changed the course of HER2-positive breast cancer, and future anti-HER2 therapies may have an even greater impact, said Kristine Abueg, RN, MSN, OCN, clinical research nurse at Kaiser Permanente in Roseville, California, who discussed “What’s New in HER2?” at the 37th Annual Congress of the Oncology Nursing Society.
In spite of a decade or so of established treatment with trastuzumab, questions still remain regarding the appropriate population to treat. In addition, many patients who respond to the drug eventually experience drug resistance and recurrence. Researchers are seeking to better understand resistance, and the pipeline is rife with agents that are effective upon trastuzumab failure, said Abueg.
Four proteins make up the members of the HER family of cell surface receptors: HER1, HER2, HER3, and HER4. Trastuzumab targets HER2, the preferred partner for binding with the other members (heterodimerization) or itself (homodimerization) to create a signaling cascade.
Trastuzumab’s dual-kill mechanism includes antibody- dependent cellular toxicity and the prevention of intracellular cell signaling, which induces apoptosis and prevents proliferation. Resistance that develops is associated with alternate signaling pathways, which are being targeted by new agents in development.
“The key to understanding and ultimately mitigating this resistance lies in the HER2 signaling pathway,” she said.
HER2 Testing: Issues of Concern
The accuracy of immunohistochemical (IHC) staining and scoring by fluorescence in situ hybridization (FISH) has become questionable, and provocative data are leading to a reexamination of current practice patterns, she said. In the pivotal studies, community pathology and central reference lab results have been discordant some 18% to 34% of the time. The implication is that a “fairly good number” of patients either receive trastuzumab unnecessarily or miss out on its benefits altogether, she said.
The American Society of Clinical Oncology and the College of American Pathologists have issued revised guidelines for HER2 testing. The most recent recommendation is to prescribe anti-HER2 treatment when the FISH result is ≥2.0, and to retest when FISH is 1.8 to 2.2. This recommendation is now, however, compulsory.
The other testing issue is the level of predictability of IHC and FISH, according to information from the pivotal trastuzumab studies. Consistent benefit from trastuzumab was observed in every subset (including patients who were actually HER2 negative), and FISH score strength was not predictive of this. Even some FISH-negative patients benefited from the drug.
“The clinical implication is whether the HER2 ‘sensitive’ population can be expanded,” Abueg explained. Clinical trials are evaluating trastuzumab in the IHC 1+ and FISH-negative populations.
Overcoming Resistance With New Agents
The powerful new agents under investigation are designed specifically to attack the proposed mechanisms of trastuzumab resistance.
Lapatinib, of course, is already established for use after progression with trastuzumab. The ALTTO study is evaluating whether the adjuvant use of lapatinib in combination with trastuzumab, prior to the development of resistance, will be more effective than either agent alone. In the neoadjuvant NeoALLTO trial, the combination produced a 51% pathologic complete response rate,1 and the hope is that this type of activity will be observed in the adjuvant setting, she said.
Even more promising could be 4 investigational agents:
- Neratinib, which works similarly to lapatinib, blocks HER2, HER1, and HER4, and inhibits intracellular cell signaling
- Everolimus, an mTOR inhibitor proven in other cancers
- Pertuzumab, a monoclonal antibody that blocks HER2/HER1 and HER2/HER3 dimerization and binds at a different site than trastuzumab
- T-DM1 (trastuzumab emtansine), an antibody-drug conjugate with highly targeted delivery
Each is backed by very encouraging data, but T-DM1 has elicited the most excitement, and for good reason, she noted.
In a phase 2 open-label study, T-DM1 resulted in a median progression-free survival of 14 months versus 9 months with trastuzumab and docetaxel, reducing the risk of disease progression by 41% and proving to be very well tolerated.2 In 2010, the FDA declined to grant accelerated approval and called for phase 3 trials to be completed. Additional studies (EMILIA, MARIANNE, THERESA) are under way.
“I have a patient on one of these trials who had an 11-cm liver metastasis and pulmonary nodules after multiple lines of treatment. Last week, she received her 47th cycle of T-DM1. Her tumor is now 1.1 cm and has been stable for two and a half years,” Abueg reported. While thrombocytopenia can be problematic, it has remained grade 1 for this patient. “I think this is a stunning result,” she commented.
References
- Baselga J, Bradbury I, Eidtmann H, et al; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-640.
- Hurvitz S, Dirix L, Kocsis J, et al. Trastuzumab emtansine (T-DM1) vs trastuzumab plus docetaxel (H+T) in previously untreated HER2-positive metastatic breast cancer (MBC): primary results of a randomized, multicenter, open-label phase II study (TDM4450g/BO21976). Presented at the 2011 European Multidisciplinary Cancer Conference. Stockholm, Sweden. September 23-27, 2011. Abstract 5001.