You wouldn't think so at first blush. But one of the challenges of targeted therapies is to figure out who will benefit from them.
In data presented at the San Antonio Breast Cancer Symposium last week and published in the Dec. 7, 2012, online issue of Cancer Discovery, clinicians identified a group of breast tumors that did not overexpress HER2, but nevertheless were sensitive to HER2 inhibitors, because they had activating mutations in their HER2/neu gene.
"Patients with these mutations will be missed by HER2 screening," Ron Bose of Washington University in St. Louis told reporters at a press briefing announcing the findings. But his team's work suggested that they could benefit from HER2-targeted cancer drugs.
There have been reports of patients who benefited from HER2-targeted drugs despite the fact that they did not overexpress HER2. Bose and his team thought such patients might have activating mutations in HER2, and so they analyzed the HER2 gene in eight sequencing studies with a total of roughly 1,500 patients.
In 25 of those patients – a proportion, Bose pointed out, that is comparable to the frequency of Alk mutations in lung cancer – the team did indeed find such mutations, many of which were either in the tyrosine kinase part of the gene or in its extracellular region.
Bose and his team then tested cell lines and xenografts of cells with such mutations for their sensitivity to Herceptin (trastuzumab, Genentech Inc.), as well as Tykerb (lapatinib, GlaxoSmithKline plc) and neratinib (Puma Biotechnology Inc.). They found that some, but not all, mutations were sensitive to Herceptin, and that several cell lines showed resistance to Tykerb but were sensitive to neratinib
Based on the results, a Phase II trial of neratinib in patients with mutations in their HER2 gene is now under way. Bose explained why his team was not using Herceptin instead. "If you have a mutation that turns on HER2 function, but HER2 is not overexpressed, are the monoclonal antibodies going to work as well? We don't have the answer to that yet."
The research is a testament to the fact that there can be more to drug targets than meets the eye, or the diagnostic test. It also shows, Bose said, how "cancer genome sequencing can be directly applied to guide individual treatment. Such sequencing is currently still expensive. But, Bose argued, not absurdly so. "A month of treatment with targeted inhibitors is in the thousands of dollars. . . . The cost of screening is much lower than that."
In other news from the meeting:
• Galena Biopharma, of Lake Oswego, Ore., presented data from a Phase I/II trial of NeuVax (nelipepimut-S) showing that NeuVax is safe and effective at raising HER2 immunity. The trial enrolled breast cancer patients who were disease-free after standard-of-care therapy, and then assigned HLA-A2/A3 patients to be vaccinated and HLA-A2/A3-negative patients to be followed prospectively as controls. At 24 months, 94.3 percent of NeuVax patients were disease-free compared to 86.8 percent of patients in the control arm. At 60 months, 98.7 percent of NeuVax patients were disease-free compared to 80.3 percent of control patients. The recurrence reduction was 47.7 percent among all patients at any dose. One of the trials also established the target patient population for a Phase III trial.
• A Phase III study of Halaven (eribulin), by Valeant Pharmaceuticals International Inc., of Montreal, in metastatic breast cancer comparing the drug to capecitabine (Xeloda, Roche Inc.) showed a trend favoring improved overall survival with Halaven in the intention-to-treat population, but the trend did not reach statistical significance. Median overall survival in the Halaven group was 15.9 months, compared to 14.5 months with capecitabine. The study did not assess status of HER2, estrogen receptor or progesterone receptor mutations.