Could Targeted Therapies Extend Survival?
Medscape: How do you approach patients with recurrent or metastatic disease? What are the key areas of focus for these patients?
Dr. D'Angelo: We know from published studies that chemotherapy works in these patients. One prospective study specifically in angiosarcoma showed an improvement in progression-free survival with paclitaxel, and other studies have shown benefit with agents that are generally used in sarcomas, such as doxorubicin, gemcitabine, and docetaxel.[8,10] All of these studies have shown median progression-free survival of about 3-5 months.
Moving forward, because angiosarcoma is a vascular tumor, there has been some interest in looking at targeted agents that inhibit various components of vasculogenesis in tumors, including bevacizumab and sorafenib.
A large study looked at sorafenib in all types of soft-tissue sarcoma, and the median progression-free survival in the 37 patients with angiosarcoma was around 3-4 months. A study of bevacizumab in 23 patients with angiosarcoma also showed a progression-free survival of around 3 months. Both of those studies looked at patients with all types of angiosarcoma.
At last year's meeting of the American Society of Clinical Oncology, I presented data on a small series of 8 patients with radiation-associated angiosarcoma. Dr. Antonescu has demonstrated that nearly all patients with radiation-associated angiosarcomas have MYC amplifications, and about one quarter of those will also harbor FLT4, or VEGF3, amplifications. I looked at a small subgroup of patients with radiation-associated breast angiosarcoma who had MYC and/or FLT4 amplifications and found that those with the coamplification had higher response rates to sorafenib. That makes sense -- we know sorafenib inhibits VEGF3, and there are some preclinical data to suggest that it can also lead to downregulation of the MYC pathway.
This suggests that targeting known genetic changes is ultimately the way the field should move forward, and the MYC/FLT4 pathway should be one avenue of study. Another avenue is KDR mutations -- Dr. Antonescu has demonstrated that 10% of angiosarcomas that arise in the breast will harbor a KDR mutation, and there is a preclinical rationale for using inhibitors of vasculogenesis in patients with KDR mutations.
The series that I looked at had only 8 patients, and none of those patients had undergone KDR-mutation testing. But it is a rational approach and the direction in which oncology is moving. Lung cancer patients with EGFR mutations respond to erlotinib, and BRAF-positive melanoma patients respond to vemurafenib; that is kind of the model that we should probably follow in this disease as well. We need to identify key genetic changes in patients with angiosarcoma and then see whether they are druggable.
Another approach is to consider the role of immune therapy in the management of sarcoma. We've seen the benefits of enhancing the immune response to cancer cells by targeting immune checkpoints like PD-1, even in solid tumors that are not typically known to be immunogenic, such as lung cancer. So perhaps we ought to consider the role of the immune system in angiosarcoma as well as other types of sarcoma. This could be a way to attack the disease from a different angle, and one that doesn't require identifying and targeting specific genetic changes.
Medscape: How would you guide practicing oncologists who have patients with angiosarcoma?
Dr. D'Angelo: Angiosarcoma is a very rare cancer with no standard of care and fairly poor outcomes, so referring patients to a tertiary center is the best approach. This will give patients access to clinical trials exploring new and novel therapeutic approaches. Many of the tools needed for molecular and genetic analyses are already available, and researchers at these tertiary centers are best equipped to use them to focus efforts on potentially improving outcomes.
Medscape Oncology © 2013 WebMD, LLC
Cite this: Angiosarcomas: Gaining a Wider Margin of Success - Medscape - Oct 22, 2013.