Irregularities in the expression of the HER2 growth-factor gene have been found in 14 different advanced solid tumors. These irregularities include mutations, amplifications, substitutions, and translocations. This study was presented at the 2013 annual meeting of the American Society of Clinical Oncology in early June in Chicago, Illinois.
These findings both surprised researchers and offered hope that some of these tumors might benefit from the three anti-HER2 therapies now in clinical use.
“No one ever thought that there would be such a variety of genomic alterations in HER2 in this many solid tumors,” said presenter Massimo Cristofanilli, MD, FACP, Professor of Medical Oncology and Director of the Jefferson Breast Center at the Kimmel Cancer Center and Thomas Jefferson University Hospital in Philadelphia, Pennsylvania.
“But this may be good news, both clinically and scientifically,” he said. “It tells us that these tumors might benefit from treatment that we already have on hand, and, from a research perspective, it builds on the idea that it is the genomic profile of a tumor that is relevant in providing biological information for planning personalized treatments—not where the cancer is located or where it develops.”
The co-authors of the study donated more than 2,000 samples, including approximately 50 metastatic breast tumor samples contributed by Cristofanilli for the analysis. One of his patients with advanced triple-negative breast cancer had a HER2 mutation. “My patient was treated with trastuzumab as well as chemotherapy, and derived clinical benefit,” he said. “No one looks for HER2 mutations in this form of breast cancer. To me, this makes the case for the value of genome-driven therapy.”
The researchers conducted a genetic screen of more than 182 genes and 14 genetic rearrangements known to be linked to cancer in 2,223 tumor specimens. Twenty different advanced solid cancers were represented. They found HER2 alterations in 14 types of solid tumors, including 29% of esophageal samples, 20% of uterine samples, 14% of breast samples, 12% of stomach carcinomas samples, and 6% of all lung cancer samples.
The HER2 irregularities varied widely, as 4.9% of the specimens had 116 different HER2 alterations. Those included 58% with amplifications, 25% with substitutions, 14% with indels (insertions/deletions of DNA), 2% with splice site variants, 2% with translocations, 5% with multiple alterations, and two tumors with both HER2 substitution and amplification.
Anti-HER2 therapies such as trastuzumab can also treat HER2 mutations, and may also help block HER2 that is altered in the ways seen in this study, Cristofanilli said.
“This study highlights the need to study a broad range of genes at a high level of sensitivity and specificity when searching for novel targets of therapy,” he said. “Widespread use of this approach could provide more treatment options and enable more rapid accrual to ongoing and planned trials of agents targeting pathways under study.”