DENVER—Women with triple-negative breast cancers—negative for estrogen receptor, progesterone receptor, and HER2 overexpression—are typically considered to have a poor prognosis due to the lack of molecular targets in the tumor and are therefore treated with conventional chemotherapy. But researchers speaking here at the AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development say that biomarker assays can identify subgroups of triple-negative tumors that do have druggable molecular targets, such as insulin-like growth factor-1 receptor (IGF-1R) and fibroblast growth factor receptor 2 (FGFR2).
IGF-1R plays a major role in cancer cell proliferation, survival, and resistance to anti-cancer therapies in many human malignancies, including breast cancer, said Agnieszka K. Witkiewicz, MD, Associate Professor of Pathology at Thomas Jefferson University Hospital in Philadelphia.
Dr. Witkiewicz reported that IGF-1R could be a valid target for receptor inhibition, and also that detecting its overexpression in a triple-negative tumor might help in predicting patient outcome.
In a study at Thomas Jefferson that evaluated the IGF-1R biomarker in 99 white and African-American women with triple-negative breast cancer, IGF-1R expression was scored according to standardized immunohistochemistry criteria originally developed for HER2. In 35 cases the IGF-1R gene copy number was also assessed by chromogenic in situ hybridization.
The assays showed that IGF-1R was statistically significantly overexpressed (3+) in 29% of specimens. IGF-1R protein overexpression also correlated with gene amplification, Dr. Witkiewicz said.
This has significant impact on prognosis, she said, as low expression of IGF-1R (0-2+) was associated in the study with a greater risk of lymph node metastasis, while high protein expression (3+) showed borderline association with smaller tumor size and no nodal involvement.
Among patients younger than age 55, a high IGF-1R score was associated with longer survival. But in older patients no significant survival differences were observed between patients with low and high IGF-1R scores. And there was no association between IGF-1R and tumor grade or race.
Dr. Witkiewicz said IGF-1R is the target of several drugs currently in clinical trials and that its blockade has been a successful therapeutic approach in sarcomas, so there is reason to believe the receptor might be a potential target in this breast cancer subtype as well.
“For now, we know that it is there and we know it is a marker of better prognosis, so the next step is to learn if triple-negative breast cancer patients benefit from targeting IGF-1R.”
FGFR2 Required for Tumor Survival
In another presentation, Jorge Reis-Filho, PhD, a clinical research fellow at the Institute of Cancer Research in London and leader of the pathology team at the Breakthrough Breast Cancer Centre there, noted that histopathologically, triple-negative tumors encompass an incredibly heterogeneous group of diseases, and that this allows for subgroups in which genes are significantly and consistently overexpressed when amplified, including known oncogenes and potential therapeutic targets.
Dr. Reis-Filho identified FGFR2 as a potentially druggable target. In a recent study from his laboratory, FGFR2 was found amplified in 4% of triple-negative breast cancers (Oncogene 2010;29:2013–2023) and the study also showed that the FGF2R inhibitor PD173074 induced apoptosis in two triple-negative breast cancer cell lines with FGFR2 amplification.
“FGFR2 is overexpressed when amplified in triple-negative breast cancer cell lines,” he said. “And expression and signaling of FGFR2 are required for the survival of triple-negative breast cancer cells with 10q26.3 amplification.”