IGF-1R OVEREXPREESION GOOD PROGNOSTIC FACTOR IN TRIPLE NEGATIVE BREAST CANCER

September 30, 2010 — Triple-negative breast cancer accounts for only a small proportion of breast cancer cases, but it is difficult to treat and might have a more aggressive clinical course than other forms of the disease.

According to data presented at the 4th American Association for Cancer Research International Conference on Molecular Diagnostics in Cancer Therapeutic Development, in Denver, Colorado, insulin-like growth-factor 1 receptor (IGF-1R) is overexpressed and amplified in a subset of triple-negative breast cancer patients.

This finding suggests that IGF-IR is a potential therapeutic target, explained study coauthor Agnieszka K. Witkiewicz, MD, associate professor of pathology at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania.

The researchers found that IGF-1R was overexpressed in 25% of cases, and a significant association was observed between IGF-1R protein expression and IGF1R gene amplification (P < .001). In patients 55 years and younger, a high IGF-1R score was associated with prolonged survival (hazard ratio, 0.13; 95% confidence interval, 0.02 - 1.00; P = .050).

During a presscast, Dr. Witkiewicz explained that even though triple-negative breast cancer accounts for only 15% to 20% of patients with the disease, it leads to half of all breast cancer deaths. Estrogen-receptor-positive breast cancer mortality has declined over the past decade, but the same is not true for triple-negative disease.

"This is one of the subsets that is most challenging to treat," said Dr. Witkiewicz. "It is more common in young women, more common in African American women, and is characterized by an aggressive course."

Therefore, there is a significant need for a better understanding of the pathogenesis of triple-negative breast cancer and a need to identify new molecular targets for treatment, she added.

IGF-1R has been known to play a major role in cancer cell proliferation, survival, and resistance to treatment in a number of human malignancies, including breast cancer, the authors write. It is also a target of several investigational drugs, both in clinical and preclinical development.

However, the authors note, there have been no systematic studies of IGF-1R expression in triple-negative breast cancer.

High Expression Equated the Better Survival

In the current study, Dr. Witkiewicz and colleagues evaluated IGF-1R expression in 99 women with triple-negative breast cancer. Immunohistochemistry was used to evaluate IGF-1R protein expression, which was scored according to standardized criteria originally developed for HER2 disease. In addition, chromogenic in situ hybridization for the IGF1R gene was performed on 35 cases.

A tumor was interpreted as positive for gene amplification when the ratio of the IGF1R gene signal to the chromosome 15 signal was 2.2 or higher; for the purpose of statistical analysis, the expression of IGF-1R was classified as low (0 to 2) or high (3).

The authors observed that IGF-1R expression was high in 29 of 99 (29%) cases and correlated with negative lymph nodes (P = .03). Gene amplification was seen is 8 of 35 cases (23%). Low IGF-1R expression was associated with lymph node metastases (P = .033); conversely, high IGF-1R expression was associated with a tumor size that was borderline significantly smaller (P = 0.080).

The authors note that there was no statistically significant association between IGF-1R expression and grade or race.

However, patient age played a role, Dr. Witkiewicz pointed out. "In patients older than 65 years, there was no difference in survival between patients with low and high IGF-1R expression," she said. "But in patients younger than 65, those with high IGF-1R expression had longer survival than those with low expression."

The longest survival was seen in younger patients with high IGF-1R expression, and the poorest survival was seen in older patients (>55 years) with low IGF-1R expression.

"For now, we know that it is there and we know it is a marker of better prognosis," said Dr. Witkiewicz. "The next step is to learn if triple-negative breast cancer patients benefit from targeting IGF-1R."

Program chair Gordon B. Mills, MD, PhD, from the Department of Systems Biology at the University of Texas M.D. Anderson Cancer Center, in Houston, noted that, based on earlier iterations of this conference and the contributions of many members of the community, "we have developed a pathway to the development of molecular diagnostics and biomarkers."

"Importantly, we have a much better concept of the limitations, challenges, and hurdles that need to be overcome for the implementation of molecular diagnostics," he told Medscape Medical News.

"Currently, the outcome for triple-negative breast cancer is poor, at least in part because of the lack of novel targets for therapy," he told Medscape Medical News. Dr. Witkiewicz and colleagues have demonstrated that IGF-1R is overexpressed in triple-negative breast cancer, warranting studies to validate IGF-1R as a target for therapy," he said.

4th American Association for Cancer Research International Conference on Molecular Diagnostics in Cancer Therapeutic Development (AACR-MDCTD): Abstract A29. Presented September 28, 2010.