A two-year international effort has brought researchers a step closer to unraveling the molecular biology of inflammatory breast cancer.
The long-term goal is to identify new targets for the treatment of the aggressive subtype of breast cancer, said Naoto T. Ueno, MD, PhD, Professor of Medicine, Executive Director of the Morgan Welch Inflammatory Breast Cancer Program and Clinic, and Chief of the Section of Translational Breast Cancer Research in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center.
“We haven't pinpointed any new therapeutic options yet,” he said following the poster discussion of the study at the CTRC-AACR San Antonio Breast Cancer Symposium (Abstract PD03-01). But by combining three distinct gene expression data sets — one from Belgium, one from France, and one from the US — the researchers now have a better idea of what is going on at the molecular level than ever before.
Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with increased invasive and metastatic potential. As a result, patient prognosis is dismal, he said, noting that while IBC accounts for only 2% to 6% of breast cancer cases, it represents about 10% of breast cancer deaths.
Several research groups have demonstrated that IBC and non-IBC have distinct gene expression patterns – for example: Bertucci et al: Cancer Research (2004;64:8558); Van Laere et al: British Journal of Cancer (2007;97:1165-1174); and Iwamoto et al: Breast Cancer Research and Treatment (2011;125:785-795).
Unfortunately, most of the studies are underpowered, mainly because IBC is rare and IBC sample sizes are small, according to the international team, led by Steven J. Van Laere, PhD, MSc, of the Translational Cancer Research Group Antwerp at General Hospital Sint-Augustinus in Wilrijk, Belgium.
So, at the First International Inflammatory Breast Cancer Conference of the World IBC Consortium in Houston in December 2008, researchers decided to work together and combine datasets to obtain more robust results.
By integrating three distinct gene expression datasets, the team was able to examine and compare gene patterns in 137 samples from IBC patients and 252 samples from patients with non-IBC.
Among the findings: Like non-IBC, inflammatory breast cancer is transcriptionally heterogeneous. Four robust sample clusters were identified that correlate with the molecular subtypes: luminal A, luminal B, ErbB2+, and basal-like.
- The molecular subtypes identified in IBC had a similar prevalence to those in non-IBC, except luminal A was a little less likely to be expressed and the ErbB2+ subtype was a little more likely to be expressed.
- A total of 632 genes were differentially expressed between the two groups, suggesting that an IBC-specific expression profile can be defined. “Previous research has also shown there are different genes in IBC and non-IBC. But now we have enhanced statistical power,” Ueno said. “IBC is unique not only clinically, but also on a genetic level.”
- The TGF-beta pathway seems to be repressed in IBC. “This was somewhat surprising to us, as TGF-beta is a key molecule of epithelial mesenchymal transition, which is pro-oncogenic, making cells more invasive. So you would not expect this to be repressed in IBC.”
- All the IBC intrinsic subtypes are associated with a poor prognosis. But surprisingly, luminal-A tumors from patients with IBC have shorter, distant-metastases-free survival intervals compared with their nonluminal counterparts. This finding is in direct contrast to the observations made in non-IBC, where luminal A is associated with improved survival, he said.
- “That's one of the most remarkable results of the study,” said the study's Discussant, Laura J. van't Veer, PhD, Professor of Laboratory Medicine at the University of California, San Francisco.
- Noting that luminal A non-IBC is typically treated with tamoxifen or an aromatase inhibitor, Ueno said, “Simply giving hormone therapy might not be good enough for patients with luminal A IBC. We really have to explore options in a clinical trial.”
- Gene expression analysis and pathway-activation analysis suggest that immunological and inflammatory processes are of importance for determining the success or failure of neoadjuvant chemotherapy in patients with IBC.
‘Strong International Voice’
Van't Veer said the study is to be commended not just for its insights into the molecular biology of IBC, but also for the strong international voice of the World IBC Consortium. She invited members of the audience to visit the site and join the effort.
The goals of the World IBC consortium are to:
- Educate the public and the medical community, that this form of breast cancer is different and sometimes escapes detection in breast examinations;
- Foster international collaboration between clinicians, translational research units, and basic cancer research labs focusing on this rare but aggressive form of breast cancer;
- Support the international IBC repository spearheaded by MD Anderson Cancer Center and provide clinical and biological data to enable answering research questions in IBC;
- Create a platform of experienced clinical units with particular expertise in order to facilitate clinical trials in IBC;
- Ultimately, prevent or cure IBC.
There is still a long way to go toward that final goal, Ueno said. “We have to test our gene expression findings at the protein level. Then we have to go back to basic science to test whether the gene expression profile is biologically meaningful. And we have to identify those molecular targets or molecular pathways that are responsible for generating IBC so we can develop new treatments.”
Conference Expected in December
The World IBC Consortium has tentatively scheduled the Third International Inflammatory Breast Cancer Conference for December 1 - 2 in Philadelphia.
Additional information about inflammatory breast cancer can be found on the Morgan Welch Inflammatory Breast Cancer Research Program and Clinic's website (mdanderson.org/IBCProgram) and Facebook page (Facebook.com/InflammatoryBreastCancer), as well as Dr. Ueno's Twitterfeed at @teamoncology