Tuma, Rabiya S. Phd
SAN FRANCISCO — Until recently, there have been few molecular markers that distinguish inflammatory breast cancer (IBC) from the non-inflammatory type. That all may have changed now, though, with data reported here at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference by Fredika M. Robertson, PhD, Professor of Experimental Therapeutics at the University of Texas MD Anderson Cancer Center, showing that the ALK (anaplastic lymphoma kinase) gene is amplified in 75% of inflammatory breast cancers (PR-4).
Preclinical testing indicates that ALK inhibitors, including the recently approved crizotinib, may cause tumor shrinkage. As a result of these data, patients are now being enrolled in a phase I trial of an experimental ALK inhibitor, LDK378.
“These studies are the first to identify activation of ALK signaling pathways in IBC, and they appear to be a prevalent alteration in IBC patients and in preclinical models,” Dr. Robertson said during a news conference. “Our data suggest—based on both our proteomic pathway activation mapping and our genetic studies—that ALK inhibitors may be important in this patient population.”
So far three IBC patients whose tumors show ALK amplification have enrolled in the Phase I trial at Fox Chase Cancer Center, noted Massimo Cristofanilli, MD, Chair of Medical Oncology at Fox Chase Cancer Center and a coauthor of the study. He declined to say whether any of the patients were showing a response so far, but did note that he and his collaborators hope, with the help of industry, to open a multi-institutional study, which hints that the early results are favorable.
“It is exciting that we have a new genetic program for IBC,” said the moderator of the news conference, Kenneth C. Anderson, MD, Kraft Family Professor of Medicine and Chief of the Division of Hematologic Neoplasias at Dana-Farber Cancer Institute and Harvard Medical School. “I think it is fair to say no one would have expected this.”
ALK Pathway Activation
Dr. Robertson and colleagues uncovered the ALK amplification as part of a larger project examining the genetic changes in inflammatory breast cancer. During a proteomic analysis of tumor samples from three preclinical mouse models, each of which recapitulates the human disease, the investigators noticed that the ALK pathway was activated at a level similar to what is seen in ALK-driven non-small cell lung cancers (NSCLC).
Turning to patient samples, Dr. Robertson said the researchers found that nine out of the 12 patient tumors tested show amplification of the ALK gene. Thus far, however, the team has not seen any mutations in the ALK gene, which have been common in other types of ALK-driven malignancies. (The team has detected an EML4-ALK gene fusion in a preclinical IBC model, but do not yet know the clinical relevance of the finding.)
Based on these data, the researchers immediately tested crizotinib in preclinical models. IBC primary cells rapidly form spheroids in culture, and this organization seems to help protect the cells from standard therapies, including paclitaxel. By contrast, the cells were sensitive to sub-micromolar concentrations of the ALK inhibitor crizotinib. The inhibitor also triggered tumor cells to undergo apoptosis in xenograft models and caused tumor shrinkage.
FREDIKA M. ROBERTSON...Image Tools
Finally, the investigators found that crizotinib blocked activation of downstream signaling, including AKT and mTOR activation, further supporting the idea that ALK is an important regulator in IBC.
Racing to Trials
Based on these data and the tremendous unmet need in IBC patients, Dr. Robertson, Dr. Cristofanilli, and colleagues wanted to test ALK inhibitors in IBC patients. While crizotinib is already approved, and thus might appear a logical choice, that option would have required establishing a new study, which would take time. Therefore, the team decided to enroll IBC patients in an ongoing Phase I trial with LDK378, an experimental ALK inhibitor from Novartis.
“We are taking advantage of a Phase I trial that was not developed for inflammatory breast cancer, but which gives us the opportunity to test this drug very early on in patients with this disease,” Dr. Cristofanilli said.
Similarly, Dr. Robertson said they are interested in testing crizotinib in this patient population, and the choice of the experimental Novartis compound was about availability and speed.
“The LDK compound was available at Fox Chase in a Phase I trial,” Dr. Robertson said. “The goal was to accelerate this process and to make it available to IBC patients. Clearly we are interested in crizotinib; we have had discussions with Pfizer.”
As with other ALK-inhibitor trials, eligibility to the LDK378 Phase I trial is restricted to patients whose tumors show ALK gene fusion or amplification. Dr. Robertson noted that the FDA-approved test used to detect ALK gene fusions in lung cancer can also be used to detect ALK amplification, in the absence of a gene fusion. The trial is currently open at several centers in the United States and elsewhere, but the number of slots are limited.
Reporting in ‘Real Time’
Dr. Robertson said that the work is still very new and the number of patients tested has been small, but that the high prevalence of ALK amplification in newly diagnosed patients suggests it really is important in the disease.
“This is the first evidence that there is a [molecular] signature in IBC,” she said, during an interview with OT. “We are really excited. This all unfolded in the last 10 months. You are seeing this in real time.”
© 2012 Lippincott Williams & Wilkins, Inc.