NATIONAL HARBOR, MD—Although both the diagnosis and treatment of patients with early-stage breast cancers have improved markedly in recent years, some 20% to 30% of patients still develop metastatic disease. The latest data on the best ways to control breast cancer metastases were reviewed here at the Breast Cancer Symposium, a meeting cosponsored by ASCO, ASTRO, the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, and the Society of Surgical Oncology.
Speakers noted that since the behavior of metastatic disease differs depending on the breast cancer subtype, new approaches are necessary to understand how the biology of a breast cancer subtype influences whether the primary tumor will spread following initial treatment, and how that metastatic spread can be blocked or controlled.
“Gene expression signatures are under development for those at risk of metastasis,” said Patricia S. Steeg, PhD, Senior Investigator in the NCI's Center for Cancer Research. “More than 20 metastasis-suppressor genes have been identified, [and now the issue is] how can we bring suppressor genes from bench to bedside?”
Speaking at a general session on breast cancer metastasis, Dr. Steeg noted that metastasis-suppressor genes inhibit metastasis without effects on the size of the primary tumor. She described her preclinical research on the G-protein coupled receptor LPA-1 (type 1 lysophosphatidic acid receptor); overexpression of LPA-1 overcomes suppression of in vitro motility and in vivo metastasis in cell lines, mouse tumors and human breast cancers.
“This suggested a novel hypothesis—that LPA-1 inhibitors may be effective in controlling metastatic disease,” she said.
Debio 0719 Investigational Drug
She described murine model-system breast cancer research with the investigational drug Debio 0719, which is a selective inhibitor of LPA-1. In these experiments, mice treated with 0719 had significantly decreased lung and liver metastases.
“This is a site-specific inhibition of metastasis by 0719. My feeling is that this is an induction of dormancy,” she said. “This is not a permanent change; it has to be given constantly. I think it's the first compound I've ever heard of that induces metastatic dormancy.”
Dr. Steeg said that based on the ability of Debio 0719 to induce dormancy in the metastatic site, it represents a new class of potential therapeutics.” Phase I trials of this compound are expected to start next year, she added.
Dr. Steeg said that because the brain is often the first site of relapse in breast cancer patients, it is essential to develop drugs that can successfully target brain metastases. “Our conclusion is that the blood-brain barrier remains a potent obstacle to therapy of brain metastases,” she said, noting that this is an area where nanotechnology might be a helpful tool.
Dr. Steeg cited vorinostat as a drug which might prove useful in treating breast cancer metastases to the brain, because it is brain permeable. In preclinical brain metastasis models, this drug prevented brain metastases only when administered early, she said; thus a potential clinical trial design might be to treat breast cancer patients with only one brain metastasis in the hope of preventing more. Vorinostat (suberoylanilide hydroxamic acid, or SAHA) has already been shown to have some activity against recurrent glioblastoma multiforme.
Inflammatory Breast Cancer
Naoto T. Ueno, MD, PhD, Professor of Medicine in the Department of Breast Medical Oncology, Breast Cancer Translational Research Laboratory, at The University of Texas MD Anderson Cancer Center, described his research on inflammatory breast cancer (IBC), which affects about 2% to 5% of women with breast cancer.
Although rare, IBC carries a poor prognosis because 70% of patients with IBC experience recurrence in the form of distant metastases, he said. Dr. Ueno described the epithelial-mesenchymal transition (EMT), the process by which cells undergo a morphological switch on the pathway to metastasis.
Noting that the epithelial growth factor receptor (EGFR) is known to be overexpressed in IBC, he and his colleagues hypothesized that EGFR suppression inhibits metastasis of EGFR-overexpressing IBC cells. In preclinical models, including a mouse xenograft model, the researchers then tested whether the EGFR-inhibitor erlotinib would have anti-metastatic activity, could inhibit invasiveness, and could reverse the unwanted mesenchymal phenotype.
Dr. Ueno and his colleagues found that erlotinib showed significant tumor growth inhibition in the inflammatory breast cancer xenograft model and could reverse the mesenchymal phenotype back to an epithelial phenotype.
A clinical trial is now under way to test the EGFR-inhibition approach to suppression of tumor growth and metastasis in IBC. “If our results are as expected, our project may lead to a new paradigm for IBC therapy: that the focus should be on developing targeted adjuvant therapy for patients whose tumors have not yet metastasized,” Dr. Ueno said. “We'd like to develop anti-metastasis or anti-EMT drugs....these studies may form the basis of a novel therapy for IBC metastases.”
Denosumab vs Zoledronic Acid for Pain
In other news on breast cancer metastases from the symposium, the results of a large, international multicenter Phase III trial of the monoclonal antibody denosumab versus zoledronic acid in controlling pain in patients with metastatic breast cancer showed that denosumab significantly extended the length of time that patients had no pain or mild pain compared with zoledronic acid.
Among patients with no pain or mild pain at baseline, fewer patients on denosumab experienced a worsening of their pain than patients on zoledronic acid did. Analyses included approximately 2,000 randomized patients, who rated their pain on the Brief Pain inventory.
Needed: Confirmatory Tissue Biopsy Before Targeted Therapy
Finally, in what was billed as an expert editorial in the symposium's daily newspaper, two researchers from the Hospital of Prato's Istituto Toscano Tumori in Italy argued strongly for a confirmatory tissue biopsy before using targeted therapy to treat patients with metastatic breast cancer.
Angelo Di Leo, MD, PhD, Chair of the hospital's Sandro Pitigliani Medical Oncology Unit, and Catherine Oakman, MD, an Australian medical oncologist working at the Italian hospital, wrote that the diagnosis of metastatic disease is often based on clinical symptoms and signs, serum tumor markers, and radiologic findings, but that more often than not, a confirmatory biopsy is not pursued.
“However, proceeding without biopsy confirmation may not be optimal,” the researchers wrote. “Not all that appears to be breast cancer recurrence is proven to be recurrent disease. Suspicious lesions may be benign or may be second malignancies.”
Drs. Di Leo and Oakman added, “Treatment selection without a biopsy relies on a historical biologic snapshot of the primary tumor, with the presumption of consistent biology in metastatic disease.”
While this assumption may be true for the majority of patients, they warned that “a substantial number of patients have discordant findings between matched biopsies of primary tumor and metastatic sites.” Further, they noted that “altered biology has significant therapeutic implications, particularly regarding targeted use of endocrine and anti-HER2 therapy.”
Drs. Di Leo and Oakman stated that a confirmatory biopsy is reported to alter immediate therapy for about one in six patients. But they noted that it remains to be seen how many of these patients derive benefit from the revised treatment option, which is why they said that clinical trials of patients with metastatic breast cancer—with an obligatory central laboratory characterization of a metastatic biopsy—would be useful in defining the biologic study population.