Targeting Metastasis

"Treatment of patients with metastatic disease always requires a delicate balance," said Dr. Kathy Miller. "Our goals are to prolong survival when we can, to palliate symptoms when they exist, and to improve and hopefully preserve the quality of life of our patients. That always requires recognition that both the disease and our treatment related toxicities can have a profound negative impact on our patients' lives."

This emphasis on strategies for metastatic breast cancer and targeting treatment resistance was prominent throughout the meeting. A panel, including BCRF grantees George W. Sledge, Jr., MD (Indiana University), immediate past president of ASCO; Fatima Cardoso, MD (Champalimaud Cancer Center); and Dr. Martine Piccart-Gebhart, addressed treatment strategies for advanced breast cancer. In his overview of the current standard of care, Dr. Sledge pointed out the great variations in the care provided to patients with metastatic disease, as well as the challenges in quality of life issues facing patients. Dr. Cardoso noted that the advances that have been made in metastatic breast cancer differed according to the breast cancer subtypes, while treatment resistance remains the greatest hurdle. She voiced the frustration of many patients and doctors that progress is still mostly measured in months, rather than years, but she expressed optimism in the pace of development of international treatment guidelines, which should produce greater benefits for all patients. Dr. Piccart-Gebhart gave a forecast of the future direction of research, which will emphasize developing drugs targeting "actionable mutations," as revealed by tumor biology, and breast cancer stem cells. She also expressed the opinion that scientists have not yet fully capitalized on the wealth of genetic discoveries into effective new therapies.

Many research efforts today center on the discovery or development of biomarkers, another tool to help predict either a patient's response or forecast disease progression and recurrence. These biomarkers can help prevent patients from undergoing therapies that yield very little benefit. In the sessions on estrogen receptor positive (ER+) and HER2+ breast cancers, several projects focused on the PI3K pathway, which was discovered by BCRF investigator Lewis Cantley, PhD (Beth Israel Deaconess Medical Center). PI3K is the most frequently mutated pathway in all types of cancer, and there are currently 20 drugs in development targeting this pathway. In his discussion of the FinHER study, Carlos Arteaga, MD (Vanderbilt University) provided constructive comparisons with earlier data on PI3K mutation and its correlation to resistance to anti-HER2 therapy such as trastuzumab.

Mitch Dowsett, PhD (The Royal Marsden Hospital) discussed a set of work on biomarker discovery to assess recurrence risk. W. Fraser Symmans, MD (MDACC) submitted a study with 605 specimens from patients that asked the question of whether genomic signatures from breast cancer samples differ according to disease stage. He also looked the changes in patients' tissues as they underwent either endocrine therapy or chemotherapy by using various markers, including one that he had developed called sensitivity to endocrine therapy (SET) index. The SET index was predictive of progression-free survival and overall survival following endocrine therapy.

Also, Dr. Dowsett discussed studies by John M.S. Bartlett, PhD (Ontario Institute for Cancer Research). "For many postmenopausal patients with hormone sensitive early breast cancer, the dilemma is whether or not to opt for adjuvant chemotherapy as well as endocrine therapy to reduce their risk of disease recurrence," said Dr. Bartlett in a later interview. His study suggests that Mammostrat, a five-gene signature assay, may provide additional information following endocrine treatment and can help patients and doctors decide future course of treatment following endocrine therapy.

In Dr. Bartlett's other study, investigators tested the validity of two forms of IHC4 in the prediction of residual risk. IHC4 is a measurement developed by Dr. Dowsett and fellow BCRF grantee, Jack Cuzick, PhD (Queen Mary, University of London), and uses the combination of hormone receptors, HER 2, and Ki67 markers to assess residual risk. Dr. Bartlett and colleagues found that this new tool should be considered in the clinical setting for prediction of residual risk in early breast cancer.

Furthermore, the collaboration between Vered Stearns, MD(JHU), a member of BCRF's Scientific Advisory Committee, fellow BCRF grantee, Seema Khan, MD (Northwestern University), and others to develop a non-invasive and cost-effective risk evaluation was discussed. Current methods to determine breast cancer risk are insufficiently sensitive and need improvement in the ability to identify women most likely to benefit from preventive strategies. Drs. Stearns and Khan are looking at various DNA methylation levels to see if they vary by menstrual phase or menopausal status. Results have been encouraging, and the investigators plan to continue their work in developing this tool.