Posted June 25, 2013
Silvia Formenti, M.D., New York University School of Medicine
Locally advanced breast cancer (LABC) is a primary breast cancer that often has lymph node involvement at the time of diagnosis, but rarely presents with distant metastases. A higher rate of treatment failure occurs in LABC, and patients have a higher mortality rate compared to those diagnosed with early stages of breast cancer. LABC is the most common presentation of breast cancer worldwide. In Fiscal Year 2003, Dr. Silvia Formenti of New York University was awarded a Breast Cancer Center of Excellence Award to define the unique molecular, immunological, and genetic characteristics of LABC and to investigate how breast cancer progresses from local disease to metastasis. This award was composed of multiple projects, including a clinical trial and basic/translational research to explore how LABC that responds to a specific neoadjuvant therapy is biologically distinct from LABC that is poorly responsive to treatment. This award also provided a platform for Dr. Formenti to study LABC in other ethnic and socioeconomic populations through national and international collaborations with investigators in the United States, South Africa, Mexico, Tanzania, and Egypt, facilitating a sociocultural study of barriers to care, attitudes toward treatment, and other factors related to diagnosis and treatment. Some of the results of this tremendous effort are discussed below.
One of the major accomplishments by Dr. Formenti and her collaborators was the development of a model for data mining and characterizing locally advanced breast cancer, as well as a patient data tracking system that contains demographic, tumor profile, treatment, and clinical trial eligibility/enrollment information. This system was applied to the clinical trial that was conducted as part of this Center of Excellence Award. Thirty-four percent of participants with LABC who underwent neoadjuvant chemotherapy (paclitaxel) with radiotherapy demonstrated significantly higher disease-free survival as well as overall survival. Women with triple-negative LABC also demonstrated a strong pathological response to this treatment protocol.
Results from the basic/translational research part of this award demonstrated that locally advanced breast cancer is distinct from inflammatory breast cancer (IBC). This was an important finding because IBC is often misdiagnosed as a type of locally advanced breast cancer, and women of African and Middle Eastern descent have a higher risk for this type breast cancer. Dr. Formenti's research team also found that certain components from the protein synthesis machinery were increased in most of the LABC specimens. One of the significant findings involved mTOR, a protein kinase that regulates cell metabolism and protein synthesis. The investigators discovered that hyperactivation of mTOR increased protein synthesis in advanced breast cancer and metastasis, which has led to new avenues of study and potential therapeutic approaches. Furthermore, overexpression of the protein synthesis factor eIF4GI affected cell survival and DNA repair following cell damage, in addition to progression of late-stage and metastatic disease.
Genetic analysis of LABC and its transition to metastatic disease resulted in two major discoveries: (1) Two microRNAs (miRNA), miR-12b and miR-183, were downregulated in LABC-derived metastatic cancer and LABC tumors that later metastasized. (2) These miRNAs could be targeted through eIF2B, a protein synthesis regulator. In addition, the investigators developed a miRNA training set profile that could predict future metastasis in a subset of LABC tumors.
The diverse populations in the New York City and Mexico City centers of this study participated in the sociocultural research program. In the Mexico City population, investigators found many barriers to patient care. Almost half of newly diagnosed breast cancer patients had locally advanced disease, and these patients had an average interval of two months between initial detection and their first primary care appointment. The investigators observed that an intervention to reduce the delay between symptom onset and primary care consultation would be beneficial for these women.
In the New York City population, investigators found that low health literacy and knowledge of breast cancer, medical mistrust, and cancer-related anxiety, worry, and fear were major psychosocial barriers. Empowering patients to make informed decisions about their disease could be critical for this population. The expense and utility of mammograms were also prevalent sociocultural issues discovered by investigators, and they noted that screening mammography is often not beneficial for women in developing and developed countries. Dr. Formenti and her collaborators suggested that it would be better to focus efforts on prevention, treatment, and management of advanced breast cancer instead of mammography.
Formenti S, Arslan AA, and Love SM. 2012. Global breast cancer: The lessons to bring home. International Journal of Breast Cancer 2012:249501.
Bright K, Barghash M, Donach M, de la Berrera MG, Scheider RJ, and Formenti SC. 2011. The role of health system factors in delaying final diagnosis and treatment of breast cancer in Mexico City, Mexico. Breast Journal 20(2):S54.
Adams S, Chakravarthy AB, Donach M, Spicer D, Lymberis S, Singh B, Bauer JA, Hochman T, Goldberg JD, Muggia F, Schneider RJ, Pietenpol JA, and Formenti SC. 2010. Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: Pathologic response correlates with five-year overall survival. Breast Cancer Research Treatment 2010 Dec;124(3):723-732.
Silvera D, Formenti SC, and Schneider RJ. 2010. Translational control in cancer. Nature Reviews Cancer 10(4):254-266.
Silvera D, Arju R, Darvishian F, Levine PH, Zolfaghari L, Goldberg J, Hochman T, Formenti SC, Schneider RJ. 2009. Essential role for eIF4GI overexpression in inflammatory breast cancer pathogenesis. Nature Cell Biology 11:903-910.
Connolly E, Braunstein S, Formenti SC, and Schneider RJ. 2006. Inhibition of translation by mTOR/4E-BP1 in hypoxic breast epithelial cells is uncoupled with transformation. Molecular Cell Biology 26:3955-3965.
Public and Technical Abstracts: Response, Resistance and Metastasis of Locally Advanced Breast Cancer in a Multiethnic Cohort