Silvia Formenti, MD

2007-2008 BCRF Project:
Made possible by generous support from Coach
Co-Investigator: Robert J. Schneider, PhD, NYU School of Medicine, New York

A unique understanding of genetic and molecular characteristics of locally advanced breast cancer (LABC) in a multi-ethnic population, and particularly the importance of the Akt/mTOR/4E-BP1 pathway, have emerged from the BCRF-funded research program of Drs. Formenti and Schneider. These findings suggest that by targeting this pathway there is a narrow but potentially effective window of opportunity for specific targeted treatment of LABC. The researchers have established the critical and under-explored importance of translational control by the Akt/mTOR/4E-BP1 pathway in LABC.

In the coming year, they will exploit these insights and converge them with the vascular normalization theory to develop a novel therapeutic approach that incorporates rapamycin specifically tailored to LABC. Preclinical modeling of mechanisms and optimal sequencing are proposed as a first phase, to generate the data necessary to inform a novel clinical protocol for LABC. In parallel, the investigators will continue to accrue patients to their tissue and clinical data bank, a unique asset to explore whether ethnicity is a determining variable in the genotype and phenotype of LABC.

Mid-Year Progress Report:
LABC tumors are large and advanced (stage III) breast cancers that are often the size of a lemon by the time of diagnosis. The cancer has often spread into surrounding lymph nodes or other tissues, but typically it has not yet undergone metastasis (spread to other parts of the body) by the time of diagnosis. LABC accounts for about half of all breast cancers in the developing world and about 30 percent of breast cancers diagnosed in low income and minority women in the US, probably as a result of barriers to early detection. There is also some evidence for increased incidence of LABC that may be related to ethnic and genetic differences. Current treatments are often ineffective because the tumors are large and advanced at presentation.

With support from BCRF, Drs. Formenti and Schneider have been conducting a clinical trial and collecting tumor tissue specimens from a multiethnic group of women treated for LABC at NYU Tisch Hospital, the NYU Clinical Cancer Center and Bellevue Hospital and at the AIMES Cancer Center in Cochin, India. A large number of these patients are minority, medically underserved and Indian women. They have accrued over 40 women into a clinical trial in New York and 15 in India in an ongoing effort, and collected tissue specimens and blood samples for their research studies on the genetic and molecular analysis of LABC. It is this research that has led to the new understanding of LABC and possibly new treatment strategies reported in several recent publications by Drs. Formenti and Schneider.

Drs. Formenti and Schneider found that a novel molecular switch activated by the Akt/mTOR pathway acts to promote an unorthodox means of protein synthesis that is critical for formation of locally advanced breast cancers. This switch seems to be specific for locally advanced tumor formation, thereby offering a unique window of opportunity for therapeutic intervention in LABC. They have conducted genetic analyses on all patients enrolled in clinical trial in which they have measured the activity of over 24,000 human genes to genetically characterize the disease, and to obtain data that might determine which patients will respond to specific treatments and which ones will not. The genetic analysis has already shown that LABC is not a single disease, that there are two very different patterns of gene expression in patients, but that there are certain genes in common that might provide a "signature" of the disease.

In collaboration with other BCRF-supported investigators, they are examining whether there are specific genetic alterations that are associated with development of LABC compared to other forms of breast cancer. In addition, they are developing laboratory models of LABC to better understand the disease and to test new treatment approaches.

Bio:
Silvia Formenti, M.D., was appointed in 2000 as the first Sandra and Edward H. Meyer Chairman of the new Department of Radiation Oncology. Widely respected for her work in breast and cervical cancer, Dr. Formenti joined NYU from the University of Southern California, Keck School of Medicine in Los Angeles, where she was a tenured Associate Professor of both Radiation Oncology and Medicine. She has been a member of the Advisory Board to the NYU Breast Cancer Program since 1996.

Dr. Formenti, a native of Milan, Italy, attended medical school at the Universita degli Studi di Milano. She completed residencies in internal medicine and medical oncology followed by one in radiology and radiation oncology in Milan, before coming to the States to work at USC in Dr. Malcolm Mitchell's laboratory, funded by a grant from the Italian National Research Committee (CNR). After a year in the lab she returned to the clinic as an Audrey Meyer Mars American Cancer Society Fellow and worked with Dr. Robert Lukes and Dr. Alexandra Levine on AIDS and Lymphomas. She then elected to permanently transfer to this country and completed an internship in general medicine and a residency in radiation oncology, before joining the faculty at USC.

A prolific researcher, Dr. Formenti started with a 3-year ACS career development award and is currently principal or co-principal investigator on five multi-year peer-reviewed grants with more than $ 3 million in total funding. She has devoted her research career to the study of women's malignancies, with a particular focus on underserved patients and Latina women. She has pioneered the use of concurrent chemo-radiation in the neo-adjuvant (before surgery) setting of LABC, an ideal setting to explore associations of pre-treatment tumor molecular markers with the extent of pathological response (response in the removed surgical specimen) after chemo-radiation. This research has been consistently funded by the NIH and ACS. The translational component of this research consists of several collaborations with basic scientists to identify in the laboratory which original tumor molecular tumor marker might determine response to a specific treatment. In addition, at NYU, in collaboration with Dr. Sandra Demaria she is studying how chemo-radiation induced cell-death affects patient's immunity.

Finally, funded by a grant from the Department of Defense, she is studying the role of partial breast radiation with an accelerated regimen, 5 instead of 30 fractions. She is also the P.I. in two other studies investigating the role of intensity modulated radiation therapy (IMRT) as a tool to reduce the number of radiation sessions required to treat small breast cancers.

In addition to her role as Chairman of the NYU Department of Radiation Oncology, Dr. Formenti is currently the Associate Director for Clinical Research as well as the Leader of the Breast Cancer Research Program of the NYU Cancer Institute, where she oversees the clinical and research efforts of over 30 investigators.