Newswise — Tumors biopsied from women with invasive breast cancer are having their genomes sequenced in an attempt to develop a DNA profile that one day may identify ahead of time the patients who will most likely respond to chemotherapy with an aromatase inhibitor. Aromatase inhibitors are a class of chemotherapeutic agents that block the production of estrogen in postmenopausal women. The genetic profiling is part of an ongoing clinical trial of more than 300 postmenopausal women who had estrogen-positive stage II or III breast cancer at the time of diagnosis. Women in the trial are being randomized to receive one of three aromatase inhibitors for four months before they go on to surgery and chemotherapy. The clinical trial is being conducted by the American College of Surgeons Oncology Group (ACOSOG).
“The over-arching goal of genome sequencing in this clinical trial is to determine, after the fact, a genetic profile of response to aromatase inhibitors, and that of resistance. If we know the genetic profile of aromatase inhibitor response and resistance, we can use this information as a decision point for the treating oncologist. If we can predict that a tumor will respond to aromatase inhibitor therapy by shrinking, there’s a good chance a woman, even with a larger tumor mass, can undergo just a lumpectomy [surgical removal of the tumor] or a local excision process as opposed to a complete radical mastectomy [surgical removal of the breast and portions of the chest wall]. This will affect all aspects of recovery, including the cosmetic effect, the need for surgical reconstruction, as well as cost,” said Elaine Mardis, PhD, Co-director of The Genome Center at Washington University, St. Louis, MO and chair of the ACOSOG Basic and Translational Science Committee.
Dr. Mardis reported on progress toward this goal at the semi-annual meeting of the ACOSOG, which is being held March 24-27, 2010, in Chicago. Most of the primary genomic sequencing data from women in the clinical trial are being collected. Dr. Mardis and her colleagues, including Dr. Matthew Ellis who originated the ACOSOG trial, are now analyzing the data so they can understand the genomic profile of women who respond to aromatase inhibitors versus the profile of women who do not respond. Profiles of the entire genome, including mutations in individual genes will be produced using next-generation sequencing instruments and advanced bioinformatic analysis approaches. The profiles will then be tested within the current ACOSOG clinical trial as well as in a new clinical trial to determine how well they predict response to an aromatase inhibitor in a clinical setting. Those trials may begin as early as this fall.
Similar types of genome-sequencing studies are being considered for other types of malignancies, such as colorectal cancer and potentially lung cancer, Dr. Mardis said.
“Genome sequencing is a rapidly changing field. Only about three years ago, it took us eight months to sequence through a whole cancer genome in a leukemia patient. In the next couple of months, we will be doing tumor and normal genomic analysis in about a week. So you can get an idea of the rate of accumulation of data and the dramatic upsweep in terms of our capacity to perform whole genome sequencing in just the last couple of years,” Dr. Mardis said.
Sequencing an entire genome tends to be costly and time-consuming. However, spot testing for the presence of a small number of genes can be performed quickly and cost-effectively, she said. “Sequence typing of specific genes is very doable in the current laboratory testing paradigm using a fairly small amount of DNA from a core biopsy. In the next few months, new technologies are coming online that will allow a genetic assay to be completed in less than a day. So you would have very fast turnaround, and the cost of the assay would be fairly low. Only time will tell whether we have to use the entire genome to make predictions about a patient’s aromatase inhibitor profile or whether we can get away with a focused, gene-by-gene approach,” she said.
The American College of Surgeons Oncology Group (ACOSOG) was established primarily to evaluate the surgical management of patients with malignant solid tumors.
The ACOSOG includes general and specialty surgeons, representatives of related oncologic disciplines and allied health professionals in academic medical centers and community practices throughout the United States of America and foreign counties.
The ACOSOG is one of ten cooperative groups funded by the National Cancer Institute (NCI) to develop and coordinate multi-institutional clinical trials and is the only cooperative group whose primary focus is the surgical management of patients with malignant solid tumors. The Cooperative Group Program was established in 1955 with an initial Congressional appropriation of $5 million. Continued growth has led to a progressive increase in funding, with an NCI appropriation of $154 million for the Cooperative Group Program in 2001.
The plan to develop a new oncology cooperative group focused on surgical therapies originated in 1993. The American College of Surgeons' Board of Regents approved the concept and established a working committee of seven surgical oncologists to devise a plan for the group's organization and structure. The committee's work was supported through a planning grant from the NCI and from funds appropriated by the Board of Regents. Many individuals contributed to the effort, including surgical oncologists, radiation and medical oncologists and biostatisticians.
After developing a set of protocols for clinical trials for a broad range of surgical specialties, a grant was submitted to the NCI, and a site visit was held at Washington University in St. Louis in June 1997. Upon recommendation of the NCI study section, the grant was funded with an official start date of May 15, 1998. The Group was initially based at the American College of Surgeons' office in Chicago.
In January 2001, the Group moved its operations to the Duke University Medical Center. This move allowed the Group to form an association with a strong academic environment and excellent faculties in biostatistics, surgery and clinical trials research, particularly with the Duke Clinical Research Institute.
The American College of Surgeons is a scientific and educational organization of surgeons that was founded in 1913 to raise the standards of surgical practice and to improve the care of the surgical patient. The College is dedicated to the ethical and competent practice of surgery. Its achievements have significantly influenced the course of scientific surgery in America and have established it as an important advocate for all surgical patients. The College has more than 77,000 members and is the largest organization of surgeons in the world.
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