Research Grants Awarded
Optimizing Endocrine Therapies For The Individual Patient With Breast Cancer: Identifying Targets For Tailored Treatment
Available endocrine therapies (ET), tamoxifen or aromatase inhibitors (AIs), are effective on average for the large population of women with steroid hormone-receptor positive (HR+) early breast cancer, but many patients still relapse and die of their disease. In order to reduce breast cancer mortality, we must optimize the use of these agents by determining features of the disease or of the patient suggesting one or the other ET is better for the individual patient, so that treatments can be better tailored to the biological targets. Because of the different endocrine milieu and mechanisms of action of ETs among pre- and postmenopausal women, tailoring may substantially differ for these two patients populations. The IBCSG is uniquely positioned to identify and study such features in two large randomized clinical trials comparing tamoxifen to AI in post- and premenopausal populations.
The IBCSG has conducted high-quality and influential clinical trials for 30 years, concentrating on chemo- and endocrine therapies and timing and duration of adjuvant therapies. Recognizing that the biology of the tumor is critical for determining response to treatments, the IBCSG has pioneered tailoring treatments within target patient population. The two clinical trials forming the basis of this proposal already have large databases and established tissue banks. This valuable resource allows us to test new molecular and biological features, and merge and analyze them with long-term follow-up information already collected, thus producing results and impacting disease mortality sooner.
The first focus of this application is tailoring adjuvant ET for postmenopausal women. The IBCSG-led BIG 1-98 trial is a randomized, phase III, 4-arm, double-blind trial comparing monotherapy with the AI letrozole or with tamoxifen for 5 yrs, or sequential administration of one agent followed by the other. The trial enrolled 8010 patients between 1998 and 2003. Letrozole alone demonstrated a reduced risk of recurrence compared with tamoxifen alone (two of the four arms) (NEJM 2005); the sequential arms will remain blinded until Fall 2008. 82% of patients? primary tumor specimens were reviewed in the IBCSG Central Pathology Laboratory; DNA and RNA will be isolated from formalin-fixed paraffin-embedded specimens. We will investigate patient and tumor features that may contribute to inter-individual variability of response to tamoxifen and letrozole, as measured by DFS. We hypothesize that polymorphisms in the drug metabolism genes CYP2D6, responsible for tamoxifen activation, CYP19A1, encoding the enzyme aromatase, in the ER?, ER? and Akt1 genes, and differential expression of breast-cancer related genes selected for a custom DASL array predict responsiveness to adjuvant ETs as defined by DFS. These molecular and biological markers may hold the key to why a patient?s disease fails to respond to tamoxifen or to letrozole.
A second, parallel focus is tailoring adjuvant ET for premenopausal women, with the IBCSG-led Tamoxifen and Exemestane Trial (TEXT) comparing ovarian function suppression plus either tamoxifen or exemestane for 5 yrs. TEXT achieved the planned enrollment of 1845 patients and accrual was suspended on 30 Nov. 2007. The pace of enrollment (64/month) was faster and the enrolled population at lower-risk than planned.
We will re-open accrual to TEXT with an additional 600 patients, which will ensure that the primary trial question is reported within the next five years. Baseline and serial blood samples during ET for specified research, storage of DNA, and measurement of serum markers will be performed in these additional patients and bone mineral density will be measured. We also plan to create a biospecimen bank by collecting a one-time blood sample for specified research and for storage of DNA from the already-enrolled patients, thus supplementing the existing tissue bank. This multi-faceted biospecimen bank allows investigating patient and tumor features that may contribute to inter-individual variability of treatment responsiveness by selecting several biomarkers as possible fast indicators of differential antitumor activity/outcome and toxicity between tamoxifen and AI in the presence of GnRH analogue. We hypothesize that polymorphisms in the drug metabolism genes CYP2D6 and CYP19A1, in ER? and ER?, and in Akt1 could precisely identify premenopausal women most likely to benefit from either GnRH+tamoxifen or GnRH+exemestane or to develop specific side effects.
Based on the central pathological assessment of ER, PgR, HER2 and Ki-67 LI on the primary tumor samples of the patients enrolled in TEXT, we will ascertain whether conclusions observed in the BIG 1-98 trial hold true for premenopausal women. We further hypothesize that serial blood assessment of IGF-I and IGFBP-3, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase could represent markers as compared to BMD to predict bone loss and fractures in young women treated with combined ET.
To take best advantage of the emerging data, it is crucial to improve upon population-level inference such as the hazard ratio by developing and validating prediction models that incorporate the array of patient and tumor features to assist in clinical decision-making and treatment selection for the individual patient. We will develop and translate novel statistical methods into practice using the data from these studies.
Currently available adjuvant endocrine therapies have greatly benefited patients on average, but further tailoring the treatment to the individual patient will result in substantial progress toward reducing breast cancer mortality.
Early stage breast cancer is treated with surgical removal of the tumor followed by treatments to destroy any remaining cancer cells and prevent their return (recurrence). Three-fourths of breast tumors are hormone-dependent, meaning they contain protein molecules called estrogen receptors. When no estrogen is present, the estrogen receptors remain inactive. When the estrogen receptors are exposed to estrogen, they trigger a chain of events that may result in tumor cell growth and multiplication. For these tumors estrogen promotes the growth of breast cancer cells.
Controlling estrogen in the body is therefore a key to reducing recurrences for these patients. The two therapies we will study both control estrogen, but through different mechanisms. Tamoxifen works by competing with estrogen to bind to estrogen receptors in breast cancer cells. Aromatase inhibitors (e.g. Femara, Arimidex, Aromasin) interfere with the production of estrogen and reduce the total amount of estrogen in the body, so less estrogen reaches breast cancer cells.
Patients whose tumors have estrogen receptors (ER-positive) are less likely to recur if they receive five years of tamoxifen or aromatase inhibitor, whereas these drugs do not benefit patients whose tumors have no estrogen receptors. Therefore the estrogen receptor is a ?target? for these drugs. Tamoxifen and aromatase inhibitors are referred to as ?tailored? treatments, because the drugs work for patients with the estrogen receptor target. Although estrogen receptor is a valuable target, these drugs do not prevent breast cancer recurring for 15% to 30% of the patients.
The goal of this research proposal is to test hypotheses for additional targets that will enable tailoring these well-established and effective treatments to the individual patient, leading to fewer recurrences; and avoiding ineffective therapies and their side effects. The proposal is to study both premenopausal and postmenopausal patients separately, because the amount of estrogen in the body differs dramatically between the two groups. In order to cure more women of breast cancer, we must make the best use of these drugs by determining features of the disease and of the patient that suggest one or the other is better for the individual patient.
The research will build on two clinical trials that already have large computerized databases containing patient and disease information, and also have established tissue banks of pieces of tumor conserved in paraffin. The trials and the proposed research are coordinated by the International Breast Cancer Study Group (IBCSG), a cooperative clinical research group that has conducted high-quality and influential clinical trials for 30 years. More than 25,000 women with early breast cancer have participated in IBCSG trials. Recognizing that the biology of the tumor is critical for determining response to treatments, the IBCSG has pioneered tailoring treatments within targeted patient populations.
In postmenopausal women we will look at alterations in genes, specifically CYP2D6, which is responsible for tamoxifen activation, and CYP19A1, which is involved in estrogen production. These genes may hold the key to why a patient benefits from tamoxifen or an aromatase inhibitor. In order to conduct this research, scientists will analyze the preserved tumors from 2,400 patients entered into the BIG 1-98 clinical trial who have already received five years of an aromatase inhibitor (Femara), tamoxifen, or a sequence of both. Other information on the patient, including whether her disease has recurred and when, is already stored on a computer, so the new information on these targets can be added to the database and conclusions can be drawn soon after.
In premenopausal women we will investigate features in the blood, tumor, and bone from the TEXT clinical trial. Patients on this trial receive five years of the drug triptorelin, which stops the ovaries from producing estrogen, along with either tamoxifen or an aromatase inhibitor (Aromasin). The trial has enrolled 1845 patients, and with the support of this grant, will enroll another 600. This larger sample size will have a twofold benefit: 1) the trial results will be more reliable and available sooner, and 2) a biospecimen bank will be developed to further study the treatments for individual patients. A blood sample will be collected from the patients already enrolled, blood samples will be collected several times for newly enrolled patients, and tumor specimens have been and will continue to be collected. As with the postmenopausal patients, the CYP2D6 and CYP19A1 genes will be studied. The suppression of estrogen can lead to bone loss in these young women. We will also investigate whether factors in the blood can give us the information on bone loss that currently requires the more costly bone mineral density test. Each of these features will be used to more precisely identify premenopausal women most likely to benefit from either of the two treatment programs.
This project will produce a lot of new information to supplement that already collected. Learning the most we can from these new and different types of data will require improvements in the methods used for data analysis, and we have therefore included development and application of new statistical methods as an important part of this integrated research program.
Our program involves global collaboration of top researchers in their fields who believe that treatments must be tailored to individual patients. The proposed research will help match the patient with the better treatment, thus improving overall the number of patients cured.