Measure for Measure
Trial signal advances in breast MRI for locally advanced breast cancer and DCIS.
Results of the ACRIN® 6657 trial, Contrast-Enhanced Breast MRI for Evaluation of Patients Undergoing Neoadjuvant Treatment for Locally Advanced Breast Cancer, reported in the June 2012 issue of Radiology, reveal that changes in tumor volume determined by MRI are a better predictor of pathological response to neoadjuvant chemotherapy than a clinical exam.1
"MRI can help us identify those patients who will respond to neoadjuvant treatment early in their treatment regimen, which has important implications for better managing a patient's treatment," explains the study's principal investigator, Nola M. Hylton, PhD, professor of radiology and director of the Breast MRI Research Program at the University of California at San Francisco.
Locally advanced breast cancers are typically large and have a poor prognosis. Neoadjuvant or pre-surgical chemotherapy is often given to women with these cancers to shrink the tumor before surgery, allow breast conservation in some women who might otherwise have needed mastectomy. "Prior to the trial's published results, no imaging standard existed for assessing primary breast cancer response to neoadjuvant chemotherapy," says Hylton. "We compared MRI findings to those from clinical examination because assessment of the tumor size by physical exam was the standard of care for monitoring response to neoadjuvant chemotherapy."
ACRIN 6657 was conducted as the imaging component of the I-SPY 1 TRIAL — a study of imaging- and tissue-based biomarkers for predicting response and survival and the largest multicenter trial of MRI to measure treatment response in primary breast cancers.
Trial investigators evaluated three MRI-derived measurements for assessing response obtained during each of four MRI scans (see Figure 1):
• Longest linear diameter measurement, as specified by the Response Evaluation Criteria in Solid Tumors — a set of published rules for evaluating cancer treatment response in solid tumors
• Tumor-volume measurement — an aggregate of all tissue that met criteria for signal enhancement ratio (SER), a voxel-based comparison of early and late contrast enhancement
• Peak SER measurement — the highest SER value, or "hot spot," of the tumor
Both tumor volume and peak SER are functional measurements that reflect a tumor's size and microvascular properties. Post-surgery pathology served as the arbiter of how accurately the MRI and clinical exam measurements were able to predict response, with tumor volume proving to be the most sensitive measurement after just one treatment cycle. As Hylton notes, "Tumor volume combined with the clinical exam provided the most accurate tumor response information."
“Prior to the trial’s published results, no imaging standard existed for the use of MRI to predict response to therapy.” — Nola M. Hylton, PhD
Quantitative analyses of tumor volume and SER were performed at the MRI laboratory at the University of California at San Francisco. Images were obtained at seven participating institutions, all using 1.5-T scanners and standardized dynamic contrast enhanced (DCE) methods. Hylton reports that analysis is well underway to support the trial's primary aim of determining the ability of MRI functional measurements to predict a three-year recurrence-free survival rate relative to clinical and pathologic response measures.
Additionally, the ACRIN 6657 study design served as a model for the recently activated ACRIN 6698 clinical trial, the imaging component of the follow-on I-SPY 2 TRIAL, which is testing multiple investigational drugs used in combination with the standard drug taxane. In addition to the DCE measurements, the trial will also evaluate diffusion weighted imaging (DWI) to measure the mobility of water molecules in vivo. DWI is sensitive to such tissue characteristics as cell density, membrane permeability, and microstructure. "Because cellularity and vascularity represent different but complementary aspects of tumor biology, evaluation using both DWI and DCE techniques together may be more informative and effective than using either procedure alone for characterizing breast cancers and their response to treatment," summarizes Hylton.
Trial to Evaluate Targeted Treatment Option for DCIS
Patients with ductal carcinoma in situ (DCIS) have historically been treated aggressively, despite estimates that progression to more significant disease would not occur in at least half of these patients. Easter Cooperative Oncology Group (ECOG) and ACRIN investigators are collaborating to develop a trial of advanced imaging techniques and biological markers to identify patients diagnosed with DCIS whose breast cancer might be managed with less aggressive intervention without sacrificing excellent patient outcomes.
"This collaboration is a prime example of the groups' synergistic expertise," says Constance D. Lehman, MD, PhD, FACR, chair of the ACRIN Breast Committee, and professor and vice chair of radiology at the University of Washington at Seattle. Lehman and Joseph A. Sparano, MD, chair of the ECOG Breast Cancer Committee, and professor of medicine and obstetrics, gynecology, and women's health at the Albert Einstein College of Medicine in the Bronx, N.Y., are leading this collaborative effort.
Patients diagnosed with DCIS who do not undergo a mastectomy typically receive radiation therapy following breast-conserving surgery. Citing an increase in DCIS cases being diagnosed through improved early cancer screening programs, the National Institutes of Health brought together content experts of the State-of-the-Science Conference dedicated to the diagnosis and management of DCIS.2 "Concern about the possible overtreatment of patients," notes Lehman, "led to a call for better understanding of the role imaging could play in identifying patients with DCIS who warrant more aggressive treatment as well as those who could safely avoid the standard therapies currently offered."
Recent advances in MRI technology emphasizing spatial resolution have allowed researchers to see breast structures in more detail than was previously possible. In addition, an increase in studies on screening high-risk patients rather than those with known cancer had led to a better understanding about the types of DCIS that are detected by MRI but missed by mammography. When combined with a greater understanding of how to interpret MR images and identify patterns of DCIS compared with normal breast tissue, these developments have resulted in current recommendations that specify MRI as is the most sensitive tool to detect and diagnose DCIS.
"Based on MRI's ability to identify invasive as well as in situ disease — and more extensive DCIS — than was possible with mammography and ultrasound, we are encouraged about its potential to guide more individualized DCIS treatment," Lehman explains.
In the proposed trial, women with DCIS diagnosed by core needle biopsy will undergo bilateral breast MRI. For breast-conserving surgery candidates (versus study participants recommended for mastectomy), oncotype DCIS score will be determined from tissue removed during surgery to obtain information about the cancer's biology. Only participants with intermediate to high scores will receive radiation treatment. "We think we can have a very acceptably low recurrence rate at five years for the group of participants with a definitive MRI, a low DCIS score, and no RT," Lehman says.
The MRI technology necessary for the proposed trial is widely available across academic and community imaging centers. "Moreover," adds Lehman, "the requirements for breast MRI accreditation by ACR reflect the level of quality sought for this trial." The NCI Division of Cancer Treatment and Diagnosis continues to work with ECOG and ACRIN investigators to develop a formal protocol for the trial, which is expected to begin in 2013.
1. Hylton NM, Blume J, Bernreuter W, et al. “Locally Advanced Breast Cancer: MR Imaging for Prediction of Response to Neoadjuvant Chemotherapy — Results from ACRIN 6657/I-SPY TRIAL.” Radiology. June 2012;263(3):663–72.
2. Virnig BA, Shamliyan T, Tuttle TM, et al. “Diagnosis and Management of Ductal Carcinoma in Situ (DCIS).” Agency for Healthcare Research and Quality. September 2009.
By Nancy Fredericks, MBA, and Julie Catagnus, MPH, ELS