MRI and Mammography Combined are Effective in Detecting Breast Cancer in Women at High Risk

Chiarelli et al in their JCO article report on Ontario’s Breast Screening Program of women age 30 to 69 years at high risk for breast cancer with annual magnetic resonance imaging (MRI) and digital mammography.

The study cohort consisted of 2,359 women. The following criteria were used to determine eligibility: known BRCA1, BRCA2 mutation, or other gene predisposing to a markedly increased risk of breast cancer, untested first-degree relative of a gene mutation carrier, family history consistent with hereditary breast cancer syndrome and estimated personal lifetime breast cancer risk of 25% or higher, or radiation therapy to the chest before age 30 years.

Digital mammograms were performed with standard craniocaudal and mediolateral oblique projections.  The minimum MRI standards were 1.5 Tesla units, gadolinium injection (0.1 to 0.2 mmol/kg) and a dedicated breast coil. Both breasts were imaged in axial and sagittal planes.  Most of the eligible women (90.7%) had their MRI within a month from their mammograms.  Of the 2,359 eligible women 2,290 were screened.  Of the women screened 2,157 had an MRI and were included in the study as women who had only a mammogram were excluded.

The recall rate of 15% was significantly higher among women who had abnormal MRI alone compared with 6.4% when mammogram alone was used.  Of the 35 breast cancers detected (16.3 per 1,000), none were detected by mammography alone, while 23 (65.7%) were detected by MRI alone (10.7 per 1,000), and 25 (71%) were detected among women who were known gene mutation carriers (30.8 per 1,000). The positive predictive value of 12.4% for detection was highest when findings from mammogram and MRI were combined.  Overall, the cancer detection rate was significantly higher for invasive cancers (12.6 per 1,000) compared with DCIS (3.7 per 1,000). Cancer detection rates were higher among women age 50 years (23.3 per 1,000) compared with women younger than age 50 years (13.3 per 1,000) and significantly higher among those who were known gene mutation carriers (30.8 per 1,000) compared with those with a family history plus an estimated lifetime cancer risk of 25% (6.9 per 1,000).

The authors conclude that screening with annual MRI combined with mammography is effective and could be implemented into an organized breast screening program for women at high risk for breast cancer as mammograms alone failed to detect early breast cancers. 

An editorial by Dr. Wendie Berg with comments on this topic was published by the Journal of Clinical Oncology.

Monitoring Metastatic Breast Cancer with Circulating Tumor DNA

Dawson et al in a NEJM article report on their research on monitoring tumor burden on patients with metastatic breast cancer by means of detecting circulating cell-free DNA carrying tumor specific alterations.

A total of 52 women with metastatic breast cancer were recruited, 30 of whom had genomic alterations suitable for monitoring. Serial blood samples were collected at intervals of 3 or more weeks. Computed tomography (CT) was performed to document response to treatment. They compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in the 30 women who were receiving systemic therapy. They used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points.

Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).

Metastatic breast cancer remains an incurable but treatable disease.  Effective monitoring of treatment response is essential in order to avoid continuing ineffective therapies and to prevent side effects.  Their research showed that circulating tumor DNA is an informative, specific, and sensitive biomarker of metastatic breast cancer.

MR Spectroscopy May Predict Disability In MS

Llufriu et al, in their article at JAMA Neurology report findings and promise of MR spectroscopy in the evaluation of clinical disability of patients with multiple sclerosis (MS). 

Their study involved 59 patients and 43 healthy controls that were included in a discovery sample and 220 patients in a confirmatory cohort.

Baseline N-acetylaspartate (NAA), myo-inositol (mI) levels in normal-appearing white and gray matter, myelin water fraction in normal-appearing white matter, markers of axonal damage, astrogliosis, and demyelination were evaluated as predictors in a preliminary data set. The potential predictors were subsequently tested for replication in a confirmatory data set. Clinical scores and percentage of brain-volume change were obtained annually over 4 years as outcomes.

NAA and mI had statistically significant effects on brain volume, prompting the use of the mI:NAA ratio in normal-appearing white matter as a predictor.   Furthermore, the mI:NAA ratio predicted clinical disability (Multiple Sclerosis Functional Composite evolution: −0.52 points annually, P < .001; Multiple Sclerosis Functional Composite sustained progression: odds ratio, 2.76/SD increase in the ratio; 95% CI, 1.32 to 6.47; P = .01) in the preliminary data set and predicted Multiple Sclerosis Functional Composite evolution (−0.23 points annually; P = .01), Expanded Disability Status Scale evolution (0.57 points annually; P = .04), and Expanded Disability Status Scale sustained progression (odds ratio, 1.46; 95% CI, 1.10 to 1.94; P = .009) in the confirmatory data set. A new MRI technique allows the estimation of myelin water content derived from the quantification of short T2 relaxometry component. The measure is specific to myelin content and/or its integrity. The myelin water fraction is commonly reduced in normal-appearing white matter, which may reflect active or chronic demyelination.  Myelin water fraction did not show predictive value.

The authors concluded that the mI:NAA ratio in normal-appearing white matter was consistent predictive regarding brain atrophy and neurological disability evolution. The combined presence of astrogliosis and axonal damage in white matter had cardinal importance in disease severity.

Combined MRS and DWI could Predict Stroke's Outcome

Parsons etal in their article that appeared in Neurology¹ report on the prognostic value of the biochemical changes seen with proton MR spectroscopy (MRS) in patients with ischemic stroke.

Nineteen patients had 36 1H MRS studies, 13 of the patients acutely (mean, 11.1 hours), 10 patients sub-acutely (mean, 3.9 days), and 13 patients at outcome (mean, 82 days). Single-voxel, long-echo, timepoint-resolved spectroscopy was used to obtain lactate, n-acetylaspartate (NAA), choline, and creatine levels from the infarct core. Diffusion-weighted imaging (DWI) was used to identify regions of ischemia for 1H MRS voxel localization.  Outcome measures were final infarct volume and clinical assessment scales (Canadian Neurological Scale, Barthel Index, and Rankin Scale).

Acute lactate/choline ratio correlated more strongly with clinical outcome scores and final infarct size than acute DWI lesion volume or acute NAA/choline ratio. Combination of acute lactate/choline ratio and DWI lesion volume improved prediction of all outcome scores. The predictive effect of acute lactate/choline ratio was independent of acute DWI lesion volume (p < 0.001). In subacute and chronic infarction, both lactate/choline and NAA/choline ratios continued to correlate with outcome (p < 0.05). At the chronic stage, persistent lactate/choline ratio elevation strongly correlated with outcome measures (r = 0.71 to 0.87).

The authors concluded that lactate/choline ratio measured in the acute infarct core by 1H MRS improves the prediction of stroke outcome and provides prognostic information complementary to DWI.

1. Parsons M, Barber P, Yang G, Darby et al: Combined (1)H MR spectroscopy and diffusion-weighted MRI improves the prediction of stroke outcome. Neurology. 2000 Aug 22;55 (4):498-505