Do some screen-detected breast cancers spontaneously regress?

An article in this weeks Archives of Internal Medicine from the Norwegian Screening Programme, discuss how there is an excess of cancers in the screened population, and how some of these regress spontaneously

Arch Intern Med. 2008;168(21):2311-2316

it appears that some breast cancers detected by repeated mammographic screening would not persist to be detectable by a single mammogram at the end of 6 years. This raises the possibility that the natural course of some screen-detected invasive breast cancers is to spontaneously regress

News from the Fall meeting of ACRIN at the Pentagon

The Fall meeting of ACRIN was held last week at Pentagon City in DC.



Of note was the report from UCSF-led ACRIN study, on the use of breast MRI in the assessment of neoadjuvant chemotherapy -

"MRI is superior to mammography for evaluating the response to neoadjuvant chemotherapy for breast cancer, according to the early results of a trial from the University of California, San Francisco (UCSF) and nine other academic centers in the U.S. The results were presented at last week's American College of Radiology Imaging Network (ACRIN) fall meeting".

The study was developed under ACRIN's protocol 6657, representing the imaging side of the larger I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) trial aimed at gauging breast cancer treatment response. Sponsored by the Cancer and Leukemia Group B Foundation (CALGB), the I-SPY trial is "testing imaging and tissue-based biomarkers in combination, predicting neoadjuvant response to standard chemotherapy," explained Nola Hylton, Ph.D., a principal investigator from UCSF who discussed the results.

Participants were scanned four times during chemotherapy, including once pretherapeutically, once after the first cycle of chemotherapy, and a third time between the anthracycline and Taxol agents. A fourth scan prior to surgery was intended to detect residual disease and evaluate the post-treatment sensitivity and specificity of MRI. Mammography scans were acquired to coincide with the first and last MRI scans

MRI measurements included morpholgic measurements of the tumors classified according to BI-RADS criteria for breast MRI, including tumor diameter measurements. "We're also measuring by computer the volume of the tumor and the microvascular parameters of the tumor, PE [percent enhancement] and SER [signal enhancement ratio]," used to distinguish malignant tissue, said Hylton.

he investigational software assesses tumor volume quantitatively based on functional rather than anatomic criteria, she explained. "We are measuring something that is based on how these tumors enhance, and assigning [volume] based on an algorithm calling it part of the tumor or not. So it's really a virtual volume [that defines] areas of the image based on function, in this case how the tumors enhance."

The investigators acquired one T1-weighted precontrast and two T2-weighted postcontrast scans, "and from that we looked at the early ratio of enhancement from the early time point to the late time point," she said. This calculation yields the signal enhancement ratio, which distinguishes tumor from nontumor. Another protocol ensures that the direction of diameter measurements remains constant over the course of multiple imaging exams

At the end of surgery, 43% of the patients were complete responders, 38% were partial responders, and 10% demonstrated stable disease. "There were a larger portion of complete responders among those who also received Taxol," she said. "And there were a total of 82 pathologic complete responders, meaning that there was no invasive disease left at pathology. Sixty percent of patients had a complete solid lesion, and 32% had two identifiable lesions in the breast.

Compliance with the study was surprisingly good, especially considering the complexity of the protocol, requiring both biopsy and multiple imaging exams in addition to treatment, she said. In addition, lesion morphology was very similar to a pilot study. There were 36 single masses; 65 multilobulated masses with well-defined margins; 66 lesions with area enhancement, irregular margins, and nodularity; 30 of the same without nodularity; and 19 patients with septal spread.

Once the analysis has been completed, more precise data will be presented at the 2008 RSNA meeting in Chicago.

Researchers Are Investigating Two New Potential Tools for Diagnosing Breast Cancer

Researchers at Jefferson Medical College of Thomas Jefferson University in Philadelphia are investigating contrast-enhanced subharmonic ultrasound as a noninvasive exam that could help physicians make a diagnosis. In subharmonic imaging, pulses are transmitted at one frequency, but only echoes at half that frequency are received

In a study reported in the September 2007 issue of Radiology, researchers tested their technique on 14 women ranging in age from 37 to 66 who had 16 biopsy-proven lesions. The researchers used a GE Logiq 9 ultrasound machine that was modified to perform grayscale subharmonic imaging, transmitting at 4.4 megahertz and receiving at 2.2 megahertz. The women underwent precontrast imaging and imaging using contrast

The researchers’ results using subharmonic imaging were better than conventional ultrasound and mammography. Of the 16 lesions, four were malignant. Mammography had 100% sensitivity and 20% specificity for these lesions. Subharmonic imaging had 75% sensitivity and 83% specificity for the same lesions.

The other tool -
Researchers at Duke University in North Carolina have developed a new scanner that they believe is better at finding early cancers in women than conventional mammography, and it can also be used for diagnosis and monitoring of therapeutic response(s). It is a hybrid between a SPECT and a CT scanner they are collectively calling mammotomography

The researchers have done imaging observer studies using phantoms to compare x-ray digital mammography with CT. “We have been able to show a significant statistical improvement using CT compared to mammography,” Tornai says. “In mammography, you lose a lot of information because you have only a 2D image. With the 3D image that the SPECT/CT scanner produces, lesions become more conspicuous because overlapping tissues are removed. In contrast to x-ray tomosynthesis, a pseudo-3D x-ray imaging modality, the SPECT/CT system produces a uniform 3D image and does not require any breast compression.”

The hybrid scanner that the researchers have built from novel configurations of conventional equipment circles the breast as the patient lies on a specially built table.

The scanner is also able to see areas, including the chest wall, that traditional mammograms may not. They have tested the hybrid scanner extensively with phantoms and has begun successfully scanning subjects with known cancer.

Because SPECT requires IV injection of imaging agents, the SPECT portion of the scanner would not likely be broadly used for routine screening mammography. However, if it proves to be more effective, the hybrid SPECT/CT system might be especially helpful for women who are at high risk for developing breast cancer because of familial history or a genetic predisposition.

Breast SPECT/CT also could be used for women with dense breasts or implants because mammography is known to miss up to 25% of cancers in these women, Tornai says. The scanner and associated imaging procedure also should be less costly to employ than MRI

Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence

Lisa J Martin; Norman F Boyd
An interesting paper published online in Breast Cancer Res. 2008;10(1) by the above authors
This is reported in a Medline article this week

There is now extensive evidence that mammographic density is a risk factor for breast cancer, independent of other risk factors, and is associated with large relative and attributable risks for the disease. The hypotheses that we have developed from the observations described above are summarized here

Cumulative Exposure to Mammographic Density and Breast Cancer Risk

Mammographic density reflects variations in the tissue composition of the breast, and is associated positively with collagen and epithelial and nonepithelial cells, and negatively with fat. Increasing age, parity, and menopause are all associated with reductions in the epithelial and stromal tissues in the breast, and with an increase in fat. These histological changes are reflected in the radiological appearance of the breast, and are consistent with mammographic density being a marker of susceptibility to breast cancer, in a manner similar to the concept of 'breast tissue age' described in the Pike model. Like breast tissue age, variations in mammographic density may reflect the mitotic activity of breast cells and differences in susceptibility to genetic damage, and cumulative exposure to density may have an important influence on breast cancer incidence.

Mitogens, Mutagens and Mammographic Density

Mammographic density is influenced by some hormones and growth factors, as well as by several hormonal interventions, and is associated with urinary levels of a mutagen. We postulate that the combined effects of cell proliferation (mitogenesis) and genetic damage to proliferating cells by mutagens (mutagenesis) may underlie the increased risk for breast cancer associated with extensive mammographic density. As described above under 'Relationship of mitogenesis and mutagenesis', mitogenesis and mutagenesis are not independent processes. Increased cell proliferation can increase lipid peroxidation, and the products of lipid peroxidation can increase cell proliferation

Potential areas for genetic influence include variation in the regulation of the hormones and growth factors that act on the breast, the response and modelling of breast tissue to these stimuli, and the processes that are involved in oxidative stress and the generation of mutagens.

Use of Lidocaine gel pre-mammo may help to reduce discomfort

Compression and the occasional discomfort and pain it brings in the breasts lead many women to avoid mammograms altogether.

However, results from a recent study from Boise, to be published in September 08 edition of Radiology, showed that application of lidocaine gel prior to a mammogram significantly reduced the degree of discomfort experienced.

Lambertz and colleagues recruited 418 women ages 32 to 89 who expected significant discomfort with screening mammography. Fifty-four of the women reported that they had probably or definitely delayed their mammograms due to concern over possible discomfort.

The women were randomized to receive placebos or premedication with acetaminophen, ibuprofen, and/or a local anesthetic gel followed by mammography screening. The gel was applied to the skin of the breasts and chest wall and then removed 30 to 65 minutes before mammography. The gel had no effect on subsequent image quality.

Results showed that oral medication produced no significant differences in breast discomfort, nor did other factors such as breast density. Women who received a topical application of 4% lidocaine gel, however, reported significantly less breast discomfort during mammography.

Eighty-eight percent of study participants indicated they would definitely get a mammogram the following year, and 10% said they would probably get a mammogram the following year.

"Women can now take charge of the situation," Lambertz said. "They can schedule a mammography appointment for a time in their cycle when their breasts are least tender, apply the gel at home, and travel to the appointment knowing they have taken steps toward a positive experience with this potentially life-saving procedure

Hot topics from Arizona - well you would expect that wouldn"t you!

Last week was the 9th International Workshop on Digital Mammography in Tuscon, Arizona.

Most of the papers given are already online - at SpringerLink

Hot topics were Tomosynthesis, Dual Energy mammography - some using subtraction techniques, and others using contrast enhancement.

John Boone, a physicist from UC Davis in Sacramento also was describing his experience with Breast CT using a cone beam - good for resolution, equivalent radiation dose, but not so good for calcifications.

Mammography screening of the elderly - controversies

Last month a paper was published in the Journal of Clinical Oncology entitled - Mammography Before Diagnosis Among Women Age 80 Years and Older With Breast Cancer from MD Anderson Cancer Center in Texas.

The study found that among those who had a mammogram every year or two before their diagnosis, 68 percent found the cancer at an early stage, compared with 33 percent of those who skipped mammograms altogether.

Their conclusion was that regular mammography among women > or = to 80 years of age was associated with earlier disease stage, although improved survival remains difficult to demonstrate. Health care providers should consider discussing the potential benefits of screening mammography with their older patients, particularly for those without significant comorbidity.

This sparked coverage by the New York Times, which did a good job of presenting the pros and cons of screening the elderly. Considering that the end point for measuring a screening program is mortality reduction, then it should be looked at in a proper light rather than just concentrating on reducing morbidity from the disease.

We have the occasional patient in San Francisco having screening mammograms in their eighties, similar to the NHS BSP in the UK, where patients can self refer. With the rising elderly population, and better breast-awareness, it may well be that we do more mammography in the elderly and reduce morbidity than we do for now.