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.

FDA relaxes rules on FFDM regulation - could enable new technologies to get to the market quicker

The FDA have made an announcement that would reclassify FFDM systems from the current class III category, which requires premarket approval (PMA) applications, to class II, which requires the less rigorous 510(k) process. The reclassification would eliminate or reduce the requirement for vendors to conduct large-scale multireader, multicase (MRMC) clinical trials prior to submitting applications for equipment approval.

If the proposal is adopted, the FDA will rely upon well-designed bench studies and limited clinical testing in lieu of large-scale MRMC clinical studies. Products using new technology, with dissimilar designs from approved systems, or having indications for use that are dissimilar from legally marketed devices of the same type, may be required to collect additional clinical data.

An MRMC study may be required to compare sensitivity, specificity, and receiver operating characteristic curves if the results of physical laboratory testing and mammographic feature analysis raise concerns by the FDA.

Vendors have been quick to respond, even with comments that the CR mammography market, particularly in Europe will not be affected due to the initial fast and extensive uptake of CR, but that newer technologies will get to market sooner. This is reflected in the announcement by Hologic, that they plan to have a device for tomosynthesis released at RSNA in 2009.

However, tomosynthesis may need to be subject to a large trial like the DMIST study, as it's eventual aim is to become the main screening tool for breast cancer detection.

MRI increases mastectomy rate

Two interesting stories hit the headlines this week. The first concerned breast density, and the fact that passing through the menopause can greatly affect the rate at which a woman's mammographic (breast) density changes over time.
This was a report from the American Journal of Epidemiology
Am. J. Epidemiol. 2008 167: 1027-1036



The researchers retrieved and digitized 5698 mammograms from 1689 women who were imaged in 1990-2003 to evaluate PD in the Minnesota Breast Cancer Family cohort. The women completed two questionnaires, the first in 1990-1996 and the second in 2001, which provided extensive risk factor data. Postmenopausal women showed a decline in PD of 1.0% over a mean of 6.2 years, while premenopausal women showed a decline in PD of 1.8% over a mean of 4.0 years.

Further analysis showed that, before the age of 50 years, postmenopausal women who never used hormones had a higher PD compared with former and current users. After the age of 50 years, women who never used hormones had larger declines in PD than current or former users.

Higher BMI was associated with lower PD among postmenopausal women at any age after adjusting for covariates. And women in the 95th (highest) percentile for baseline PD showed greater declines in PD over time than women in the 5th (lowest) percentile.

You can get a FREE PDF of the paper from - here

The other story was widely reported in the NEW YORK TIMES this Friday. Thanks to press releases, details about the study which will be presented in Chicago at the annual meeting of the American Society of Clinical Oncology, which begins May 30 has got into the media.

The study revealed that "the percentage of women opting for mastectomy rather than lumpectomy began rising sharply after 2003." A possible explanation for the increase is that MRI "detects more possibly cancerous growths than mammography," which "could be causing patients and doctors to conclude that a lumpectomy, which removes just the part of the breast containing the primary tumor, may not be sufficient."

We certainly are doing far more MRIs, but in our case at UCSF, many of these patients are in trials. Wait until we start following the American Cancer Society Guidelines for women at high risk of breast cancer, with the increase in false positives we get, plus the increased anxiety because of family history...........

Ultrasound screening in HIGH RISK WOMEN - article in JAMA May 2008

Wendy Berg and her ACRIN group published the results of Combined Screening With Ultrasound and Mammography vs Mammography Alone in high risk women in JAMA.

The ACRIN study in full is listed here

The JAMA abstract is here

Conclusions Adding a single screening ultrasound to mammography will yield an additional 1.1 to 7.2 cancers per 1000 high-risk women, but it will also substantially increase the number of false positives.

Breast cancer risk and aspirin use - report from the National Cancer Institute

Nonsteroidal anti-inflammatory drugs and breast cancer risk in the National Institutes of Health-AARP Diet and Health Study

Gretchen L Gierach, James V Lacey Jr, Arthur Schatzkin, Michael F Leitzmann, Douglas Richesson, Albert R Hollenbeck, Louise A Brinton
Breast Cancer Research 2008, 10:R38 (30 April 2008)
Available online through breast cancer research

Conclusions
Breast cancer risk was not significantly associated with NSAID use, but daily aspirin use was associated with a modest reduction in ER-positive breast cancer. Our results provide support for further evaluating relationships by NSAID type and breast cancer subtype.

This story hit the headlines in the USA last night, with several analyses on NBC news. Overall the reaction and advice was sensible, but yet again we will have more questions to answer when we see our patients this week

NEW BIRADS FAQs released by the ACR

While we discuss the pros and cons of some of our 1-5 grading systems, the American College of Radiologists has released an updated FAQ about the BIRADS classification system for breast imaging, widely used in Europe as well as North America.

Here is the link to the PDF file

Accreditation for Digital Mammography

I have just posted a PDF document on the website advertising a course to see and experience a fully digital breast unit on the website - see the news at the top of the page. You could of course come and visit us at UCSF to experience this

In the USA, mammography is highly regulated under the MQSA (Mammography Standards Quality Act). Congress enacted MQSA in 1997, to ensure that all women have access to quality mammography for the detection of breast cancer in its earliest, most treatable stage.

This ensures mandatory minimum standards and accreditation of both equipment and staff

• Equipment has to be accredited each year
• Typical examinations for each breast type have to be submitted by the hospital
• Reporting mammographers have to meet a minimum number of examinations per year

As part of accreditation of mammography units (we were just commissioning a new Hologic Selenia in our screening pavillion), all 'attendings' reporting digital mammograms require 8 hours of training/background knowledge, to legally report digital mammograms. This is checked by the FDA inspectors whose job is to insure compliance with the 'Act'.

Part of the training can be with an applications specialist, enabling you to get the most from your workstation, and how to use (and not abuse) your digital workstations. We were running a breast imaging update course in San Francisco last weekend, and covered Digital Mammography with 4.5 hours of AMA accredited CME, covering all aspects of Digital, including medico-legal aspects, pitfalls in reporting, IHE applied to FFDM, review of the trials and recent reviews, the use of CAD etc.

Some of the issues of working in a mixed environment (due to economic constraints) we are encountering every day, as we work with a mix of analogue, FUJI CR and Hologic FFDM. Our workstations are Selenia's but do not display the FUJI images as intended, which is where IHE is supposed to come in and ensure that images can be displayed, independent of vendor.

ARRS MRI Course

The course was excellent, and covered the range of MRI based information with case studies, as well as Jeffrey Weinreb giving an excellent coverage over the debate about NSF and gadolinium based contrast agents

There was one registrant from Cheshire, but never got to see them there.

If this is repeated next year, I would recommend folks considering applying and attending for CME.

Viva Las Vegas!

Well today I was supposed to be travelling to Las Vegas, where the American Roentgen Ray Society (ARRS) are hosting a Practical Breast MRI session at the Westin, similar to that held by the Radiology Academy in Norwich last April.

Weather has conspired against this so far. In California the rain is teeming down and 2 runways have been closed at San Francisco International Airport, with the associated delays, I am now experiencing what most Americans have to put up with on a regular basis. Hopefully will get off before midnight as we have a 7am start tomorrow.

The mid-West are having serious arctic weather right now, just like the UK appear to be having a similar arctic blast for the end of the week.

Does this remind you of the film - 'the day after tomorrow'?

Latest analysis of the DMIST trial - subset of women under 50 years

In the February edition of Radiology, Eta Pisano reports on some of the sub-group analysis of the DMIST study data.
Radiology, February 2008, Vol. 246:2, pp. 376-383
The subgroup of pre- or perimenopausal women younger than 50 years old with dense breasts was the only one for which FFDM performed significantly better than FSM.
The AUC for digital mammography was 0.79 versus 0.54 for film-screen mammography. Sixteen cancers in this group were found with digital and missed with film-screen mammography, while only two were found with film-screen and missed with digital.

The results also showed a trend toward improved accuracy of FSM over FFDM in women age 65 or over with fatty breasts, but it was not significant, according to the researchers. In this group, 15 cancers were found with film-screen mammography and missed with digital, and four were found with digital and missed with film-screen mammography

Motile in-situ cancer cells (DCIS)

Reported in this month's edition of The Journal of Cell Biology, there is evidence that malignant epithelial cells become motile within their own environment, similar to that occurring in the development of organs during embyrogenesis.

Although the cancer cells are not yet invasive (they do not have the ability to pass through basement membranes), motile cells may indicate the development of a higher grade, or aggressive form of cancer that is developing.
These type of motile cell may require fewer mutations to become fully invasive. Further work needs to be done to see if we can identify what cell lines are developing this way, and devise a test that will differentiate the more aggressive form of DCIS which needs a more aggressive surgical treatment from the outset.

Cost-Effectiveness of Digital Mammography Breast Cancer Screening

A paper in the Annals of Internal Medicine published today 1 January 2008, Volume 148 Issue 1, Pages 1-10, was part of the economic analysis of implementing the move to digital mammography as part of the ACRIN 6652 DMIST study, which reported in October 2006.

The authors Dr. Anna Tosteson et al, from Dartmouth Medical School, performed a discrete event-simulation model to evaluate the cost effectiveness of Digital Mammography (FFDM) compared with analogue (film-screen) mammography. The headline result shows that there are NO cost savings by moving to digital unless breast screening is targeted to a higher risk population where digital mammography has been proven to have a better track record for detecting cancer like younger women with dense breasts.

While this study is useful as it relates to QALYs and cost per life year saved, there are other real world events that also have to be taken into consideration when deciding whether to upgrade your mammography machine to digital.

One of these factors is the decreasing production of medical x-ray film and chemicals, which will eventually be phased out. There are other benefits of moving to digital, which include the eventual elimination of film libraries, physical film hanging, along with the elimination of having to deal with dangerous chemicals and the environmental aspects of disposal of the used developer and fixer. Photographic emulsions are steadily being phased out, so in the medium to long term, there is no real question that digital mammography has to be the final solution.

Perhaps we were originally aiming too high in the original trials, as scientifically it is correct that there has to be a benefit compared with the gold standard examination. An economic evaluation was correctly performed but maybe the most important finding is that digital mammography in its 2003-4 iteration was as good as, and occasionally more accurate than conventional mammography.

Pragmatically, when replacing a mammography unit, a digital one should be purchased. Newer versions of FFDM are better quality, and can only improve our ability to diagnose breast cancer. Workstations and comparison with prior mammograms are now the current challenges facing us as we move forward in attempting to advance the diagnosis of breast cancer.