Note: If you haven’t already, you should read PART 1 of this two-part series. It defines several terms that I will be using in this post, and I don’t plan on explaining them again, given that they were explained in detail in Part 1. Of course, if you’re a medical professional and already know what lead time bias, length bias, and stage migration are, then it goes without saying that you should still read Part 1 for its scintillating prose.
When last I left this topic three weeks ago, I had discussed why detecting cancer at ever-earlier stages and ever-smaller sizes is not necessarily an unalloyed good. At that time, I discussed in detail a landmark commentary in the New England Journal of Medicine entitled, . The article, although nearly 15 years old, rings just as true today in its cautioning doctors about whether ever-increasing diagnostic sensitivity that imaging technology and new blood tests were (and are) providing was actually helping patients as much as we thought it was. Before we dive into this problem as applied to breast cancer, let’s review what Drs. Black and Welch had to say about screening tests for breast cancer 15 years ago, as way of background and linking my last post and this one:
Before the widespread use of mammography, most breast cancers were discovered on physical examination, as palpable lumps. In one of the few studies to assess directly the accuracy of physical examination in screening for breast cancer, only 27 percent of tumors more than 1.0 cm in diameter and 10 percent of those less than 1.0 cm in diameter were detected by physical examination. However, the mean size of breast cancers detected by state-of-the-art screening mammography is about 1.0 cm, and many of the cancers detected as microcalcifications are only a few millimeters in size.
Again, prevalence depends on the degree of scrutiny. According to the Connecticut Tumor Registry, clinically apparent breast cancer afflicts about 1 percent of all women between the ages of 40 and 50 years. In a recent medicolegal autopsy study, however, small foci of breast cancer were found in 39 percent of women in this age group. Most cancers were in the form of ductal carcinoma in situ. Furthermore, over 45 percent of the women with cancer had two or more lesions, and over 40 percent had bilateral lesions. Although it has been argued that such small in situ lesions are not detected by and are therefore irrelevant to screening mammography, about half the lesions in that study were detected, usually as microcalcifications, on postmortem plain-film radiography of the resected breasts. Because of continual technical improvements and increasingly broad criteria for the interpretation of mammograms, the detection threshold for breast cancer has fallen considerably since the time of the Breast Cancer Screening Project of the Health Insurance Plan of Greater New York (1963 to 1975). This can explain the increased prevalence of cancer on mammographic screening, from 2.717 to 7.614 per 1000 examinations (with the incidence increasing from 1.517 to 3.214 per 1000 examinations). The lower detection threshold can also explain the increase in the percentage of carcinomas in situ (stage 0) among all mammographically detected cancers — from 12.7 percent to over 30 percent. The principal indication for biopsy has changed from suspicious mass to suspicious microcalcifications. This can explain why the reported incidence of breast cancer has increased and why most of the increase is in smaller lesions, particularly ductal carcinoma in situ.
About a year ago, three major articles hit the medical press that made me start thinking about this more than I had in the past. It’s my job, after all, because breast cancer surgery is a large part of my practice, and I do breast cancer lab-based research. What also tweaked me not to put off doing part 2 of this series is that, just two days ago, there was an abstract presented at the American Society of Clinical Oncology Meeting (where I still am today) that also serves to highlight just how difficult this question of integrating a test as sensitive as MRI into a screening regimen for and preoperative evaluation of breast cancer is and how MRI should fit into in this regimen can be.
Let’s begin with the older data. A little more than a year ago, a major set of metanalyses looking at the value of screening mammography in younger women (ages 40-49) was published in the Annals of Internal Medicine as a a pair of companion articles, one as a metanalysis and another as clinical guidelines. Remember, as mentioned for prostate cancer and thyroid cancer in my previous post, a large percentage of apparently healthy women, if you look at their breast tissue closely enough, will have evidence of ductal carcinoma in situ (DCIS), the latter of which is, depending on how you look at things, either a premalignant lesion or cancer that has not invaded outside of the breast ducts yet. Either way, very few women die of DCIS if they are treated. We do not know how many would die if untreated, but we do know that the vast majority of women from 40-49 with microscopic evidence of breast cancer or DCIS will never die of cancer, because either the cancer does not progress or progresses so slowly that, even in the 30-40 years remaining for women in this age range, it does not manifest itself as clinical cancer and the women die of something else. This situation is a classic example of how lead time bias and length bias lead to an increase in the number of diagnoses of cancer and a shift towards less rapidly progressive disease being diagnosed, as I described in part 1. The problem, of course, is that we have no way of identifying which of these lesions will turn into clinically apparent cancer, leaving little choice but to treat all detected cancer, even tiny microscopic lesions, as though they are potentially life-threatening.
The issues complicating the question of mammographic screening of women under 50 are now, as they were then, that breast cancer is not nearly as common in this age group as it is in women over 50, for whom the preponderance of evidence from clinical trials and epidemological studies support the value of mammographic screening in decreasing mortality from breast cancer. In contrast, the value of yearly screening mammography in women aged 40-49 has historically been somewhat more controversial controversial, and a recent set of guidelines published in the Annals of Internal Medicine, includes a on screening mammography in this age range, accompanied by a set of consensus . The sums up the data fairly well:
In the United States, breast cancer is one of the most common causes of death for women in their 40s. In 2002, almost 5000 women between 40 and 49 years of age died of breast cancer, compared with the 6800 women who died of heart disease or 1500 women who died of HIV (5). However, despite the relative importance of breast cancer in this age group, the burden of breast cancer among women in their 40s is low for a population-based screening program. More than 98% of women will not develop breast cancer between 40 and 50 years of age, but they will be subject to the risks of population-based screening. Of the 44,000 women who die of breast cancer each year, fewer than one fifth received their diagnoses between the ages of 40 and 49 years.
That is indeed the problem with all mass screening programs. For a mass screening program to be effective, the disease being screened for must be common and treatable, and there must be a screening test that has an acceptable sensitivity and does not turn up too many false positives. In other words, it must be common enough so that the “noise” from false positives from the test is small in comparison to the true incidence of the disease being screend for. In addition, if it is being applied to mass populations, a test must also be inexpensive and safe. For women over 50, these conditions certainly apply with respect to breast cancer and mammography, and, indeed, studies of the issue, taken together, support the conclusion that there is a 20-25% reduction in breast cancer mortality in this age range in populations that are screened with mammography compared to populations that are not. In contrast, for women from 40-49 years of age, the benefit is clearly more modest, and some argue that there is really no benefit at all. What is cited is approximately a 15% decrease in mortality after 14 years; however the error bars are fairly wide. Indeed, the low end of the range is a mere 1% benefit in decreased mortality. This is one of the reasons why some European countries do not recommend routine screening mammography for breast cancer until age 50, unless there are risk factors, such as a strong family history or mutations in breast cancer susceptibility genes, such as BRCA1 and BRCA2.
Among the other findings of the metanalysis was that the risk from the radiation is quite small. However, the most problematic finding was that the risk of false positive results is high. After 10 mammograms, there is a 20-56% risk of a false positive. All of these will require, at the minimum, further imaging and workup; some will require a referral to a breast surgeon for evaluation and some of those will end up getting biopsies, the majority of which (75-80%) will be benign. This does not even count the mental and emotional distress that abnormal mammograms cause between the time the woman is informed of the result and the time that either additional imaging or a biopsy. Given this information, unfortunately, the guidelines suggested by the ACP last year were so vague as to be almost useless, at least to me:
- In women 40 to 49 years of age, clinicians should periodically perform individualized assessment of risk for breast cancer to help guide decisions about screening mammography.
- Clinicians should inform women 40 to 49 years of age about the potential benefits and harms of screening mammography.
- For women 40 to 49 years of age, clinicians should base screening mammography decisions on benefits and harms of screening, as well as on a woman’s preferences and breast cancer risk profile.
- We recommend further research on the net benefits and harms of breast cancer screening modalities for women 40 to 49 years of age.
Those of you who are gynecologists, internists, or family practice docs (you know, the docs who generally take care of routine screening tests), tell me: Do those guidelines help you at all to decide whether you should screen women between 40-49? The problem is, the above guidelines do not tell me as a clinician how I should balance risk and benefit and how I should counsel patients to balance risks and benefits, and, quite frankly, the discussion after each guideline in the original paper do not help much. In addition, the elephant in the room that no one wants to acknowledge is the medical-legal climate. In the United States, one of the most common causes of lawsuits, if not the most common, is failure to diagnose breast cancer. What primary care doctor has the intestinal fortitude not to screen women from 40-49, when the majority of radiology and medical organizations still recommend mammography every 1-2 years between ages 40 and 50, even if the evidence upon which they base these recommendations is not as compelling as that for women over 50? Not too many. Indeed, in the U.S. it is not uncommon for me to see women in the 35 to 40 year old age range being referred to me after their first mammograph turns up an abnormality that is almost certainly not cancer but has to be evaluated.
There is, of course, now a newer imaging modality that really brings home the points in the Black and Welch commentary from 14 years ago. I am referring, of course, to MRI. MRI stands for magnetic resonance imaging, and, over the last decade, MRI of the breast has been developed and fine-tuned. MRI can produce stunning images and is highly sensitive. There’s little doubt that it can pick up lesions that mammography can miss, although it is not as good for picking up DCIS as it is for breast cancer. Given that we have probably come close to the limits of resolution and sensitivity in mammography with the newer digital mammography machines, not surprisingly, the question of what role MRI should play in the screening of women for the early detection of breast cancer is now coming to the forefront. There is good evidence that MRI adds benefit in the screening young women at a high risk of breast cancer, such as women carrying BRCA1 or BRCA2 mutations. But what about the general population, whose age-adjusted risk of breast cancer is average and thus much lower than these very high risk women?
Enter the second article last year, namely a review by the , which tried to come up with some for when using MRI as an adjunct to screening mammography is appropriate. The last time it had updated its guidelines in 2003, at which time the ACS stated that there was insufficient evidence to recommend MRI as a screening test, except perhaps for women at high risk of breast cancer. I’ll boil down the most recent recommendations, which come in a large paper published in by listing them as the appear in Table 1:
Recommend Annual MRI Screening (Based on Evidence*)
First-degree relative of BRCA carrier, but untested
Lifetime risk 20-25% or greater, as defined by BRCAPRO or other models that
are largely dependent on family history
Recommend Annual MRI Screening (Based on Expert Consensus Opinion)
Radiation to chest between age 10 and 30 years
Li-Fraumeni syndrome and first-degree relatives
Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives
Insufficient Evidence to Recommend for or Against MRI Screening
Lifetime risk 15-20%, as defined by BRCAPRO or other models that are largely
dependent on family history
Lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH)
Atypical ductal hyperplasia (ADH)
Heterogeneously or extremely dense breast on mammography
Women with a personal history of breast cancer, including DCIS
Recommend Against MRI Screening (Based on Expert Consensus Opinion)
Women at <15% lifetime risk
Of course, it’s hard not to point out that recommending MRI screening for women with BRCA mutations is nothing new; such women are at extraordinarily high risk for developing breast and ovarian cancer, with some variants producing a lifetime risk of cancer as high as 80%. Indeed, these are the women who often undergo prophylactic bilateral mastectomies or take estrogen-blocking drugs in order to try to decrease their risk. What I am unclear about is how the ACS came up with the recommendation that women who have a lifetime risk of developing breast cancer of 20% or greater should undergo MRI screening. The rationale for choosing that number as the cutoff was not at all clear to me from reading the paper; certainly no clear risk-benefit analysis was presented that suggests that, above a 20% risk MRI is worthwhile and below a 15% risk it is not.
Once again, consistent with the Black and Welch paper, I will point out that the increased sensitivity of MRI comes at a price. If a woman gets an MRI, she is twice as likely to get a biopsy as compared to getting just a mammogram and, if needed, an ultrasound. Remember, MRI is more sensitive than but not as specific as mammography. It picks up all sorts of lesions that mammography misses, but most of them are not cancer. Remember, also, the possible confounding effects of lead time bias and length bias. It is not at all clear if detecting breast cancer by MRI at an even earlier point in its development than it would be detected by mammography and/or physical examination will truly improve breast cancer survival independent of lead time bias, nor is it clear what percentage of these smaller cancers would ever grow to cause any problems at all. Remember the autopsy study cited earlier. Among even 40-50 year old women, 40% will have microscopic evidence of breast cancer if you look hard enough. Also, if you look at the , it’s pretty easy to come up with a common scenario that pushes a patient’s lifetime risk of breast cancer to 20% or more. For instance, I modeled a 40 year old woman with a single breast biopsy (which was benign), age at first menstruation of 11, and her age at first childbirth over 30, and the lifetime risk is already approaching 18%. True, the Gail model has its problems, but it is still widely used. It doesn’t take much to reach this level of risk.
MRI has also been increasingly used for preoperative evaluation of women with breast cancer. It’s not hard to see why it’s attractive; the images it can produce are stunning, and it can give an idea of extent of disease that MRI and ultrasound may not always be able to. However, as with using MRI for screening, this increased sensitivity when MRI is used for preoperative evaluation may come with a price: More mastectomies. Around the same time last year, there was another study that, perhaps more than any single study, drove surgeons to order more preoperative MRIs in their breast cancer patients. Indeed, it had a huge impact when it landed on the pages of the and simultaneously all over the news media. Before I discuss it, remember two terms from last time: stage migration and the Will Rogers effect. (If you don’t know what they are, go back and read part 1.) As a background, I will mention that careful evalution of the opposite breast in newly diagnosed breast cancer patients will reveal occult tumors up to 10% of the time, a statistic known for quite some time. Here’s a summary of the findings:
MRI detected clinically and mammographically occult breast cancer in the contralateral breast in 30 of 969 women who were enrolled in the study (3.1%). The sensitivity of MRI in the contralateral breast was 91%, and the specificity was 88%. The negative predictive value of MRI was 99%. A biopsy was performed on the basis of a positive MRI finding in 121 of the 969 women (12.5%), 30 of whom had specimens that were positive for cancer (24.8%); 18 of the 30 specimens were positive for invasive cancer. The mean diameter of the invasive tumors detected was 10.9 mm. The additional number of cancers detected was not influenced by breast density, menopausal status, or the histologic features of the primary tumor.
This study, as the others did, got wide play in the media at the time. Indeed, my partner at the time, whose practice is nearly 100% breast surgery, quipped during one tumor board while presenting a patient that his patient had come in the day after the results of this study had been announced and wanted bilateral MRI; so she was getting a bilateral breast MRI. Period. Such is the power of media hype of a study.
Unfortunately, this particular study told us little to help us decide whether detecting these tumors at the time of diagnosis of the main breast cancer, as opposed to later, when clinically relevant tumors would certainly show up on mammography or ultrasound, improves patient survival at all. All it says is that they can be detected. Not surprisingly, some of the media accounts featured women in which MRI found small cancers in the opposite breast telling how MRI “saved my life.” It’s possible that that might be true in some women, but we do not know what proportion or even if earlier detection in this scenario saves any women. Remember again the concepts of lead time and length biases. Indeed, for really small tumors in the other breast (particularly DCIS) that will now be detected by MRI, it is quite possible that the adjuvant chemotherapy given after surgery could well eradicate a significant percentage of them such that they never become a problem or that small foci of DCIS might never grow to cause the patient problems. We just don’t know. Finally, also remember that only 3% of breast cancer patients in this study had a tumor found in the other breast that was not apparent on mammography. That’s a pretty small number. In addition, only 18 of these (approximately 1.8%) were invasive cancer; the rest were DCIS, a precancerous lesion whose course we cannot predict and some percentage of which may never turn into cancer. So, if you boil it all down, you have to do MRI on close to 10,000 breast cancer patients to identify 18 cancers in the opposite breast in order that they can be treated simultaneously instead of sequentially.
Adding to the concern that MRIs are leading to more radical surgery, two days ago a study out of the Mayo Clinic in Rochester entitled was presented at the ASCO Meeting, and this study was suggestive that just such a negative effect on mastectomy rates may well be occurring due to preoperative MRI. I attended the session and took some notes. This was a retrospective study looking at the rates of mastectomy in women who had undergone a preoperative MRI of the breasts. By way of background to introduce the study, ever since the NIH consensus conference in 1990 that stated that long term survival rates for women undergoing mastectomy or breast-conserving surgery (lumpectomy and radiation) are equal, there has been a trend towards doing fewer mastectomies. At least there was. Over the last five years or so, however, there has been a reversal of that trend, with more women opting for mastectomy. One hypothesis is that a major contribution to this reversal is the emergence of MRI, which has been demonstrated to find up to 16% more lesions in the ipsilateral and 3% in the contralateral breast, as a preoperative imaging modality. This study was designed to look at just that question.
Basically, the investigators examined mastectomy rates for women being treated for breast cancer at the Mayo Clinic in Rochester from 1997-2006 and correlated them with pre-operative MRI. The first data shown was that there was a very nice correlation of an increasing mastectomy rate since 2003 with an increase in the use of MRI, with 2003 being the year in which the mastectomy rate was the lowest. Of course, readers of this know that correlation does not necessarily equal causation; so multivariate analyses were performed in a model adjusted for age, stage, contralateral breast cancer, and density. both MRI and surgical year were independent predictors of mastectomy, with the odds ratio of MRI being 1.7, meaning a woman who underwent an MRI was 70% more likely to undergo mastectomy. This being a retrospective study, however, there was difficulty controlling for confounders. Perhaps the most glaring one was that the mastectomy rate also increased from 2003 to 2006 in women who did not undergo preoperative MRI studies; it just didn’t increase as much. Something else is going on there. One of the questions asked was whether a surgeon with a bias toward mastectomy joined the Mayo faculty in 2003, which could partially explain the results. None had. Although it’s likely that MRI did contribute to an increased mastectomy rate in this study, there do appear to be other factors driving the trend towards mastectomy for smaller tumors as well. Speculation included better reconstructive options, patient preference for whatever reason, and increased emphasis on family history and genetic testing. Still, it is curious that, after decades worth of high quality, long term data showing that, using mammography and ultrasound alone to evaluate extent of disease within the breasts showing equivalent survival between breast-conserving therapy and mastectomy, more surgeons and women are opting for mastectomy.
MRI has other problems as well. For one thing, it’s expensive, easily costing up to $1,000 for the test. In addition, it requires the intravenous injection of a contrast agent, . It’s a safe contrast agent, but if we start doing millions of screening MRIs every year we’re going to start seeing a lot more adverse and allergic reactions to it. Finally, there is a big access problem. Although the large urban areas are almost covered, MRI is still not available everywhere, particularly in rural areas (in some rural areas, there aren’t enough mammography machines to go around). There are also not enough radiologists trained in reading breast MRI to permit any sort of mass screening of even high risk women, nor are there enough genetic counselors to identify all the women who might be at high enough risk to qualify for MRI screening. Moreover, there are not enough facilities with the capability of doing MRI-guided biopsies of lesions that aren’t visible on any other imaging study. Finally, these recommendations were made on the basis of zero data regarding whether such screening results in a decrease in mortality due to breast cancer in the population undergoing MRI. Once again, remember lead time and length bias.
I’m beginning to fear that the increase in mastectomy rates could well be an unintended consequence that is happening now as MRIs are done for most patients with breast cancer, at least in urban centers. For this discussion, remember the terms “stage migration” and overtreatment. There is little doubt that MRI will be more likely to find additional suspicious lesions in the breast with the known cancer an/or to indicate that the cancer goes further than it appears on mammography. As I asked three weeks ago (rhetorically, of course), how can this not be good thing? Four years ago, , then Chairman of the Department of Surgical Oncology at the Fox Chase Cancer Center was frighteningly prescient in an editorial in an editorial in :
Is it possible to reconcile the fact that MRI detects additional carcinoma [in the same breast] in as many as a third of patients, yet clinical outcomes for patients undergoing breast-conserving therapy on the basis of clinical and mammographic selection are excellent? At this point, some clinicians may be experiencing a sense of déjà vu. In the 1970s when the prospective randomized trials of breast conserving therapy were being initiated, pathological studies demonstrating multicentric foci of carcinoma separate from the primary tumor site in 38% to 54% of patients were used to argue that even early stage breast carcinoma was a disease of the entire breast, and treatment with less than complete mastectomy was inappropriate. Extensive clinical experience has shown that the majority of these tumor foci are controlled with breast irradiation and these deposits of microscopic cancer have largely been forgotten for the past 20 years. Now, MRI technology is capable of identifying some of these occult tumor foci. Is this an appropriate reason to start doing more mastectomies? The answer is no. Prior to adopting MRI as a routine part of the evaluation of the patient with breast cancer, there should be evidence of benefit to the patient in the form of a reduced rate of ipsilateral breast tumor recurrence. This reduction in breast recurrences will need to be weighed against the number of extra biopsies resulting from the routine use of MRI, the cost, and the delay in surgical treatment.
In the absence of trials with a clinical end point, breast cancer patients undergoing MRI should be advised that this step forward in technology may take them right back to the 1970s and result in a mastectomy for disease that can be controlled with radiation.
Exactly, or, as Dr. Seema Khan of Northwestern University :
In some cases, the additional tumors that MRI reveals might be effectively treated with more limited therapies, such as removing the initial lump followed by radiation and hormone treatment, said Dr. Seema Khan, director of the program for early detection and prevention of breast cancer at Northwestern Memorial Hospital. But once a scan uncovers additional tumors, many patients instinctively opt for a full mastectomy.
“There’s a huge question of whether we’re being led down a path of overtreatment by routinely using MRI,” said Khan, who was not part of the Mayo research team.
Everything old is new again. Alas, the older I get, the more I realize how often this is the case in medicine, with the very same issues popping up decade after decade in new guises. Black and Welch nailed it 14 years ago when they wrote:
Misperceptions of disease prevalence and therapeutic effectiveness can promote a cycle of increasing medical intervention, despite the best intentions of all parties. The cycle usually begins with some form of increased testing that lowers the threshold for detecting disease, such as technical improvement in imaging tests, more frequent testing, or closer scrutiny of the images. This immediately leads to a higher diagnostic yield of the disease and a spectrum of milder cases. These effects are almost always interpreted as indicating progress and provide immediate reinforcement for the increased testing, despite the caveat that earlier detection is a double-edged sword…Tests that are more sensitive…are accepted as better, even though they detect a broader spectrum of disease that includes a subgroup whose natural history and response to intervention are unknown. Consequently, the assessment legitimizes the use of the more sensitive imaging test and becomes a distraction from the fundamental question: How should patients with this newly detectable subclinical disease be treated?
Don’t get me wrong. I’m no Luddite; I love new gadgets and tests as much as the next doctor. Nor am I saying that MRI doesn’t have a role in breast screening or the workup of breast cancer. There is little doubt that a major cause of the decline in breast cancer mortality since the 1980’s has been the detection of breast cancer at earlier stages with mammography. It is quite possible that detecting tumors at still smaller and earlier stages with MRI could result in a modest further decrease in mortality from breast cancer, even taking into account the confounding factor of lead time bias. Moreover, there is an argument that taking care of the cancer in the opposite breast at the same time saves the patient with a synchronous contralateral cancer a second set of operations and treatments when her second tumor manifests itself clinically. It is nonetheless premature to conclude that MRI should be used in screening for any but the highest risk women or that MRI should be part of the routine battery of tests that women newly diagnosed with breast cancer undergo. It’s an expensive test (radiologists like it because they get paid a lot more for it than mammography); it’s operator-dependent and has a steep learning curve; there is no evidence that using it decreases mortality in women screened by it; and there is no evidence that its wanton use improves survival or decreases recurrence in patients with breast cancer thought to be treatable with breast conserving therapy, such as lumpectomy. Moreover, it has the real potential to result in more aggressive and disfiguring surgery for an unclear and possibly even nonexistent benefit to patients. More studies are clearly needed to determine whether MRI screening decreases mortality.
Unfortunately, in the wake of these new recommendations and studies, doing the high quality followup studies that answer the question of whether the use of MRI truly improves breast cancer care will be very difficult, and it will be very difficult for a clinician to justify not doing bilateral breast MRIs in, for example, patients with newly diagnosed cancer. Because of the medical-legal climate with respect to malpractice in this country coupled with media coverage that stokes patient demand, I reluctantly predict that it will not be long before all women (at least those with insurance, anyway) will undergo MRI screening (and a lot more biopsies as a result) and every breast cancer patient will have bilateral breast MRI upon diagnosis (and a lot more mastectomies as a result). It will take several years, if not a decade, to sort out whether this change in the standard of care for screening and for breast cancer patients actually results in improved survival and/or decreased rates of recurrence, or whether even the best technology and intentions will be thwarted again by lead time bias, length bias, and stage migration.
Back to the future we go!
1. Armstrong, K., et al. (2007). Screening Mammography in Women 40 to 49 Years of Age: A Systematic Review for the American College of Physicians. Annals of Internal Medicine, 146(7), 516-526.
2. Qaseem, A., et al. (2007). Screening Mammography for Women 40 to 49 Years of Age: A Clinical Practice Guideline from the American College of Physicians. Annals of Internal Medicine, 146(7), 511-515.
3. Saslow, D., et al. (2007). American Cancer Society Guidelines for Breast Screening with MRI as an Adjunct to Mammography. CA: A Cancer Journal for Clinicians, 57, 75-89.
4. Lehman, C.D., et al. (2007). MRI Evaluation of the Contralateral Breast in Women with Recently Diagnosed Breast Cancer. New England Journal of Medicine, 356, 1295-1303.