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Breast Magnetic Resonance Imaging As It Is, in Contrast to How We Wish It to Be Richard J. Bleicher, Fox Chase Cancer Center, Philadelphia, PA See accompanying article on page 392

There is perhaps no imaging, laboratory, or other study in modern breast care that has become more contentious or emotionally debated than breast magnetic resonance imaging (MRI). The first study on this modality in breast cancer was published 30 years ago.1 Since that time, breast MRI has had its share of supporters and detractors, and the meta-analysis2 that accompanies this editorial may unfortunately be either celebrated or reviled in various circles, depending on one’s stance or hopes for the modality. Irrespective of one’s thoughts about the promise of MRI (or lack thereof), the study’s significance lies in the fact that now, more than ever, today’s costconscious health care world dictates that we must demonstrate improved outcomes (or some other substantial benefit) to justify costs. The study by Houssami et al2 is the first meta-analysis to evaluate local and distant recurrence in individuals undergoing preoperative MRI who underwent at least an attempt at breast conservation, compared with those who did not have an MRI preoperatively. The study is an effort to consolidate and more definitively investigate a field of data3-7 that is comprised of small retrospective studies and prospective trials that have short published follow-up. Using individual patientlevel data (as opposed to pooled published data) to potentially reduce publication bias, the meta-analysis notes no improvement in local or distant recurrence associated with the modality. In short, the authors concluded that routine use of MRI preoperatively does not reduce the risk of ipsilateral local or distant recurrence and, with that in mind, MRI should not be used routinely in the preoperative setting. This study could face challenges in that the authors were unable to obtain data from all eligible studies, that not all studies evaluating MRI provide recurrence data or comparison (no MRI) cohorts, making them ineligible for analysis, and that for those studies included, there was short overall follow-up. These caveats suggest that continued evaluation of the modality remains appropriate, but considerable data on MRI to date have not shown the promise in the routine preoperative setting for which many have hoped. Although the recurrence data that are presented here may be disappointing, we must not ignore a growing body of literature that overwhelmingly reaches the same conclusion. Breast MRI, like so many other tests, has advantages for particular clinical scenarios, but not as a routine, reflexively ordered test to be used in all cancer patients preoperatively. Although this meta-analysis adds significant strength to a body of literature, several hopes for MRI in the nonhigh-risk setting had already been dashed before this publication. There has been little suggestion, even among strong routine-MRI advocates, that the modality 370

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could improve survival. This is because breast conservation therapy has long had survival equivalent to mastectomy—well before MRI was even used.8-10 Thus, the possibility that MRI could improve on lumpectomy by making survival better than that achieved via mastectomy is nearly nonexistent. Volumes of data have also found that surgical improvements in technique are not improved by MRI,11,12 and so now, with doubts cast on its ability to improve local or distant recurrence as well, the prospects for justifying the modality’s routine preoperative use in the nonhigh-risk setting have nearly disappeared. However, ultimately, when readers review the MRI meta-analysis by Houssami et al,2 they will ask themselves: do the data make sense? We have a modality that is more accurate for judging lesion size and more sensitive for detecting otherwise subclinical cancer foci, and yet MRI series demonstrate no improvement in our ability to perform breast conservation,3,5,7,11-15 and now, no ability to lower the recurrence rate. Viewed solely in that light, the data do not at first seem to make sense, but this assumes that MRI enables us to rid a significantly greater amount of disease from the breast than we could otherwise, that such disease is clinically significant and requires resection, that systemic therapy and radiotherapy add little to surgical removal, and that MRI provides a sufficiently accurate depiction of the cancer to reliably assist the surgeon. Although the idea conflicts with our instinctive fear of cancer, not all disease is clinically significant, and not all breast cancer requires resection because of our multimodal therapy paradigm. The most recent example of this in a prospective study was for the axilla in the American College of Surgeons Oncology Group Z0011 trial,16 in which 30% of patients with undissected positive nonsentinel nodes in the observation arm developed no increase in recurrence or difference in overall survival. The breast is subject to a similar effect. Before MRI was in frequent use, radiotherapy was established as critical to reduce local recurrence in breast conservation, and, initially, we could only speculate as to why. Then along came breast MRI, making multifocal and multicentric disease visible, and confirming what had been forgotten about mastectomy studies: that multiple foci exist in the breast in up to 63% of tumors,17,18 even when not visible on mammography. These foci have been treated reasonably well for decades, long before we could so easily see them with MRI, although understandably, simply knowing that cancer is present does not frighten us nearly as much as actually seeing it on film. But recurrence rates, even without the use of MRI, are now merely 2% to 4% at 5 years19 because of radiotherapy and systemic Journal of Clinical Oncology, Vol 32, No 5 (February 10), 2014: pp 370-372

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Editorial

agents. This occurs despite the fact that experimental reresection after negative margins often finds additional, previously unknown foci,20 and despite the fact that pathologists’ declarations of which oriented margins require reresection may be incorrect in up to 78% of patients.21 Systemic agents are clearly improving, and we need only look to the effects of such therapy on the contralateral breast, given that the risk of contralateral breast cancer continues to decline.22,23 If one decides to question the legitimacy of the results of the meta-analysis by Houssami et al,2 one must be sure to ask what specific MRI benefit is believed, realistically, to potentially change the recurrence rate. Although MRI is the most accurate modality we have to image the breast so far, it remains imperfect, overestimating tumor size in 11% to 70% of patients,24,25 and underestimating it in 10% to 56% of patients,24,26 while also impelling unnecessary biopsies as a result of the false positives. The only possible way that MRI could improve local recurrence would be for it to identify true-positive foci that are both occult on standard imaging and become clinically significant despite radiation and adjuvant therapy. Indeed, some foci it identifies probably are significant at the outset, but radiotherapy alone reduces the breast conservation local recurrence rate by 40%,27 and systemic and endocrine therapy add local control benefits as well. Although overall, MRI detects foci not seen with other imaging in 8.2% to 40.0% of patients, only 1.7% to 14.6% of patients are found on MRI to have foci outside of the quadrant of the primary,14 where MRI may assist less with recurrence because of wide local excision and the radiotherapy boost to the area surrounding the cavity. Some of these 1.7% to 14.6% of patients may benefit from resection, but we know little about which foci are significant and, false positives aside, the likelihood is that not all of them are significant, further lowering this number and the potential impact of MRI. In a study by the American Society of Breast Surgeons evaluating the local recurrence rates in individuals who underwent partial breast irradiation but were believed to be unsuitable for it because of the characteristics of their disease, the local recurrence rates were not increased compared with those of patients deemed optimal for partial breast irradiation.28 This underscores the fact that we have yet to accurately determine who is at high risk for recurrence and how to predict tumor behavior. What has been equally disappointing is that MRI has not been demonstrated to improve our ability to excise even the most obvious disease in the breast: the primary tumor. It does not improve our assessment of breast conservation candidacy and does not decrease negative margin rates.12 This too seems counterintuitive, given MRI’s greater sensitivity and better accuracy for lesion size. But if physical guidance via needle localization all of these years has not improved our ability to achieve negative margins,29 would a clearer image do so? Even when using bracketed needle localizations (with or without MRI) that are designed to physically guide the surgeon’s extent of resection, margins do not improve.30-33 If we have not been able to use the physical assistance of the radiologist to improve our technique, simply having a so-called clearer picture is unlikely to help. There are several reasons for this. Although MRI is sensitive, some disease is only seen on final pathologic evaluation microscopically and is too small to be seen on MRI. Breast tissue and tumors themselves34 are also malleable, and whereas mammography compresses and splays tissue in one direction, MRI positions the breast to hang dependent and uncompressed, and surgery positions the patient supine with breast flattened against the chest wall. These differences probably create sufficiently differing distances to landmarks to negate www.jco.org

the improvements in imaging clarity. MRI is also poor for some ductal carcinoma in situ,35 which is frequently at the periphery of a lesion and the cause for reexcision when MRI is performed.33 And so, in summary, MRI assists little with either the primary12 or other disease within the breast, resulting in the local recurrence results seen in this study.2 When considering all of these additional data, the results of the study by Houssami et al2 no longer seem anomalous. If the modality’s finite resolution does not help us resect tumors completely, if many true-positive MRI findings are resolved by systemic therapy and radiotherapy, and if other disease (which could theoretically be significant) is too small for even MRI to visualize, it should be of no surprise to us that MRI images, no matter how detailed and beautiful, may not improve patient outcomes. So what of the data that comprise the cohort in the study by Houssami et al?2 One could be dismissive of this meta-analysis for including studies using older MRI machines, for having radiologists who may not be so-called MRI experts, and for localizations that might have been suboptimally performed. But even if it were true that the MRIs and the techniques of the specialists using them were not perfect, these studies likely reflect the widespread reality of the technology and expertise as it has recently existed or currently exists today, presenting outcomes as they are rather than as they should be, so to speak. Even modest benefits might have justified the high cost of breast MRI36 in the nonhigh-risk, routine, preoperative setting, but we can no longer afford to use imaging where benefits are not demonstrable, despite trying over and over again. We must also at least consider that in the United States, imaging is increasingly accounting for a greater proportion of rising annual breast cancer evaluation and treatment costs.37 At this point we must acknowledge that the routine use of preoperative breast MRI has demonstrated neither surgical or outcomes benefits. Although not a prospective study, the meta-analysis by Houssami et al2 adds strength to a growing body of data that suggests that we are unlikely to ever see such improvement in outcomes by using the modality routinely in the nonhigh-risk preoperative setting. We must therefore move forward by focusing on its use for entities such as Paget’s disease, occult primaries, and in deleterious BRCA mutation carriers, where it has been demonstrated to be definitively advantageous.36,38-44 AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. REFERENCES 1. El Yousef SJ, Duchesneau RH: Magnetic resonance imaging of the human breast: A phase I trial. Radiol Clin North Am 22:859-868, 1984 2. Houssami N, Turner R, Macaskill P, et al: An individual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer recurrence. J Clin Oncol 32:392-401, 2014 3. Turnbull L, Brown S, Harvey I, et al: Comparative effectiveness of MRI in breast cancer (COMICE) trial: A randomised controlled trial. Lancet 375:563-571, 2010 4. Peters NH, van Esser S, van den Bosch MA, et al: Preoperative MRI and surgical management in patients with nonpalpable breast cancer: The MONET— Randomised controlled trial. Eur J Cancer 47:879-886, 2011 5. Solin LJ, Orel SG, Hwang WT, et al: Relationship of breast magnetic resonance imaging to outcome after breast-conservation treatment with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ. J Clin Oncol 26:386-391, 2008 6. Shin HC, Han W, Moon HG, et al: Limited value and utility of breast MRI in patients undergoing breast-conserving cancer surgery. Ann Surg Oncol 19:25722579, 2012

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7. Hwang N, Schiller DE, Crystal P, et al: Magnetic resonance imaging in the planning of initial lumpectomy for invasive breast carcinoma: Its effect on ipsilateral breast tumor recurrence after breast-conservation therapy. Ann Surg Oncol 16:3000-3009, 2009 8. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 320:822-828, 1989 9. van Dongen JA, Voogd AC, Fentiman IS, et al: Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 92:1143-1150, 2000 10. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227-1232, 2002 11. Bleicher RJ, Ciocca RM, Egleston BL, et al: Association of routine pretreatment magnetic resonance imaging with time to surgery, mastectomy rate, and margin status. J Am Coll Surg 209:180-187, 2009 12. Houssami N, Turner R, Morrow M: Preoperative magnetic resonance imaging in breast cancer: Meta-analysis of surgical outcomes. Ann Surg 257:249255, 2013 13. Peters NH, Borel Rinkes IH, Mali WP, et al: Breast MRI in nonpalpable breast lesions: A randomized trial with diagnostic and therapeutic outcome— MONET study. Trials 8:40, 2007 14. Houssami N, Hayes DF: Review of preoperative magnetic resonance imaging (MRI) in breast cancer: Should MRI be performed on all women with newly diagnosed, early stage breast cancer? CA Cancer J Clin 59:290-302, 2009 15. Houssami N, Macaskill P, Marinovich ML, et al: Meta-analysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. Eur J Cancer 46:3219-3232, 2010 16. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305:569-575, 2011 17. Sarnelli R, Squartini F: Multicentricity in breast cancer: A submacroscopic study. Pathol Annu 21:143-158, 1986 (part 1) 18. Holland R, Veling SH, Mravunac M, et al: Histologic multifocality of Tis, T1-2 breast carcinomas: Implications for clinical trials of breast-conserving surgery. Cancer 56:979-990, 1985 19. Arvold ND, Taghian AG, Niemierko A, et al: Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol 29:3885-3891, 2011 20. Neuschatz AC, DiPetrillo T, Steinhoff M, et al: The value of breast lumpectomy margin assessment as a predictor of residual tumor burden in ductal carcinoma in situ of the breast. Cancer 94:1917-1924, 2002 21. Molina MA, Snell S, Franceschi D, et al: Breast specimen orientation. Ann Surg Oncol 16:285-288, 2009 22. Nichols HB, Berrington de Gonza´lez A, Lacey JV Jr, et al: Declining incidence of contralateral breast cancer in the United States from 1975 to 2006. J Clin Oncol 29:1564-1569, 2011 23. Bernstein JL, Lapinski RH, Thakore SS, et al: The descriptive epidemiology of second primary breast cancer. Epidemiology 14:552-558, 2003 24. Boetes C, Veltman J, van Die L, et al: The role of MRI in invasive lobular carcinoma. Breast Cancer Res Treat 86:31-37, 2004 25. Behjatnia B, Sim J, Bassett LW, et al: Does size matter? Comparison study between MRI, gross, and microscopic tumor sizes in breast cancer in lumpectomy specimens. Int J Clin Exp Pathol 3:303-309, 2010 26. Onesti JK, Mangus BE, Helmer SD, et al: Breast cancer tumor size: Correlation between magnetic resonance imaging and pathology measurements. Am J Surg 196:844-850, 2008

27. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011 28. Beitsch P, Vicini F, Keisch M, et al: Five-year outcome of patients classified in the “unsuitable” category using the American Society of Therapeutic Radiology and Oncology (ASTRO) Consensus Panel guidelines for the application of accelerated partial breast irradiation: An analysis of patients treated on the American Society of Breast Surgeons MammoSite Registry trial. Ann Surg Oncol 17:219-225, 2010 (suppl 3) 29. Atkins J, Al Mushawah F, Appleton CM, et al: Positive margin rates following breast-conserving surgery for stage I-III breast cancer: Palpable versus nonpalpable tumors. J Surg Res 177:109-115, 2012 30. Cordiner CM, Litherland JC, Young IE: Does the insertion of more than one wire allow successful excision of large clusters of malignant calcification? Clin Radiol 61:686-690, 2006 31. Burkholder HC, Witherspoon LE, Burns RP, et al: Breast surgery techniques: Preoperative bracketing wire localization by surgeons. Am Surg 73:574579, 2007 32. Kirstein LJ, Rafferty E, Specht MC, et al: Outcomes of multiple wire localization for larger breast cancers: When can mastectomy be avoided? J Am Coll Surg 207:342-346, 2008 33. Wallace AM, Daniel BL, Jeffrey SS, et al: Rates of reexcision for breast cancer after magnetic resonance imaging-guided bracket wire localization. J Am Coll Surg 200:527-537, 2005 34. Itoh A, Ueno E, Tohno E, et al: Breast disease: Clinical application of US elastography for diagnosis. Radiology 239:341-350, 2006 35. Kuhl CK, Schrading S, Bieling HB, et al: MRI for diagnosis of pure ductal carcinoma in situ: A prospective observational study. Lancet 370:485-492, 2007 36. Plevritis SK, Kurian AW, Sigal BM, et al: Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging. JAMA 295:2374-2384, 2006 37. Dinan MA, Curtis LH, Hammill BG, et al: Changes in the use and costs of diagnostic imaging among Medicare beneficiaries with cancer, 1999-2006. JAMA 303:1625-1631, 2010 38. Rijnsburger AJ, Obdeijn IM, Kaas R, et al: BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: Longterm follow-up of the Dutch MRISC Screening Study. J Clin Oncol 28:5265-5273, 2010 39. Leach MO, Boggis CR, Dixon AK, et al: Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: A prospective multicentre cohort study (MARIBS). Lancet 365: 1769-1778, 2005 40. Griebsch I, Brown J, Boggis C, et al: Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs X-ray mammography of women at a high familial risk of breast cancer. Br J Cancer 95:801-810, 2006 41. Henry-Tillman RS, Harms SE, Westbrook KC, et al: Role of breast magnetic resonance imaging in determining breast as a source of unknown metastatic lymphadenopathy. Am J Surg 178:496-500, 1999 42. Buchanan CL, Morris EA, Dorn PL, et al: Utility of breast magnetic resonance imaging in patients with occult primary breast cancer. Ann Surg Oncol 12:1045-1053, 2005 43. Siponen E, Hukkinen K, Heikkila¨ P, et al: Surgical treatment in Paget’s disease of the breast. Am J Surg 200:241-246, 2010 44. Loo CE, Straver ME, Rodenhuis S, et al: Magnetic resonance imaging response monitoring of breast cancer during neoadjuvant chemotherapy: Relevance of breast cancer subtype. J Clin Oncol 29:660-666, 2011

DOI: 10.1200/JCO.2013.54.0039; published online ahead of print at www.jco.org on January 6, 2014

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JOURNAL OF CLINICAL ONCOLOGY

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Breast magnetic resonance imaging as it is, in contrast to how we wish it to be.

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