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Journal of Clinical Oncology, Vol 24, No 31 (November 1), 2006: pp. 4971-4975 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.6067 Locoregional Control of Clinically Diagnosed Multifocal or Multicentric Breast Cancer After Neoadjuvant Chemotherapy and Locoregional Therapy
From the Departments of Radiation Oncology, Surgical Oncology, Diagnostic Radiology, Pathology and Breast, Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Julia L. Oh, MD, Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcolmbe Blvd, Unit 1202, Houston, TX 77030; e-mail: joh{at}mdanderson.org
Purpose: The purpose was to assess whether patients with clinical multifocal or multicentric (MFMC) breast cancer determined by mammogram, ultrasound, or physical examination have inferior outcome compared with patients with clinical unicentric lesions. Patients and Methods: We retrospectively analyzed 706 consecutive patients with stages I-III breast cancer treated at the M.D. Anderson Cancer Center (Houston, TX) from 1976 to 2003 who received neoadjuvant anthracycline-based chemotherapy followed by breast conservation therapy (BCT), mastectomy alone, or mastectomy plus postmastectomy radiation therapy. Results: The mean follow-up was 66 months. At presentation, 97 of 706 patients had clinically MFMC disease (13.7%). The 5-year rate of locoregional failure was 10% for unicentric disease compared with 7% for MFMC disease (P = .78). Subset analyses of patients by treatment groups confirmed no statistical difference in locoregional control regardless of the type of locoregional treatment. Among patients with multifocal disease treated with BCT, there were no in-breast recurrences and one supraclavicular recurrence. Five-year disease-free survival and overall survival was equivalent between patients with MFMC and unicentric breast cancers. Conclusion: Patients with clinical MFMC breast cancer at the time of diagnosis treated with neoadjuvant chemotherapy followed by locoregional therapy have similar 5-year rates of locoregional control, disease-free survival, and overall survival as those with unicentric disease. Clinically detected MFMC disease did not predict for inferior outcome.
Clinical multifocality and multicentricity (MFMC) are frequently used descriptors in the initial assessment of the extent of disease in patients presenting with breast cancer. With the increasing use of whole breast ultrasound and magnetic resonance imaging (MRI), clinical MFMC breast cancer is more commonly diagnosed. Wilkinson and colleagues1 reported an increased diagnosis of MFMC breast cancers from 15% with mammography to 34% with the use of adjuvant bilateral ultrasound. In addition, breast MRI is reported to have superior sensitivity for diagnosing foci of MFMC breast cancer in dense breasts versus mammography.2 How the presence of clinically detectable MFMC affects locoregional treatment outcome is unclear. This question is of particular relevance for patients treated with neoadjuvant chemotherapy in that the pathological extent of disease at the time of surgery does not provide information about the original volume of disease. The purpose of this study was to compare outcome in patients with or without clinically detected MFMC breast cancer treated with neoadjuvant chemotherapy and stage appropriate locoregional therapy. We compared the locoregional control, disease-free survival, and overall survival (OS) in patients with clinically detected MFMC versus unicentric disease inclusive of all variations of local treatments, including breast conservation therapy (BCT), mastectomy alone, or mastectomy plus postmastectomy radiation therapy (PMRT). Statistical analyses comparing patients with MFMC versus unicentric tumors by each type of locoregional therapy were also performed.
We retrospectively analyzed 706 consecutive breast cancer patients with stages I to III breast cancer treated at the M.D. Anderson Cancer Center (Houston, TX) from October 1977 to June 2003 with anthracycline-based neoadjuvant chemotherapy followed by BCT, mastectomy alone, or mastectomy plus PMRT. The definitions of MFMC breast cancer used in this study were based on the classic definition of two or more separate lesions located in the same breast quadrant (multifocal) or in distinct breast quadrants (multicentric).3 Tumor classification as either MFMC or unicentric was determined on pretreatment physical examination, breast ultrasound, mammography, or a combination of the three modalities. Breast MRI was not routinely used during this time period. In order to be MFMC, two or more lesions had to have normal breast tissue between the lesions. In rare cases, if the tumor appeared bilobed with stranding between the lesions, the tumor was classified as unicentric. If the lesions straddled the 3 o'clock, 6 o'clock, 9 o'clock, or 12 o'clock lines drawn on the breast, although the distance of separation between lesions was small and both lesions were removed by a single lumpectomy, they were classified as multicentric due to the working definition of separate lesions in separate quadrants of the breast. Only the patients with pre-existing reports of MFMC disease were reviewed by a single radiologist (M.D.). From this MFMC patient group, if there was a discrepancy, the obtained imaging studies concerning whether the disease was multicentric, multifocal, or both, this single radiologist made the final determination. All patients were staged according to the updated American Joint Committee on Cancer (AJCC) sixth edition of cancer staging. Therefore, clinical MFMC breast cancer was assigned a tumor stage dictated by the maximum diameter of the largest focus.4 Pathology for each patient with MFMC disease was reviewed at the M.D. Anderson Cancer Center but pathology was not re-examined for this study. Biopsy confirmation of malignancy was typically performed on only one of the two breast lesions if the lesions shared highly malignant features on mammogram and/or ultrasound. If the second lesion was of lower suspicion radiographically, then a separate biopsy was obtained. Every effort was made to give each patient the opportunity for breast conservation therapy if desired. The neoadjuvant chemotherapy regimens were in accordance to prospective institutional trials during the study period. Each protocol was reviewed and approved by an institutional review board. For patients who were treated on prospective trials, patient entry required written informed consent. However, some of the patients were treated outside the context of a clinical trial. Nearly all patients received an anthracycline containing regimen with a median number of four cycles given before surgery. Patients received external beam radiation therapy as a component of their treatment if they had breast conserving surgery or if indicated, after a mastectomy. The indications for PMRT were T3N0M0 stage IIB, stage III disease (N2 or N3 nodal disease), or close (< 1 mm) or positive margins. In addition, a small number of patients (3.8%) who had one to three positive lymph nodes received PMRT due to sufficient additional risk factors felt to warrant PMRT for T1-2N1 disease. Typically, 50 Gy was delivered in 25 fractions to the breast or chest wall using tangential fields, followed by a 10 Gy boost to the tumor bed or chest wall scar using an appositional electron field. Patients treated with PMRT received comprehensive irradiation to the chest wall and regional nodal lymphatics including supraclavicular and internal mammary chain fields. For BCT patients, regional nodal radiation was delivered at the discretion of the radiation oncologist.
Statistical Analysis
We identified 97 of 706 patients with clinical MFMC disease. The median age was 44 years old in the MFMC group and 45 years old in the unicentric group. Fifty percent of MFMC patients had estrogen receptor positive tumors; 58% of these patients (185 of 319) received tamoxifen.  2 testing for patient and tumor characteristics between the MFMC and unicentric groups was not statistically significant for differences in patient age, tumor nuclear grade, tumor stage, lymph node stage, overall stage, or estrogen receptor status (Table 1). Ninety-seven patients (13.7%) had clinically multifocal (n = 58) or multicentric (n = 39) disease at presentation. All 97 patients with pre-existing reports of MFMC disease had mammograms and ultrasound images and reports reviewed by a single radiologist for accuracy and no patient was reclassified from MFMC to unicentric. The stage distribution among patients with unicentric lesions (n = 609) was 52% with clinical stage I to II and 48% with stage III. The group with clinically MFMC disease had 61% with clinical stage I to II and 39% with stage III (Table 1).
The mean follow-up was 66 months. At 5-years, the rate of locoregional failure among patients with MFMC disease was 7% compared with 10% in patients with clinically unicentric tumors (P = .78; Fig 1). Separate analyses of patients separated by the locoregional treatment received after neoadjuvant chemotherapy also failed to detect a statistically significant difference in the 5-year rate of locoregional control between clinically unicentric versus MFMC tumors (Figs 2, 3, and 4). After neoadjuvant chemotherapy and BCT, the 5-year rate of locoregional control in patients with solitary lesions was 89% versus 94% among patients with MFMC tumors (P = .92; Fig 2). All of the patients with MFMC disease who were treated with BCT had multifocal disease rather than multicentric disease. The rate of locoregional control in the patients treated with neoadjuvant chemotherapy and mastectomy was 84% for unicentric lesions versus 91% for MFMC lesions (P = .26; Fig 3). Patients treated with neoadjuvant chemotherapy, mastectomy plus PMRT exhibited 90% and 93% rates of locoregional control at 5-years for unicentric versus MFMC lesions, respectively (P = .78; Fig 4). Therefore, when analyzed separately or inclusive of all local therapy received, the patients with clinical MFMC lesions did not have a statistically significant difference in locoregional control compared with patients with unifocal tumors.
Locoregional control as a function of patient age was statistically significant for patients younger than 35 years of age having a higher risk of locoregional failure (Fig 5). Five-year disease-free survival was 78% for patients with unicentric tumors compared with 86% for patients with MFMC disease. This was not statistically significant (P = .16). Finally, both patient groups had equivalent OS at 5-years, 83% for patients with unicentric disease and 86% for patients with MFMC disease (online only Fig A1).
This is the first study examining the impact of clinical MFMC breast cancer on locoregional control, disease-free survival, and OS in patients treated with neoadjuvant chemotherapy followed by locoregional treatment. Previous reports have found an increased incidence of nodal involvement with pathologic MFMC breast cancers but data on clinical outcome end points has never before been reported. Pathologists Andea and colleagues5 analyzed the relationship between aggregate tumor size and lymph node status in MFMC breast cancer and reported a higher frequency of lymph node involvement compared with unifocal tumors. However, their MFMC specimens were from a different hospital than the control group of patients and no details regarding their clinical outcome were provided. A recent report published in the Journal of Clinical Oncology by Coombs and Boyages6 from the New South Wales Breast Cancer Institute examined the utility of aggregate tumor dimension rather than the diameter of the largest tumor focus to predict axillary nodal involvement in MFMC breast cancer patients. This study was limited to patients treated with breast conservation therapy and excluded any patients who received neoadjuvant chemotherapy. Among 848 patients, 94 patients with pathologically detected multifocal tumors had a higher incidence of nodal involvement, 52.1% compared with 37.5% (P = .007). The multifocal group did however have a statistically significant younger mean age of patients than the unifocal group that may have contributed to the increased incidence of involved nodes. However, similar to Andea et al, Coombs and Boyages6 expressed concern that MFMC breast cancer ought to be viewed in terms of total tumor burden and not limited to the diameter of the largest focus. Data on MFMC breast cancer as a risk factor for increased LRR after BCT or mastectomy are scant. In the National Surgical Adjuvant Breast Project, an analysis on local breast recurrences in multicentric breast cancers was performed. Fisher et al7 reported on 110 local breast recurrences in 1,108 pathologically assessable patients. Among the women treated by mastectomy for their recurrence, a 10% rate of multicentric cancers was observed. Still, the breast recurrences occurred within or close to the same quadrant as the index tumor and had significant concordance in histology and nuclear grade. In view of this observed recurrence pattern, the authors suggested that some multicentric foci of cancer may be of minimal biologic and clinical significance.7 Fowble et al compared outcome from 88 stage I to II breast cancer patients with clinically or mammographically evident gross multicentric disease or diffuse microcalcifications treated with mastectomy to 1,295 patients with unifocal clinical stage I to II breast cancer treated with breast conservation therapy. They found that multicentric tumors treated with a mastectomy did not have an increased risk of LRR compared with unifocal, stage I to II disease treated by breast conserving therapy. The 5-year actuarial rate of LRR in the study was 7% for unifocal disease versus 8% for gross multicentric disease (P = .89).8 The only indications for PMRT significant for locoregional control were four or more positive axillary nodes and close/positive margins.8 The authors concluded that clinically multicentric disease was not an independent risk factor to warrant PMRT. Our findings suggest that patients with clinical MFMC breast cancer treated with contemporary treatment comprised of neodjuvant doxorubicin-based chemotherapy and stage-appropriate locoregional therapy, regardless of locoregional therapy, do not carry an increased risk for LRR compared with patients with solitary lesions. Our data thus refute the notion of clinical MFMC breast cancer as an independent high-risk feature for LRR in patients treated with neoadjuvant chemotherapy followed by locoregional therapy. It is important to recognize however, that all of the patients in this series who were treated with BCT had clinical mutifocal rather than multicentric disease. Therefore, we cannot comment concerning the risk of local recurrence for patients treated with BCT for multicentiric disease. This report is especially but not exclusively pertinent for patients receiving neoadjuvant chemotherapy. For every patient, at the onset of treatment recommendations, it is critical to accurately assess the extent of disease, assign a clinical stage, and take into consideration any patient or tumor factors to estimate their risk and counsel individuals accordingly. The clinical presentation of MFMC lesions may influence whether or not the patient is suitable for BCT or mastectomy. In patients who undergo a mastectomy, clinical MFMC disease should not be viewed as an independent predictor of increased risk of locoregional failure. This false assumption may lead to treating patients who do not stand to benefit from the addition of PMRT. Furthermore, the decision to recommend PMRT or not has subsequent impact on the timing of breast reconstruction. Limitations of this study are its retrospective design and modest sample size when analyzed by individual locoregional therapies. Only the 97 patients with previous report of having MFMC disease were reanalyzed; therefore it is possible that the prevalence of MFMC disease in the study may be higher. However, our rate of MFMC breast cancer is consistent with that published in other studies5,6,9 so this source of error, if present, is likely small. There is also the possibility that clinically diagnosed MFMC disease was in fact unicentric because pathologic confirmation of malignancy was typically performed on only the larger of the two MFMC lesions. However, mammogram and ultrasound characteristics of malignancy were consistently described for both lesions in the radiology reports and in select cases where the radiologist felt uncertain of malignancy, a separate biopsy from the second lesion was confirmed. Our data are the first to provide evidence that clinically detected MFMC breast cancer is not an independent high-risk feature for LRR in patients treated with neoadjuvant chemotherapy followed by locoregional therapy. If a mastectomy is indicated for locoregional control, clinical MFMC disease is not an indication for adjuvant irradiation and standard guidelines for PMRT should apply. Furthermore, we did not observe any in-breast recurrences among the patients with multifocal breast cancers treated with BCT as they had equivalent locoregional control as patients with unicentric disease. We therefore do not alter our recommendations for postoperative irradiation in either the mastectomy or breast conservation setting based on clinical multicentric or multifocal disease at presentation. One should expect patients with clinical MFMC breast cancer to do equally well in terms of locoregional control, disease-free survival, and OS when compared with their unicentric cohorts.
The authors indicated no potential conflicts of interest.
Presented in part at the 47th Annual Meeting of the American Society of Therapeutic Radiology and Oncology, Denver, CO, May 14-17, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Wilkinson LS, Given-Wilson R, Hall T, et al: Increasing the diagnosis of multifocal primary breast cancer by the use of bilateral whole-breast ultrasound. Clin Radiol 60:573-578, 2005[CrossRef][Medline] 2. Sardanelli F, Giuseppetti GM, Panizza P, et al: Sensitivity of MRI versus mammography for detecting foci of multifocal, multicentric breast cancer in fatty and dense breasts using the whole-breast pathologic examination as a gold standard. AJR Am J Roentgenol 183:1149-1157, 2004 3. Holland R, Veling SH, Vravunac M, et al: Histologic multifocality of Tis, T1-2 breast carcinomas: Implications for clinical trials of breast conserving surgery. Cancer 56:979-991, 1985[CrossRef][Medline] 4. Greene FL, Page DP, Fleming ID, et al: American Joint Committee on Cancer Staging Handbook (6 ed). 2001, pp 256-281 5. Andea AA, Wallis T, Newman LA: Pathological analysis of tumor size and lymph node status in multifocal/multicentric breast cancer. Cancer 94:1383-1390, 2002[CrossRef][Medline] 6. Coombs NJ, Boyages J: Multifocal and multicentric breast cancer: Does each focus matter? J Clin Oncol 23:7497-7512, 2005 7. Fisher ER, Sass R, Fisher B, et al: Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol 6): II, Relation of local breast recurrence to multicentricity. Cancer 57:1717-1724, 1986[CrossRef][Medline] 8. Vlastos G, Rubio IT, Mirza NQ, et al: Impact of multicentricity on clinical outcome in patients with T1-2, N0-1, M0 breast cancer. Ann Surg Oncol 7:581-587, 2000[Abstract] 9. Fowble B, Yeh IT, Schultz DJ, et al: The role of mastectomy in patients with stage I-II breast cancer presenting with gross multifocal or multicentric disease or diffuse microcalcifications. Int J Radiat Oncol Biol Phys 27:567-573, 1993[Medline] Submitted May 25, 2006; accepted September 5, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.05 were considered significant. End points analyzed were LRR, disease-free survival, and OS. 
