Breast Cancer Res Treat (2014) 145:91–100 DOI 10.1007/s10549-014-2920-z
CLINICAL TRIAL
Diagnostic performance of breast-specific gamma imaging in the assessment of residual tumor after neoadjuvant chemotherapy in breast cancer patients Hyo Sang Lee • Beom Seok Ko • Sei Hyun Ahn • Byung Ho Son • Jong Won Lee • Hee Jeong Kim • Jong Han Yu • Sung-Bae Kim • Kyung Hae Jung • Jin-Hee Ahn • Joo Hee Cha • Hak Hee Kim • Hee Jin Lee • In-Hye Song • Gyungyub Gong • Seol-Hoon Park • Jong Jin Lee • Dae Hyuk Moon Received: 13 March 2014 / Accepted: 15 March 2014 / Published online: 27 March 2014 Ó Springer Science+Business Media New York 2014
Abstract To evaluate the diagnostic performance of breast-specific gamma imaging (BSGI) in the assessment of residual tumor after neoadjuvant chemotherapy (NAC) in breast cancer patients, female breast cancer patients who underwent NAC, preoperative 99mTc-sestamibi BSGI, and subsequent definitive breast surgery were enrolled retrospectively. The accuracy of BSGI in the assessment of residual tumor presence and residual tumor size was evaluated and compared to that of magnetic resonance imaging (MRI) using pathology results as the gold standard. The sensitivity and specificity of BSGI for residual tumor detection in 122 enrolled patients were 74.0 and 72.2 %, respectively, and were comparable to those of MRI (81.7 and 72.2 %; P [ 0.100). The residual tumor size was significantly underestimated by BSGI in the luminal subtype (P = 0.008) and by MRI in the luminal (P \ 0.001) and HER2 subtypes (P = 0.032), with a significantly lesser degree of underestimation by BSGI than MRI in both subtypes. In the triple-negative subtype, both BSGI and MRI generated accurate tumor size measurements. The Hyo Sang Lee and Beom Seok Ko have contributed equally to the work and are co-first authors. H. S. Lee J. J. Lee D. H. Moon (&) Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Republic of Korea e-mail: [email protected] B. S. Ko S. H. Ahn B. H. Son J. W. Lee H. J. Kim J. H. Yu Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
residual cellularity of triple-negative tumors was significantly higher than that of the non-triple-negative tumors (P = 0.017). The diagnostic performance of BSGI in the assessment of residual tumor is comparable to that of MRI in breast cancer patients. The assessment of residual tumor extent by BSGI depends on the molecular subtype, but BSGI may be more accurate than MRI. Underestimation of tumor size in the luminal and/or HER2 subtypes by BSGI and MRI may be due to low-residual cellularity. Keywords Breast-specific gamma imaging Breast cancer Magnetic resonance imaging Neoadjuvant chemotherapy Residual tumor size
Introduction Neoadjuvant chemotherapy (NAC) for breast cancer is performed to downstage the tumor, thereby rendering inoperable tumors operable and allowing breast-conserving surgery in patients who otherwise would undergo mastectomy [1]. J. H. Cha H. H. Kim Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea H. J. Lee I.-H. Song G. Gong Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea S.-H. Park Department of Nuclear Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
S.-B. Kim K. H. Jung J.-H. Ahn Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Accurate assessment of residual tumor extent after NAC using imaging modalities is important for surgical planning. Overestimation of the tumor extent may lead to unnecessary mastectomy in patients for whom breast-conserving surgery would be sufficient, and underestimation may increase the risk of positive surgical margins. Contrast-enhanced breast magnetic resonance imaging (MRI) is increasingly used for preoperative work-up after NAC. Post-NAC tumor extent assessed by MRI was reported to be more accurate than that assessed by mammography, ultrasonography, or palpation [2–5]. However, even for MRI, residual tumor extent is often significantly over- or under-estimated. Some studies suggested that this inaccuracy is related to various factors, such as chemotherapy response, chemotherapeutic agent (taxane), or molecular subtype of the tumor [6–9]. In particular, several recent papers reported that MRI accuracy varies depending on the molecular subtype of breast cancer, namely luminal, HER2, and triple-negative subtypes [7–10]. Breast-specific gamma imaging (BSGI) using 99mTcsestamibi is a relatively new nuclear medicine imaging technique for breast tumor detection. BSGI shows higher sensitivity than conventional scintimammography in the detection of small breast cancer lesions owing to its high resolution [11]. BSGI is a useful complementary tool to mammography in breast cancer diagnosis, especially in dense breasts and multifocal or multicentric disease [12– 14]; however, little is known about the ability of BSGI to detect residual tumor and predict the size of cancer after NAC. BSGI provides high-resolution multiple-angle images of the breasts, which makes a 3-dimensional assessment of the tumor size feasible. BSGI may be of value in assessing residual cancer after NAC. This study evaluated the diagnostic performance of BSGI in assessing residual tumor extent after NAC in breast cancer patients. First, the accuracy of BSGI in assessing residual tumor presence (i.e., whether pathologic complete response [pCR] was achieved or not), residual tumor size, and multifocality was evaluated using pathology results as the gold standard. Second, the performance of BSGI was compared to that of MRI. Finally, the effect of the molecular subtype of breast cancer on diagnostic performance was analyzed.
Materials and methods Study design and patients This is a single-center, retrospective study conducted to evaluate the performance of BSGI in the diagnosis of residual breast cancer after NAC. Eligibility criteria included female sex, pathologically confirmed invasive
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breast cancer, and NAC followed by definitive breast surgery. Patients who received definitive breast surgery from March 2011 to December 2012 were enrolled. BSGI was performed to assess residual disease after NAC. Exclusion criteria were previous breast implant surgery at the time of initial diagnosis and neoadjuvant endocrine treatment. Patients who did not undergo BSGI were also excluded. Follow-up of patients was conducted at Asan Medical Center. This study was approved by the Institutional Review Board of Asan Medical Center (2013-0255). Diagnosis and initial work-up were performed as described previously [15]. The NAC regimen used for breast cancer was primarily anthracycline and taxanebased depending on axillary lymph node involvement. After completion of NAC, patients underwent BSGI and dynamic contrast-enhanced breast MRI. Board-certified radiologists with subspecialty experience in breast imaging determined the location and size of residual disease (SMRI) on dynamic MRI as described previously [16]. Patients underwent either mastectomy or breast-conserving surgery with axillary lymph node dissection based on the response to NAC and patient preference. Surgeons consulted BSGI and MRI preoperatively for surgical planning. The reference was the presence and extent of residual tumor determined by pathology examination after surgery. We assessed the sensitivity and specificity of BSGI in detecting residual disease. In addition, residual tumor size and identification of multifocal disease by BSGI were evaluated. The diagnostic performance was also compared among molecular tumor subtypes, including luminal, HER2, and triple-negative disease [17]. Data were collected from consecutive patients by two breast surgeons (B.S.K and S.H.A). BSGI and image interpretation BSGI was conducted as described previously [18]. Patients were injected intravenously with 740 MBq (20 mCi) of 99m Tc-sestamibi via an upper-extremity vein on the opposite side of the malignant lesion. Ten minutes after injection, BSGI was conducted using a breast-dedicated gamma camera (Dilon 6800Ò; Dilon Technologies, Newport News, VA, USA). In each patient, craniocaudal and mediolateral oblique images of both breasts were acquired (120,000 counts or 5 min minimum). Board-certified nuclear medicine physicians (H.S.L and S.H.P) reviewed the images retrospectively. During the retrospective review, the readers were informed of the results of baseline mammography and/or ultrasonography before NAC, but were blind to the results of post-NAC imaging studies, including MRI and pathology. Discordant interpretation between readers was settled by consensus.
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First, we assessed whether there was a residual viable tumor using BSGI. From the baseline mammography, we identified the cancer location in the breast. A residual tumor on post-NAC BSGI was defined as a mild or moderate-to-intense uptake in or around the baseline cancer location that was distinct from background breast parenchymal activity [15]. Second, in cases with residual viable tumor on BSGI, we measured tumor size (SBSGI) using the size measurement function of the picture archiving and communication system of our hospital (Petavision for Diagnosis; Asan Medical Center, Seoul, Korea). The longest diameters of a tumor on craniocaudal and mediolateral oblique images were measured, and the larger diameter was selected as the tumor size. In case of multifocal breast cancer, the largest single-tumor diameter was measured. For tumor size measurement, tumor boundaries were delineated visually, and no methods of automatic delineation or uptake quantification were employed. Third, we assessed whether the residual breast cancer was multifocal. Multifocal breast cancer on BSGI was defined as two or more localized areas of increased activity clearly distinct from each other. Pathologic examination All archived hematoxylin and eosin staining were reviewed by two or more pathologists. Histologic and nuclear grades, and level of expression of estrogen receptor (ER) and progesterone receptor (PR) by immunostaining were assessed as described previously [19]. HER2/neu was determined to be positive in the case of strong (3?) membranous staining in at least 10 % of tumor cells, or in the case of 2? staining intensity with unequivocal gene amplification by silver in situ hybridization. Tumors were classified in three molecular subtypes according to their receptor status: luminal (ER? or PR?), HER2 (ER-, PR-, and HER2/ neu?), and triple-negative (ER-, PR-, and HER2/neu-). Surgical breast specimens were sectioned in 5-mm-thick slices and evaluated for the presence of macroscopic and microscopic residual tumor. The histopathologic size of the invasive carcinoma, and the size of the whole carcinoma, including the surrounding in situ component (SPATH), if any, were determined in all slices by pathologists specialized in breast pathology. The definition of pCR was the complete disappearance of the invasive and noninvasive components of the tumor [20]. Residual pathologic tumor size was defined as the longest diameter of the largest single tumor, including both invasive and noninvasive components. Non-pCR was further graded using residual tumor cellularity, which was defined as the proportion of the residual tumor bed containing invasive carcinoma [21]. The cellularity of the residual in situ disease was regarded as 0.
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Statistical analysis All statistical analyses were patient-based. Comparison of the means of continuous variables was performed using independent samples t test or paired-samples t test. Paired proportions were compared using the McNemar test. A twotailed P value \ 0.05 was considered statistically significant. Interobserver reproducibility of the determination of tumor presence or absence by BSGI was demonstrated using Cohen’s kappa statistics. Interobserver reliability of size measurement by BSGI was determined as the mean difference (bias), the standard deviation (SD) of the difference, the limit of agreement (mean ± 1.96 SD), the standard error of the mean difference, and the 95 % confidence interval (CI) of the mean difference (mean ± 1.96 standard error). Intraclass correlation coefficient was determined by the two-way random-effects model. The sensitivity of BSGI was defined as the proportion of patients with positive BSGI among those with residual viable tumor. Specificity was defined as the proportion of patients with negative BSGI among those without residual tumor. Tumor size measured by BSGI was compared to that measured by pathologic examination, which was considered as the gold standard. Bland–Altman analysis was also used to demonstrate the agreement in tumor size between imaging and pathology [22]. Correlations were assessed using Pearson’s correlation coefficient (r). All statistical analyses used MedCalc software for Windows (version 12.4.0.0; MedCalc Software, Mariakerke, Belgium).
Results Patient characteristics From March 2011 to December 2012, 122 patients were eligible for the study. During the same period, 111 patients did not undergo BSGI. All eligible patients underwent dynamic contrast-enhanced breast MRI preoperatively. The median time interval between BSGI and surgery was 8 days (range 0–40 days), and that between MRI and surgery was 13 days (range 1–43 days). The demographics and characteristics of the enrolled patients are shown in Table 1. The 111 patients who did not undergo BSGI did not significantly differ from the 122 enrolled patients in terms of clinical and tumor characteristics, including diagnostic sensitivity and specificity of MRI in the detection of residual disease (data not shown). Interobserver reliability of BSGI interpretation Overall interobserver agreement on the diagnosis of residual tumor was 95.9 % (117/122), and Cohen’s kappa
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Table 1 Patient characteristics Characteristic
Patient number (%) or mean ± SD
Age (years)
45.9 ± 9.5 (range 29–71)
Pathologic type IDC
115 (94)
Othersa
7 (6)
Clinical T stage T1
13 (11)
T2
85 (69)
T3
21 (17)
T4
3 (3)
Clinical N stage N0
35 (28)
N1
62 (51)
N2
8 (7)
N3
17 (14)
NAC regimen AC
37 (30)
AC ? T
78 (64)
Others
7 (6)
Type of surgery Breast-conserving surgery
78 (64)
Mastectomy
44 (36)
statistics for interobserver reproducibility was 0.908. The mean difference and limits of agreement between the size measurements were 1.0 mm (95 % CI -0.5 to 2.5 mm) and -13.8 to 15.8 mm, respectively. The intraclass correlation coefficient was 0.822. Detection of residual tumor Of the 122 patients, residual viable tumor was pathologically proven in 104 patients (85.2 %). Among them, 11 patients had in situ residuals only. Six of 66 patients (9.1 %) with the luminal subtype, two of 22 (9.1 %) with the HER2 subtype and ten of 34 (29.4 %) with the triplenegative subtype achieved pCR. The sensitivity of BSGI and MRI in detecting residual tumor is summarized in Table 2. The sensitivity of BSGI in detecting residual tumor was 74.0 % (77/104). Of 77 patients with residual disease by BSGI, 49 had moderate-to-intense uptake, and 28 showed mild uptake. The specificity of BSGI was 72.2 % (13/18). All five false-positive cases had mild uptake. The absence of increased uptake by BSGI predicted pCR in only 32.5 % (13/40) of patients. Mild and moderate-to-intense uptake predicted residual disease in 84.8 % (28/33) and 100 % (49/49) of patients, respectively. The
Surgical margin Positive
4 (3)
Negative
118 (97)
Table 2 Sensitivity of BSGI and MRI in detecting residual tumor after NAC N
Histologic grade I
3 (2)
II
74 (61)
III
45 (37)
Sensitivity (%) BSGI
MRI
Pa
Residual cellularity
Nuclear grade
0%
11
27.2 (3/11)
54.5 (6/11)
0.375
1–10 %
26
61.5 (16/26)
53.8 (14/26)
0.754
I
4 (3)
II
73 (60)
11–40 %
37
89.2 (33/37)
100.0 (37/37)
0.125
III
45 (37)
[40 %
30
83.3 (25/30)
93.3 (28/30)
0.250
(\0.001)
(\0.001)
52.8 (19/36)
63.9 (23/36)
(P for v2 test for trend)
Estrogen receptor
Residual tumor size
Positive
65 (53)
Negative
57 (47)
1–15 mm 16–40 mm
46
84.8 (39/46)
93.5 (43/46)
0.219
Positive
49 (40)
[40 mm
22
86.4 (19/22)
86.4 (19/22)
1.000
Negative
73 (60)
(0.002)
(0.010)
Progesterone receptor
HER2/neu
36
(P for v2 test for trend) Molecular subtype
0.344
Positive
38 (31)
Luminal
60
73.3 (44/60)
81.7 (49/60)
0.302
Negative
84 (69)
HER2
20
85.0 (17/20)
75.0 (15/20)
0.500
Triple-negative
24
66.7 (16/24)
87.5 (21/24)
0.063
(0.135)
(0.104)
Molecular subtype Luminal
66 (54)
HER2
22 (18)
Triple-negative
34 (28)
Total
Invasive mammary carcinoma (n = 5), mucinous carcinoma (n = 1), and metaplastic carcinoma (n = 1)
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Invasiveness
122 (100)
SD standard deviation, IDC invasive ductal carcinoma, NAC neoadjuvant chemotherapy, AC anthracycline plus cyclophosphamide, T taxane a
(P for v2 test) Invasive residual
93
79.6 (74/93)
84.9 (79/93)
0.332
In situ residual
11
27.3 (3/11)
54.5 (6/11)
0.375
(\0.001)
(0.040)
74.0 (77/104)
81.7 (85/104)
2
(P for v test) Total a
McNemar test
104
0.134
Breast Cancer Res Treat (2014) 145:91–100 Table 3 Tumor sizes measured by imaging studies and pathology
Subgroup
Luminal
95
N
60
Pa
Tumor size (mean ± SEM) (mm) Pathology*
MRI
BSGIà
32.1 ± 2.9
19.1 ± 2.0
25.2 ± 2.6
* vs. : \0.001 * vs. à: 0.008
HER2
20
29.7 ± 4.7
18.3 ± 4.0
26.7 ± 4.4
* vs. : 0.032 * vs. à: 0.408
Triple-negative
24
18.4 ± 3.0
18.7 ± 3.6
17.1 ± 3.7
* vs. : 0.882 * vs. à: 0.592
SEM standard error of the mean a
Total
104
28.5 ± 2.1
P value for paired-samples t test
specificity of BSGI and MRI was 72.2 % (13/18). The sensitivity and specificity of MRI were not significantly different from those of BSGI (P = 0.134 and 1.000, respectively). The detection sensitivity of BSGI was significantly associated with the residual tumor cellularity and size as shown in Table 2. Sensitivity was also lower in patients with ductal carcinoma in situ. The detection sensitivity was only 51.4 % (19/37) for tumors with cellularity B10 %, whereas it was 86.6 % (58/67) for tumors with cellularity [10 %. The sensitivity was only 52.8 % (19/36) for residual tumor sizes B15 mm, whereas it was 85.3 % (58/68) for tumor sizes [15 mm. All ten false-negative cases out of the 68 tumors with size [15 mm showed lowresidual tumor cellularity (seven cases with cellularity B10 %, two cases with cellularity = 20 %, and one case with cellularity = 30 %). Of these false-negative cases, eight were detected by MRI. A similar association of detection sensitivity with residual tumor cellularity and residual tumor size was found for MRI (Table 2). Of six false-negative cases by MRI with sizes[15 mm, four cases were detected by BSGI.
18.8 ± 1.6
23.6 ± 1.9
* vs. : \0.001 * vs. à: 0.005
(P \ 0.001). The degree of underestimation was smaller for BSGI (P = 0.002). The size of the luminal tumors was underestimated by both SBSGI and SMRI (Fig. 2). In HER2 tumors, only SMRI significantly underestimated the tumor size (Fig. 3). The underestimation by SBSGI was less than that by SMRI in the luminal (P = 0.004) and HER2 subtypes (P = 0.042). In the triple-negative subtype, both SBSGI and SMRI generated the most accurate tumor size measurements (Fig. 4). To assess the contributing factor(s) of this subtype dependence of accuracy, residual tumor cellularity was consulted. The residual cellularity of the triple-negative tumors (39.0 ± 27.3 %) was significantly higher than that of the nontriple-negative tumors (25.3 ± 23.2 %; P = 0.017). Moreover, in the luminal or HER2 subtypes, largest residual tumors often showed lower residual cellularity; this tendency was not observed in the triple-negative subtype (Fig. 5). In patients with tumor sizes [40 mm, 14 (88 %) of 16 luminal tumors and four (80 %) of five HER2 tumors had residual cellularity \40 %. There was one triple-negative tumor with size [40 mm, the cellularity of which was 60 % (Fig. 5). Assessment of multifocal or multicentric disease
Estimation of residual tumor size Among the 104 patients with residual viable tumor, SBSGI and SMRI were concordant within 1 cm from SPATH in 66.3 % (69/104) and 67.3 % (70/104), respectively (P = 1.000). SPATH was overestimated by more than 1 cm in 8.7 % of the cases (9/104) for BSGI and in 2.9 % (3/ 104) for MRI (P = 0.137), and underestimated by more than 1 cm in 25.0 % (26/104) of the cases for BSGI and 29.8 % (31/104) for MRI (P = 0.534). The mean and standard error of SPATH, SBSGI, and SMRI for the 104 patients are listed in Table 3. Figure 1 shows the mean differences and the limits of agreement between tumor sizes measured by imaging studies and SPATH in the entire population and in subgroups. SPATH was significantly underestimated by both SBSGI (P = 0.005) and SMRI
Among the 104 patients with residual viable tumor, multifocal tumors were pathologically proven in 28.8 % of them (30/104). Among these 30 patients, BSGI and MRI correctly identified tumor multifocality in 46.7 % (14/30) and 66.7 % (20/30), respectively (P = 0.070). Among the 74 patients with unifocal tumor, BSGI and MRI correctly reported tumor unifocality in 98.6 % (73/74) and 93.2 % (69/74), respectively (P = 0.211).
Discussion This study evaluated the diagnostic performance of BSGI in the detection of residual tumor after NAC in breast cancer patients. The sensitivity and specificity of BSGI for
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b Fig. 1 Bland–Altman plots of the agreement between the tumor sizes
measured by BSGI (SBSGI) and pathology (SPATH) and between those measured by MRI (SMRI) and SPATH in the entire population (a, b), in the luminal subtype (c, d), in the HER2 subtype (e, f), and in the triple-negative subtype (g, h)
Fig. 4 A 32-year-old patient with a triple-negative breast tumor. Post-neoadjuvant BSGI showed an intense tumor uptake in the left outer breast (left panel). The size of the tumor uptake was measured as 2.6 cm. By MRI, the tumor size was measured as 3.0 cm (right panel). Surgical pathology revealed a 2.4 cm viable tumor
Fig. 2 A 43-year-old patient with a luminal breast tumor. Postneoadjuvant BSGI showed a tumor uptake in the right outer breast (left panel; black arrow). The size of the tumor uptake was measured as 4.7 cm. By MRI, the tumor size was measured as 1.1 cm (right panel; white arrow). Surgical pathology revealed a 6.0 cm viable tumor
Fig. 3 A 58-year-old patient with a HER2 breast tumor. Postneoadjuvant BSGI showed a mild tumor uptake in the right inner breast (left panel; black arrow). The size of the tumor uptake was measured as 5.2 cm. By MRI (right panel), there was no early enhancement, and the tumor was assessed as completely regressed. Surgical pathology revealed a 6.6 cm viable tumor
residual tumor detection were comparable to those of MRI. The sensitivity of BSGI was dependent on residual tumor cellularity and residual tumor size. BSGI accurately estimated tumor size in the HER2 and triple-negative subtypes, but significantly underestimated tumor size in the luminal subtype; however, the underestimation was smaller than that of MRI. Underestimation of tumor size in the luminal
and/or HER2 subtypes by BSGI and MRI may be due to low-residual cellularity. The detection of multifocal disease by BSGI was also comparable to that of MRI. Our results suggest the potential diagnostic value of BSGI after NAC in patients with breast cancer. Overall, we found BSGI to have a good diagnostic performance in detecting residual disease; however, the sensitivity of BSGI was not perfect even in patients with tumors[15 mm. The absence of increased uptake by BSGI was not necessarily predictive of pCR. The suboptimal sensitivity and low-predictive value of pCR in the present study are most likely associated with low cellularity after NAC. Residual tumors with low cellularity would be missed by BSGI because the tumor uptake of 99mTc-sestamibi is not sufficiently high to be distinguished from background parenchymal uptake. In this study, we regarded mild uptake (or higher) in the known cancer location as residual viable tumor. In the setting of initial diagnosis of breast cancer, mild uptake due to heterogeneous glandular activity is frequently seen, and many false-positives would be generated if we count mild uptake as cancer. This heterogeneous glandular activity is often associated with the menstrual cycle [23, 24]; however, heterogeneous glandular uptake was seldom observed in our study, probably because menstruation ceases after the beginning of NAC. We believe that it is justified to regard mild uptake in the baseline cancer location as residual cancer. Our findings suggest that interpretation of pCR by BSGI may need to be conservative. From the surgical point of view, the proportion of cases with small size discrepancies (for example, discrepancy \1 cm) between imaging studies and pathology results is important. In this study, BSGI showed a tendency toward underestimation of the residual tumor size. As in MRI
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Fig. 5 Scatter diagrams showing the distribution of the residual tumor cellularity and the residual tumor size in all patients with the luminal (a), HER2 (b), and triple-negative subtypes (c)
studies [7–10], BSGI was more likely to underestimate residual tumor size in luminal tumors than in HER2 or triple-negative tumors. MRI underestimated residual tumor size in both the luminal and HER2 subtypes with less underestimation by BSGI in both groups in this study. Invasive breast cancers often show heterogeneous responses to NAC. Good chemotherapeutic response, shown by a large reduction in cellularity, does not always imply a large reduction in tumor size [25]. Large residual tumors with scattered cancer cells sometimes occur [6, 26]. We suggest that the luminal and HER2 subtypes are predisposing factors for the occurrence of large residual tumors with low cellularity (Fig. 5). The biologic mechanism underlying this observation is not clear. The observation might be partially explained by the fact that patients with luminal or HER2 tumors are likely to have larger residual disease, as shown in this study; however, this does not explain why the luminal or HER2 subtypes have a tendency to form larger residual tumors with low cellularity. The accuracy of the tumor size measurements by MRI, which is significantly dependent on the biological tumor subtype, may be consistent with previous studies although some controversies still remain about the HER2 subtype [7–10]. The biologic mechanism explaining MRI accuracy has not yet been demonstrated; however, it was suggested that residual disease that presented as scattered cells or small foci made MRI diagnosis difficult, and these lesions were missed by MRI because of the lack of enhancement [8].
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The similar molecular subtype dependence of residual tumor measurements by BSGI and MRI suggests that there may be a common mechanism. Dynamic contrast-enhanced breast MRI visualizes tissue changes caused by tumor cells, i.e., neoangiogenic vascular changes [27]. 99mTc-sestamibi uptake also depends on the delivery of the tracer to the tumor via blood vessels in addition to cellular uptake mechanisms [28]. The underlying mechanism, therefore, may be higher capillary permeability in triple-negative breast cancer [25, 29]. Further detailed studies must be conducted to elucidate the underlying mechanism. Importantly, in the luminal and HER2 subtypes, the underestimation by BSGI was smaller in magnitude than that of MRI. Tumoral uptake of 99mTc-sestamibi, despite limited blood supply, may explain the difference. Mechanistic studies are required. Multifocality is an important attribute relevant to the decision of surgical extent. In this study, BSGI showed relatively poor sensitivity (46.7 %) in assessing multifocality. Since BSGI is not a multislice cross-sectional imaging modality, overlapping multifocal tumor uptakes are often not distinct from each other, which may give a false impression of unifocal cancer [30]. Although the sensitivity was low, the specificity was high (98.6 %). This high specificity resulted in a high-positive predictive value (93.3 %) in this population, meaning that multifocal tumor uptakes by post-NAC BSGI represent true multifocal residual tumors in most cases. This finding could be helpful for surgical decision-making.
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Our study has some limitations. First, the retrospective study design introduces the risk of selection bias. There were 111 patients who met the inclusion criteria but did not undergo BSGI in the study period; however, since the characteristics of these 111 patients were not significantly different from those of the 122 patients included in the study, potential selection bias would not have significantly affected the main result. Second, there may be some subjectivity between observers in delineating tumor boundaries. However, we think that the subjectivity is tolerable because good inter-observer reproducibility was demonstrated by the high-intraclass correlation coefficient (0.822) between the observers. Third, we could not analyze the impact of BSGI on surgical decision-making. The surgeons consulted both BSGI and MRI before surgery, but we could not separate the contributions of BSGI from those of MRI. It is unclear how the use of BSGI affected the success of breast conservation, the re-excision rate, and the overall margin status. Further studies are necessary to assess the success of breast conservation in relation to the BSGIestimated tumor size and molecular subtype. Finally, most patients with the HER2 subtype were not treated with trastuzumab in the regimen. It is possible that the accuracy of BSGI would be different after treatment with HER2targeted agents.
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Conclusion The diagnostic performance of BSGI in the assessment of residual tumor after NAC in breast cancer patients is comparable to that of MRI. In the assessment of residual tumor extent, BSGI is dependent on molecular tumor subtypes, but may be more accurate than MRI in the luminal and HER2 subtypes. Our results suggest the potential diagnostic value of BSGI after NAC in patients with breast cancer. This result may serve as a reference for a prospective study designed to evaluate the impact of BSGI on surgical decision-making. Acknowledgments This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI06C0868). Conflict of interest of interest.
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The authors declare that they have no conflict
Ethical standards Experiments performed in this study comply with the current laws of the Republic of Korea.
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CLINICAL TRIAL
Diagnostic performance of breast-specific gamma imaging in the assessment of residual tumor after neoadjuvant chemotherapy in breast cancer patients Hyo Sang Lee • Beom Seok Ko • Sei Hyun Ahn • Byung Ho Son • Jong Won Lee • Hee Jeong Kim • Jong Han Yu • Sung-Bae Kim • Kyung Hae Jung • Jin-Hee Ahn • Joo Hee Cha • Hak Hee Kim • Hee Jin Lee • In-Hye Song • Gyungyub Gong • Seol-Hoon Park • Jong Jin Lee • Dae Hyuk Moon Received: 13 March 2014 / Accepted: 15 March 2014 / Published online: 27 March 2014 Ó Springer Science+Business Media New York 2014
Abstract To evaluate the diagnostic performance of breast-specific gamma imaging (BSGI) in the assessment of residual tumor after neoadjuvant chemotherapy (NAC) in breast cancer patients, female breast cancer patients who underwent NAC, preoperative 99mTc-sestamibi BSGI, and subsequent definitive breast surgery were enrolled retrospectively. The accuracy of BSGI in the assessment of residual tumor presence and residual tumor size was evaluated and compared to that of magnetic resonance imaging (MRI) using pathology results as the gold standard. The sensitivity and specificity of BSGI for residual tumor detection in 122 enrolled patients were 74.0 and 72.2 %, respectively, and were comparable to those of MRI (81.7 and 72.2 %; P [ 0.100). The residual tumor size was significantly underestimated by BSGI in the luminal subtype (P = 0.008) and by MRI in the luminal (P \ 0.001) and HER2 subtypes (P = 0.032), with a significantly lesser degree of underestimation by BSGI than MRI in both subtypes. In the triple-negative subtype, both BSGI and MRI generated accurate tumor size measurements. The Hyo Sang Lee and Beom Seok Ko have contributed equally to the work and are co-first authors. H. S. Lee J. J. Lee D. H. Moon (&) Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Republic of Korea e-mail: [email protected] B. S. Ko S. H. Ahn B. H. Son J. W. Lee H. J. Kim J. H. Yu Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
residual cellularity of triple-negative tumors was significantly higher than that of the non-triple-negative tumors (P = 0.017). The diagnostic performance of BSGI in the assessment of residual tumor is comparable to that of MRI in breast cancer patients. The assessment of residual tumor extent by BSGI depends on the molecular subtype, but BSGI may be more accurate than MRI. Underestimation of tumor size in the luminal and/or HER2 subtypes by BSGI and MRI may be due to low-residual cellularity. Keywords Breast-specific gamma imaging Breast cancer Magnetic resonance imaging Neoadjuvant chemotherapy Residual tumor size
Introduction Neoadjuvant chemotherapy (NAC) for breast cancer is performed to downstage the tumor, thereby rendering inoperable tumors operable and allowing breast-conserving surgery in patients who otherwise would undergo mastectomy [1]. J. H. Cha H. H. Kim Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea H. J. Lee I.-H. Song G. Gong Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea S.-H. Park Department of Nuclear Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
S.-B. Kim K. H. Jung J.-H. Ahn Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Accurate assessment of residual tumor extent after NAC using imaging modalities is important for surgical planning. Overestimation of the tumor extent may lead to unnecessary mastectomy in patients for whom breast-conserving surgery would be sufficient, and underestimation may increase the risk of positive surgical margins. Contrast-enhanced breast magnetic resonance imaging (MRI) is increasingly used for preoperative work-up after NAC. Post-NAC tumor extent assessed by MRI was reported to be more accurate than that assessed by mammography, ultrasonography, or palpation [2–5]. However, even for MRI, residual tumor extent is often significantly over- or under-estimated. Some studies suggested that this inaccuracy is related to various factors, such as chemotherapy response, chemotherapeutic agent (taxane), or molecular subtype of the tumor [6–9]. In particular, several recent papers reported that MRI accuracy varies depending on the molecular subtype of breast cancer, namely luminal, HER2, and triple-negative subtypes [7–10]. Breast-specific gamma imaging (BSGI) using 99mTcsestamibi is a relatively new nuclear medicine imaging technique for breast tumor detection. BSGI shows higher sensitivity than conventional scintimammography in the detection of small breast cancer lesions owing to its high resolution [11]. BSGI is a useful complementary tool to mammography in breast cancer diagnosis, especially in dense breasts and multifocal or multicentric disease [12– 14]; however, little is known about the ability of BSGI to detect residual tumor and predict the size of cancer after NAC. BSGI provides high-resolution multiple-angle images of the breasts, which makes a 3-dimensional assessment of the tumor size feasible. BSGI may be of value in assessing residual cancer after NAC. This study evaluated the diagnostic performance of BSGI in assessing residual tumor extent after NAC in breast cancer patients. First, the accuracy of BSGI in assessing residual tumor presence (i.e., whether pathologic complete response [pCR] was achieved or not), residual tumor size, and multifocality was evaluated using pathology results as the gold standard. Second, the performance of BSGI was compared to that of MRI. Finally, the effect of the molecular subtype of breast cancer on diagnostic performance was analyzed.
Materials and methods Study design and patients This is a single-center, retrospective study conducted to evaluate the performance of BSGI in the diagnosis of residual breast cancer after NAC. Eligibility criteria included female sex, pathologically confirmed invasive
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breast cancer, and NAC followed by definitive breast surgery. Patients who received definitive breast surgery from March 2011 to December 2012 were enrolled. BSGI was performed to assess residual disease after NAC. Exclusion criteria were previous breast implant surgery at the time of initial diagnosis and neoadjuvant endocrine treatment. Patients who did not undergo BSGI were also excluded. Follow-up of patients was conducted at Asan Medical Center. This study was approved by the Institutional Review Board of Asan Medical Center (2013-0255). Diagnosis and initial work-up were performed as described previously [15]. The NAC regimen used for breast cancer was primarily anthracycline and taxanebased depending on axillary lymph node involvement. After completion of NAC, patients underwent BSGI and dynamic contrast-enhanced breast MRI. Board-certified radiologists with subspecialty experience in breast imaging determined the location and size of residual disease (SMRI) on dynamic MRI as described previously [16]. Patients underwent either mastectomy or breast-conserving surgery with axillary lymph node dissection based on the response to NAC and patient preference. Surgeons consulted BSGI and MRI preoperatively for surgical planning. The reference was the presence and extent of residual tumor determined by pathology examination after surgery. We assessed the sensitivity and specificity of BSGI in detecting residual disease. In addition, residual tumor size and identification of multifocal disease by BSGI were evaluated. The diagnostic performance was also compared among molecular tumor subtypes, including luminal, HER2, and triple-negative disease [17]. Data were collected from consecutive patients by two breast surgeons (B.S.K and S.H.A). BSGI and image interpretation BSGI was conducted as described previously [18]. Patients were injected intravenously with 740 MBq (20 mCi) of 99m Tc-sestamibi via an upper-extremity vein on the opposite side of the malignant lesion. Ten minutes after injection, BSGI was conducted using a breast-dedicated gamma camera (Dilon 6800Ò; Dilon Technologies, Newport News, VA, USA). In each patient, craniocaudal and mediolateral oblique images of both breasts were acquired (120,000 counts or 5 min minimum). Board-certified nuclear medicine physicians (H.S.L and S.H.P) reviewed the images retrospectively. During the retrospective review, the readers were informed of the results of baseline mammography and/or ultrasonography before NAC, but were blind to the results of post-NAC imaging studies, including MRI and pathology. Discordant interpretation between readers was settled by consensus.
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First, we assessed whether there was a residual viable tumor using BSGI. From the baseline mammography, we identified the cancer location in the breast. A residual tumor on post-NAC BSGI was defined as a mild or moderate-to-intense uptake in or around the baseline cancer location that was distinct from background breast parenchymal activity [15]. Second, in cases with residual viable tumor on BSGI, we measured tumor size (SBSGI) using the size measurement function of the picture archiving and communication system of our hospital (Petavision for Diagnosis; Asan Medical Center, Seoul, Korea). The longest diameters of a tumor on craniocaudal and mediolateral oblique images were measured, and the larger diameter was selected as the tumor size. In case of multifocal breast cancer, the largest single-tumor diameter was measured. For tumor size measurement, tumor boundaries were delineated visually, and no methods of automatic delineation or uptake quantification were employed. Third, we assessed whether the residual breast cancer was multifocal. Multifocal breast cancer on BSGI was defined as two or more localized areas of increased activity clearly distinct from each other. Pathologic examination All archived hematoxylin and eosin staining were reviewed by two or more pathologists. Histologic and nuclear grades, and level of expression of estrogen receptor (ER) and progesterone receptor (PR) by immunostaining were assessed as described previously [19]. HER2/neu was determined to be positive in the case of strong (3?) membranous staining in at least 10 % of tumor cells, or in the case of 2? staining intensity with unequivocal gene amplification by silver in situ hybridization. Tumors were classified in three molecular subtypes according to their receptor status: luminal (ER? or PR?), HER2 (ER-, PR-, and HER2/ neu?), and triple-negative (ER-, PR-, and HER2/neu-). Surgical breast specimens were sectioned in 5-mm-thick slices and evaluated for the presence of macroscopic and microscopic residual tumor. The histopathologic size of the invasive carcinoma, and the size of the whole carcinoma, including the surrounding in situ component (SPATH), if any, were determined in all slices by pathologists specialized in breast pathology. The definition of pCR was the complete disappearance of the invasive and noninvasive components of the tumor [20]. Residual pathologic tumor size was defined as the longest diameter of the largest single tumor, including both invasive and noninvasive components. Non-pCR was further graded using residual tumor cellularity, which was defined as the proportion of the residual tumor bed containing invasive carcinoma [21]. The cellularity of the residual in situ disease was regarded as 0.
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Statistical analysis All statistical analyses were patient-based. Comparison of the means of continuous variables was performed using independent samples t test or paired-samples t test. Paired proportions were compared using the McNemar test. A twotailed P value \ 0.05 was considered statistically significant. Interobserver reproducibility of the determination of tumor presence or absence by BSGI was demonstrated using Cohen’s kappa statistics. Interobserver reliability of size measurement by BSGI was determined as the mean difference (bias), the standard deviation (SD) of the difference, the limit of agreement (mean ± 1.96 SD), the standard error of the mean difference, and the 95 % confidence interval (CI) of the mean difference (mean ± 1.96 standard error). Intraclass correlation coefficient was determined by the two-way random-effects model. The sensitivity of BSGI was defined as the proportion of patients with positive BSGI among those with residual viable tumor. Specificity was defined as the proportion of patients with negative BSGI among those without residual tumor. Tumor size measured by BSGI was compared to that measured by pathologic examination, which was considered as the gold standard. Bland–Altman analysis was also used to demonstrate the agreement in tumor size between imaging and pathology [22]. Correlations were assessed using Pearson’s correlation coefficient (r). All statistical analyses used MedCalc software for Windows (version 12.4.0.0; MedCalc Software, Mariakerke, Belgium).
Results Patient characteristics From March 2011 to December 2012, 122 patients were eligible for the study. During the same period, 111 patients did not undergo BSGI. All eligible patients underwent dynamic contrast-enhanced breast MRI preoperatively. The median time interval between BSGI and surgery was 8 days (range 0–40 days), and that between MRI and surgery was 13 days (range 1–43 days). The demographics and characteristics of the enrolled patients are shown in Table 1. The 111 patients who did not undergo BSGI did not significantly differ from the 122 enrolled patients in terms of clinical and tumor characteristics, including diagnostic sensitivity and specificity of MRI in the detection of residual disease (data not shown). Interobserver reliability of BSGI interpretation Overall interobserver agreement on the diagnosis of residual tumor was 95.9 % (117/122), and Cohen’s kappa
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Table 1 Patient characteristics Characteristic
Patient number (%) or mean ± SD
Age (years)
45.9 ± 9.5 (range 29–71)
Pathologic type IDC
115 (94)
Othersa
7 (6)
Clinical T stage T1
13 (11)
T2
85 (69)
T3
21 (17)
T4
3 (3)
Clinical N stage N0
35 (28)
N1
62 (51)
N2
8 (7)
N3
17 (14)
NAC regimen AC
37 (30)
AC ? T
78 (64)
Others
7 (6)
Type of surgery Breast-conserving surgery
78 (64)
Mastectomy
44 (36)
statistics for interobserver reproducibility was 0.908. The mean difference and limits of agreement between the size measurements were 1.0 mm (95 % CI -0.5 to 2.5 mm) and -13.8 to 15.8 mm, respectively. The intraclass correlation coefficient was 0.822. Detection of residual tumor Of the 122 patients, residual viable tumor was pathologically proven in 104 patients (85.2 %). Among them, 11 patients had in situ residuals only. Six of 66 patients (9.1 %) with the luminal subtype, two of 22 (9.1 %) with the HER2 subtype and ten of 34 (29.4 %) with the triplenegative subtype achieved pCR. The sensitivity of BSGI and MRI in detecting residual tumor is summarized in Table 2. The sensitivity of BSGI in detecting residual tumor was 74.0 % (77/104). Of 77 patients with residual disease by BSGI, 49 had moderate-to-intense uptake, and 28 showed mild uptake. The specificity of BSGI was 72.2 % (13/18). All five false-positive cases had mild uptake. The absence of increased uptake by BSGI predicted pCR in only 32.5 % (13/40) of patients. Mild and moderate-to-intense uptake predicted residual disease in 84.8 % (28/33) and 100 % (49/49) of patients, respectively. The
Surgical margin Positive
4 (3)
Negative
118 (97)
Table 2 Sensitivity of BSGI and MRI in detecting residual tumor after NAC N
Histologic grade I
3 (2)
II
74 (61)
III
45 (37)
Sensitivity (%) BSGI
MRI
Pa
Residual cellularity
Nuclear grade
0%
11
27.2 (3/11)
54.5 (6/11)
0.375
1–10 %
26
61.5 (16/26)
53.8 (14/26)
0.754
I
4 (3)
II
73 (60)
11–40 %
37
89.2 (33/37)
100.0 (37/37)
0.125
III
45 (37)
[40 %
30
83.3 (25/30)
93.3 (28/30)
0.250
(\0.001)
(\0.001)
52.8 (19/36)
63.9 (23/36)
(P for v2 test for trend)
Estrogen receptor
Residual tumor size
Positive
65 (53)
Negative
57 (47)
1–15 mm 16–40 mm
46
84.8 (39/46)
93.5 (43/46)
0.219
Positive
49 (40)
[40 mm
22
86.4 (19/22)
86.4 (19/22)
1.000
Negative
73 (60)
(0.002)
(0.010)
Progesterone receptor
HER2/neu
36
(P for v2 test for trend) Molecular subtype
0.344
Positive
38 (31)
Luminal
60
73.3 (44/60)
81.7 (49/60)
0.302
Negative
84 (69)
HER2
20
85.0 (17/20)
75.0 (15/20)
0.500
Triple-negative
24
66.7 (16/24)
87.5 (21/24)
0.063
(0.135)
(0.104)
Molecular subtype Luminal
66 (54)
HER2
22 (18)
Triple-negative
34 (28)
Total
Invasive mammary carcinoma (n = 5), mucinous carcinoma (n = 1), and metaplastic carcinoma (n = 1)
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Invasiveness
122 (100)
SD standard deviation, IDC invasive ductal carcinoma, NAC neoadjuvant chemotherapy, AC anthracycline plus cyclophosphamide, T taxane a
(P for v2 test) Invasive residual
93
79.6 (74/93)
84.9 (79/93)
0.332
In situ residual
11
27.3 (3/11)
54.5 (6/11)
0.375
(\0.001)
(0.040)
74.0 (77/104)
81.7 (85/104)
2
(P for v test) Total a
McNemar test
104
0.134
Breast Cancer Res Treat (2014) 145:91–100 Table 3 Tumor sizes measured by imaging studies and pathology
Subgroup
Luminal
95
N
60
Pa
Tumor size (mean ± SEM) (mm) Pathology*
MRI
BSGIà
32.1 ± 2.9
19.1 ± 2.0
25.2 ± 2.6
* vs. : \0.001 * vs. à: 0.008
HER2
20
29.7 ± 4.7
18.3 ± 4.0
26.7 ± 4.4
* vs. : 0.032 * vs. à: 0.408
Triple-negative
24
18.4 ± 3.0
18.7 ± 3.6
17.1 ± 3.7
* vs. : 0.882 * vs. à: 0.592
SEM standard error of the mean a
Total
104
28.5 ± 2.1
P value for paired-samples t test
specificity of BSGI and MRI was 72.2 % (13/18). The sensitivity and specificity of MRI were not significantly different from those of BSGI (P = 0.134 and 1.000, respectively). The detection sensitivity of BSGI was significantly associated with the residual tumor cellularity and size as shown in Table 2. Sensitivity was also lower in patients with ductal carcinoma in situ. The detection sensitivity was only 51.4 % (19/37) for tumors with cellularity B10 %, whereas it was 86.6 % (58/67) for tumors with cellularity [10 %. The sensitivity was only 52.8 % (19/36) for residual tumor sizes B15 mm, whereas it was 85.3 % (58/68) for tumor sizes [15 mm. All ten false-negative cases out of the 68 tumors with size [15 mm showed lowresidual tumor cellularity (seven cases with cellularity B10 %, two cases with cellularity = 20 %, and one case with cellularity = 30 %). Of these false-negative cases, eight were detected by MRI. A similar association of detection sensitivity with residual tumor cellularity and residual tumor size was found for MRI (Table 2). Of six false-negative cases by MRI with sizes[15 mm, four cases were detected by BSGI.
18.8 ± 1.6
23.6 ± 1.9
* vs. : \0.001 * vs. à: 0.005
(P \ 0.001). The degree of underestimation was smaller for BSGI (P = 0.002). The size of the luminal tumors was underestimated by both SBSGI and SMRI (Fig. 2). In HER2 tumors, only SMRI significantly underestimated the tumor size (Fig. 3). The underestimation by SBSGI was less than that by SMRI in the luminal (P = 0.004) and HER2 subtypes (P = 0.042). In the triple-negative subtype, both SBSGI and SMRI generated the most accurate tumor size measurements (Fig. 4). To assess the contributing factor(s) of this subtype dependence of accuracy, residual tumor cellularity was consulted. The residual cellularity of the triple-negative tumors (39.0 ± 27.3 %) was significantly higher than that of the nontriple-negative tumors (25.3 ± 23.2 %; P = 0.017). Moreover, in the luminal or HER2 subtypes, largest residual tumors often showed lower residual cellularity; this tendency was not observed in the triple-negative subtype (Fig. 5). In patients with tumor sizes [40 mm, 14 (88 %) of 16 luminal tumors and four (80 %) of five HER2 tumors had residual cellularity \40 %. There was one triple-negative tumor with size [40 mm, the cellularity of which was 60 % (Fig. 5). Assessment of multifocal or multicentric disease
Estimation of residual tumor size Among the 104 patients with residual viable tumor, SBSGI and SMRI were concordant within 1 cm from SPATH in 66.3 % (69/104) and 67.3 % (70/104), respectively (P = 1.000). SPATH was overestimated by more than 1 cm in 8.7 % of the cases (9/104) for BSGI and in 2.9 % (3/ 104) for MRI (P = 0.137), and underestimated by more than 1 cm in 25.0 % (26/104) of the cases for BSGI and 29.8 % (31/104) for MRI (P = 0.534). The mean and standard error of SPATH, SBSGI, and SMRI for the 104 patients are listed in Table 3. Figure 1 shows the mean differences and the limits of agreement between tumor sizes measured by imaging studies and SPATH in the entire population and in subgroups. SPATH was significantly underestimated by both SBSGI (P = 0.005) and SMRI
Among the 104 patients with residual viable tumor, multifocal tumors were pathologically proven in 28.8 % of them (30/104). Among these 30 patients, BSGI and MRI correctly identified tumor multifocality in 46.7 % (14/30) and 66.7 % (20/30), respectively (P = 0.070). Among the 74 patients with unifocal tumor, BSGI and MRI correctly reported tumor unifocality in 98.6 % (73/74) and 93.2 % (69/74), respectively (P = 0.211).
Discussion This study evaluated the diagnostic performance of BSGI in the detection of residual tumor after NAC in breast cancer patients. The sensitivity and specificity of BSGI for
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b Fig. 1 Bland–Altman plots of the agreement between the tumor sizes
measured by BSGI (SBSGI) and pathology (SPATH) and between those measured by MRI (SMRI) and SPATH in the entire population (a, b), in the luminal subtype (c, d), in the HER2 subtype (e, f), and in the triple-negative subtype (g, h)
Fig. 4 A 32-year-old patient with a triple-negative breast tumor. Post-neoadjuvant BSGI showed an intense tumor uptake in the left outer breast (left panel). The size of the tumor uptake was measured as 2.6 cm. By MRI, the tumor size was measured as 3.0 cm (right panel). Surgical pathology revealed a 2.4 cm viable tumor
Fig. 2 A 43-year-old patient with a luminal breast tumor. Postneoadjuvant BSGI showed a tumor uptake in the right outer breast (left panel; black arrow). The size of the tumor uptake was measured as 4.7 cm. By MRI, the tumor size was measured as 1.1 cm (right panel; white arrow). Surgical pathology revealed a 6.0 cm viable tumor
Fig. 3 A 58-year-old patient with a HER2 breast tumor. Postneoadjuvant BSGI showed a mild tumor uptake in the right inner breast (left panel; black arrow). The size of the tumor uptake was measured as 5.2 cm. By MRI (right panel), there was no early enhancement, and the tumor was assessed as completely regressed. Surgical pathology revealed a 6.6 cm viable tumor
residual tumor detection were comparable to those of MRI. The sensitivity of BSGI was dependent on residual tumor cellularity and residual tumor size. BSGI accurately estimated tumor size in the HER2 and triple-negative subtypes, but significantly underestimated tumor size in the luminal subtype; however, the underestimation was smaller than that of MRI. Underestimation of tumor size in the luminal
and/or HER2 subtypes by BSGI and MRI may be due to low-residual cellularity. The detection of multifocal disease by BSGI was also comparable to that of MRI. Our results suggest the potential diagnostic value of BSGI after NAC in patients with breast cancer. Overall, we found BSGI to have a good diagnostic performance in detecting residual disease; however, the sensitivity of BSGI was not perfect even in patients with tumors[15 mm. The absence of increased uptake by BSGI was not necessarily predictive of pCR. The suboptimal sensitivity and low-predictive value of pCR in the present study are most likely associated with low cellularity after NAC. Residual tumors with low cellularity would be missed by BSGI because the tumor uptake of 99mTc-sestamibi is not sufficiently high to be distinguished from background parenchymal uptake. In this study, we regarded mild uptake (or higher) in the known cancer location as residual viable tumor. In the setting of initial diagnosis of breast cancer, mild uptake due to heterogeneous glandular activity is frequently seen, and many false-positives would be generated if we count mild uptake as cancer. This heterogeneous glandular activity is often associated with the menstrual cycle [23, 24]; however, heterogeneous glandular uptake was seldom observed in our study, probably because menstruation ceases after the beginning of NAC. We believe that it is justified to regard mild uptake in the baseline cancer location as residual cancer. Our findings suggest that interpretation of pCR by BSGI may need to be conservative. From the surgical point of view, the proportion of cases with small size discrepancies (for example, discrepancy \1 cm) between imaging studies and pathology results is important. In this study, BSGI showed a tendency toward underestimation of the residual tumor size. As in MRI
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Fig. 5 Scatter diagrams showing the distribution of the residual tumor cellularity and the residual tumor size in all patients with the luminal (a), HER2 (b), and triple-negative subtypes (c)
studies [7–10], BSGI was more likely to underestimate residual tumor size in luminal tumors than in HER2 or triple-negative tumors. MRI underestimated residual tumor size in both the luminal and HER2 subtypes with less underestimation by BSGI in both groups in this study. Invasive breast cancers often show heterogeneous responses to NAC. Good chemotherapeutic response, shown by a large reduction in cellularity, does not always imply a large reduction in tumor size [25]. Large residual tumors with scattered cancer cells sometimes occur [6, 26]. We suggest that the luminal and HER2 subtypes are predisposing factors for the occurrence of large residual tumors with low cellularity (Fig. 5). The biologic mechanism underlying this observation is not clear. The observation might be partially explained by the fact that patients with luminal or HER2 tumors are likely to have larger residual disease, as shown in this study; however, this does not explain why the luminal or HER2 subtypes have a tendency to form larger residual tumors with low cellularity. The accuracy of the tumor size measurements by MRI, which is significantly dependent on the biological tumor subtype, may be consistent with previous studies although some controversies still remain about the HER2 subtype [7–10]. The biologic mechanism explaining MRI accuracy has not yet been demonstrated; however, it was suggested that residual disease that presented as scattered cells or small foci made MRI diagnosis difficult, and these lesions were missed by MRI because of the lack of enhancement [8].
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The similar molecular subtype dependence of residual tumor measurements by BSGI and MRI suggests that there may be a common mechanism. Dynamic contrast-enhanced breast MRI visualizes tissue changes caused by tumor cells, i.e., neoangiogenic vascular changes [27]. 99mTc-sestamibi uptake also depends on the delivery of the tracer to the tumor via blood vessels in addition to cellular uptake mechanisms [28]. The underlying mechanism, therefore, may be higher capillary permeability in triple-negative breast cancer [25, 29]. Further detailed studies must be conducted to elucidate the underlying mechanism. Importantly, in the luminal and HER2 subtypes, the underestimation by BSGI was smaller in magnitude than that of MRI. Tumoral uptake of 99mTc-sestamibi, despite limited blood supply, may explain the difference. Mechanistic studies are required. Multifocality is an important attribute relevant to the decision of surgical extent. In this study, BSGI showed relatively poor sensitivity (46.7 %) in assessing multifocality. Since BSGI is not a multislice cross-sectional imaging modality, overlapping multifocal tumor uptakes are often not distinct from each other, which may give a false impression of unifocal cancer [30]. Although the sensitivity was low, the specificity was high (98.6 %). This high specificity resulted in a high-positive predictive value (93.3 %) in this population, meaning that multifocal tumor uptakes by post-NAC BSGI represent true multifocal residual tumors in most cases. This finding could be helpful for surgical decision-making.
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Our study has some limitations. First, the retrospective study design introduces the risk of selection bias. There were 111 patients who met the inclusion criteria but did not undergo BSGI in the study period; however, since the characteristics of these 111 patients were not significantly different from those of the 122 patients included in the study, potential selection bias would not have significantly affected the main result. Second, there may be some subjectivity between observers in delineating tumor boundaries. However, we think that the subjectivity is tolerable because good inter-observer reproducibility was demonstrated by the high-intraclass correlation coefficient (0.822) between the observers. Third, we could not analyze the impact of BSGI on surgical decision-making. The surgeons consulted both BSGI and MRI before surgery, but we could not separate the contributions of BSGI from those of MRI. It is unclear how the use of BSGI affected the success of breast conservation, the re-excision rate, and the overall margin status. Further studies are necessary to assess the success of breast conservation in relation to the BSGIestimated tumor size and molecular subtype. Finally, most patients with the HER2 subtype were not treated with trastuzumab in the regimen. It is possible that the accuracy of BSGI would be different after treatment with HER2targeted agents.
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Conclusion The diagnostic performance of BSGI in the assessment of residual tumor after NAC in breast cancer patients is comparable to that of MRI. In the assessment of residual tumor extent, BSGI is dependent on molecular tumor subtypes, but may be more accurate than MRI in the luminal and HER2 subtypes. Our results suggest the potential diagnostic value of BSGI after NAC in patients with breast cancer. This result may serve as a reference for a prospective study designed to evaluate the impact of BSGI on surgical decision-making. Acknowledgments This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI06C0868). Conflict of interest of interest.
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The authors declare that they have no conflict
Ethical standards Experiments performed in this study comply with the current laws of the Republic of Korea.
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