Research ArticleClinical Studies

Relative Uptake Factor of Invasive Ductal Breast Cancer in Breast-specific Gamma Imaging as a Surrogate Parameter for Sub-typing

THOMAS MEISSNITZER, MATTHIAS WOLFGANG MEISSNITZER, ALEXANDER SEYMER, KLAUS HERGAN and DANIEL NEUREITER
Anticancer Research October 2015, 35 (10) 5671-5677;

Abstract

Aim: The retrospective evaluation of correlations between semi-quantitative breast-specific gamma imaging (BSGI) and invasive ductal breast cancer (IDC) sub-types. Materials and Methods: The biopsy specimen of 50 histologically-proven IDCs were retrospectively evaluated concerning receptor status, human epidermal growth factor receptor 2 (HER2/Neu) status, Ki-67 level and classification into IDC sub-types. These results were compared to the relative uptake factor (RUF) in BSGI. Depending on RUF, we described four categories to outline the predictive value of RUF. Results: A total of 50 IDCs with a mean diameter of 20.36 mm were included. RUF differed reliably between luminal-A and non-luminal-A IDCs. RUF exceeding 6.5 pointed to non luminal A-carcinoma, with a specificity and positive predictive value of 100%. RUF of less than 2.6 was unlikely to be associated with a non-luminal A-carcinoma (negative predictive value: 76.5%). Comparable results were calculated for the correlation between RUF and the K-67 level. Conclusion: RUF may help classify the sub-type of an IDC in addition to pathology.

The aim of our study was to evaluate the performance of the relative uptake factor (RUF) in breast-specific gamma imaging (BSGI) to assess immunohistochemical characteristics of invasive ductal cancer (IDC) cells. IDC is a heterogeneous disease concerning histopathological and immunohistochemical features, the risk of local recurrence, dissemination (with various patterns) and thus prognosis and outcome. This variability is based on different intrinsic sub-types, described for the first time by Perou et al. (1).

Current strategies to treat IDC are based on histopathological as well as immunohistochemical examinations of biopsy specimens and the evaluation of the spread of disease using imaging examinations. In fact, histopathological diagnosis and marker profile are determined by the pathologists. However, we believe that semi-quantitative BSGI may help overcome limitations in the assessment of biopsy specimen and to increase reliability of diagnosis.

In contrast to former studies, such as by Park et al. (2) or Tadwalker et al. (3), we specifically evaluated IDCs which were detected unequivocally in BSGI. We determined quantitatively the tracer accumulation of the various IDC subtypes and the correlations to certain parameters.

Materials and Methods

This retrospective analysis is based on the data of our previous prospective study highlighting the diagnostic value of BSGI in the workup of breast lesions categorized as Breast Imaging and Data System (BI-RADS) IV or V in morphological imaging modalities (4). Fifty histologically proven IDCs with complete diagnostic work-up were included in this study, which was approved by the Local Ethics Committee [E-no: 1508, 415-EP/73/439-2014]. Written informed consent was obtained from each patient.

Breast Specific Gamma Imaging. BSGI particularly depicts perfusion and energy demand of breast cancer cells and so it is called a functional imaging modality, in contrast to morphological imaging modalities, such as mammography, ultrasound and magnetic resonance imaging. By calculating a semi-quantitative uptake factor we were able to evaluate scintigrams not only visually, but also quantitatively.

BSGI was performed at presentation at our Breast Cancer Center to further characterize breast lesions of categories IV and V according to BI-RADS, initially diagnosed with mammography and ultrasound (5). In compliance with the guidelines of the European Association of Nuclear Medicine 740-1100 MBq (20-30 mCi) [mean=843.8 MBq, 22.8 mCi] 99mTechnetium SestaMIBI (CarioTOP, National Centre for Nuclear Research, Otwock, Poland) were injected in an upper extremity vein contralateral to the affected breast (6). Ten minutes after the injection, scintigrams were performed using a dedicated gamma camera for BSGI Dilon 6800 (Dilon Technologies, Newport NEWS, VA, USA) in craniocaudal and mediolateral-oblique projections, comparable to mammograms. After transmission to the electronic image archive, tracer distribution was analyzed not only visually as described by Brem et al. (7) but also semiquantitatively by calculating a relative uptake factor (RUF).

Figure 1.
Figure 1.

Positioning of the regions of interest (ROI) to calculate the relative uptake factor (RUF). A: Circumference; U: diameter; avg: average (count=SI); sd: standard deviation; max: maximum (count, SI); min: minimum (count, SI).

RUF was calculated according to the ratio RUF= CmaxL/CmaxBG. CmaxL was the highest count within the clearly definable MIBI accumulation, CmaxBG reflected the highest count within the reference region, which was always placed two cm dorsal to the nipple in an unsuspicious area (see Figure 1). The higher ratio of the two projections was used for statistics. Further technical data of BSGI and procedural instructions are described by Meissnitzer et al. (4). The size of the IDCs evaluated in this study was determined with morphological imaging modalities, in the majority with ultrasound due to accurate demarcation.

Histopathological and immunohistochemical analyses. The results of histopathological and immunohistochemical examinations of the biopsy specimen were the gold standard for this retrospective work-up, which were carried out by a pathologist with 20 years' experience in breast diagnosis. These specimen were obtained by image-guided biopsy without biopsy-related complications. Either ultrasound-guided (49 specimen) or stereotactic vacuum-assisted biopsies (1 specimen) were performed. The retrospective evaluation of the biopsy samples included verification of former diagnosis as IDC, analyses of receptor status [estrogen (ER), progesterone (PR) and human epidermal growth factor 2 (HER2/Neu) receptors], as well as Ki-67 expression and, as the final result, the assignment to the different subtypes of IDC according to the decisions of the 2011 St. Gallen International Breast Cancer Conference (8). In this classification, ER-positive IDCs are subdivided into luminal-A or -B subtypes depending on their Ki-67 expression: Luminal-A carcinomas exhibit a Ki-67 index of less than 14% and are PR-positive or-negative and HER2/Neu-negative; luminal-B carcinomas have a Ki-67 index of 14% or higher and are PR-positive or -negative and HER2/Neu-positive or -negative; non-luminal carcinomas are either HER2/Neu-positive and negative for both endocrine receptors (ER, PR) or triple-negative (basal-like carcinomas).

Immunohistochemistry. Immunohistochemical stainings were performed on the whole slides for ER (Novacastra, Leica Biosystems Nussloch GmbH, Nussloch, Germany), PR (Novacastra, Leica Biosystems Nussloch GmbH, Nussloch, Germany), Ki-67 (Dako, Dako Austria GmbH, Vienna, Austria) and HER2/Neu (Ventana, Ventana Medical Systems, Inc., Tucson, AZ, USA) on an Autostainer Plus (Dako® Austria GmbH, Vienna, Austria) and Ventana®-Ultra (Roche Austria GmbH, Vienna, Austria), routinely according to the manufacturers' recommendations [heat-induced epitope retrieval (Dako® Austria GmbH, Vienna, Austria) at 95°C for 40 min for the applied antibodies [dilutions: ER: 1:100, PR: 1:200, Ki-67: 1:500) and for HER2/Neu (ready-to use)].

In situ hybridization. In cases of a HER2/Neu score of 2+ an additional Her-2-SISH was performed on a Ventana® XT Stainer (Roche Austria GmbH, Vienna, Austria) routinely according to the manufacturer's recommendations to analyze the HER2 gene amplification (9).

Interpretation of immunohistochemistry. The interpretation of ER and PR expression was performed according to Remmele and Stegner (10) by evaluating the intensity (0: negative, 1: weak, 2: moderate, 3: strong) and the percentage of positive cells (0: negative, 1 <10%, 2: 10 to 50%, 3: 51 to 80% and 4: >80%). As a result, a score from 0 to 12 was calculated.

The Ki-67-based proliferation rate was assessed with the optimized particle analysis module according to the software manual ImageAccess 9 Enterprise (Imagic Bildverarbeitung AG, Glattbrugg, Switzerland) on three digitized hot-spot areas and related to the total number of cells as published earlier (11). The expression of HER2/Neu was determined according to the recent recommendations of the American Society of Clinical Oncology, ranging from negative (score 0 and 1+) to weakly positive (2+) and positive (3+) (12).

Figure 2.
Figure 2.

Correlations of relative uptake factor (RUF), Ki-67 values and invasive ductal cancer (IDC) sub-types in the scatterplot. A relative uptake factor (RUF) of 2.6 and 6.5 can be regarded as valid thresholds.

Statistical analysis. The RUFs as well as the immunohistochemical features of all included IDCs (ER, PR, Ki-67, HER2/Neu) and the resulting sub-categories were noted in an Excel spreadsheet (Microsoft Corporation, Redmond, WA, USA). Sensitivity, specificity, predictive values [positive predictive value (PPV), negative predictive value (NPV)] and accuracy statistically outlined the performance of RUF. Additionally, the area under the receiver operating characteristics curve (AUC) was calculated to summarize sensitivity and specificity of each parameter and to determine thresholds for RUF. DeLongs difference test was used to define differences in AUC values. Cohen's Kappa outlined the concordance of the different RUF levels with IDC subtypes as well as the correlation of RUF and the abovementioned markers. Similarly, the McNemar test described the level of compliance.

Calculations and graphics were created with R 3.1.2, pROC, ggplot2 and package psych (13-16). In order to determine the best performance for RUF in distinguishing non luminal-A cancer from the other subtypes of IDCs, three different thresholds were evaluated: The lowest threshold was 2.6 and was derived from the AUC curves, 3.04 was identified in our previous study to reliably subdivide malignant and benign lesions. The highest threshold of 6.5 was based on the assessment of the scatter plot (see Figure 2).

Results

In our previous prospective study, 92 lesions were detected in 67 patients and histopathological analyses of biopsy specimen revealed 67 malignant lesions. Among the latter, immunohistochemical work-up was fully-available or retrospectively feasible in 50 IDCs with a mean size of 20.36 mm [standard error (SE)=1.3 mm] because the other patients were treated elsewhere. There were a total of 25 luminal-A and 18 luminal-B IDCs, 7 were non-luminal IDCs; among the latter, 2 were classified as HER2/Neu-positive and negative for endocrine receptors, and 5 were basal-like carcinomas (triple-negative). The calculated mean values for Ki-67, ER, PR, RUF and size including SEs are listed in Table I.

View this table:
Table I.

Descriptive statistics.

View this table:
Table II.

Statistics of the different relative uptake factor (RUF) categories.

Although our data showed no statistically valid correlation between RUF and ER or PR status, we found a relationship between RUF and the IDC sub-type, that is to say to the differentiation between luminal-A versus the others. RUF exceeding 6.5 excludes luminal-A IDC with a maximum specificity and PPV of 100% and an acceptable AUC (p<0.05). For RUF between 2.6 and 6.5, no reliable conclusion about the sub-type could be drawn according to the low PPVs and NPVs. A RUF of below 2.6 points to a luminal-A IDC, as the NPV for a non-luminal-A IDC reaches at least 77% (Figure 2 and Table II).

As a consequence, we suggest the application of RUF comparable to a traffic light: RUF exceeding 6.5 excludes a luminal-A IDC (red light), a value of between 2.6 and 6.5 is inconclusive (yellow light) and RUF of below 2.6 identifies a luminal-A IDC (green light).

Comparable results were calculated for the abovementioned categories of RUF and the Ki-67 level of IDCs as the most important proliferation marker (Figure 3). Table II lists statistical parameters for distinguishing the different types of IDCs correlated with RUF.

Discussion

Considering the pharmacokinetics of SestaMIBI, correlations between SestaMIBI uptake in IDCs and their biologic behavior can be expected. We postulate that if the RUF could be linked to a certain histological subtype of IDC, the accuracy of diagnosis based on imaging examinations and the analysis of biopsy specimen could be increased: For radiologists, not only the assessment of a breast lesion as suspicious or unsuspicious, but also the selection of biopsy site (according to the region with the highest uptake) could be facilitated. Pathologists could focus on the analysis of samples from areas with the highest uptake. Moreover, therapeutic decisions could also be based on semi-quantitative BSGI, especially if there exist uncertainties in the histopathological classification.

BSGI and pharmacokinetics of SestaMIBI. 99mTechnetium SestaMIBI [Hexakis (2-methoxy-2-methylpropylisonitrile)] is a lipophilic cationic compound and an isonitrile. Being lipid-soluble, it diffuses passively from the blood into the cytoplasm and is retained in the region of the mitochondria because of the electrostatic attraction between the positive charge of the 99mTechnetium SestaMIBI and the negative charge of the mitochondria (17, 18). Uptake and retention of 99mTechnetium SestaMIBI depend on angiogenesis and regional perfusion, plasma and mitochondrial membrane potentials and thus the level of tissue metabolism (19, 20).

Quantification of SestaMIBI uptake. As opposed to the study of Park et al. (21), influencing factors on the calculation of the relative tracer uptake, such as differences in positioning of the breast on the detector or a varying background activity due to asymmetry of glandular tissue are less significant using our method. By the use of the absolute count within an exactly defined region of interest (ROI), significant fluctuations of the standard deviations in counts within the applied small ROIs can be neglected. The size of a lesion, its distance from the detector and the breast thickness were not taken into account, as we used a single-head detector to calculate an approximate RUF. Hence there exist significant differences compared to the results acquired with dedicated dual-head cameras, as described by Hruska et al. (22).

Correlations between RUF and immunohistochemical characteristics of IDC. Our former prospective study described the outstanding diagnostic potential of BSGI compared to morphological imaging modalities, especially concerning specificity and PPV for malignancy of a lesion. A poor sensitivity of 60% for lesions smaller than 1 cm was the only relevant limitation of BSGI.

In the current study, we demonstrated that more aggressive, often locally advanced IDCs, such as luminal-B, non-luminal or triple-negative sub-types exhibit higher energy demand because of up-regulated angiogenesis, increased perfusion, higher proliferative activity and surrounding inflammation and clear correlations demonstrated between SestaMIBI uptake and immunohistochemical characteristics, also shown by Mankoff et al. (23) and Scopinaro et al. (24). The exact characterization of IDCs is decisive for the choice of therapy and prognosis because nowadays we understand IDCs to be a heterogeneous group of different biological sub-types (1). The genetic fundamentals of these cancer sub-types are well-known (25). The proliferative signature, which is crucial for the distinction between luminal-A and non luminal-A IDCs, is routinely determined by immunohistochemical investigation of the Ki-67 level encoded by MKI67 and 14% is a generally accepted cut-off level (26). Trihia et al. described the Ki-67-index as a surrogate parameter for prognosis and grading, which can be assessed in biopsy specimen (27). Recent studies have demonstrated the increased and premature incidence of local recurrence, as well as metastasis, of IDCs with certain marker profiles, for example if Ki-67 exceeds 14% and cancer cells are HER2/Neu-positive (28, 29). Nishimura et al. underlined the baseline Ki-67 value as a significant predictor for time and site of breast cancer recurrence with lower index values in patients with bone metastases and higher levels in patients with liver and brain metastases. Additionally, higher nuclear grade and ER−, PR− and HER2/Neu-negative IDCs with shorter disease-free interval were correlated with higher Ki-67 values (30).

Figure 3.
Figure 3.

Correlations between relative uptake factor (RUF) and Ki-67 levels outlined in a Receiver Operating Characteristic plot.

The accuracy and reproducibility of proliferative markers and hormone receptor status examined in biopsy specimen are limited due to small sample volume, heterogeneous expression, different lab methods and subjective reading (31). For IDCs exceeding a diameter of 1 cm, these limitations are irrelevant for BSGI. Moreover, reliability of diagnosis also depends on the biopsy site within a tumor chosen by the radiologist. Increased MIBI uptake within a certain part of a tumor points to the most dedifferentiated and thus most aggressive part, which should be biopsied. Thereby, sample error may be obviated. According to our data, areas with a RUF exceeding 2.6 require biopsy.

Our findings are in accordance with those of Tilling et al., Maini et al. and Tofani et al., who reported no statistically significant correlations between SestaMIBI uptake and receptor status (32-34).

Potential role of RUF in therapeutic decisions. Biomarkers decisively determine timing and type of adjuvant therapy (28). In this context, not only improved response rates of non luminal-A IDCs to chemotherapy, but also the lack of response of ER+ IDCs (luminal-A and luminal-B) to tamoxifen can be highly relevant. In particular if ER+ IDCs lack PRs, tamoxifen may act as an estrogen agonist via ERs by activating growth factors (35). Nevertheless, first results on the additional use of signal transduction inhibitors, such as inhibitors of mechanistic targets of rapamycin (everolismus, temsirolismus), phosphoinositide 3-kinase, tyrosine kinases, insulin-like growth factor-receptors and epidermal growth factor receptors to overcome tamoxifen resistance are promising (36).

A RUF higher than 6.5, indicating a highly aggressive IDC sub-type, may support the decision for additional chemotherapy, especially if the results of histopathological and immunohistochemical examinations of the biopsy specimen are equivocal. Despite shorter disease-free survival, triple-negative (basal-like) and HER2/Neu-enriched IDCs have the highest response rate to chemotherapy, a fact known as the ‘triple-negative paradox’ (37).

In contrast, a RUF below 2.6 indicates a less aggressive sub-type, such as luminal-A IDC, with a significantly better prognosis. Voduc et al. for example, described a local recurrence rate of 8% within 10 years for luminal-A cancer, whereas HER2/Neu-positive and triple-negative sub-groups exhibited local recurrence rates of 21% and 14% respectively (38). These patients would expect little benefit from chemotherapy, even though they would be exposed to its side-effects (39).

Another possible reason for the low chemosensitivity of IDCs with low RUF may be an increased expression of the multidrug-resistance P-glycoprotein because as a substrate of this transport protein, SestaMIBI is more rapidly eliminated from cancer cells rich in P-glycoprotein (40).

Limitations of our study. Our results were obtained by retrospective work-up of a relatively small sample of 50 biopsy specimen. This may be the reason why the correlations between RUF and the receptor status did not have a higher statistical validity. However, there exist clear indications for an association between RUF and the Ki-67 level, as well as for the highly relevant distinction between luminal-A and the other IDC-subtypes.

Regarding the thresholds for RUF, it should be mentioned that a RUF exceeding 6.5 excludes luminal-A IDC with great reliability. Conversely, below a RUF of 6.5 there is a wide gray zone concerning the classification of IDCs.

Conclusion

The RUF may be used as a surrogate parameter for the classification of IDCs into different sub-types. Due to simple and rapid calculation at presentation, the RUF can be regarded as a basis for treatment decisions and prognostic evaluations, in addition to the examinations of biopsy specimen by the pathologists and by staging with imaging modalities.

  • Received June 4, 2015.
  • Revision received July 12, 2015.
  • Accepted July 14, 2015.

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Relative Uptake Factor of Invasive Ductal Breast Cancer in Breast-specific Gamma Imaging as a Surrogate Parameter for Sub-typing
THOMAS MEISSNITZER, MATTHIAS WOLFGANG MEISSNITZER, ALEXANDER SEYMER, KLAUS HERGAN, DANIEL NEUREITER
Anticancer Research Oct 2015, 35 (10) 5671-5677;
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