Hyeon-Man Baek

Predicting Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer by Using MR Imaging and Quantitative 1H MR Spectroscopy

PURPOSE To compare changes in the concentration of choline-containing compounds (tCho) and in tumor size at follow-up after neoadjuvant chemotherapy (NAC) between patients who achieved pathologic complete response (pCR) and those who did not (non-pCR). MATERIALS AND METHODS This study was approved by the institutional review board and was compliant with HIPAA; each patient gave informed consent. Thirty-five patients (mean age, 48 years +/- 11 [standard deviation]; range, 29-75 years) with breast cancer were included. Treatment included doxorubicin and cyclophosphamide followed by a taxane-based regimen. Changes in tCho and tumor size in pCR versus non-pCR groups were compared by using the two-way Mann-Whitney nonparametric test. Receiver operating characteristic (ROC) analysis was performed to differentiate between them and the area under the ROC curve (AUC) was compared. RESULTS In the pCR group, the tCho level change was greater compared with change in tumor size (P = .003 at first follow-up, P = .01 at second follow-up), but they were not significantly different in the non-pCR group. Changes in tumor size and tCho level at the first follow-up study were not significantly different between the pCR and non-pCR groups but reached significance at the second follow-up. In ROC analysis, the magnetic resonance (MR) imaging and MR spectroscopic parameters had AUCs of 0.65-0.68 at first follow-up; at second follow-up, AUC for change in tumor size was 0.9, AUC for change in tCho was 0.73. CONCLUSION Patients who show greater reduction in tCho compared with changes in tumor size are more likely to achieve pCR. The change in tumor size halfway through therapy was the most accurate predictor of pCR.

Estrogen receptor and breast MR imaging features: A correlation study

To compare the MRI features between estrogen receptor (ER) positive and negative breast cancers.

Detection of choline signal in human breast lesions with chemical-shift imaging.

To investigate the application of MR spectroscopy using chemical‐shift imaging (CSI) for characterizing human breast lesions at 1.5T, and to evaluate the diagnostic performance using ROC (receiver operating characteristics) analysis.

Clinical characteristics and biomarkers of breast cancer associated with choline concentration measured by 1H MRS

This study investigated the association between the total choline (tCho) concentration and the clinical characteristics and biomarker status of breast cancer. Sixty‐two patients with breast cancer, 1.5 cm or larger in size on MR images, were studied. The tCho concentration was correlated with the MRI features, contrast enhancement kinetics, clinical variables and biomarkers. Pairwise two‐tailed Spearmans nonparametric test was used for statistical analysis. The tCho concentration was higher in high‐grade than moderate‐/low‐grade tumors (p = 0.04) and in tumors with higher Ktrans and kep (p < 0.001 for both). The association of tCho concentration with age (p = 0.05) and triple negative biomarker (p = 0.09) approached significance. tCho was not detected in 17 patients, including 15 with invasive ductal cancer and two with infiltrating lobular cancer. Fifteen of the 17 patients had moderate‐ to low‐grade cancers, and 11 had human epidermal growth factor‐2‐negative cancer, suggesting that these two factors might lead to false‐negative choline. Higher tCho concentration in high‐grade tumors and tumors with higher Ktrans and kep indicates that choline is associated with cell proliferation and tumor angiogenesis. The higher choline level in younger women may be caused by their more aggressive tumor type. The results presented here may aid in the better interpretation of 1H MRS for the diagnosis of breast lesions. Copyright

Proton MR spectroscopy for monitoring early treatment response of breast cancer to neo-adjuvant chemotherapy

With respect to treatment monitoring, conventional modalities such as physical examination, ultrasonography, and mammography are frequently used, but vary in reliability for measuring tumor’s therapeutic response [1, 2]. Magnetic resonance imaging (MRI) is increasingly being used to evaluate locally advanced breast cancer undergoing neo-adjuvant chemotherapy. However, changes in lesion size or dynamic contrast enhanced MRI are not detected until several weeks following chemotherapy [3]. Recently, proton magnetic resonance spectroscopy (1H-MRS) has been proven helpful for the diagnosis of breast cancer based on total choline-containing compounds (tCho). The presence of tCho may indicate active cell replication, thus can be used for diagnosis. The role of 1H-MRS at 1.5 T for therapy response prediction is less established [4, 5]. Authors of this earlier study did not categorize which patients had a change in tCho signal nor did they describe when the change in the signal occurred. In this study, we applied longitudinal quantitative 1H-MRS using the internal reference method to monitor the change of tCho level during the full course of neo-adjuvant chemotherapy. The aim of our study was to determine whether the early changes can predict clinical response in women undergoing neo-adjuvant chemotherapy. Twenty breast cancer patients (range 32-76 years old, mean 50 years) enrolled from June 2004 to December 2006, who were scanned with the MRI/MRS protocol, were included in this study. The inclusion criteria were patients with biopsy-confirmed diagnosis of malignant lesions that measured 2.4 cm or larger on MR images. All patients received biweekly doxorubicin (adriamycin) and cyclophosphamide (AC) as their first-line regimen. After the first two cycles, an oncologist evaluated patient response using all information available at that time (clinical examination, patient’s tolerance, sonography, etc), and the oncologist decided whether the patient should continue to receive two additional cycles of AC or should be switched to a taxane-based regimen. In all patients, MRI and 1H-MRS were performed before treatment as the baseline, then at least two follow-up (F/U) times, F/U-1 after one to two cycles AC and F/U-2 after four cycles AC or two cycles AC followed by the first cycle of a taxane regimen. The MRI study was carried out using a 1.5 T Phillips Eclipse MR scanner with a standard bilateral breast coil (Philips Medical Systems, Cleveland, OH). The imaging protocol consisted of high- resolution precontrast imaging from the concerned breast, bilateral dynamic contrast-enhanced imaging, and 1H-MR spectroscopy. For dynamic acquisition, the MR contrast agent gadodiamide (Omniscan®, GE Healthcare AS, Oslo, Norway, 1 cm3/10 lbs body weight) was manually injected. After the MRI study was completed, single-voxel 1H-MRS was carried out using a point-resolved spin-echo sequence (PRsESS). The spectroscopic voxel was carefully positioned to maximize the coverage of the contrast-enhanced lesions while minimizing the inclusion of adipose tissue. The voxel size was from 2.4 to 8.0 ml. The absolute tCho concentration was analyzed using as an internal reference method [6]. Tumor size was measured by a radiologist based on the maximum intensity projection of the contrast subtraction images. Based on the one-dimensional RECIST criteria [7], patients were categorized into one of two groups: responders or nonresponders. Responders were defined as subjects with ≥30% one-dimensional tumor size reduction at F/U-2 compared with the baseline. Nonresponders were patients with a <30% of tumor size or no change. In this study, 14 of 16 patients who were responders had positive tCho before treatment. There is no significant difference in tCho level at the baseline between responder and nonresponder groups (2.30 ± 2.24 versus 2.51 ± 2.27 mmol/kg, P = 0.67). The mean percentage change in tCho level after one to two cycles AC was -50%, while the mean percentage change in lesion size was -18% (Figure 1). After completing F/U-2, all patients did not have positive tCho. The mean percentage change in lesion size in F/U-2 study was -76%. Three patients were classified as nonresponders. All three patients had a positive tCho at the baseline. The mean percentage change in tCho level after one to two cycles AC was -14%, while the mean percentage change in lesion size was -15%. Of them, two patients showed increased tCho in F/U-2, and the remaining one patient showed decreased tCho but was still positive. The mean percentage changes in tCho level and lesion size in F/U-2 study were 3.3% and -27%, respectively. For the responder group, significant reductions in tCho level and tumor size were observed at the early F/U-1 with respect to the baseline (P < 0.002, P < 0.008), whereas no significant change was observed for either in the nonresponder group. Figure 1 A 33-year-old young woman with locally advanced breast cancer who were undergoing neoadjuvant chemotherapy. The core biopsy revealed an invasive ductal carcinoma. The tumor was a triple negative cancer, found to be negative for estrogen, progesterone, ... As the therapeutic agents become more effective, more patients can achieve the pathological complete response which is expected to lead to a better prognosis. Our study carried out on breast cancer treated with chemotherapy showed that in the responder group the reduction in tCho level at the first follow-up (F/U-1, one to two cycles AC) was significantly higher compared with the reduction in the tumor size (P < 0.005). The result demonstrates that the metabolic changes were greater than the size changes, suggesting that they might have occurred before gross morphological changes. An early reduction of tCho level can be interpreted as reflecting the inhibition of cellular proliferation and the cytotoxic effect of chemotherapy. In addition, the tCho level showed significant reduction in the response group but not in the nonresponse group, suggesting an early response predictor. This finding suggests that a greater reduction in tCho at the F/U-1 may be associated with a final complete response, so they may help to predict pathological complete response.

Magnetic resonance imaging features of fibrocystic change of the breast.

PURPOSE Studies specifically reporting MRI of fibrocystic change (FCC) of the breast are very few and its MRI features are not clearly known. The purpose of this study was to analyze the MRI features of FCC of the breast. MATERIALS AND METHODS Thirty-one patients with pathologically proven FCC of the breast were retrospectively reviewed. The MRI study was performed using a 1.5-T MR scanner with standard bilateral breast coil. The imaging protocol consisted of pre-contrast T1-weighed imaging and dynamic contrast-enhanced axial T1-weighed imaging. The MRI features were interpreted based on the morphologic and enhancement kinetic descriptors defined on ACR BIRADS-MRI lexicon. RESULTS FCC of the breast had a wide spectrum of morphologic and kinetic features on MRI. Two types of FCC were found, including a more diffuse type of nonmass lesion (12/31, 39%) showing benign enhancement kinetic pattern with medium wash-in in early phase (9/10, 90%) and a focal mass-type lesion (11/31, 35%) with enhancement kinetic usually showing rapid up-slope mimicking a breast cancer (8/11, 73%). CONCLUSION MRI is able to elaborate the diverse imaging features of FCC of the breast. Our result showed that FCC presenting as a focal mass-type lesion was usually overdiagnosed as malignancy. Understanding MRI of FCC is important to determine which cohort of patients should be followed up alone or receive aggressive management.

Choline as a biomarker for cell proliferation: do the results from proton MR spectroscopy show difference between HER2/neu positive and negative breast cancers?

HER2/neu gene is a member of family of genes encoding trans-membrane receptors for four growth factors, including the epidermal growth factor receptor (EGFR), HER2/neu, HER-3, and HER-4. The intracellular domain of HER2/neu has tyrosine kinase activity which regulates cell growth and proliferation [1-5]. Overexpression of HER2/neu can transform cultured cells into more aggressive phenotype and accelerate tumorigenesis [1, 6]. HER2/neu is overexpressed in 20−25% of invasive breast cancers and associated with an aggressive tumor, an early relapse and reduced survival rate [7-9]. It has been found that a tumor cell line overexpressing HER2/neu resulted in an increase in levels of choline-containing compounds (tCho) measured by in-vitro proton MR spectroscopy (MRS), including phosphocholine (PCho), glycerophosphocholine (GPC), and choline [10]. It was postulated that growth factor-mediated activation of the tyrosine kinase cascade can lead to an increase in phosphocholine levels [10]. The proton MRS has been proven very useful in differentiating between benign and malignant breast lesions based on elevated tCho [11-14]. Choline measured by MRS may provide an imaging marker for cell proliferation. Our recently published article [15] analyzing the MR imaging features with respect to HER2/neu overexpression in invasive breast cancer demonstrated a higher choline detection rate in HER2/neu positive compared to negative cancer. The number of patients in that study was however very small and conclusion could not be drawn. Here we reported a larger series study to further investigate the choline expression between HER2/neu +/− cancers. Sixty-six breast cancer patients (range 32−76 years old, mean 51 years) enrolled from March 2005 to October 2006, who were scanned with the MRI/MRS protocol were included in this study. The inclusion criteria were patients with biopsy confirmed diagnosis of malignant lesions that measured 1.5 cm or larger on MR images. Of the 66 malignant lesions, 41 (77%) were invasive ductal carcinomas, 7 (11%) were invasive lobular carcinomas, and the other 8 (12%) were mixed invasive ductal and lobular carcinomas. HER2/neu status was determined initially using the immunohistochemical staining (IHC), positive in tumors with 3+ staining score, and negative for score of 0 and 1+. For those with IHC 2+ staining, fluorescent in situ hybridization (FISH) was conducted to determine the status. The examinations were performed on a clinical 1.5T scanner (Eclipse; Philips Medical System, Cleveland, Ohio) with a dedicated four-channel phased-array breast coil. After the MRI study was completed, single-voxel MRS was performed using a point-resolved spin-echo sequence (PRESS). The spectroscopic voxel was carefully positioned to maximize the coverage of the contrast-enhanced lesions while minimizing the inclusion of adipose tissue. The voxel size was from 2.4 to 8.0 mL. The absolute tCho concentration was analyzed using as an internal reference method [16]. The tumor size was measured by a radiologist based on the maximum intensity projection (MIP) of the contrast subtraction images. Of 66 cancers, 45 (68%) were HER2/neu negative, and 21 (32%) were HER2/neu positive. The mean size of 66 malignant tumors was 3.4 cm (range, 1.5 − 8.6 cm). The 1H-MRS result was positive for tCho in 53 (80%) of 66 patients. The measured Cho levels ranged from 0 to 8.5 mmol/kg (mean ± SD, 1.9 ± 1.9 mmol/kg), which were consistent with the previously published value by Bolan et al. [16]. Table 1 summarizes in vivo breast 1H-MRS results in HER2/neu positive and negative groups. The choline detection rate was higher in HER2/neu positive group (91%) than in HER2/neu negative group (76%), but not reaching significant level (p = 0.26, chi-square test). Table 1 Sensitivity and tCho Concentration in HER/neu Positive and Negative Breast Cancers Using In Vivo MR Spectroscopy HER2 receptor mediates signaling to cancer cells and stimulates proliferation [3-5]. In vitro cell line study by overexpressing HER2/neu in MCF7 cells showed higher proliferation rate [17]. Overexpression/amplification of HER2 is associated with tumor aggressiveness and a poor prognosis in breast cancer. Limited literature is available correlating MR imaging features with HER-2 biomarkers expressed in invasive breast cancer. Tse et al. [18] reported 17 out of 19 breast cancer patients showing positive choline detection. The two false negative cases were negative for HER-2/neu oncogene expression, suggesting that a false-negative spectroscopic result may be related to an absence of Her-2 overexpression in carcinoma of the breast. Agrawal et al. [15] also showed more choline detection rate in HER-2/neu positive patients compared to Her-2/neu negative cohort in small number of patients (4/7 vs. 0/8, P< 0.05). The case number was too small in the two aforementioned studies. In this much larger series study, the sensitivity of in vivo 1H-MRS in HER2/neu negative group, although lower, was not significantly different from that of HER2/neu positive group, and also the absolute tCho levels did not appear to be related to HER2/neu overexpression. Our observation suggests that in vivo 1H-MR spectroscopy may play a very limited role for characterizing HER2/neu overexpression in carcinoma of the breast.