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A common malignancy that affects women is breast cancer. It is the second leading cause of cancer-related death among women. Metabolic reprogramming occurs during cancer growth, invasion, and metastases. Functional magnetic resonance (MR) methods comprising an array of techniques have shown potential for illustrating physiological and molecular processes changes before anatomical manifestations on conventional MR imaging. Among these, in vivo proton (1H) MR spectroscopy (MRS) is widely used for differentiating breast malignancy from benign diseases by measuring elevated choline-containing compounds. Further, the use of hyperpolarized 13C and 31P MRS enhanced the understanding of glucose and phospholipid metabolism. The metabolic profiling of an array of biological specimens (intact tissues, tissue extracts, and various biofluids such as blood, urine, nipple aspirates, and fine needle aspirates) can also be investigated through in vitro high-resolution NMR spectroscopy and high-resolution magic angle spectroscopy (HRMAS). Such studies can provide information on more metabolites than what is seen by in vivo MRS, thus providing a deeper insight into cancer biology and metabolism. The analysis of a large number of NMR spectral data sets through multivariate statistical methods classified the tumor sub-types. It showed enormous potential in the development of new therapeutic approaches. Recently, multiparametric MRI approaches were found to be helpful in elucidating the pathophysiology of cancer by quantifying structural, vasculature, diffusion, perfusion, and metabolic abnormalities in vivo. This review focuses on the applications of NMR, MRS, and MRI methods in understanding breast cancer biology and in the diagnosis and therapeutic monitoring of breast cancer. [ABSTRACT FROM AUTHOR]

Breast cancer poses a significant health care challenge worldwide requiring early detection and effective treatment strategies for better patient outcome. A deeper understanding of the breast cancer biology and metabolism may help developing better diagnostic and therapeutic approaches. Metabolomic studies give a comprehensive analysis of small molecule metabolites present in human tissues in vivo. The changes in the level of these metabolites provide information on the complex mechanism of the development of the disease and its progression. Metabolomic approach using analytical techniques such as magnetic resonance spectroscopy (MRS) has evolved as an important tool for identifying clinically relevant metabolic biomarkers. The metabolic characterization of breast lesions using in‐vivo MRS has shown that malignant breast tissues contain elevated levels of choline containing compounds (tCho), suggesting rapid proliferation of cancer cells and alterations in membrane metabolism. Also, tCho has been identified as one of the important biomarkers that help to enhance the diagnostic accuracy of dynamic contrast enhanced magnetic resonance imaging and also for monitoring treatment response. Further, metabolome of malignant tissues can be studied using ex vivo and in vitro MRS at high magnetic fields. This provided the advantage of detection of a large number of compounds that facilitated more comprehensive insight into the altered metabolic pathways associated with the cancer development and progression and also in identification of several metabolites as potential biomarkers. This article briefly reviews the role of MRS based metabolic profiling in the discovery of biomarkers and understanding of the altered metabolism in breast cancer. [ABSTRACT FROM AUTHOR]

Dynamic contrast enhanced MRI (DCEMRI), diffusion weighted imaging (DWI) and in vivo proton (1H) magnetic resonance spectroscopy (MRS) provides functional and molecular nature of breast cancer. This study evaluates the potential of the combination of three MR parameters [curve kinetics, apparent diffusion coefficient (ADC) and total choline (tCho) concentration] determined from these techniques in increasing the sensitivity of breast cancer detection. MR investigations were carried out at 1.5 T on 56 patients with cytologically/histologically confirmed breast carcinoma. Single-voxel MRS was used to determine the tCho concentration. 3D FLASH was used for DCEMRI while single shot EPI based DWI was used for ADC determination. On DCEMRI, one patient showed type I curve, while 8 showed type II and 47 showed type III curve thus giving a sensitivity of 83.9% as detection rate of malignancy. tCho concentration was above cut-off value (2.54 mmol/kg) for 50/56 cases giving a sensitivity of 89.3%. Among 9 indeterminate DCEMRI cases, tCho showed malignancy in 6 cases with type II curve. DWI detected malignancy in 54/56 cases that included 9 cases that were false negative on DCEMRI, yielding a sensitivity of 96.4%. A total of 54 cases showed malignancy when any two of the three MR parameters was positive for malignancy yielding a sensitivity of 96.4% while it increased to 100% when any one parameters showed positive result. DWI showed highest sensitivity of detection compared to DCEMRI and MRS. Multi-parametric approach yielded 96.4% and 100% sensitivity when any two or one of the three parameters was taken as positive for malignancy, respectively. Also the results demonstrated that addition of DWI and MRS play a significant role in establishing the final diagnosis of malignancy, especially in cases where DCEMRI is indeterminate. [ABSTRACT FROM AUTHOR]

The potential of total choline (tCho), apparent diffusion coefficient (ADC) and tumor volume, both individually and in combination of all these three parameters (multi-parametric approach), was evaluated in predicting both pathological and clinical responses in 42 patients with locally advanced breast cancer (LABC) enrolled for neoadjuvant chemotherapy (NACT). Patients were sequentially examined by conventional MRI; diffusion weighted imaging and in vivo proton MR spectroscopy at 4 time points (pre-therapy, after I, II, and III NACT) at 1.5 T. Miller Payne grading system was used for pathological assessment of response. Of the 42 patients, 24 were pathological responders (pR) while 18 were pathological non-responders (pNR). Clinical response determination classified 26 patients as responders (cR) while 16 as non-responders (cNR). tCho and ADC showed significant changes after I NACT, however, MR measured tumor volume showed reduction only after II NACT both in pR and cR. After III NACT, the sensitivity to detect responders was highest for MR volume (83.3% for pR and 96.2% for cR) while the specificity was highest for ADC (76.5% for pR and 100% for cR). Combination of all three parameters exhibited lower sensitivity (66.7%) than MR volume for pR prediction, however, a moderate improvement was seen in specificity (58.8%). For the prediction of clinical response, multi-parametric approach showed 84.6% sensitivity with 100% specificity compared to MR volume (sensitivity 96.2%; specificity 80%). Kappa statistics demonstrated substantial agreement of clinical response with MR volume (k = 0.78) and with multi-parametric approach (k = 0.80) while moderate agreement was seen for tCho (k = 0.48) and ADC (k = 0.46). The values of k for tCho, MR volume and ADC were 0.31, 0.38, and 0.18 indicating fair, moderate, and slight agreement, respectively with pathological response. Moderate agreement (k = 0.44) was observed between clinical and pathological responses. Our study demonstrated that both tCho and ADC are strong predictors of assessment of early pathological and clinical responses. Multi-parametric approach yielded 100% specificity in predicting clinical response. Following III NACT, MR volume emerged as highly suitable predictor for both clinical and pathological assessments. PCA demonstrated separate clusters of pR vs. pNR and cR vs. cNR at post-therapy while with some overlap at pre-therapy. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the utility of fat fraction (FF) for the differentiation of different breast tissues and in various breast tumor subtypes using in vivo proton ( 1 H) magnetic resonance spectroscopy (MRS). Methods 1 H MRS was performed on 68 malignant, 35 benign, and 30 healthy volunteers at 1.5 T. Malignant breast tissues of patients were characterized into different subtypes based on the differences in the expression of hormone receptors and the FF was calculated. Further, the sensitivity and specificity of FF to differentiate malignant from benign and from normal breast tissues of healthy volunteers was determined using receiver operator curve (ROC) analysis. Results A significantly lower FF of malignant (median 0.12; range 0.01–0.70) compared to benign lesions (median 0.28; range 0.02–0.71) and normal breast tissue of healthy volunteers (median 0.39; range 0.06–0.76) was observed. No significant difference in FF was seen between benign lesions and normal breast tissues of healthy volunteers. Sensitivity and specificity of 75% and 68.6%, respectively was obtained to differentiate malignant from benign lesions. For the differentiation of malignant from healthy breast tissues, 76% sensitivity and 74.5% specificity was achieved. Higher FF was seen in patients with ER−/PR− status as compared to ER+/PR+ patients. Similarly, FF of HER2neu+ tumors were significantly higher than in HER2neu− breast tumors. Conclusion The results showed the potential of in vivo 1 H MRS in providing insight into the changes in the fat content of different types of breast tissues and in various breast tumor subtypes. [ABSTRACT FROM AUTHOR]

The role of apparent diffusion coefficient (ADC) in the diagnosis of breast cancer and its association with molecular biomarkers was investigated in 259 patients with breast cancer, 67 with benign pathology, and 54 healthy volunteers using diffusion-weighted imaging (DWI) at 1.5 T. In 59 breast cancer patients, dynamic contrast-enhanced MRI (DCEMRI) was also acquired. Mean ADC of malignant lesions was significantly lower (1.02 ± 0.17 x 10-3 mm²/s) compared to benign (1.57 ± 0.26 x 10-3 mm²/s) and healthy (1.78 ± 0.13 x 10-3 mm²/s) breast tissues. A cut-off ADC value of 1.23 x 10-3 mm²/s (sensitivity 92.5%; specificity 91.1%; area under the curve 0.96) to differentiate malignant from benign diseases was arrived by receiver operating curve analysis. In 10/59 breast cancer patients, indeterminate DCE curve was seen, while their ADC value was indicative of malignancy, implying the potential of the addition of DWI in increasing the specificity of DCEMRI data. Further, the association of ADC with tumor volume, stage, hormonal receptors [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor (HER2)], and menopausal status was investigated. A significant difference was seen in tumor volume between breast cancer patients of stages IIA and IIIA, IIB and IIIA, and IIB and III (B + C), respectively (P < 0.05). Patients with early breast cancer (n = 52) had significantly lower ADC and tumor volume than those with locally advanced breast cancer (n = 207). No association was found in ADC and tumor volume with the menopausal status. Breast cancers with ER-, PR-, and triple-negative (TN) status showed a significantly larger tumor volume compared to ER+, PR+, and nontriple- negative (nTN) cancers, respectively. Also, TN tumors showed a significantly higher ADC compared to ER+, PR+, and nTN cancers. Patients with ER- and TN cancers were younger than those with ER+ and nTN cancers. The present study demonstrated that ADC may increase the diagnostic specificity of DCEMRI and be useful for treatment management in clinical setting. Additionally, it provides an insight into characterization of molecular types of breast cancer and may serve as an indicator of metabolic reprogramming underlying tumor proliferation. [ABSTRACT FROM AUTHOR]

Diffusion weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique that provides information on in vivo diffusion of water molecules in tissues which is referred as apparent diffusion coefficient (ADC). The advantage of DWI is the intrinsic tissue contrast it provides because of its sensitivity to the changes in cellular environment. Malignant breast tissues are characterized by low ADC while benign breast tissues and normal breast tissues of volunteers show high ADC values. Addition of DWI as an adjunct to the contrast-enhanced MRI of breast lesions has been shown to improve the specificity and the diagnostic accuracy. Despite significant technical improvements in DWI, small lesions are sometimes difficult to visualize on ADC maps due to low spatial resolution and it is often difficult to differentiate non-mass like lesions using ADC values. Further, ADC values have the potential to delineate necrotic portions of the tumor from the viable tumor regions. Studies have shown that DWI has the potential to predict early response of tumors to therapeutic intervention in breast tumors. In recent years, numerous applications of DWI in breast tissue evaluation have been documented; however, there is a need for standardized methods for acquisition and processing of diffusion data for effective clinical applications. [ABSTRACT FROM AUTHOR]

Abstract: We carried out retrospective analysis of apparent diffusion coefficient (ADC) values in 48 infiltrating ductal breast cancer patients who had dynamic contrast-enhanced magnetic resonance imaging (DCEMRI; Group I) and in 53 patients (Group II) for whom DCEMRI data were not available. Twenty-three patients of Group I showed no necrosis (Group Ia), while in 25 patients, both viable (nonnecrotic) and necrotic tumor areas (Group Ib) were observed on DCEMRI. T1-weighted, fat-suppressed and short inversion recovery images were used to identify the viable and necrotic tumor areas in Group II patients, and necrosis was not seen in 11 patients (Group IIa), while 42 (Group IIb) showed both viable and necrotic tumor areas. The ADCs of the necrotic area of Group Ib (1.79±0.30 ×10−3 mm2/s) and Group IIb (1.83±0.40 ×10−3 mm2/s) patients were similar and significantly higher (P<.01) compared to the ADCs of the viable tumor area of Group Ia (0.96±0.21 ×10−3 mm2/s) and Group IIa (0.90±0.17 ×10−3 mm2/s) patients. Proton MR spectroscopy (MRS) data were also available in these patients, and the ADC values were retrospectively determined from the voxel from which MR spectrum was obtained. These values were compared with the ADC obtained for the viable and necrotic areas of the tumor. ADC of the MRS voxel was similar to that obtained for the viable tumor area in patients of both groups. This interesting observation reveals the potential utility of using ADC values to identify viable tumor area for positioning of voxel for MRS in the absence of DCEMRI data. [Copyright &y& Elsevier]

Synchronous breast cancer (SBC) refers to one or more breast cancers detected either simultaneously or within a few months of the primary index cancer. This retrospective study included a cohort of 464 early breast cancer patients with ER+/HER2- receptor status, of which 34 patients diagnosed with 44 SBC (34 ipsilateral, 10 contralateral) were studied. As their work is limited to the SBC patients with ER+/HER2- receptor status, future studies may incorporate the other receptor statuses as well as explore the relationship between the receptor status and the imaging phenotypes. [Extracted from the article]

Using one-dimensional (1D) and two-dimensional (2D) proton nuclear magnetic resonance (NMR) methods, the perchloric acid extract of involved (n = 11) and noninvolved (n = 12) axillary lymph nodes (ALN) of breast cancer patients was investigated. Resonances from 40 metabolites such as lactate (Lac), glucose, several amino acids (alanine, lysine, glutamic acid, glutamine, etc.), nucleotides (adenosine triphosphate, guanosine triphosphate, uridine triphosphate, uridine monophosphate, etc.), membrane metabolites [glycerophosphocholine (GPC), phosphocoline (PC), phosphoethanolamine (PE), choline] were unambiguously assigned in both the involved and noninvolved ALN. The concentration of PC/GPC (p = 0.002) was significantly higher in the involved compared to noninvolved nodes. In addition, the concentration of glycolytic product Lac (p = 0.0001) was also found to be significantly higher in involved nodes. Increased concentration of membrane metabolites PC/GPC may be attributed to increased membrane synthesis in malignant cells and, therefore, suggests the presence of metastatic cells in lymph nodes. The higher concentration of Lac is indicative of the presence of malignant cells that derive energy via anaerobic glycolytic pathway. Present results demonstrate the potentials of in vitro proton NMR in detecting malignant cells in ALN and such studies may have an important bearing in determining the prognosis of breast cancer patients. [Copyright &y& Elsevier]

Abstract: Focused pathological evaluation of axillary lymph nodes in breast cancer is gaining importance. Nuclear magnetic resonance (NMR) spectroscopy that assesses the whole of the specimen has the potential in evaluating micrometastases. The biochemical changes associated with breast cancer metastases in axillary nodes by in vitro NMR and its use in the detection of axillary metastases in a clinical setting in comparison with conventional histopathology is presented in this study. Eighty-eight lymph nodes obtained from 30 patients with breast cancer were investigated. Histopathology revealed metastases in 20 nodes from 11 patients, while in vitro NMR spectroscopy revealed metastases in 22 nodes. Out of these 22 nodes, 16 were the same, which showed metastases on histopathology, while 6 nodes have shown metastases only on in vitro magnetic resonance spectroscopy (MRS). These 6 nodes with suspicion of metastases on MRS were subjected to reevaluation with serial sectioning and immunohistochemistry, but no additional metastases were revealed. Forty metabolites could be identified from the MR spectrum of lymph nodes. The levels of the glycerophosphocholine-phosphocholine (GPC-PC), choline, lactate, alanine and uridine diphosphoglucose were elevated significantly in nodes with metastases. In addition, the intensity ratio of GPC-PC/threonine (Thr) was higher in nodes with metastases, and using this as marker, MRS detected the axillary metastases with a sensitivity, specificity and accuracy of 80%, 91% and 88%, respectively. Neoadjuvant chemotherapy (NACT) lowered the concentrations of GPC-PC and GPC-PC/Thr ratio. The accuracy of MRS in detecting metastases was 75% in patients who received NACT (n=9) as compared to 96% in those who did not (n=21). Our results demonstrate the potential of in vitro MRS in characterizing the metabolite profile of the axillary nodes with breast cancer metastases. It detected axillary metastases with reasonable accuracy and can be complementary to histopathological evaluation and immunohistochemistry. [Copyright &y& Elsevier]