Dynamic Contrast-enhanced MRI To Predict Response Of Breast Cancer After Neoadjuvant Chemotherapy And The Association With Molecular Subtypes

Part I Dynamic contrast-enhanced MRI to predict response for breast cancer patients undergoing neoadjuvant chemotherapyObjective To investigate whether dynamic contrast-enhanced MRI (DCE-MRI) could predict final pathologic response in primary breast cancer patients undergoing neoadjuvant chemotherapy (NAC).Materials and Methods112patients (age range,23-67years; median age,48years) with primary breast carcinoma and scheduled to receive NAC were recruited from May2011to January2014. DEC-MRI examination was performed before NAC and after2cycles of treatment. The longest diameters of three dimension, the semi-quantitative parameters maximum slope of increase (MSI), signal enhancement ratio at the second phase (SI2%) and the peak (SIpeak%), positive enhancement integral (PEI), maximum slope of decrease (MSD), time to peak (TTP) with ROIwhole and ROIhs, and the quantitative parameters volume transfer constant (Ktrans), rate constant (Kep) and extravascular extracellular space fractional volume (Ve) with ROIWhole were measured. Histological response was categorized as major histological response (MHR) and non-major histological response (NMHR). The baseline parameters and the ones after2cycles of NAC of both MHR and NMHR were compared. Moreover, parameter changes after2cycles of NAC, as well as the baseline parameters were compared between MHR and NMHR. Independent-samples (or paried-sampels) T test was used for the normal distribution and independent-samples (or related-sampels) nonparametric test for the abnormal distribution. Receiver operating characteristic curve (ROC) was used to determine the best predictor and cutoff value and the predictive efficiency of the two ROI methods was compared.Results Among the72patients included in the semi-quantitative study,19are grouped into MHR and53are NMHR.17are enrolled in MHR and53are NMHR for quantitative analysis. The longest diameters before NAC and the ones after2cycles of NAC are significantly different in both MHR and NMHR (P<0.001). In MHR, there is significant difference between DCE-MRI parameters of the baseline and the ones after2cycles of NAC (P<0.05). In NMHR, the DEC-MRI parameters are significantly different except MSD(ROIWhole), MSD(ROIhs), TTP(ROIhs), Kepand Ve (P value are0.615,0.205,0.085,0.118and0.236, respectively). The changes of the longest diameters and DCE-MRI parameters show significantly different between MHR and NMHR (P<0.05). There is more dramatic decline in MHR than in NMHR. Pretreatment parameters have no significant difference between the two groups (P>0.05). The ROC curve analysis indicates that area under the curve(AUR), sensitivity, specificity, accuracy and the cutoff value are0.908,84.2%,92.5%,-43.7%for the change of geometric mean of the three longest diameters (ΔG), and are0.890.16.5%,93.3%,-54.8%for the change of KeP. AUR of MSI, SI2%, SIPeak%, PEI and MSD changes for predicting NAC between the two ROC methods are compared with P value0.769,0.588,0.490,0.807and0.793, respectively.Conclusion DCE-MRI parameters can predict final pathologic response in primary breast cancers after2cycles of NAC. However, the baseline parameters haven’t possessed the predictive ability. The changes of G and Kep are the better predictors. The two ROI methods have the comparable predictive efficiency. Part Ⅱ Association of of dynamic contrast-enhanced MRI parameters with molecular subtypes of breast carcinomaObjective To explore dynamic contrast-enhanced MRI (DCE-MRI) in patients with different subtypes of breast carcinoma, and the association between DCE-MRI parameters and prognostic factors.Materials and Methods112patients from part I with primary breast carcinoma and scheduled to receive neoadjuvant chemotherapy (NAC) were recruited between May2011and January2014. DEC-MRI examination was performed before treatment. The semi-quantitative parameters maximum slope of increase (MSI), signal enhancement ratio at the second phase (SI2%) and the peak (SIpeak%), positive enhancement integral (PEI),1maximum slope of decrease (MSD), time to peak (TTP) with ROIwhole and ROIhs, and the quantitative parameters volume transfer constant (Ktrans), rate constant (Kep) and extravascular extracellular space fractional volume (Ve) with ROIwhole were measured. ER, PR, HER-2and Ki-67were obtained by immunohistochemistry (IHC) SP method and those of HER-2(++) were further tested by fluorescence in situ hybridization (FISH) analysis. Then four subtypes of Luminal A, Luminal B, HER-2+and triple-negative breast cancer (TNBC) were established. Independent-samples T test or Mann-Whitney U test was used to compare the DCE-MRI parameters between different receptors status. The semi-quantitative parameters of different subtypes were compared by one way ANOVA and pairwise comparision of the quantitative parameters was performed by Mann-Whitney U test. Results Among the101available cases for semi-quantitative analysis,4are excluded forno FISH test.15are Luminal A,56are Luminal B,12are HER-2+, and14are TNBC.MSD of PR+is significantly higher than that of PR-(P=0.002,0.016). MSI of HER-2+is significantly higher than that of HER-2-(P=0.021,0.011). SI2%(ROIwhole) of PR-is significantly higher than that of PR+(P=0.031). TTP(ROIhs) of HER-2-is significantly higher than that of HER-2+(P=0.029). The other semi-quantitative parameters have no significant difference between different receptors status (P>0.05). There is no significant difference of the semi-quantitative parameters between different subtypes except MSD(ROIwhole)(P=0.045). However, futher pairwise comparision for MSD(ROIwhole) doesn’t showed any significant difference. Among the82patients included in the quantitative study,3are excluded for no FISH test.13are Luminal A,42are Luminal B.11are HER-2+, and13are TNBC. There is no significant difference between different receptors status (P>0.05). Ktrans for Luminal A showes significant difference from TNBC and HER-2+(P=0.026,0.047). Kep between Luminal B and TNBC haven’t significant difference (P=0.013). There is no significant difference for any other two subtypes.Conclusion MSD of PR+is significantly higher than those of PR-. MSI of HER-2overexpression is significantly higher than the nomal one’s. Ktrans for TNBC and HER-2+is significantly higher than Luminal A. Kep for TNBC is significantly higher than Luminal B. On the other hand, TNBC and HER-2+are high perfusion tumors, Luminal A and Luminal B are just the opposite. Every molecular subtype of breast carcinoma reveals unique biological characteristics. Part III Dynamic contrast-enhanced MRI predicting response for breast cancer after neoadjuvant chemotherapy in various subtypesObjective To evaluate the relevance of breast cancer subtypes for dynamic contrast-enhanced MRI (DCE-MRI) parameters predicting response of breast cancer after neoadjuvant chemotherapy (NAC).Materials and Methods112patients with primary breast carcinoma and scheduled to receive NAC were recruited from May2011to January2014. DEC-MRI examination was performed before NAC and after2cycles of treatment. The longest diameters of three dimension, the semi-quantitative parameters maximum slope of increase (MSI), signal enhancement ratio at the second phase (SI2%) and the peak (SIpeak%), positive enhancement integral (PEI), maximum slope of decrease (MSD), time to peak (TTP) with ROIwhoie and ROIhs, and the quantitative parameters volume transfer constant (Ktrans), rate constant (Kep) and extravascular extracellular space fractional volume (Ve) with ROIwhole were measured. Histological response was categorized as major histological response (MHR) and non-major histological response (NMHR). ER. PR, HER-2and Ki-67were obtained by immunohistochemistry (IHC) SP method and those of HER-2(++) were further tested by fluorescence in situ hybridization (FISH) analysis. Then four subtypes of Luminal A, Luminal B, HER-2+and triple-negative breast cancer (TNBC) were established. Factors which affect the consistency between pathology results and imaging evaluation, were screened from age, tumor morphology, chemotherapy regimen and molecular subtype by binary Logistic regression. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy for predicting NAC of different breast cancer subtypes were calculated.Results Among the69patients included,19are grouped into MHR and50are NMHR.9are Luminal A,39are Luminal B,8are HER-2+, and13are TNBC. Molecular subtype is filtered as the only factor which affects the consistency, especially for SIpeak%(ROIwhole), MSD(ROIwhole) and SI2%(ROIhs). The odds ratios are2.580,0.437and2.569, respectively. The quantitative parameters (Ktrans, Kep and Ve), as well as laterolateral diameter have comparative accuracy for different subtypes. For anteroposterior diameters and MSD (ROIwhole), Luminal (accuracy:87.5%,89.6%) is more accurate than HER-2+(accuracy:75.0%,87.5%) and TNBC (accuracy:76.9%,61.5%). For craniocaudal diameters and semi-quantitative parameters MSI(ROIWhole), SI2%(ROIwhole), SIpeak%(ROIwhole), PEI(ROIwhole), MSI(ROIhs), SI2%(ROIhs), SIpeak%(ROIhs), PEI(ROIhs), MSD(ROIhs), Luminal has the poor accuracy (68.7%,77.1%,70.8%,62.5%,73.0%,79.2%,64.6%,64.6%,66.7%and72.9%, respectively) and HER-2+(accuracy:100.0%,87.5%,87.5%,87.5%,87.5%,100.0%,100.0%,87.5%,87.5%and100.0%, respectively)and TNBC (accuracy:92.3%,100.0%,100.0%,100.0%,100.0%,100.0%,100.0%,100.0%,92.3%and84.6%, respectively) are just the reverse. Conclusion The quantitative parameters, as well as laterolateral diameter obtained on delayed images (high resolution) show considerable accuracy for predicting response of breast cancer after NAC regardless of molecular subtypes. For most of the semi-quantitative parameters, TNBC and HER-2+are more accurate than Luminal breast cancer.