Morphological and pathological response in primary systemic therapy of patients with breast cancer and the prediction of disease free survival

AIM: To identify breast cancer subtypes likely to respond to primary systemic therapy (PST or neoadjuvant therapy) and to assess the accuracy of physical examination (PE) and breast ultrasonography (US) in evaluating and predicting residual size of breast carcinoma following PST. METHODS: 116 patients who received at least two cycles of PST between 1998 and 2009 were selected from a prospectively collected clinical database. Radiological assessment was done by mammography and US. Prior to PST, tumors were subclassified according to core biopsy (NCB) and/or fine-needle aspiration-based immunohistochemical profiles of NCB. Pathological response rates were assessed following the surgeries by using Chevallier classification. Tumor measurements by PE and US were obtained before and after PST. Different clinical measurements were compared with histological findings. Disease-free survival (DFS) was assessed. RESULTS: Pathological complete remission (pCR=Chevallier I/II) was observed in 25 patients (21.5%), 44% of whom had triple negative histology, 28% Her2 positive and 76% had high-grade tumor. Of 116 patients, 24 received taxane-based PST, 48 combined taxane + anthracycline treatment, 8 trastuzumab combinations, 21 anthracycline-based treatments, and 15 other treatments. In the taxane treated group, the pCR rate was 30%, in the taxane + anthracycline group 25%, in the anthracycline group 9.5%, and in trastuzumab group 37.5%. After PST, PE and US were both significantly associated with pathology (P<0.001 and P=0.004, respectively). Concerning OS, significant difference was observed between the Chevallier III and IV group (P=0.031) in favor of Chevallier III group. In the pCR group, fewer events were observed during the follow-up period. CONCLUSIONS: Our results show that even limited, routinely used immunohistochemical profiling of tumors can predict the likelihood of pCR to PST: patients with triple negative and Her2-positive cancers are more likely to achieve pCR to PST. Also, PE is better correlated with pathological findings than US

Dynamic FDG-PET/CT in the Initial Staging of Primary Breast Cancer

Our aim was to evaluate correlation between clinicopathological features (clinical T and clinical N stages; histological type; nuclear grade; hormone-receptor and HER2 status, proliferation activity and tumor subtypes) of breast cancer and kinetic parameters measured by staging dynamic FDG-PET/CT examinations. Following ethical approval and patients' informed consent we included 34 patients with 35 primary breast cancers in our prospective study. We performed dynamic PET imaging, and assessed plasma activity noninvasively. To delineate primary tumors we applied a frame-by-frame semi-automatic software-based correction of motion artefacts. FDG two-compartment kinetic modelling was applied to assess K1, k2, k3 rate coefficients and to calculate Ki (tracer flux constant) and MRFDG (FDG metabolic rate). We found that k3, Ki and MRFDG were significantly higher in higher grade (p = 0.0246, 0.0089 and 0.0076, respectively), progesterone-receptor negative (p = 0.0344, 0.0217 and 0.0132) and highly-proliferating (p = 0.0414, 0.0193 and 0.0271) tumors as well as in triple-negative and hormone-receptor negative/HER2-positive subtypes (p = 0.0310, 0.0280 and 0.0186). Ki and MRFDG were significantly higher in estrogen-receptor negative tumors (p = 0.0300 and 0.0247, respectively). Ki was significantly higher in node-positive than in node-negative disease (p = 0.0315). None of the assessed FDG-kinetic parameters showed significant correlation with stromal TIL. In conclusion, we confirmed a significant relationship between kinetic parameters measured by dynamic PET and the routinely assessed clinicopathological factors of breast cancer: high-grade, hormone-receptor negative tumors with high proliferation rate are characterized by higher cellular FDG-uptake and FDG-phosphorylation rate. Furthermore, we found that kinetic parameters based on the dynamic examinations are probably not influenced by stromal TIL infiltration

Response evaluation after primary systemic therapy of Her2 positive breast cancer - an observational cross-sectional study

AIM: To evaluate (I) trastuzumab-containing primary systemic therapy (PST) in human epidermal growth factor receptor 2 (Her2) overexpressing breast carcinomas.; (II) compare the patients who achieved and those who did not achieve pathological complete remission (pCR), and (III) analyze the accuracy of different clinical-imaging modalities in tumor response monitoring. METHODS: 188 patients who received PST between 2008 and 2014 were reviewed and 43 Her2 overexpressing breast cancer patients (28 Luminal B/Her2-positive and 15 Her2-positive) were enrolled. 26 patients received mostly taxane-based PST without trastuzumab (Group 1) and 17 patients received trastuzumab-containing PST (Group 2). We compared the concordance between pCR and complete remission (CR) defined by breast-ultrasound, CR defined by standard 18F-fluoro-deoxy-glucose positron emission tomography and computerized tomography (FDG-PET/CT) criteria (Method 1) and CR defined by a novel, breast cancer specific FDG-PET/CT criteria (Method 2). Sensitivity (sens), specificity (spec), and positive (PPV) and negative predictive values (NPV) were calculated. RESULTS: Ten patients (38.5%) in Group 1 and eight (47%) in Group 2 achieved pCR. pCR was significantly more frequent in Her2-positive than in Luminal B/Her2-positive tumors in both Group 1: (P=0.043) and Group 2: (P=0.029). PET/CT evaluated by the breast cancer specific criteria (Method 2) differentiated pCR from non-pCR more accurately in both groups (Group 1: sens=77.8%, spec=%, PPV=100%, NPV=71.4%; Group 2: sens=87.5%, spec=62.5%, PPV=70%, NPV=83.3%) than standard PET/CT criteria (Method 1) (Group 1: sens=22.2% spec=100% PPV=100% NPV=41.7%; in Group 2: sens=37.5%, spec=87.5%, PPV=75% NPV=58.3%) or breast ultrasound (Group 1, sens=83.3% spec=25% PPV=62.5% NPV=50%; Group 2, sens=100% spec=12.5% PPV=41.6% NPV=100%). CONCLUSION: The benefit of targeted treatment with trastuzumab-containing PST in Her2 overexpressing breast cancer was defined in terms of pCR rate. Luminal B/Her2-positive subtype needs further subdivision to identify patients who would benefit from PST. Combined evaluation of tumor response by our novel, breast cancer specific FDG-PET/CT criteria accurately differentiated pCR from non-pCR patients

Response evaluation after primary systemic therapy of Her2 positive breast cancer – an observational cross-sectional study

Aim To evaluate (I) trastuzumab-containing primary systemic therapy (PST) in human epidermal growth factor receptor 2 (Her2) overexpressing breast carcinomas.; (II) compare the pa - tients who achieved and those who did not achieve pathologi - cal complete remission (pCR), and (III) analyze the accuracy of different clinical-imaging modalities in tumor response moni - toring. Methods 188 patients who received PST between 2008 and 2014 were reviewed and 43 Her2 overexpressing breast can - cer patients (28 Luminal B/Her2-positive and 15 Her2-positive) were enrolled. 26 patients received mostly taxane-based PST without trastuzumab (Group 1) and 17 patients received tras - tuzumab-containing PST (Group 2). We compared the con - cordance between pCR and complete remission (CR) defined by breast-ultrasound, CR defined by standard 18F-fluoro-de - oxy-glucose positron emission tomography and computer - ized tomography (FDG-PET/CT) criteria (Method 1) and CR defined by a novel, breast cancer specific FDG-PET/CT criteria (Method 2). Sensitivity (sens), specificity (spec), and positive (PPV ) and negative predictive values (NPV ) were calculated. Results Ten patients (38.5%) in Group 1 and eight (47%) in Group 2 achieved pCR. pCR was significantly more frequent in Her2-positive than in Luminal B/Her2-positive tumors in both Group 1: ( P = 0.043) and Group 2: ( P = 0.029). PET/CT evaluated by the breast cancer specific criteria (Method 2) differentiated pCR from non-pCR more accurately in both groups (Group 1: sens = 77.8%, spec = 100%, PPV = 100%, NPV = 71.4%; Group 2: sens = 87.5%, spec = 62.5%, PPV = 70%, NPV = 83.3%) than standard PET/CT criteria (Method 1) (Group 1: sens = 22.2% spec = 100% PPV = 100% NPV = 41.7%; in Group 2: sens = 37.5%, spec = 87.5%, PPV = 75% NPV = 58.3%) or breast ultrasound (Group 1, sens = 83.3% spec = 25% PPV = 62.5% NPV = 50%; Group 2, sens = 100% spec = 12.5% PPV = 41.6% NPV = 100%). Conclusion The benefit of targeted treatment with trastu - zumab-containing PST in Her2 overexpressing breast cancer was defined in terms of pCR rate. Luminal B/Her2-positive subtype needs further subdivision to identify patients who would benefit from PST. Combined evaluation of tumor re - sponse by our novel, breast cancer specific FDG-PET/CT crite - ria accurately differentiated pCR from non-pCR patients

Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy

BACKGROUND: Studies have partly demonstrated the clinical validity of Ki-67 as a predictive marker in the neoadjuvant setting, but the question of the best cut-off points as well as the importance of this marker as a prognostic factor in partial responder/non-responder groups remains uncertain. METHODS: One hundred twenty patients diagnosed with invasive breast cancer and treated with neoadjuvant chemotherapy (NAC) between 2002 and 2013 were retrospectively recruited to this study. The optimal cut-off value for Ki-67 labeling index (LI) to discriminate response to treatment was assessed by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier curve estimation, log-rank test and cox regression analysis were carried out to reveal the association between Ki-67 categories and survival (DMFS = Distant metastases-free survival, OS = Overall survival). RESULTS: Twenty three out of 120 patients (19.2%) achieved pathologic complete remission (pCR), whereas partial remission (pPR) and no response (pNR) to neoadjuvant chemotherapy (NAC) was detected in 60.8% and 20.0%, respectively. The distribution of subtypes showed a significant difference in pathological response groups (p < 0.001). Most of the TNBC cases were represented in pCR group. The most relevant cut-off value for the Ki-67 distinguishing pCR from pNR cases was 20% (p = 0.002). No significant threshold for Ki-67 was found regarding DMFS (p = 0.208). Considering OS, the optimal cut-off point occurred at 15% Ki-67 (p = 0.006). The pPR group represented a significant Ki-67 threshold at 30% regarding OS (p = 0.001). Ki-67 and pPR subgroups were not significantly associated (p = 0.653). For prognosis prediction, Ki-67 at 30% cut-off value (p = 0.040) furthermore subtype (p = 0.037) as well as pathological response (p = 0.044) were suitable to separate patients into good and unfavorable prognosis cohorts regarding OS. However, in multivariate analyses, only Ki-67 at 30% threshold (p = 0.029), and subtype (p = 0.008) were independently linked to OS. CONCLUSIONS: NAC is more efficient in tumors with at least 20% Ki-67 LI. Both Ki-67 LI and subtype showed a significant association with pathological response. Ki-67 LI represented independent prognostic potential to OS in our neoadjuvant patient cohort, while pathological response did not. Additionally, our data also suggest that if a tumor is non-responder to NAC, increased Ki-67 is a poor prognostic marker

Prognostic impact of progesterone receptor expression in HER2-negative luminal B breast cancer

Aim: The new classification of breast cancer is based on microarray studies. Within the estrogen receptor (ER) positive breast carcinoma subtype further subgroups could be identified. In the present study, we analyzed the Her2 negative, highly proliferative subgroup (Luminal B1-like, LUMB1) with emphasis on their clinicopathological characteristics and progesterone receptor (PR) expression. Patients and methods: Our retrospective study concerned the period between 2000 and 2010. 158 patients were selected with ER positive, Her2 negative, Ki67>15% breast cancer. The pathological and clinical data were collected and analyzed. Age, tumor grade and stage, ER, PR, Her2 and Ki67 expression were recorded. The clinicopathological variables were correlated to PR expression. Results: The mean age of the patients was 57.5 (28-75) years. The ratio of patients younger than 40, was 8.86%. Shorter metastasis-free survival was observed in this young age group (P=0.044). The majority of our cases belonged to the pT1-pT2 stages (41.28% and 44.95%, respectively) whereas pT3 and T4 stage was detected in 5.50% and 8.25% of the cases, respectively. Almost half of the cases had no axillary lymph node metastasis (pN0: 48.91%), 1-3 lymph node metastases were detected in 38.04% (pN1), 4-10 metastatic lymph nodes were identified in 9.78% (pN2) and pN3 stage was found in 3.26% of the cases. Most commonly the tumors were either grade 2 or 3 (44.16% and 45%, respectively). The median value of Ki67 labeling index was 30%. Disease progression was detected in 36.19% of the patients. According to PR expression, a tendency to better prognosis (i.e. longer disease free- and overall survival) was detected in cases showing >10% PR positivity. However, no difference was found regarding tumor size, axillary stage, grade and age when comparing lower and higher PR expressing tumors. Conclusions: LUMB1 breast carcinomas are typically grade 2 and grade 3, the Ki67 labeling index is often 30% or higher. Distant metastases occur in more than one third of the cases. Within this subgroup, those cases with low PR expression represent a poor prognostic cohort. These findings require further investigations in larger number of LUMB1 breast cancer cases

Az FDG-PET-CT szerepe az emlőrák primer szisztémás kezelése során: a metabolikus változások és a patológiai remisszió összefüggései = The Role of FDG-PET-CT in the Evaluation of Primary Systemic Therapy in Breast Cancer: Links Between Metabolic and Pathological Remission

Introduction: FDG-PET-CT is highly sensitive in detection of viable tumour tissue, giving an importance for that in oncological diagnostics. Aim: The authors analysed retrospectively the relationship between metabolic response and changes in Ki-67, a proliferation marker. Methods: Staging FDG-PET-CT scans (before and after therapy) SUVs (Standardized Uptake Value), and morphological changes in the primary tumour and axillary lymph node region were evaluated in 30 patients with breast cancer. Calculated ΔSUV were compared with Ki-67 proliferation marker (measured in biopsies and surgical specimens). Results: The decrease of SUV and size were significant in the primary tumour and the axillary lymph node region. Decrease of Ki-67 was significant. Significant correlation was found between Ki-67 and SUV before therapy, initial Ki-67 and ΔSUV, and ΔKi-67 and ΔSUV. Conclusions: The metabolic changes were more sensitive in the measurement of the therapeutic response than morphological remission, and they correlated well with the pathological response, in not standardized clinical conditions even. Orv. Hetil., 2012, 153, 1958–1964. </jats:p