[Chemobrain]. / Chemobrain.

Over the past ten years, in oncology there is an increased interest in understanding the cognitive dysfunction caused by chemotherapy also known as chemobrain or chemofog. As a result of oncological therapies the number of survivors of malignant diseases has increased considerably, but the side effects also appear to be more prevalent and severe including persistent cognitive symptoms. Symptoms of chemobrain include memory impairment, loss of concentration, speech and psychomotor deceleration, attention and learning coordination problems, and disturbance of executive functions. The symptoms may be transient but are often long-lasting, the latter negatively affecting functionality and quality of life. Structural and functional imaging studies (MRI, fMRI, PET) and neuropsychological tests are not consistent in the diagnosis of chemobrain. Several factors are suspected leading to the appearance of symptoms, but the specific patomechanism is not yet known. Nutrition status, age, anemia, inflammatory cytokines, stress, and depression can all affect the quality of life and may be related to cognitive symptoms. Currently, there is no treatment strategy for preventing or alleviating cognitive impairement related to chemobrain, and several pharmacotherapies are under investigation. Results imply that understanding the patomechanism of chemobrain can also yield a deeper understanding of cognitive dysfunction associated with depression.

Morphological and pathological response in primary systemic therapy of patients with breast cancer and the prediction of disease free survival: a single center observational study.

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.

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.

Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors.

Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian cancer genes BRCA1 and BRCA2. In the remaining cases, the disease is caused by acquired somatic genetic and epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), have emerged in treating cancers associated with germline BRCA mutations since 2014. The first PARPi was FDA-approved initially for ovarian cancer patients with germline BRCA mutations. Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency status have been strong predictors of response to PARPi in a few solid tumors since then. However, the relevance of somatic BRCA mutations is less clear. Somatic BRCA-mutated tumors might also respond to this new class of therapeutics. Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.

Cerebral iodized lipid embolization via a pulmonary arteriovenous shunt: rare complication of transcatheter arterial embolization for hepatocellular carcinoma.

We report the first European case of cerebral iodized lipid embolism post transcatheter arterial embolization for hepatocellular carcinoma. Lipiodol emboli and corresponding multifocal brain ischemia were documented with computed tomography (CT) and magnetic resonance (MR) in the acutely symptomatic patient. Transcranial Doppler sonography with contrast indicated a right-to-left shunt, while on a follow-up CT scan lipiodol embolization was detected in both lungs. Dilated pulmonary vessels and thick vascular channels were seen in the vicinity of the right diaphragm suggestive of pulmonary arteriovenous shunt. The patient symptoms regressed with supportive care alone, but he died 5 months later due to hepatic failure unrelated to the procedure.

Influence of the duration of type 2 diabetes mellitus on colorectal cancer outcomes.

Type 2 diabetes mellitus (T2DM) is a progressive disease, which affects colorectal cancer (CRC) survival. However, data on the relationship between CRC survival and T2DM duration is scarce and controversial. A retrospective observational study was conducted. Sub-cohorts were created based on the duration of T2DM as follows, ≤ or > 5/10/15/20 years. 204 of the 817 (24.95%) included study participants had T2DM at any point of CRC. 160 of the 204 CRC + T2DM patients had detailed T2DM duration data. At the time of CRC diagnosis, 85, 50, 31, and 11 patients had T2DM for > 5/10/15/20 years, respectively, which increased to 110, 71, 45, and 17 during the course of the study. Despite constant glycated hemoglobin values throughout the study, shorter overall and disease-specific survival times were observed for the > 5/10/15 years cohorts and longitudinal survival modeling techniques confirmed the significant effect of T2DM duration in all cohorts. While in the first 3 years after CRC diagnosis, the best survival was found for the ≤ 5 years cohort, all diabetes cohorts had the same survival thereafter. T2DM duration affected CRC survival significantly, therefore, a closer follow-up of this sub-populations is suggested.

[The role of FDG-PET-CT in the evaluation of primary systemic therapy in breast cancer: links between metabolic and pathological remission]. / Az FDG-PET-CT szerepe az emlorák primer szisztémás kezelése során: a metabolikus változások és a patológiai remisszió összefüggései.

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.

[Morphological and immunophenotypical heterogeneity in breast cancers of young and elderly women]. / Fiatal- és idõskori emlõdaganatok morfológiai és molekuláris sajátosságai közötti összefüggések.

There is a reasonable heterogeneity in the morphological appearance and the immunohistochemical properties of distinct breast tumors. Furthermore, it is also known that cancer arising in young women have different prognosis than the ones developing in the elderly. We analyzed breast tumors of 41 young (<35 years) and 33 older women (>65 years) regarding histopathological properties and immunohistochemical reactions for ER, PgR, HER2 and Ki-67, as well as HER2 FISH. The longest diameters, thus largest available surface areas of the tumors were included in the evaluation. Different regions were marked for morphology and in all immunohistochemical reactions. The regions in the distinct tumors showing different pathological and immunohistochemical appearance were identical (p<0.001). The number of morphologically different tumor regions were more frequent in tumors developing in the young (1.82 vs. 1.48 regions/tumor), and 53.6% of tumors with heterogeneous architecture were in young vs. 39.4% in the elderly. However, regarding HER2 staining, cancers in the young patients have shown greater variability among the different tumor areas (p=0.007). The origin of tumor cells predicting prognosis remains undetermined. Whether the analysis of the expression pattern of the whole tumor is conducted or the minute regions are separately examined and averaged, the same results can be achieved. With the development of molecular techniques and accurate prognostic and treatment information rendered to samples the question may be soon answered.

[Treatment of pregnancy associated breast cancer]. / A várandósság alatti emlorák kezelése.

Pregnancy-associated breast cancer (PABC) is defined as cancer of the breast diagnosed during pregnancy and up to 1 year postpartum. The crude incidence is 1/3000 pregnant women. As women delay childbearing the incidence of PABC increases with age. Young patients with PABC do not have worse prognosis compared with those with non-PABC; however, pregnancy can contribute to a delay in breast cancer diagnosis, evaluation, and treatment. Primary care physicians and gynecologists should be careful in the thorough workup of breast symptoms in the pregnant population to expedite diagnosis and allow multidisciplinary treatment as early as possible following the established diagnosis. Authors report a case of a 30-year-old pregnant woman, who detected inflammatory signs of her right breast and a palpable axillary mass at the 21st week of gestation. Her symptoms did not improve with administration of antibiotics. Therefore fine needle aspiration biopsy of the axillary lump was performed, with the result of unequivocal diagnosis of metastatic invasive carcinoma. The patient was referred to the multidisciplinary tumor board of our Department at the 27st week of gestation with the symptoms of inflammatory breast cancer, palpable right axillary and supraclavicular lymph nodes. Core biopsy showed an ER and PR negative, Her-2 positive, grade 3, infiltrating ductal carcinoma of the breast. After multidisciplinary team consultation the patient declined any kind of therapy during her pregnancy. On the 30th week of gestation caesarean section was performed. The premature baby girl was treated in the Neonatal Intensive Care Unit. Imaging modalities revealed no evidence of distant metastases short after the delivery. After 6 cycles of chemotherapy (docetaxel-doxorubicin-cycclophosphamid) the patient underwent right mastectomy and axillary lymph node dissection. Complete pathological response was diagnosed, since no residual tumor was found in the surgical resection specimen. After radiotherapy, trastuzumab medication was initiated. To date, there is no evidence of local recurrence or distant metastases during her 24 months follow-up. The newborn is on close neurohabilitation follow-up due to the evidence of generalized muscle dystonia. Had the patient accepted chemotherapy, the damage of the newborn baby would have been avoidable.

[Comparison of breast cancer in young and old women based on clinicopathological features]. / A fiatal- és idoskori emlorák összehasonlítása klinikopatológiai jellemzok alapján.

The two far ends of the age at the diagnosis of breast cancer are the age of younger than 35, and that of older than 70. Most probably, these two groups of patients differ in many ways. The aim of our present study was to underline the fact that age at the diagnosis of breast cancer is indeed a prognostic factor. Between October 1995 and March 2009, 80 old and 51 young breast cancer patients were treated at the Department of Diagnostic Radiology and Oncotherapy, Semmelweis University, Budapest. The prognostic and predictive factors of the tumors were analysed together with the disease-free and overall survival data. There were statistically significant differences between the two groups concerning the menstrual and reproductive factors, histological characteristics and immunophenotype of the tumors. Tumor size, nodal status and the Nottingham Prognostic Index did not show statistically significant differences. A trend to a shorter disease-free survival, higher rate of distant metastases and disease-specific death was seen in the group of young patients, but it was not significant. Overall survival was significantly shorter in the group of young patients. Therefore, we can state that young patients have a more aggressive disease and worse outcome. There is an increased importance of self examination in these groups, since both age groups are beyond the age limits of the screening population in Hungary. The media and primary school education as well should be involved in educating women concerning this aspect. The individual follow-up of young patients with positive family history should also be established.

Prognostic and Clinicopathological Correlations of Cell Cycle Marker Expressions before and after the Primary Systemic Therapy of Breast Cancer.

We aimed to analyze the expression of cell-cycle regulation markers - minichromosome maintenance protein 2 (MCM2), Ki-67, Cyclin-A and phosphohistone-H3 (PHH3) - in pre-treatment core-biopsy samples of breast carcinomas in correlation with known predictive and prognostic factors. Totally 52 core biopsy samples obtained prior to neoadjuvant therapy were analyzed. Immunohistochemistry was performed to analyze the expression of MCM2, Ki-67, Cyclin A and PHH3, which were correlated with the following clinicopathological parameters: clinical TNM, tumor grade, biological subtype, the presence of tumor infiltrating lymphocytes (TIL), pathological tumor response rate to the neoadjuvant therapy and patient survival. All investigated markers showed higher expression in high grade and in triple negative tumors (p < 0.01 and p < 0.05, respectively). Hormone receptor negative tumors showed significantly higher expression of Ki-67 (p < 0.01), MCM2 (p < 0.01) and Cyclin A (p < 0.01) than hormone receptor positive ones. Tumors with increased TIL showed significantly higher Ki-67 expression (p = 0.04). Pattern analysis suggested that novel cell-cycle marker-based subgrouping reveals predictive and prognostic potential. Tumors with high MCM2, Cyclin A or PHH3 expression showed significantly higher rate of pathological complete remission. Tumors with early relapse (progression-free survival ≤2 years) and shortened overall survival also show a higher rate of proliferation. Our cell cycle marker (Ki-67, MCM2, Cyclin A, PHH3) based testing could identify tumors with worse prognosis, but with a favorable response to primary systemic therapy. The pattern of cell-cycle activity could also be useful for predicting early relapse, but our findings need to be further substantiated in larger patient cohorts.

[Immunohistochemical phenotype of breast carcinomas predicts the effectiveness of primary systemic therapy]. / Az emlodaganatok primer szisztémás kemoterápiára adott válasza az immunhisztokémiai fenotípus tükrében.

The purpose of the study was to identify breast cancer subtypes by immunohistochemistry likely to respond to neoadjuvant chemotherapy and to analyze the used chemotherapy regimen and the range of response rates. Analysis of a collected database was performed. Ninety-two patients were identified in our files who received neoadjuvant chemotherapy between 1998 and 2009. We used immunohistochemical profiles (ER, PgR, HER2, Ki-67 and p53) of NCB, FNAB and surgical breast specimens to subclassify the tumors. Pathological response rates were assessed following surgical removal of tumors by using the Chevallier classification. DFS and OS was measured in 88 cases from the date of definitive surgery to the date of last follow-up or death. Pathological complete or near-complete remission (pCR = Chevallier I and II) was observed in 13 of 92 cases (14.1%). According to the preoperative characteristics of the 13 tumors achieving pCR, 9 of the cases were triple negative, one of 13 was ER-/HER2+ and three of 13 ER+/HER2+. Twenty-four of 92 patients received taxane based neoadjuvant chemotherapy, 30 of 92 anthracycline based neoadjuvant chemotherapy, 33 of 92 taxane + anthracycline regimen and 2 of 92 CMF regimen. In the taxane treated group of patients the pCR rate was 29.1%, in the anthracycline group 6.6% and in the taxane + anthracycline treated group 12.1%. Concerning DFS, significant difference was observed between the Chevallier III and IV groups (p=0.006), and less events were observed in the pCR group (not significant). pCR was associated with significantly better OS (p=0.050). It seems that even limited, routinely used immunohistochemical profiling of tumors is able to predict the likelihood of pCR to neoadjuvant chemotherapy. Patients with triple negative and HER2-positive cancers are likely to achieve pCR after neoadjuvant chemotherapy.

Review of the Clinical Evidences of Modulated Electro-Hyperthermia (mEHT) Method: An Update for the Practicing Oncologist.

Background: Modulated electro-hyperthermia (mEHT) is a variation of the conventional hyperthermia which selectively targets the malignant cell membranes in order to heat the malignant tissue and sensitize the tissue to oncology treatments. Although widely applied, the formulation of guidelines for the use thereof is still in progress for many tumors. Aim: In this paper we review the literature on the effects of mEHT in cancer patients on local disease control and survival. Methodology: Our review on data presents the collected experience with capacitive hyperthermia treatments with the EHY-2000+ device (OncoTherm Ltd., Germany). A literature search was conducted in Pubmed and articles were grouped and discussed according to: trial type, animal studies, in vitro studies, and reviews. Search results from Conference Abstracts; Trial Registries; Thesis and Dissertations and the Oncothermia Journal were included in the discussions. Results: Modulated electro-hyperthermia is a safe form of hyperthermia which has shown to effectively sensitizes deep tumors, regardless of the thickness of the adipose layers. The technology has demonstrated equal benefits compared to other forms of hyperthermia for a variety of tumors. Given the effective heating ability to moderate temperatures, the improved tumor perfusion, and ability to increase drug absorption, mEHT is a safe and effective heating technology which can be easily applied to sensitize tumors which have demonstrated benefits with the addition of hyperthermia. Modulated electro-hyperthermia also appears to improve local control and survival rates and appears to induce an abscopal (systemic) response to ionizing radiation. Conclusion: Based on clinical studies, the method mEHT is a feasible hyperthermia technology for oncological applications. Concomitant utilization of mEHT is supported by the preclinical and clinical data.

Successful treatment of three synchronous primary malignant tumours-reflection on surgical, pathological and oncological aspects and decision making.

We report a case of a patient with triple synchronous primary malignancies (breast, colon, kidney) which has not been previously reported in the literature. A 70-year-old woman was diagnosed with invasive ductal carcinoma of the left breast with axillary lymph node metastasis. During the staging period, renal cell carcinoma on the left kidney and mucinous adenocarcinoma in the proximal colon were found. Since the breast tumour demonstrated favourable biology, aromatase inhibitor therapy had been started and simultaneous right colectomy and left nephrectomy was performed. Six months after the first diagnosis, left sector excision and axillary block dissection were performed. Adjuvant FEC chemotherapy was administered, followed by radiotherapy. During the 16-month follow-up period disease recurrence was not detected.

[Chemotherapy for advanced gastric cancer--our possibilities in 2007]. / Az elôrehaladott gyomorrák gyógyszeres kezelésének lehetôségei 2007-ben.

Gastric cancer is the fourth most common malignancy in Hungary. Surgery remains the mainstay of any curative treatment, however, approximately two-thirds of patients diagnosed with gastric cancer have unresectable (locally advanced and/or metastatic) disease. In that stage, palliative chemotherapy is of crucial importance. Gastric cancer is heterogeneous regarding location, etiology, histology and natural course. This diversity is reflected in the results of randomized controlled trials as well. Patient selection, location of primary, stage and pretreatment of the tumor, as well as the reference treatment, patient stratification and endpoints have varied among trials. Based on the results of the clinical trials of the past decades, gastric cancer is chemosensitive, however, patient prognosis remains very poor, with a median survival of less than one year, and therapy-associated toxicity remains an issue. Based on the aforementioned, no standard regimens have yet been established worldwide. New compounds and targeted biological treatment make the development of more effective, less toxic, individualized treatment modalities possible.

Predictive and prognostic value of FDG-PET/CT imaging and different response evaluation criteria after primary systemic therapy of breast cancer.

OBJECTIVES: (1) To predict pathological complete remission (pCR) and survival after primary systemic therapy (PST) in patients diagnosed with breast cancer by using two different PET/CT based scores: a simplified PERCIST-based PET/CT score (Method 1) and a combined PET/CT score supplemented with the morphological results of the RECIST system (Method 2) and (2) to assess the effect of different breast carcinoma subtypes on tumor response and its evaluation. METHODS: Eighty-eight patients were enrolled in the study who underwent PET/CT imaging before and after PST. PET/CTs were evaluated by changes in maximum Standardized Uptake Value (SUVmax) and tumor size. Method 1 and 2 were applied to predict pathological complete remission (pCR). Kaplan-Meier analyses for survival were performed. Classification into biological subtypes was performed based on the pre-therapeutic tumor characteristics. RESULTS: A total of 30/88 patients showed pCR (34.1 %). Comparing pCR/non-pCR patient groups, significant differences were detected by changes in SUVmax (p < 0.001) and tumor size (p < 0.001) regarding the primary breast lesions. To predict pCR, Method 2 had higher sensitivity (72.4 % vs. 44.8 %) and negative predictive value (57.9 % vs. 45.8 %) with lower false negativity rate (16 vs. 32) than Method 1. pCR rate was higher in Her2-positive and triple negative tumors. Despite the significant differences detected between the biological subtypes regarding changes in primary tumor SUVmax (p = 0.007) and size (p = 0.015), the subtypes only had significant impact on response evaluation with Method 2 and not with Method 1. In our study, neither clinical nor pathological CR were predictors of longer progression-free survival. CONCLUSIONS: Our results suggest that combined PET/CT criteria are more predictive of pCR. The effect of biological subtypes is significant on pCR rate as well as on the changes in FDG-uptake and morphological tumor response. Response evaluation with combined criteria was also able to reflect the differences between the biological behavior of breast tumor subtypes.

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.

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations.

Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common 'metastatic precursor'. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination.

Erratum: Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations.

This corrects the article DOI: 10.1038/ncomms14944.

Expression of cell cycle markers is predictive of the response to primary systemic therapy of locally advanced breast cancer.

We aimed to analyze to what extent expression of four cell cycle regulation markers-minichromosome maintenance protein (MCM2), Ki-67, cyclin A, and phosphohistone-H3 (PHH3)-predict response to primary systemic therapy in terms of pathological complete remission (pCR). In search of an accurate and reproducible scoring method, we compared computer-assisted (CA) and routine visual assessment (VA) of immunoreactivity. We included 57 patients with breast cancer in the study. The cell cycle markers were detected using immunohistochemistry on pre-therapy core biopsy samples. Parallel CA (validated by manual labeling) and standard VA were performed and compared for diagnostic agreement and predictive value for pCR. CA and VA results were dichotomized based on receiver operating characteristic analysis defined optimal cut-off values. "High" was defined by staining scores above the optimal cut-off, while "low" had staining scores below the optimal cut-off. The CA method resulted in significantly lower values for Ki-67 and MCM2 compared to VA (mean difference, -3.939 and -4.323). Diagnostic agreement was highest for cyclin A and PHH3 (-0.586 and -0.666, respectively). Regardless of the method (CA/VA) used, all tested markers were predictive of pCR. Optimal cut-off-based dichotomization improved diagnostic agreement between the CA and VA methods for every marker, in particular for MCM2 (κ = 1, p < 0.000). Cyclin A displayed excellent agreement (κ = 0.925; p < 0.000), while Ki-67 and PHH3 showed good agreement (κ = 0.789, p < 0.000 and κ = 0.794, p < 0.000, respectively). We found all cell cycle markers (Ki-67, MCM2, cyclin A, and PHH3) predictive of pCR. Diagnostic agreement between CA and VA was better at lower staining scores but improved after optimal cut-off-based dichotomization.