Primary results of the AGO-Zervix-1 Study: A prospective, randomized phase III study to compare the effects of paclitaxel and topotecan with those of cisplatin and topotecan in the treatment of patients with recurrent and persistent cervical cancer.

BACKGROUND: Before the era of immunotherapies and antibody-drug conjugates, there were limited chemotherapeutic options for patients with recurrent and metastatic cervical cancer. Combination therapies with cisplatin have shown some superiority over monotherapy. This study examined platinum-free treatment regimens, comparing a combination of topotecan and paclitaxel (TP) with topotecan and cisplatin (TC) in patients with recurrent or metastatic cervical cancer, with or without prior platinum-based treatment. METHODS: The AGO-Zervix-1 Study (NCT01405235) is a prospective, randomized phase III study in which patients were randomly assigned at a 1:1 ratio to treatment within the control arm with topotecan (0.75 mg/m2) on days 1-3 and cisplatin (50 mg/m2) on day 1 every 3 weeks and in the study arm topotecan (1.75 mg/m2) and paclitaxel (70 mg/m2) on days 1, 8, and 15 every 4 weeks or treatment. The primary study aim was overall survival; progression-free survival, toxicity, and quality of life were secondary aims. The interim and final analysis is here reported after recruitment of 173 of 312 planned patients. RESULTS: Median overall survival in the TP arm was 9.6 months, compared with 12.0 months in the TC arm (log-rank test, P = 0.33). Median progression-free survival rates were 4.4 months with TP and 4.2 months with TC (log-rank test, P = 0.47). Leukopenia and nausea/vomiting were more frequent in the cisplatin-containing arm. Otherwise, toxicity profiles were comparable. There were no differences in FACT-G-assessed quality of life. CONCLUSION: Platinum-based combination chemotherapy remains the standard of care chemotherapy regimen for patients with recurrent or metastatic cervical cancer.

Correlation of RANK and RANKL with mammographic density in primary breast cancer patients.

PURPOSE: The receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) have been shown to promote proliferation of the breast and breast carcinogenesis. The objective of this analysis was to investigate whether tumor-specific RANK and RANKL expression in patients with primary breast cancer is associated with high percentage mammographic density (PMD), which is a known breast cancer risk factor. METHODS: Immunohistochemical staining of RANK and RANKL was performed in tissue microarrays (TMAs) from primary breast cancer samples of the Bavarian Breast Cancer Cases and Controls (BBCC) study. For RANK and RANKL expression, histochemical scores (H scores) with a cut-off value of > 0 vs 0 were established. PMD was measured in the contralateral, non-diseased breast. Linear regression models with PMD as outcome were calculated using common predictors of PMD (age at breast cancer diagnosis, body mass index (BMI) and parity) and RANK and RANKL H scores. Additionally, Spearman rank correlations (ρ) between PMD and RANK and RANKL H score were performed. RESULTS: In the final cohort of 412 patients, breast cancer-specific RANK and RANKL expression was not associated with PMD (P = 0.68). There was no correlation between PMD and RANK H score (Spearman's ρ = 0.01, P = 0.87) or RANKL H score (Spearman's ρ = 0.04, P = 0.41). RANK expression was highest in triple-negative tumors, followed by HER2-positive, luminal B-like and luminal A-like tumors, while no subtype-specific expression of RANKL was found. CONCLUSION: Results do not provide evidence for an association of RANK and RANKL expression in primary breast cancer with PMD.

Return of individual genomic research results within the PRAEGNANT multicenter registry study.

PURPOSE: The PRAEGNANT study is a registry study for metastatic breast cancer patients, focusing on biomarker detection. Recently, within this study, genetic alterations in 37 breast cancer predisposition genes were analyzed and genetic findings were detected for 396 participants. The aim of this project was to return genetic results to the physicians and to analyze actions taken (e.g., disclosure of results to patients, validation of results, clinical impact, and impact on the patient's quality of life) using a questionnaire. METHODS: 235 questionnaires were sent out to the study centers, with each questionnaire representing one patient with a genetic finding. The questionnaire consisted of twelve questions in the German language, referring to the disclosure of results, validation of test results, and their impact on treatment decisions and on the patient's quality of life. RESULTS: 135 (57.5%) questionnaires were completed. Of these, 46 (34.1%) stated that results were returned to the patients. In 80.0% (N = 36) of cases where results were returned, the patient had not been aware of the finding previously. For 27 patients (64.3%), genetic findings had not been validated beforehand. All validation procedures (N = 15) were covered by the patients' health insurance. For 11 (25.0%) patients, physicians reported that the research results influenced current or future decision-making on treatment, and for 37.8% (N = 17) the results influenced whether family members will be genetically tested. CONCLUSION: This study provides novel insights into the return of research results and into clinical and personal benefits of disclosure of genetic findings within a German registry.

Learning laparoscopic hysterectomy: analysis of different surgeons' individual learning curves.

OBJECTIVE: The aim of this study was to examine the development of surgical skills among surgeons learning total laparoscopic hysterectomy (TLH), using differences in complication rates between surgeons with different levels of experience and analyzing the development of individual operating times. STUDY DESIGN: This retrospective, single-center cohort study included 576 total laparoscopic hysterectomy procedures conducted between January 2015 and December 2019 at the municipal hospital in Karlsruhe, Germany. All TLHs were performed by eight surgeons, two of whom were experienced and six inexperienced. Complications were graded using the Clavien-Dindo classification. RESULTS: No differences in complication rates were seen between experienced and inexperienced surgeons. With growing numbers of procedures, most surgeons quickly became faster, leading to reduced operating times. However, experienced surgeons who had performed more than 100 procedures also became faster, not reaching a time plateau after adjustment for weight of the uterus, presurgery score, and adnexal score. CONCLUSIONS: Learning laparoscopic hysterectomy in routine practice is safe for patients, and surgeons rapidly become faster as growing numbers of procedures are performed. Operating times for experienced surgeons who have carried out more than 100 operations also improve, and a time plateau is not reached.

Genetic variants in the genes of the sex steroid hormone metabolism and depressive symptoms during and after pregnancy.

PURPOSE: The aim of this study was to conduct an association analysis of depressive symptoms and polymorphisms in the ESR1, PGR, CYP19A1, and COMT genes in pregnant and postpartum women. METHODS: The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for assessment of maternal and fetal health. The German version of the 10-item Edinburgh Postnatal Depression Scale (EPDS) was completed at three time points in this prospective cohort study. Visit 1 was at study entry in the third trimester of pregnancy, visit 2 was shortly after birth, and visit 3 was 6-8 months after birth. Germline DNA and depression measurements from 361 pregnant women were available for analysis. Six single nucleotide polymorphisms (SNPs) in the above-mentioned genes were genotyped. After reconstruction of haplotypes for PGR (rs1042838 and rs10895068) and CYP19A1 (rs10046 and rs4646), a multifactorial linear mixed model was applied to the data to describe the association between haplotypes and depression values. The single SNPs for ESR1 (rs488133) and COMT (rs4680) were analyzed separately using linear mixed models analogously. RESULTS: The mean antepartum EPDS measurement was 5.1, the mean postpartal measurement after 48-72 h was 3.5, and the mean value 6-8 months postpartum was 4.2. The SNPs in PGR were reconstructed into three haplotypes. The most common haplotype was GG, with 63.43% of patients carrying two copies and 33.52% carrying one copy. For haplotype GA, the group of carriers of two copies (0.28%) was combined with the carriers of one copy (9.70%). Haplotype reconstruction using CYP19A1 SNPs resulted in three haplotypes. The most common haplotype was TC, with 25.48% of patients carrying two copies and 51.52% one copy. None of the haplotype blocks and neither of the two single SNPs showed any significant associations with EPDS values. CONCLUSIONS: The candidate haplotypes analyzed in PGR and CYP19A1 and single SNPs in ESR1 and COMT did not show any association with depression scores as assessed by EPDS in this cohort of healthy unselected pregnant women.

The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C.

BACKGROUND: Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy. METHODS: Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models. RESULTS: AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89-1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80-1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86-1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77-1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3-4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology. CONCLUSION: For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy.

Genetic variants in the glucocorticoid pathway genes and birth weight.

PURPOSE: The aim of this study was to examine associations between single nucleotide polymorphisms (SNPs) that tag genetic variation in the glucocorticoid pathways (particularly in maternal genes FKBP5, NR3C1, and CRHR1) and birth weight. METHODS: The Franconian Maternal Health Evaluation Study (FRAMES) recruited healthy pregnant women prospectively for the assessment of maternal and fetal health. Germline DNA was collected from 375 pregnant women. Nine SNPs in the above-mentioned genes were genotyped. After reconstruction of haplotypes for each gene, a linear regression model was applied to the data to describe the association between haplotypes and birth weight. RESULTS: Female sex in the newborn (compared to male) was associated with lower birth weight, whereas a later week of gestation, higher body mass index pre-pregnancy, and higher parity were associated with higher birth weight. No association with birthweight was shown for the haplotypes of the selected SNPs. CONCLUSIONS: In this cohort of healthy unselected pregnant women, the analyzed candidate haplotypes in FKBP5, NR3C1, and CRHR1 did not show any association with birth weight. This might be in line with several other studies that have found no influence of fetal polymorphisms in the glucocorticoid receptor gene or triggers of the maternal HPA axis such as stress and psychosocial problems on birth weight. However, the small sample size in this study and the lack of consideration of individual risk factors and levels of stress in this cohort needs to be taken into account when interpreting the results.

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial.

BACKGROUND: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. METHODS: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. RESULTS: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. CONCLUSION: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. TRIAL REGISTRATION: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

Impact of fibroblast growth factor receptor 1 (FGFR1) amplification on the prognosis of breast cancer patients.

PURPOSE: Various aberrations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3 are found in different cancers, including breast cancer (BC). This study analyzed the impact of FGFR amplification on the BC prognosis. METHODS: The study included 894 BC patients. The amplification rates of FGFR1, FGFR2, and FGFR3 were evaluated on tissue microarrays using fluorescence in situ hybridization (FISH). Associations between these parameters and prognosis were analyzed using multivariate Cox regression analyses. RESULTS: FGFR1 FISH was assessable in 503 samples, FGFR2 FISH in 447, and FGFR3 FISH in 562. The FGFR1 amplification rate was 6.6% (n = 33). Increased FGFR2 copy numbers were seen in 0.9% (n = 4); only one patient had FGFR3 amplification (0.2%). Most patients with FGFR1 amplification had luminal B-like tumors (69.7%, n = 23); only 32.6% (n = 153) of patients without FGFR1 amplification had luminal B-like BC. Other patient and tumor characteristics appeared similar between these two groups. Observed outcome differences between BC patients with and without FGFR1 amplification did not achieve statistical significance; however, there was a trend toward poorer distant metastasis-free survival in BC patients with FGFR1 amplification (HR = 2.08; 95% CI 0.98 to 4.39, P = 0.05). CONCLUSION: FGFR1 amplification occurs most frequently in patients with luminal B-like BC. The study showed a nonsignificant correlation with the prognosis, probably due to the small sample size. Further research is therefore needed to address the role of FGFR1 amplifications in early BC patients. FGFR2 and FGFR3 amplifications are rare in patients with primary BC.

Heregulin (HRG) assessment for clinical trial eligibility testing in a molecular registry (PRAEGNANT) in Germany.

BACKGROUND: Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry. METHODS: Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor-positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria. RESULTS: Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive. CONCLUSION: Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials. TRIAL REGISTRATION: Clinicaltrials, NCT02338167 , Registered 14 January 2015 - retrospectively registered.

Analysis of motives and patient satisfaction in oncological second opinions provided by a certified university breast and gynecological cancer center.

PURPOSE: Second opinions in oncology are becoming increasingly important in an era of more complex treatments and a growing demand for information by patients. Therefore, we analyzed their effects and influencing factors like patients' motives, subjective extent of information and satisfaction with communications. METHODS: This prospective study evaluated second opinions for patients with breast cancer or gynecological malignancy. The patients received a questionnaire before and two months after, which inquired expectations, reasons, and satisfaction with the second opinion and the attending physicians. RESULTS: A total of 164 patients were included and the majority had breast cancer (75.0%). Receiving the second opinion made 89.7% feel better informed, their need for information decreased (from 75.3% to 39.2%, P < 0.0001), and satisfaction with doctor-patient communications increased (from 61.9 to 91.8%, P = 0.0002). There were various reasons for requesting a second opinion, e.g., the extremely stressful situation of a cancer diagnosis, hope for change in the treatment recommendation or dissatisfaction with the initial physicians. CONCLUSIONS: Second opinions can lead to significantly greater patient satisfaction, meeting the need for information and leading to better management of patients in the extremely stressful situation of a cancer diagnosis. Doctor-patient communications play a key role.

Preexisting musculoskeletal burden and its development under letrozole treatment in early breast cancer patients.

One of the most common adverse events (AEs) occurring during treatment with aromatase inhibitors (AIs) is musculoskeletal pain. The aim of our study was to analyze the influence of preexisting muscle/limb pain and joint pain on the development of AI-induced musculoskeletal AEs. Women eligible for upfront adjuvant endocrine therapy with letrozole were included in the PreFace study, a multicenter phase IV trial. During the first treatment year, they were asked to record musculoskeletal AEs monthly by answering questions regarding pain symptoms and rating the pain intensity on a numeric rating scale from 0 (no pain) to 10 (very strong pain). Pain values were compared using nonparametric statistical tests. Overall, 1,416 patients were evaluable. The average pain value over all time points in women with preexisting muscle/limb pain was 4.3 (median 4.3); in those without preexisting pain, it was 2.0 (median 1.7). In patients without preexisting muscle/limb pain, pain levels increased relatively strongly within the first 6 months (mean increase +0.9, p < 0.00001) in comparison with those with preexisting pain (mean increase +0.3, p < 0.001), resulting in a statistically significant difference (p < 0.00001) between the two groups. The development of joint pain was similar in the two groups. Women without preexisting muscle/limb pain or joint pain have the greatest increase in pain after the start of adjuvant AI therapy. Women with preexisting pain have significantly higher pain values. The main increase in pain values takes place during the first 6 months of treatment.

Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer.

PURPOSE: Several clinical trials have investigated the prognostic and predictive usefulness of molecular markers. With limited predictive value, molecular markers have mainly been used to identify prognostic subgroups in which the indication for chemotherapy is doubtful and the prognosis is favorable enough for chemotherapy to be avoided. However, limited information is available about which groups of patients may benefit from additional therapy. This study aimed to describe the prognostic effects of Ki-67 in several common subgroups of patients with early breast cancer. METHODS: This retrospective study analyzed a single-center cohort of 3140 patients with HER2-, hormone receptor-positive breast cancer. Five-year disease-free survival (DFS) rates were calculated for low (< 10%), intermediate (10-19%), and high (≥ 20%) Ki-67 expression levels, as assessed by immunohistochemistry, and for subgroups relative to age, body mass index, disease stage, tumor grade, and (neo-)adjuvant chemotherapy. It was also investigated whether Ki-67 had different effects on DFS in these subgroups. RESULTS: The 5-year DFS rates for patients with low, intermediate, and high levels of Ki-67 expression were 0.90, 0.89, and 0.77, respectively. Ki-67 was able to further differentiate patients with an intermediate prognosis into different prognostic groups relative to common clinical parameters. Patients with stage II breast cancer had 5-year DFS rates of 0.84, 0.88, and 0.79 for low, intermediate, and high levels of Ki-67 expression. Ki-67 had different prognostic effects in subgroups defined by age and tumor grade. CONCLUSIONS: Ki-67 may help identify patients in intermediate prognostic groups with an unfavorable prognosis who may benefit from further therapy.

Efficacy of neoadjuvant pertuzumab in addition to chemotherapy and trastuzumab in routine clinical treatment of patients with primary breast cancer: a multicentric analysis.

PURPOSE: Neoadjuvant combination treatment with chemotherapy (CTX), trastuzumab (TZM), and pertuzumab (PTZ) has been shown to result in higher pathological complete response rates (pCR) in comparison with treatment with chemotherapy and trastuzumab (CTX/TZM). This analysis was aimed at real-world validation of these results from prospective randomized trials. METHODS: In a retrospective analysis conducted in the PRAEGNANT network, patients were eligible for inclusion if they had either received neoadjuvant therapy with CTX/TZM or chemotherapy, trastuzumab, and pertuzumab (CTX/TZM/PTZ) and subsequently underwent surgery for their primary breast cancer. The effect of the two neoadjuvant regimens on pCR in addition to commonly applicable predictors of pCR was analyzed in 300 patients from three study sites, using logistic regression analyses with treatment arm, age, clinical tumor stage, grading, and hormone receptor status as predictors. RESULTS: pCR with complete disappearance of all tumor cells was seen in 30.2% (n = 58) of patients treated with CTX/TZM and in 52.8% (n = 57) of those treated with CTX/TZM/PTZ. CTX/TZM/PTZ was positively associated with pCR (adjusted odds ratio 2.44; 95% CI 1.49-4.02). Mastectomy rates were not influenced by the therapy. CONCLUSIONS: The results of clinical trials were confirmed in this dataset of patients who were treated outside of clinical trials in everyday routine work. pCR rates can be improved by 20% with pertuzumab in routine clinical use.

Association between breast cancer risk factors and molecular type in postmenopausal patients with hormone receptor-positive early breast cancer.

PURPOSE: Evidence shows that genetic and non-genetic risk factors for breast cancer (BC) differ relative to the molecular subtype. This analysis aimed to investigate associations between epidemiological risk factors and immunohistochemical subtypes in a cohort of postmenopausal, hormone receptor-positive BC patients. METHODS: The prospective, single-arm, multicenter phase IV PreFace study (Evaluation of Predictive Factors Regarding the Effectivity of Aromatase Inhibitor Therapy) included 3529 postmenopausal patients with hormone receptor-positive early BC. Data on their epidemiological risk factors were obtained from patients' diaries and their medical histories. Data on estrogen receptor, progesterone receptor, and HER2 receptor status were obtained from pathology reports. Patients with incomplete information were excluded. Data were analyzed using conditional inference regression analysis, analysis of variance, and the chi-squared test. RESULTS: In a cohort of 3392 patients, the strongest association with the molecular subtypes of BC was found for hormone replacement therapy (HRT) before diagnosis of early BC. The analysis showed that patients who took HRT at diagnosis had luminal A-like BC more often (83.7%) than those who had never taken HRT or had stopped taking it (75.5%). Luminal B-like BC and HER2-positive BC were diagnosed more often in women who had never taken HRT or had stopped taking it (13.3% and 11.2%, respectively) than in women who were taking HRT at diagnosis of BC (8.3% and 8.0%, respectively). CONCLUSIONS: This analysis shows an association between HRT and the distribution of molecular subtypes of BC. However, no associations between other factors (e.g., age at diagnosis, body mass index, smoking status, age at menopause, number of deliveries, age at first delivery, breastfeeding history, or family history) were noted.

The effect of participation in neoadjuvant clinical trials on outcomes in patients with early breast cancer.

BACKGROUND: Clinical trials can offer novel and more advanced and/or novel treatments to cancer patients in advance of them being approved and available for all patients. While several studies have examined the effect of clinical trial participation on prognosis, there has been no clear conclusion from these studies. Therefore, we chose to test the influence of trial participation on pathological complete response (pCR) and mastectomy rates after neoadjuvant chemotherapy. METHODS: In this retrospective study, all patients treated with neoadjuvant chemotherapy from 2001 to 2014 were selected. A total of 1038 patients with complete treatment, patient, and tumor characteristics were included. A total of 260 of those were treated in clinical trials. We examined whether study participation status in addition to commonly known predictors for pCR improves prediction of pCR. Similar analyses were conducted for the mastectomy rate outcome measure. Finally, survival analyses were also conducted as part of an exploratory analysis. RESULTS: Study participation was an independent predictor of pCR in addition to commonly known predictors. Adjusted odds ratio (OR) for trial participants versus non-participants was 1.53 (95% CI 1.03-2.28). Additionally, study participation improved the prediction of mastectomy risk. The adjusted OR for trial participants versus non-participants was 0.62 (95% CI 0.42-0.90). Subgroup-specific differences concerning the impact of study participation could not be shown for either pCR or mastectomy rate. Survival comparisons could not be conducted due to large differences in follow-up data in patients participating in clinical trials versus those who did not participate; however, pCR was a predictor of prognosis in both groups. CONCLUSION: Patients taking part in neoadjuvant chemotherapy clinical trials have a higher pCR rate and a lower mastectomy risk than patients not participating in clinical trials for their cancer care. This finding is a supporting factor for trial participation in neoadjuvant chemotherapy trials.

BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients.

PURPOSE: BRCA1/2 mutations influence the molecular characteristics and the effects of systemic treatment of breast cancer. This study investigates the impact of germline BRCA1/2 mutations on pathological complete response and prognosis in patients receiving neoadjuvant systemic chemotherapy. METHODS: Breast cancer patients were tested for a BRCA1/2 mutation in clinical routine work and were treated with anthracycline-based or platinum-based neoadjuvant chemotherapy between 1997 and 2015. These patients were identified in the tumor registry of the Breast Center of the University of Erlangen (Germany). Logistic regression and Cox regression analyses were performed to investigate the associations between BRCA1/2 mutation status, pathological complete response, disease-free survival, and overall survival. RESULTS: Among 355 patients, 59 had a mutation in BRCA1 or in BRCA2 (16.6%), 43 in BRCA1 (12.1%), and 16 in BRCA2 (4.5%). Pathological complete response defined as "ypT0; ypN0" was observed in 54.3% of BRCA1/2 mutation carriers, but only in 22.6% of non-carriers. The adjusted odds ratio was 2.48 (95% CI 1.26-4.91) for BRCA1/2 carriers versus non-carriers. Patients who achieved a pathological complete response had better disease-free survival and overall survival rates compared with those who did not achieve a pathological complete response, regardless of BRCA1/2 mutation status. CONCLUSIONS: BRCA1/2 mutation status leads to better responses to neoadjuvant chemotherapy in breast cancer. Pathological complete response is the main predictor of disease-free survival and overall survival, independently of BRCA1/2 mutation status.

Prediction of pathological complete response and prognosis in patients with neoadjuvant treatment for triple-negative breast cancer.

BACKGROUND: It has been reported that pathological complete response is an important surrogate marker for disease-free survival and overall survival in patients with triple-negative breast cancer. This study investigates predictors of the response to neoadjuvant platinum-based or anthracycline-based treatment, and of the prognosis, in patients with triple-negative breast cancer. METHODS: A total of 121 patients with triple-negative breast cancer received neoadjuvant treatment with either platinum or anthracycline between 2008 and 2013. Pathological complete response was assessed relative to different treatments using logistic regression models with age, clinical tumor stage, grading, and Ki-67 as predictors and interaction terms, to obtain adjusted and subgroup-specific results. The impact of the pathological complete response rate on disease-free survival and overall survival was also analyzed. RESULTS: The pathological complete response rate was higher after platinum/taxane treatment compared with anthracycline/taxane (50.0% vs. 41.8%), but this was not significant in the adjusted analysis (OR 1.44; 95% CI, 0.68 to 3.09). A high histological grade (G3) was a predictor for higher pathological complete response in platinum-based therapy (OR 2.27; 95% CI, 1.00 to 5.30). The effect of neoadjuvant chemotherapy on pathological complete response was significantly different for G1-2 vs. G3 (Pinteraction = 0.013), and additional subgroup-specific differences were noted. Pathological complete response was a predictor for improved disease-free survival and overall survival in both treatment groups, with and without platinum chemotherapy. CONCLUSIONS: This retrospective study of patients with triple-negative breast cancer adds to the evidence that the treatment effect of platinum may be greatest particularly in G3 tumors. In addition, the effect of pathological complete response on the prognosis does not depend on the treatment used.

Filtration based assessment of CTCs and CellSearch® based assessment are both powerful predictors of prognosis for metastatic breast cancer patients.

BACKGROUND: The assessment of circulating tumor cells (CTCs) has been shown to enable monitoring of treatment response and early detection of metastatic breast cancer (MBC) recurrence. The aim of this study was to compare a well-established CTC detection method based on immunomagnetic isolation with a new, filtration-based platform. METHODS: In this prospective study, two 7.5 ml blood draws were obtained from 60 MBC patients and CTC enumeration was assessed using both the CellSearch® and the newly developed filtration-based platform. We analyzed the correlation of CTC-positivity between both methods and their ability to predict prognosis. Overall survival (OS) was calculated and Kaplan-Meier curves were estimated with thresholds of ≥1 and ≥5 detected CTCs. RESULTS: The CTC positivity rate of the CellSearch® system was 56.7% and of the filtration-based platform 66.7%. There was a high correlation of CTC enumeration obtained with both methods. The OS for patients without detected CTCs, regardless of the method used, was significantly higher compared to patients with one or more CTCs (p < 0.001). The median OS of patients with no CTCs vs. ≥ 1 CTC assessed by CellSearch® was 1.83 years (95% CI: 1.63-2.02) vs. 0.74 years (95% CI: 0.51-1.52). If CTCs were detected by the filtration-based method the median OS times were 1.88 years (95% CI: 1.74-2.03) vs. 0.59 years (95% CI: 0.38-0.80). CONCLUSIONS: The newly established EpCAM independently filtration-based system is a suitable method to determine CTC counts for MBC patients. Our study confirms CTCs as being strong predictors of prognosis in our population of MBC patients.

Predicting attention deficit hyperactivity disorder using pregnancy and birth characteristics.

PURPOSE: The aim of this study was to evaluate maternal, prenatal, perinatal, and postpartum parameters as risk factors for the later development of an attention deficit hyperactivity disorder (ADHD) in the child. METHODS: Women who had given birth at Erlangen University Hospital between 1996 and 1999 were sent a questionnaire in 2009. The results of the questionnaire were correlated with the prospectively collected data for the births in 1996-1999. RESULTS: A total of 573 mother and child pairs were analyzed. Forty-four of the mothers reported that their child had ADHD (7.7%). No significant associations were found for the following parameters: mother's age; mother's educational level; number of the pregnancy; maternal weight before and at the end of pregnancy; mother's height; alcohol consumption during pregnancy; mode of delivery; gestational week; birthweight; umbilical artery blood values; Apgar score at 5 and 10 min; or breastfeeding. The parameters of smoking in pregnancy and an Apgar score lower than 7 after 1 min were significantly associated with a risk for later development of ADHD. CONCLUSIONS: This analysis of maternal, prenatal, perinatal, and postnatal parameters found that smoking in pregnancy and a low Apgar score 1 min after birth are associated with a significantly greater risk for the development of ADHD. Beyond the question of the causal mechanism involved, this is a relevant finding, since smoking during pregnancy is a preventable risk factor.