Prognostic Impact of CD38- and IgκC-Positive Tumor-Infiltrating Plasma Cells in Triple-Negative Breast Cancer.

Due to a higher mutational load, triple-negative breast cancer (TNBC) is characterized by a higher immunogenicity compared to other subtypes. In this context, we analyzed the prognostic significance of tumor-infiltrating plasma cells in a cohort of 107 triple-negative breast cancer patients. Tumor-infiltrating plasma cells were analyzed via immunohistochemistry using the plasma cell markers CD38 and IgκC. The prognostic impact of the CD38 and IgκC expression was evaluated using the Kaplan-Meier plots and Cox regression analyses. A Spearman-Rho correlation coefficient was used to evaluate a possible association between plasma cell infiltration and the BRCA mutation status. The study cohort consisted of 107 patients with early-stage TNBC, who were treated between 2009 and 2016 at the Department of Gynecology and Obstetrics, University Medical Center Mainz, Germany. The median follow-up was five years. The Kaplan-Meier survival analysis showed that higher tumor infiltration with CD38-positive plasma cells was associated with significantly longer metastasis-free survival (MFS) (p = 0.039 Log Rank). In the multivariate Cox regression analysis for metastasis-free survival, in which additional clinicopathological factors (age, tumor size, nodal status, and grading) were considered, CD38 was identified as an independent prognostic factor within the analyzed cohort (HR 0.438, 95% CI 0.195-0.983; p = 0.045). In addition to the CD38 expression, the nodal status was also identified as an independent prognostic factor in multivariate Cox regression. Regarding the IgκC expression, a higher IgκC expression was shown to be associated with a better outcome, although this effect was not statistically significant. Furthermore, we were able to show a significant correlation between plasma cell infiltration and the BRCA mutation status. A favorable prognostic significance of tumor-infiltrating plasma cells could be demonstrated in triple-negative breast cancer immunohistochemically analyzed for the CD38 and IgκC expression. CD38 was identified as an independent prognostic factor via multivariate Cox regression.

Prognostic Significance of Interferon-γ and Its Signaling Pathway in Early Breast Cancer Depends on the Molecular Subtypes.

Interferons are crucial for adaptive immunity and play an important role in the immune landscape of breast cancer. Using microarray-based gene expression analysis, we examined the subtype-specific prognostic significance of interferon-γ (IFN-γ) as a single gene as well as an IFN-γ signature covering the signaling pathway in 461 breast cancer patients. Prognostic significance of IFN-γ, as well as the IFN-γ signature for metastasis-free survival (MFS), were examined using Kaplan-Meier as well as univariate and multivariate Cox regression analyses in the whole cohort and in different molecular subtypes. The independent prognostic significance of IFN-γ as a single gene was limited to basal-like breast cancer (hazard ratio (HR) 2.779, 95% confidence interval (95% CI) 1.117-6.919, p = 0.028). In contrast, the IFN-γ-associated gene signature was an independent prognostic factor in the whole cohort (HR 2.287, 95% CI 1.410-3.633, p < 0.001) as well as in the basal-like (HR 3.458, 95% CI 1.154-10.359, p = 0.027) and luminal B (HR 2.690, 95% CI 1.416-5.112, p = 0.003) molecular subtypes. These results underline the subtype-dependent prognostic influence of the immune system in early breast cancer.

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.

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 active role of the transcription factor Sp1 in NFATc2-mediated gene regulation in pancreatic cancer.

BACKGROUND: Adenocarcinoma of the pancreas is one of the most aggressive tumor diseases affecting the human body. The oncogenic potential of pancreatic cancer is mainly characterized by extremely rapid growth triggered by the activation of oncogenic signaling cascades, which suggests a change in the regulation of important transcription factors. Amongst others, NFAT transcription factors are assumed to play a central role in the carcinogenesis of pancreatic cancer. Recent research has shown the importance of the transcription factor Sp1 in the transcriptional activity of NFATc2 in pancreatic cancer. However, the role of the interaction between these two binding partners remains unclear. The current study investigated the role of Sp1 proteins in the expression of NFATc2 target genes and identified new target genes and their function in cells. A further objective was the domain of the Sp1 protein that mediates interaction with NFATc2. The involvement of Sp1 proteins in NFATc2 target genes was shown by means of a gene expression profile analysis, and the results were confirmed by quantitative RT-PCR. The functional impact of this interaction was shown in a thymidine incorporation assay. A second objective was the physical interaction between NFATc2 and different Sp1 deletion mutants that was investigated by means of immunoprecipitation. RESULTS: In pancreatic cancer, the proto-oncogene c-Fos, the tumor necrosis factor TNF-alpha, and the adhesion molecule integrin beta-3 are target genes of the interaction between Sp1 and NFATc2. Loss of just one transcription factor inhibits oncogenic complex formation and expression of cell cycle-regulating genes, thus verifiably decreasing the carcinogenic effect. The current study also showed the interaction between the transcription factor NFATc2 and the N-terminal domain of Sp1 in pancreatic cancer cells. Sp1 increases the activity of NFATc2 in the NFAT-responsive promoter. CONCLUSIONS: The regulation of gene promotors during transcription is a rather complex process because of the involvement of many proteins that - as transcription factors or co-factors - regulate promotor activity as required and control cell function. NFATc2 and Sp1 seem to play a key role in the progression of pancreatic cancer.

A retrospective analysis of immunohistochemically determined IRF4 (interferon regulating factor 4) expression in a consecutive cohort of 114 ovarian cancer patients.

BACKGROUND: Tumor-infiltrating lymphocytes influence the prognosis of solid tumors, including ovarian cancer (OC). The immunoregulatory transcription factor (IRF4) is mainly expressed in plasma cells and regulates immunoglobulin class switch recombination as well as plasma cell differentiation. Therefore, we analyzed the impact of IRF4 expression in a consecutive cohort of OC patients. METHODS: IRF4 expression was evaluated by immunostaining. Differences in IRF4 expression among the subgroups of the established clinical-pathological features like age, histological subtype, tumor stage, histological grading, postoperative tumor burden, and completeness of chemotherapy were determined by χ2 test. The impact of IRF4 expression on progression-free survival (PFS) and overall survival (OS) was examined by univariate and multivariate Cox analysis adjusted for established clinical-pathological factors and Kaplan-Meier survival analysis. RESULTS: 114 patients entered this study. IRF4 was expressed in 51.7% of the entire cohort. 72.3% patients with high-grade serous OC showed IRF4 expression compared to 37.3% patients with a non-high-grade serous OC (p < 0.001). Univariate Cox-regression analysis revealed no prognostic impact of IRF4 expression in terms of PFS (p = 0.35) and OS (p = 0.98). Kaplan-Meier plots failed to show any prognostic impact for PFS (p = 0.35) and OS (p = 0.98), too. Established clinical-pathological factors retained their prognostic impact as tumor stage in terms of PFS (< 0.001) and as postoperative residual tumor burden (p = 0.04), tumor stage (< 0.001), histological grade (p = 0.02), and completeness of chemotherapy (p < 0.001) in terms of OS, respectively. CONCLUSION: Immunohistochemically determined IRF4 expression correlated with high-grade serous OC. However, it failed to show any prognostic impact in this cohort of 114 patients.

Prognostic impact of CD4-positive T cell subsets in early breast cancer: a study based on the FinHer trial patient population.

BACKGROUND: The clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer. We investigated the clinical significance of CD4, forkhead box P3 (FOXP3), and B cell attracting chemokine leukocyte chemoattractant-ligand (C-X-C motif) 13 (CXCL13) in early breast cancer. METHODS: The study is based on the patient population of the randomized FinHer trial, where 1010 patients with early breast cancer were randomly allocated to adjuvant chemotherapy containing either docetaxel or vinorelbine, and human epidermal growth factor receptor 2 (HER2)-positive patients were also allocated to trastuzumab or no trastuzumab. Breast cancer CD4, FOXP3, and CXCL13 contents were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), and their influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates in the entire cohort and in selected molecular subgroups. Interactions between variables were analyzed using Cox regression. The triple-negative breast cancer (TNBC) subset of the HE10/97 randomized trial was used for confirmation. RESULTS: High CXCL13 was associated with favorable DDFS in univariable analysis, and independently in multivariable analysis (HR 0.44, 95% CI 0.29-0.67, P ≤ 0.001), most strongly in TNBC (HR 0.39, 95% CI 0.19-0.79, P = 0.009). No significant interaction with chemotherapy or trastuzumab administration was detected. Neither tumor CD4 content nor FOXP3 content was associated with DDFS. The favorable prognostic influence of CXCL13 was confirmed in the HE10/97 trial patient population with TNBC (HR 0.30, 95% CI 0.09-0.93; P = 0.038). CONCLUSIONS: The results provide a high level of evidence that humoral immunity influences the survival outcomes of patients with early breast cancer, in particular of those with TNBC. TRIAL REGISTRATION: The study reports retrospective biomarker analyses in the prospective FinHer trial and the prospective HE10/97 trial. ISRCTN76560285 . Registered on 18 March 2005. ACTRN12611000506998 . Registered on 16 May 2011.

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.

Interaction between NFATc2 and the transcription factor Sp1 in pancreatic carcinoma cells PaTu 8988t.

BACKGROUND: Nuclear factors of activated T-cells (NFATs) have been mainly characterized in the context of immune response regulation because, as transcription factors, they have the ability to induce gene transcription. NFAT proteins are found in several types of tumors, for instance, pancreatic carcinoma. The role of NFATs in carcinogenesis is regulating central genes in cell differentiation and cell growth. NFAT proteins are primarily located in cytoplasm and only transported to the cell nucleus after activation. Here, they interact with other transcription factors cooperating with NFAT proteins, thus influencing the selection and regulation of NFAT-controlled genes. To identify and characterize possible interaction partners of the transcription factor NFATc2 in pancreatic carcinoma cells PaTu 8988t. METHODS: NFATc2 expression and the mode of action of Ionomycin in the pancreatic tumor cell lines PaTu 8988t were shown with Western blotting and immunofluorescence tests. Potential partner proteins were verified by means of immunoprecipitation and binding partners, their physical interactions with DNA pull-down assays, siRNA technologies, and GST pull-down assays. Functional evidence was complemented by reporter-promoter analyses. RESULTS: NFATc2 and Sp1 are co-localized in cell nuclei and physically interact at the NFAT target sequence termed NFAT-responsive promotor construct. Sp1 increases the functional activity of its binding partner NFATc2. This interaction is facilitated by Ionomycin in the early stimulation phase (up to 60 min). CONCLUSIONS: Oncological therapy concepts are becoming more and more specific, aiming at the efficient modulation of specific signal and transcription pathways. The oncogenic transcription partner Sp1 is important for the transcriptional and functional activity of NFATc2 in pancreatic carcinoma. The binding partners interact in cells. Further studies are necessary to identify the underlying mechanisms and establish future therapeutic options for treating this aggressive type of tumor.

Validation of a two-tier grading system in an unselected, consecutive cohort of serous ovarian cancer patients.

PURPOSE: New insights into the carcinogenesis of ovarian cancer (OC) lead to the definition of low-grade and high-grade serous OC. In this study, we validated the MD Anderson Cancer Center (MDACC) two-tier grading system and compared it with the traditional three-tier grading system as suggested by the International Federation of Gynecology and Obstetrics (FIGO). METHODS: Consecutive patients with serous OC were enrolled. These two grading systems were assessed independently from each other. Kaplan-Meier estimates and Cox-regression analyses were performed to validate and compare their prognostic impact. RESULTS: 143 consecutive patients entered the study. According to the Kaplan-Meier estimates, the MDACC grading system (p = 0.001) predicted the progression free survival (PFS) more precisely than the FIGO system (p = 0.025). The MDACC grading system (p = 0.008) but not the FIGO system (p = 0.329) showed a statistically significant difference in terms of disease specific survival (DSS). Multivariable Cox-regression analyses revealed an independent prognostic impact of the MDACC grading system but not of the FIGO system for PFS (HR 1.570; 95 % CI 1.007-2.449; p = 0.047, and HR 0.712; 95 % CI 0.476-1.066; p = 0.099, respectively). Concerning DSS, the two-tier grading system but not the FIGO system showed a prognostic impact in a univariable Cox-regression analysis (HR 2.152; 95 % CI 1.207-3.835; p = 0.009, and HR 1.258; 95 % CI 0.801-1.975; p = 0.319, respectively). CONCLUSIONS: We were able to validate the MDACC grading system in serous OC. Moreover, this grading system was stronger associated with survival than the FIGO system.

Management of recurrent or metastatic endometrial cancer in Germany: results of the nationwide AGO pattern of care studies from the years 2013, 2009 and 2006.

PURPOSE: The available literature on the treatment options for recurrent or metastatic endometrial cancer (EC) is full of controversies. Therefore, we explore the results of the AGO pattern of care studies from the years 2013, 2009 and 2006. METHODS: A questionnaire was developed and sent to all 682 German gynecological departments in 2013 (775 in 2009, 500 in 2006, respectively). The results of the questionnaires were compared with each other using Fisher's exact test. RESULTS: Responses were available in 40.0 % in 2013, 33.3 % in 2009 and 35.8 % in 2006. In 2013 the most preferred endocrine drug was progestin (79.8 %), followed by tamoxifen (42.8 %), aromatase inhibitor (19.8 %), fulvestrant (16.3 %) and a combination (3.9 %) (p < 0.001). 65.3, 59.8, 51.7 and 38.2 % of the participants used platinum, taxane, a combination of cytostatic drugs, anthracycline in metastatic EC, respectively (p = 0.215). 96.2, 92.7, 49.8 and 60.9 % of the participants performed an operation, radiotherapy, endocrine therapy and chemotherapy in 2013 because of a local recurrence, respectively (p < 0.001). Compared to 2009 and 2006 these rates remained stable (no p value <0.05). Because of a distant metastasis 50.4, 64.2, 78.5 and 90.8 % of the participants performed an operation, radiotherapy, endocrine therapy and chemotherapy in 2013, respectively (p < 0.001). Compared to 2009 and 2006 more participants performed an operation or radiotherapy and less an endocrine treatment. CONCLUSIONS: Whereas progestin was the favorite drug, the participants of this study did not prefer a specific cytostatic drug for metastatic EC in 2013. This might have reflected the available literature, which did not provide a real standard of care.

Occurrence and Management of Immunotherapy-Associated Adverse Events in Patients with Gynecological Cancers.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have emerged as an essential therapeutic approach in treating many solid tumors. ICIs enhance the body's anti-tumor T-cell activity, resulting in a novel spectrum of immunotherapy-related side effects. This novel spectrum of adverse events differs significantly from the side effects of conventional chemotherapy. It, therefore, requires special attention in the diagnosis and management of immunotherapy-related adverse events (irAEs). The present study aimed to retrospectively analyze the incidence, diagnosis, and management of irAEs in patients with gynecologic malignancies who received ICIs and to discuss these findings in the context of the recent literature. METHODS: In the present retrospective overview, we evaluated patients with gynecologic malignancies (breast, endometrial, cervical, ovarian) who received ICIs with regard to the incidence, type, and time to onset of irAEs. A total of 61 patients treated at the Department of Gynecology and Obstetrics, University Medical Center Mainz, Germany, between 2018 and 2023 were included in the analysis. RESULTS: A total of 32.8% of patients developed an irAE of any grade or type. The median time to irAE was 24 weeks. The most frequently observed irAEs were grade 1 (20%) or 2 (35%). Immunotherapy-related grade 3 or 4 adverse events occurred in 45% of patients (40% grade 3, 5% grade 4). The most common type of irAE in our cohort was hypothyroidism, followed by hepatitis and colitis. Cox regression analysis identified the duration of ICI therapy as the only significant factor influencing the incidence of irAEs (p = 0.004). CONCLUSION: The broad spectrum of irAEs and the onset time of irAEs are important challenges of therapy with ICIs, requiring proactive monitoring and tailored management strategies to optimize the safety and efficacy of immunotherapy.

BRCA1, BRCA2 and PALB2 mRNA Expression as Prognostic Markers in Patients with Early Breast Cancer.

Breast cancer (BC) poses a challenge in establishing new treatment strategies and identifying new prognostic and predictive markers due to the extensive genetic heterogeneity of BC. Very few studies have investigated the impact of mRNA expression of these genes on the survival of BC patients. METHODS: We examined the impact of the mRNA expression of breast cancer gene type 1 (BRCA1), breast cancer gene type 2 (BRCA2), and partner and localizer of BRCA2 (PALB2) on the metastasis-free survival (MFS) of patients with early BC using microarray gene expression analysis. RESULTS: The study was performed in a cohort of 461 patients with a median age of 62 years at initial diagnosis. The median follow-up time was 147 months. We could show that the lower expression of BRCA1 and BRCA2 is significantly associated with longer MFS (p < 0.050). On the contrary, the lower expression of PALB2 was correlated with a shorter MFS (p = 0.049). Subgroup survival analysis identified the prognostic influence of mRNA expression for BRCA1 among patients with luminal-B-like BC and for BRCA2 and PALB2 in the subset of patients with luminal-A-like BC (p < 0.050). CONCLUSIONS: According to our observations, BRCA1, BRCA2, and PALB2 expression might become valuable biomarkers of disease progression.

Efficacy of pembrolizumab in advanced cancer of the vulva: a systematic review and single-arm meta-analysis.

Introduction: Vulvar cancer carries a favourable prognosis in early stages. However, therapeutic options for advanced or recurrent cases are limited despite a variety of therapeutic modalities, such as extensive surgical resection, chemotherapy, and radiotherapy. The most important emerging treatment modalities are immune checkpoint inhibitors. This systematic review and meta-analysis aims to assess the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, in women with advanced vulvar cancer. Materials and methods: Following a comprehensive search, review, and appraisal, two relevant single-arm studies were included. Meta-analysis was conducted using R4.3.0 software and RStudio 2023.03.0, presenting the overall effect size with a 95% confidence interval. Heterogeneity was assessed using I2 and the Cochrane Q χ2 statistics. Results: Out of 154 studies screened for eligibility, two single-arm studies involving 119 patients receiving pembrolizumab for advanced vulvar cancer were included. The pooled objective response rate (ORR) was overall 10% (95% CI: 0.00-0.84) and 9% (95% CI: 0.00-0.89) in the PD-L1 positive subgroup. In the intention-to-treat (ITT) population, 31% (95% CI: 0.04-0.85) exhibited any clinical benefit (complete response, partial response, or stable disease). In the ITT population at six months, progression-free survival (PFS) was 19% (95% CI: 0.01-0.82), and overall survival (OS) was 48% (95% CI: 0.08-0.90). At 12 months, PFS decreased to 9% (95% CI: 0.00-0.85), and OS was 33% (95% CI: 0.04-0.85). No statistically significant heterogeneity was observed in PFS and OS analyses. Discussion and conclusion: This study suggests that one-third of women with advanced or recurrent vulvar cancer may, without the influence of PD-L1 status, benefit from pembrolizumab treatment despite a decline in both PFS and OS at 12 months. These findings provide support for considering pembrolizumab in the treatment paradigm for this specific subset of cancer patients. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023391888.

Correction: Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

[This corrects the article DOI: 10.1055/a-2238-3153.].

Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

Introduction: Adjuvant treatment of patients with early-stage breast cancer (BC) should include an aromatase inhibitor (AI). Especially patients with a high recurrence risk might benefit from an upfront therapy with an AI for a minimum of five years. Nevertheless, not much is known about the patient selection for this population in clinical practice. Therefore, this study analyzed the prognosis and patient characteristics of postmenopausal patients selected for a five-year upfront letrozole therapy. Patients and Methods: From 2009 to 2011, 3529 patients were enrolled into the adjuvant phase IV PreFace clinical trial (NCT01908556). Postmenopausal hormone receptor-positive BC patients, for whom an upfront five-year therapy with letrozole (2.5 mg/day) was indicated, were eligible. Disease-free survival (DFS), overall survival (OS) and safety in relation to patient and tumor characteristics were assessed. Results: 3297 patients started letrozole therapy. The majority of patients (n = 1639, 57%) completed the five-year treatment. 34.5% of patients continued with endocrine therapy after the mandated five-year endocrine treatment. Five-year DFS rates were 89% (95% CI: 88-90%) and five-year OS rates were 95% (95% CI: 94-96%). In subgroup analyses, DFS rates were 83%, 84% and 78% for patients with node-positive disease, G3 tumor grading, and pT3 tumors respectively. The main adverse events (any grade) were pain and hot flushes (66.8% and 18.3% of patients). Conclusions: The risk profile of postmenopausal BC patients selected for a five-year upfront letrozole therapy showed a moderate recurrence and death risk. However, in subgroups with unfavorable risk factors, prognosis warrants an improvement, which might be achieved with novel targeted therapies.

Prognostic relevance of Ki-67 in the primary tumor for survival after a diagnosis of distant metastasis.

Prediction of the prognosis for metastatic breast cancer patients depends on molecular subtypes similar to those found in patients with primary breast cancer. Several studies have shown that estrogen receptor (ER) and progesterone receptor (PR) status determine the course of the disease and the prognosis. As Ki-67 helps to differentiate molecular subtypes in patients with primary breast cancer, the aim of this study was to assess the prognostic relevance of Ki-67 in the primary tumor in relation to its prognostic relevance for patients with metastatic breast cancer. A total of 467 patients with invasive breast cancer were identified in the database of a single breast cancer center, in whom Ki-67 had been assessed in tumor material from the breast at the time of the primary diagnosis and who had developed a metastasis at any time during the subsequent course. For these patients, tumor and patient characteristics were used to determine prognostic factors relative to overall survival after the diagnosis of distant metastases. Ki-67 was added to this model to investigate whether this might improve the prediction of overall survival. In the multivariate Cox model, age at diagnosis, body mass index, nodal status, tumor size, ER and PR status, and time from diagnosis to metastasis were identified as relevant prognostic factors. Adding Ki-67 to the model improved the prediction of overall survival. There was also a significant and relevant interaction with the PR status. In patients with a low-proliferation primary tumor, a high level of PR expression would indicate an extraordinarily good prognosis (HR 0.39; 95 % CI, 0.23-0.66). In patients with higher-proliferation primary tumors, PR status was not capable of differentiating prognostic groups. Ki-67 is useful in addition to known prognostic factors for breast cancer. It is able to indicate a group of women with a poorer prognosis, specifically in the group of patients with PR-positive breast cancer.

Immunohistochemical markers of prognosis in adult granulosa cell tumors of the ovary - a review.

BACKGROUND: Granulosa cell tumors (GCT) are rare malignant ovarian tumors. The two subtypes, adult and juvenile granulosa cell tumors, differ in clinical and molecular characteristics. GCT are low-malignant tumors and are generally associated with favorable prognosis. However, relapses are common even years and decades after diagnosis. Prognostic and predictive factors are difficult to assess in this rare tumor entity. The purpose of this review is to provide a comprehensive overview of the current state of knowledge on prognostic markers of GCT to identify patients with a high risk of recurrence. METHODS: Systematic research for adult ovarian granulosa cell tumors and prognosis revealed n = 409 English full text results from 1965 to 2021. Of these articles, n = 35 were considered for this review after title and abstract screening and topic-specific matching. A specific search for pathologic markers with prognostic relevance for GCT identified n = 19 articles that were added to this review. RESULTS: FOXL2 mutation and FOXL2 mRNA were inverse and immunohistochemical (IHC) expression of CD56, GATA-4 and SMAD3 was associated with reduced prognosis. IHC analysis of estrogen receptor, Anti-Mullerian hormone (AMH) and inhibin was not associated with prognosis for GCT. Analyses of mitotic rate, Ki-67, p53, ß-catenin and HER2 revealed inconsistent results.

Real-World Experience of Metronomic Chemotherapy in Metastatic Breast Cancer: Results of a Retrospective Unicenter Study.

Introduction: Metronomic chemotherapy (MCT) is increasingly used in oncology due to its favorable therapeutic index. There is still a lack of evidence for MCT in metastatic breast cancer (MBC). In this retrospective unicenter study, we demonstrated real-word data on MCT in MBC. Methods: MBC patients who received metronomic oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day), CTX and capecitabine (CAPE) (500 mg thrice daily), CTX, or vinorelbine (VRL) (30 mg daily) alone for at least 4 weeks between 2009 and 2021 were included. The primary endpoint was disease control rate (DCR) ≥24 weeks. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Patient characteristics and therapy response were analyzed using χ2 test. For survival analyses, Kaplan-Meier estimator and log-rank test were used. Results: Seventy-two patients were identified. Sixty-two patients received CTX/MTX, three CTX/CAPE, two CTX, and five VRL. Median age at diagnosis MBC and at start of MCT was 59.0 years and 64.5 years, respectively. 72.2% tumors were hormone receptor positive and 27.8% were triple-negative. 54.2% patients had more than two different metastases. 80.6% patients showed visceral involvement. 31.9% patients achieved DCR ≥24 weeks. Median PFS was 17.0 weeks (95% CI 14.5-19.5) and median OS was 58.0 weeks (95% CI 29.0-87.0). MCT showed similar DCR ≥24 weeks and clinically meaningful but not statistically significant shorter median PFS compared to prior therapy (31.9% versus 32.8% [p = 0.570] and 17.0 weeks versus 20.0 weeks [p = 0.093], respectively) and statistically significant higher DCR ≥24 weeks and longer median PFS compared to subsequent therapy (31.9% versus 17.4% [p = 0.038] and 17.0 weeks versus 12.0 weeks [p = 0.006], respectively). Three (4.2%) patients terminated MCT because of toxicity. Conclusion: In this real-world retrospective study, MCT was effective and well tolerated and may thus represent a valuable treatment option in selected MBC patients.

Effects of intermittent fasting on quality of life tolerance of chemotherapy in patients with gynecological cancers: study protocol of a randomized-controlled multi-center trial.

Fatigue is a very common side effect during intravenous chemotherapy. Unfortunately, only few effective therapeutic options are available, mostly based on daily activity. In our pilot trial we were able to demonstrate that intermittent fasting can reduce fatigue in healthy people, thus we aimed to assess the effects of the fasting dietary on quality of life during chemotherapy in patients with gynecological cancer, especially on the domain of fatigue. The IFAST trial is designed as a prospective, randomized-controlled, multi-center trial. Participation will be offered to women with gynecological cancers (breast cancer, ovarian cancer including peritoneal and fallopian tube cancers, endometrial cancer and cervical cancer) who are planned to receive intravenous chemotherapy for at least three months. Eligible patients will be randomized 1:1, stratified by tumor type and study center. Primary endpoint is the difference in mean change in fatigue, assessed with the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT- FS©). Exploratory secondary endpoints will include general Quality of Life impairment, tolerance of chemotherapy, immunological changes, peripheral cell damage in blood cells, as well as tumor response to chemotherapy. There is new evidence that prolonged fasting periods of 46-96 hours during chemotherapy can positively influence the quality of life during chemotherapy. However, these fasting regiments are not feasible for many patients. Intermittent fasting could be a feasible (manageable) option for many patients to actively improve their quality of life and tolerance to chemotherapy and possibly even enhance the effectiveness of chemotherapy. Trial Registration: https://drks.de, identifier DRKS00031429.