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.

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.

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.

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.

Current Approaches to the Management of Sentinel Node Procedures in Early Vulvar Cancer in Germany: A Web-Based Nationwide Analysis of Practices.

BACKGROUND: Lymph node involvement is the most important prognostic factor for recurrence and survival in vulvar cancer. Sentinel node (SN) procedure can be offered in well-selected patients with early vulvar cancer. This study aimed to assess current management practices with respect to the sentinel node procedure in women with early vulvar cancer in Germany. METHODS: A Web-based survey was conducted. Questionnaires were e-mailed to 612 gynecology departments. Data were summarized as frequencies and analyzed using the chi-square test. RESULTS: A total of 222 hospitals (36.27%) responded to the invitation to participate. Among the responders, 9.5% did not offer the SN procedure. However, 79.5% evaluated SNs by ultrastaging. In vulvar cancer of the midline with unilateral localized positive SN, 49.1% and 48.6% of respondents, respectively, would perform ipsilateral or bilateral inguinal lymph node dissection. Repeat SN procedure was performed by 16.2% of respondents. For isolated tumor cells (ITCs) or micrometastases, 28.1% and 60.5% of respondents, respectively, would perform inguinal lymph node dissection, whereas 19.3% and 23.8%, respectively, would opt for radiation without further surgical intervention. Notably, 50.9% of respondents would not initiate any further therapy and 15.1% would opt for expectant management. CONCLUSIONS: The majority of German hospitals implement the SN procedure. However, only 79.5% of respondents performed ultrastaging and only 28.1% were aware that ITC may affect survival in vulvar cancer. There is a need to ensure that the management of vulvar cancer follows the latest recommendations and clinical evidence. Deviations from state-of-the-art management should only be after a detailed discussion with the concerned patient.

Anti-tumor effects of low-dose metronomic vinorelbine in combination with alpelisib in breast cancer cells.

In metastatic breast cancer (MBC), PIK3CA mutations, activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway seem to be associated with chemotherapy resistance and poor outcome. Inhibition of the PI3K signaling pathway may lead to sensitization and prevention of the development of resistance to cytotoxic drugs. The present study aimed to investigate the anti-tumor activity of low-dose vinorelbine (VRL) combined with alpelisib, an α-selective PI3K inhibitor and degrader, in breast cancer (BC) cells. Human BC cell lines MCF-7, T-47D [both hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated], MDA-MB-231 and BT-549 (both triple-negative, wild-type PIK3CA) were exposed to a combination of low-dose VRL and alpelisib for 3 and 7 days. Cell viability was detected by the Alamar blue assay, and cell proliferation was determined by the BrdU incorporation. The effect of the substances on the p110α protein expression that is encoded by PIK3CA gene was investigated by Western blot. Low-dose VRL plus alpelisib showed synergistic anti-tumor effects and significantly inhibited cell viability and proliferation of MCF-7 and T-47D cells. Even lower alpelisib concentrations (10 ng/ml and 100 ng/ml) combined with low-dose metronomic VRL led to a significant reduction of cell viability of PIK3CA-mutated cells, and the anti-tumor activity was comparable with the effects at 1000 ng/ml alpelisib. Cell viability and proliferation of MDA-MB-231 and BT-549 cells were inhibited by VRL but not by alpelisib alone. This indicates that alpelisib did not significantly affect the cell growth of triple-negative, PIK3CA wild-type BC cells. The p110α expression was downregulated or not affected in PIK3CA-mutated cell lines, and not significantly upregulated in PIK3CA wild-type cell lines. In conclusion, combination of low-dose metronomic VRL and alpelisib showed synergistic anti-tumor effects and significantly inhibited the growth of HR-positive, HER2-negative, PIK3CA-mutated BC cells, providing a rationale for further efforts to evaluate this combination in vivo.

Discordance of HER2-Low between Primary Tumors and Matched Distant Metastases in Breast Cancer.

We examined differences in HER2 expression between primary tumors and distant metastases, particularly within the HER2-negative primary breast cancer cohort (HER2-low and HER2-zero). The retrospective study included 191 consecutive paired samples of primary breast cancer and distant metastases diagnosed between 1995 and 2019. HER2-negative samples were divided into HER2-zero (immunohistochemistry [IHC] score 0) and HER2-low (IHC score 1+ or 2+/in situ hybridization [ISH]-negative). The main objective was to analyze the discordance rate between matched primary and metastatic samples, focusing on the site of distant metastasis, molecular subtype, and de novo metastatic breast cancer. The relationship was determined by cross-tabulation and calculation of Cohen's Kappa coefficient. The final study cohort included 148 paired samples. The largest proportion in the HER2-negative cohort was HER2-low [primary tumor 61.4% (n = 78), metastatic samples 73.5% (n = 86)]. The discordance rate between the HER2 status of primary tumors and corresponding distant metastases was 49.6% (n = 63) (Kappa -0.003, 95%CI -0.15-0.15). Development of a HER2-low phenotype occurred most frequently (n = 52, 40.9%), mostly with a switch from HER2-zero to HER2-low (n = 34, 26.8%). Relevant HER2 discordance rates were observed between different metastatic sites and molecular subtypes. Primary metastatic breast cancer had a significantly lower HER2 discordance rate than secondary metastatic breast cancer [30.2% (Kappa 0.48, 95%CI 0.27-0.69) versus 50.5% (Kappa 0.14, 95% CI -0.03-0.32)]. This highlights the importance of evaluating potentially therapy-relevant discordance rates between a primary tumor and corresponding distant metastases.

Prognostic Impact of LAG-3 mRNA Expression in Early Breast Cancer.

Background: Monoclonal antibodies against PD-1 or PD-L1 have been established in clinical practice for the treatment of both early and advanced/metastatic triple-negative breast cancer. Beyond the established immune checkpoints (ICPs) (PD-1 and CTLA-4), additional ICPs, such as lymphocyte activation gene-3 (LAG-3), are subject of current research. In the present retrospective gene-expression analysis, we evaluated the prognostic significance of LAG-3 in 461 patients with early breast cancer. In addition, we examined whether there was a correlation between the different ICP and CD8 expressions. Methods: Using microarray-based gene-expression analysis, we examined the prognostic significance of LAG-3 mRNA expression for metastasis-free survival (MFS) in the whole cohort of 461 breast cancer patients and among different molecular subtypes. Correlations were analyzed using Spearman's rho correlation coefficient. Results: In the whole cohort, LAG-3 expression had no significant impact on MFS (p = 0.712, log-rank). In the subgroup analyses, there was a trend that a higher LAG-3 expression was associated with a favorable outcome in the luminal B (p = 0.217), basal-like (p = 0.370) and HER2 (p = 0.089) subtypes, although significance was not reached. In contrast, in a multivariate Cox regression analysis, adjusted for age, tumor size, axillary nodal status, histological grade of differentiation and proliferation marker Ki-67, LAG-3 showed a significant influence on MFS (HR 0.574; 95% CI 0.369−0.894; p = 0.014). High LAG-3 significantly correlated with CD8 (ρ = 0.571; p < 0.001). Conclusions: LAG-3 expression had an independent impact on MFS. In addition to PD-1 and PD-L1, further immune checkpoints, such as LAG-3, could serve as therapeutic targets in breast cancer.

Resilience as a Source of Easement to Health-Related Worries in Women at Increased Risk for Breast or Ovarian Cancer During the COVID-19 Pandemic.

Purpose: The COVID-19 pandemic has affected individuals' and society's physical and psychological well-being. The study was conducted in order to assess the predictors for health-related worries during the COVID-19 pandemic in vulnerable populations. Patients and Methods: A cross-sectional web-based survey of women who had a higher risk of developing breast cancer (BC) or ovarian cancer (OC) was conducted, regardless of whether they had experienced an active malignant disease during the pandemic. A self-reported questionnaire was designed for this study to assess health-related worries. The PHQ-4 questionnaire was used to evaluate mental health, and the Brief Resilience Scale (BRS) questionnaire was employed to investigate resilience. Results: History of BC or OC was recognized as an independent significant risk factor for worries regarding being more susceptible to a more severe course of COVID-19 disease (OR 3.593; 95% CI 1.030-12.536; p = 0.045). High scores in the BRS questionnaire were negatively correlated with health-related worries, such as an increased risk for occurrence of BC or OC (OR 0.332; 95% CI 0.118-0.933; p = 0.37) or worsening of oncological outcome as a result of an infection with the SARS-CoV-2 virus (OR 0.330; 95% I 0.114-0.956; p = 0.041). Conclusion: The obtained findings determined resilience as an independent and potent protective parameter in terms of health-related concerns in women at high risk for BC and OC. The results may assist in identifying women at risk for health-related concerns during adverse life events, allowing healthcare providers to respond fast and according to the patients´ needs.

Long-term prognostic significance of HER2-low and HER2-zero in node-negative breast cancer.

BACKGROUND: Recently, novel antibody--drug conjugates (ADCs) showed clinical activity in a subset of advanced human epidermal growth factor receptor 2 (HER2)-negative patients. We investigated the prognostic significance of HER2-low and HER2-zero tumours. PATIENTS AND METHODS: The retrospective cohort study included 410 consecutive node-negative breast cancer patients without adjuvant systemic therapy treated between 1985 and 2000 (median follow-up: 16.73 [IQR 8.58-23.45] years). 351 (85.6%) were HER-2 negative and subdivided into HER2-zero (immunohistochemistry [IHC] score 0) and HER2-low (IHC score 1+ or 2+/in situ hybridisation [ISH]-negative). HER2 gene expression was available in 170 (48.4%) patients. Differences in HER2 status for immunohistochemistry, gene expression and clinico-pathologic parameters were assessed using Fisher's exact test, Pearson's correlation and Mann-Whitney test. Prognosis was investigated using the Kaplan-Meier method and Cox regression analyses. RESULTS: Of the 351 HER2-negative patients, 198 (56.4%) had HER2-low tumours and 153 (43.6%) were HER2-zero. Significant differences between HER2-zero and HER2-low tumours were found in histologic grading (P = 0.001), Ki-67 (P = 0.013) and HER2 gene expression (P = 0.002). HER2-low patients had significantly longer disease-free survival (DFS) (15-year rate: 67.5% [95% CI 61.0-74.7] vs. 47.3% [95% CI 39.9-56.1], P < 0.001) and overall survival (OS) (15-year rate: 75.4% [95% CI 69.4-81.9] vs. 66.8% [95% CI 59.5-74.9], P = 0.009). The OS difference was observed in hormone receptor (HR)-positive (P = 0.039) but not HR-negative (P = 0.086) tumours. The results of multivariable analyses confirmed the independent prognostic significance of HER2 status (DFS: HR, 0.546; 95% CI, 0.402-0.743; P < 0.001; OS: HR, 0.653; 95% CI, 0.458-0.932; P = 0.019). CONCLUSION: HER2-low patients had a better survival than HER2-zero patients.

G-8 Geriatric Screening Tool Independently Predicts Progression-Free Survival in Older Ovarian Cancer Patients Irrespective of Maximal Surgical Effort: Results of a Retrospective Cohort Study.

BACKGROUND: We evaluated the prognostic impact of various global health assessment tools in patients older than 60 years with ovarian cancer (OC). METHODS: G-8 geriatric screening tool (G-8 score), Lee Schonberg prognostic index, Eastern Cooperative Oncology Group (ECOG) performance status, and Charlson Comorbidity Index (CCI) were determined retrospectively in a consecutive cohort of elderly patients with OC. Univariate and multivariate Cox regression analyses and Kaplan-Meier method were performed to analyze the impact of the preoperative global health status on survival. RESULTS: 116 patients entered the study. In multivariate analysis adjusted for clinical-pathological factors, only the G-8 score retained significance as a prognostic parameter of progression-free survival (PFS) (hazard ratio [HR]: 1.970; 95% confidence interval [CI] [1.056-3.677]; p = 0.033). Fifty-six patients were classified as G-8-nonfrail with an increased PFS compared to 50 G-8-frail patients (53.4% vs. 16.7%; p = 0.010). A higher CCI was associated with decreased PFS (45.1% vs. 22.2%; p = 0.012), but it did not influence the risk of recurrences or death (p = 0.360; p = 0.111). The Lee Schonberg prognostic index, the ECOG, and age were not associated with survival. CONCLUSIONS: The G-8 score independently predicted PFS in elderly OC patients regardless of maximal surgical effort. Thus, it could be useful to assess surgical treatment based on frailty rather than age alone.

Prognostic Impact of Immunoglobulin Kappa C in Breast Cancer Patients Treated with Adjuvant Chemotherapy.

INTRODUCTION: Immunoglobulin κC (IGKC)-positive tumor-infiltrating plasma cells are associated with better prognosis in node-negative breast cancer patients without adjuvant systemic therapy. In the present study we evaluated the prognostic significance of IGKC in breast cancer patients treated with adjuvant chemotherapy ± tamoxifen. METHODS: IGKC expression was immunohistochemically analyzed in 193 breast cancer patients who were treated with adjuvant chemotherapy, either with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) between 1993 and 2001 with a median follow-up of 11 years. The prognostic impact of IGKC expression was evaluated by Kaplan-Meier survival analyses as well as uni- and multivariate Cox regression. An interaction term was used to investigate a possible association between tamoxifen treatment and prognostic effect of IGKC expression. RESULTS: Kaplan-Meier analyses identified IGKC as a prognostic marker for metastasis-free survival (MFS): higher IGKC expression was associated with a better outcome (p = 0.02, log rank). Results of univariate Cox regression confirmed the prognostic impact of IGKC expression: patients with a strong IGKC expression had a longer MFS (hazard ratio [HR] 1.931; 95% confidence interval [CI] 1.087-3.431; p = 0.025). Multivariate Cox regression analysis showed the independent prognostic significance of IGKC expression (HR 2.070; 95% CI 1.088-3.938; p = 0.027). The interaction term confirmed a significant interaction between tamoxifen treatment and the prognostic impact of IGKC expression (pinteraction = 0.04). CONCLUSION: IGKC expression had an independent prognostic impact in early breast cancer patients who received adjuvant chemotherapy. There was a significant interaction with the use of tamoxifen.

Immunomodulating Therapies in Breast Cancer-From Prognosis to Clinical Practice.

The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the "immune checkpoint". Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as "brakes" on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.

Prognostic Impact of Immunoglobulin Kappa C (IGKC) in Early Breast Cancer.

We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1010 patients with early breast cancer were randomly allocated to either docetaxel-containing or vinorelbine-containing adjuvant chemotherapy. HER2-positive patients were additionally allocated to either trastuzumab or no trastuzumab. Hormone receptor-positive patients received tamoxifen. IGKC was evaluated in 909 tumors using quantitative real-time polymerase chain reaction, and the influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates. Interactions were analyzed using Cox regression. IGKC expression, included as continuous variable, was independently associated with DDFS in a multivariable analysis also including age, molecular subtype, grade, and pT and pN stage (HR 0.930, 95% CI 0.870-0.995, p = 0.034). An independent association with DDFS was also found in a subset analysis of triple-negative breast cancers (TNBC) (HR 0.843, 95% CI 0.724-0.983, p = 0.029), but not in luminal (HR 0.957, 95% CI 0.867-1.056, p = 0.383) or HER2-positive (HR 0.933, 95% CI 0.826-1.055, p = 0.271) cancers. No significant interaction between IGKC and chemotherapy or trastuzumab administration was detected (Pinteraction = 0.855 and 0.684, respectively). These results show that humoral immunity beneficially influences the DDFS of patients with early TNBC.

The Impact of Insulin on Low-dose Metronomic Vinorelbine and Mafosfamide in Breast Cancer Cells.

BACKGROUND/AIM: Breast cancer (BC) may be affected by diabetes and anti-diabetic medication, as well as its therapeutic agents. Low-dose metronomic chemotherapy (LDMC) is an available treatment option in BC. We investigated the impact of insulin on low-dose metronomic vinorelbine and mafosfamide in BC cell lines. MATERIALS AND METHODS: Human BC cell lines T-47D, MCF-7, MDA-MB-231, BT-549 and non-tumorigenic breast cell line MCF-10A were exposed to 0.01 µg/ml and 10 µg/ml insulin in combination with low-dose metronomic vinorelbine or mafosfamide. The cell viability was determined after 24-72 hours using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: Insulin, especially at a concentration of 10 µg/ml, seemed to increase viability of vinorelbine-treated hormone receptor-positive BC cells, whereas low-dose mafosfamide treatment tended to be potentiated by insulin in triple-negative cells. CONCLUSION: Our findings suggest that insulin may influence the cytotoxic activity of LDMC depending on insulin concentration, type of cytotoxic drug used and BC cell line.

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.

Evaluation of a novel monoclonal antibody against tumor-associated MUC1 for diagnosis and prognosis of breast cancer.

There is still a great unmet medical need concerning diagnosis and treatment of breast cancer which could be addressed by utilizing specific molecular targets. Tumor-associated MUC1 is expressed on over 90 % of all breast cancer entities and differs strongly from its physiological form on epithelial cells, therefore presenting a unique target for breast cancer diagnosis and antibody-mediated immune therapy. Utilizing an anti-tumor vaccine based on a synthetically prepared glycopeptide, we generated a monoclonal antibody (mAb) GGSK-1/30, selectively recognizing human tumor-associated MUC1. This antibody targets exclusively tumor-associated MUC1 in the absence of any binding to MUC1 on healthy epithelial cells thus enabling the generation of breast tumor-specific radiolabeled immune therapeutic tools. Methods: MAb GGSK-1/30 was used for immunohistochemical analysis of human breast cancer tissue. Its desferrioxamine (Df')-conjugate was synthesized and labelled with 89Zr. [89Zr]Zr-Df'-GGSK-1/30 was evaluated as a potential PET tracer. Binding and pharmacokinetic properties of [89Zr]Zr-Df'-GGSK-1/30 were analyzed in vitro using human and murine cell lines that express tumor-associated MUC1. Self-generated primary murine breast cancer cells expressing human tumor-associated MUC1 were transplanted subcutaneously in wild type and human MUC1-transgenic mice. The pharmacology of [89Zr]Zr-Df'-GGSK-1/30 was investigated using breast tumor-bearing mice in vivo by PET/MRT imaging as well as by ex vivo organ biodistribution analysis. Results: The mAb GGSK-1/30 stained specifically human breast tumor tissue and can be possibly used to predict the severity of disease progression based on the expression of the tumor-associated MUC1. For in vivo imaging, the Df'-conjugated mAb was radiolabeled with a radiochemical yield of 60 %, a radiochemical purity of 95 % and an apparent specific activity of 6.1 GBq/µmol. After 7 d, stabilities of 84 % in human serum and of 93 % in saline were observed. In vitro cell studies showed strong binding to human tumor-associated MUC1 expressing breast cancer cells. The breast tumor-bearing mice showed an in vivo tumor uptake of >50 %ID/g and clearly visible specific enrichment of the radioconjugate via PET/MRT. Principal conclusions: Tumor-associated MUC1 is a very important biomarker for breast cancer next to the traditional markers estrogen receptor (ER), progesterone receptor (PR) and HER/2-neu. The mAb GGSK-1/30 can be used for the diagnosis of over 90% of breast cancers, including triple negative breast cancer based on biopsy staining. Its radioimmunoconjugate represents a promising PET-tracer for breast cancer imaging selectively targeting breast cancer cells.

Risk Factors for Chemotherapy-Associated Venous Thromboses in Gynaecological Oncology Patients.

Introduction Venous thromboses and their consequences are among the main causes of death in patients with tumour diseases. The objective of this study is the analysis of risk factors and the evaluation of the applicability of two risk scores in a purely gynaecological oncology patient collective. The identification of patients at high risk for the occurrence of venous thromboses could enable the implementation of targeted medication-based thrombosis prophylaxis which has a significant benefit and, simultaneously, a low risk. Materials and Methods A retrospective case-control study on 152 patients who were undergoing oncological treatment in the Department of Gynaecology of the Mainz University Medical Centre between 2006 and 2013 investigated the data from 104 patients with breast, 26 with ovarian and 22 with cervical cancer. A control was assigned to 76 subjects in the case group who suffered a venous thrombosis during chemotherapy and this control coincided in the points of tumour location, age, lymph node involvement, metastasis and time of initial diagnosis. The group differences were analysed using the χ 2 test, t test, Mann-Whitney-U test and a logistic regression analysis. Results There were clear group differences in the lack of inpatient thrombosis prophylaxis (p = 0.014), elevated leukocyte counts (p = 0.018) prior to the start of chemotherapy and port systems (p = 0.032). Surgical interventions were confirmed to be an independent risk factor (p ≤ 0.001). The Khorana and Protecht scores did not emerge from the analysis as independent predictors for a thrombosis. More patients died in the case group than in the control group (p = 0.028; OR: 8.1; CI: 1.254 - 52.162). Conclusion In this patient collective, surgeries represent an independent risk factor for venous thromboses. In addition, a correlation was seen between inpatient thrombosis prophylaxis, leukocytosis as well as port systems and an increased risk of thrombosis. Neither the Khorana nor the Protecht score were independent risk factors for venous thromboses. Significantly more thrombosis patients died during the observation period.

Reduced Breast Tumor Growth after Immunization with a Tumor-Restricted MUC1 Glycopeptide Conjugated to Tetanus Toxoid.

Preventive vaccination against tumor-associated endogenous antigens is considered to be an attractive strategy for the induction of a curative immune response concomitant with a long-lasting immunologic memory. The mucin MUC1 is a promising tumor antigen, as its tumor-associated form differs from the glycoprotein form expressed on healthy cells. Due to aberrant glycosylation in tumor cells, the specific peptide epitopes in its backbone are accessible and can be bound by antibodies induced by vaccination. Breast cancer patients develop per se only low levels of T cells and antibodies recognizing tumor-associated MUC1, and clinical trials with tumor-associated MUC1 yielded unsatisfactory therapeutic effects, indicating an urgent need to improve humoral immunity against this tumor entity. Herein, we demonstrate that preventive vaccination against tumor-associated human MUC1 results in a specific humoral immune response, a slowdown of tumor progression and an increase in survival of breast tumor-bearing mice. For preventive vaccination, we used a synthetic vaccine containing a tumor-associated glycopeptide structure of human MUC1 coupled to Tetanus Toxoid. The glycopeptide consists of a 22mer huMUC1 peptide with two immune dominant regions (PDTR and GSTA), glycosylated with the sialylated carbohydrate STN on serine-17. PyMT (polyomavirus middle T-antigen) and human MUC1 double-transgenic mice expressing human tumor-associated MUC1 on breast tumor tissue served as a preclinical breast cancer model.

Atezolizumab for the treatment of triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) is associated with poor prognosis and limited treatment options. However, TNBC is known to be more immunogenic compared to other breast cancer subtypes, with tumor-infiltrating lymphocytes playing an important prognostic and predictive role. Furthermore, TNBC has a higher level of programmed cell death-ligand 1 (PD-L1) expression. Therapeutic blockade of PD-L1 using atezolizumab is thus expected to activate and enhance tumor-specific T-cell responses, resulting in improved anti-tumor activity. Areas covered: This review summarizes the development and the impact of the PD-L1 inhibitor atezolizumab in advanced TNBC; it examines the mechanism of action, pharmacokinetics and the available preclinical and clinical data. Expert opinion: Atezolizumab, a novel immune checkpoint inhibitors targeting PD-L1, is an effective and well-tolerated treatment option for metastatic TNBC. In general, TNBC has a high unmet medical need, hence the clinical development of atezolizumab should continue, particularly for TNBC. Indeed, atezolizumab has the potential to substantially augment the therapeutic armamentarium for TNBC. This should lead to improved immunotherapeutic strategies and the enhancement of the outcome for this group of breast cancer patients.