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This article explores the impact of cancer-associated fibroblasts (CAFs) on the effectiveness of neoadjuvant chemotherapy (NAC) in breast cancer patients. The study reveals that a chemo-resistant stroma (CRS) signature is linked to poorer outcomes and lower survival rates in breast cancer patients. Furthermore, the research demonstrates that CAFs play a significant role in NAC resistance and cancer progression. The findings emphasize the importance of considering the tumor microenvironment when predicting NAC response and developing effective treatment strategies. The study also suggests that targeting CAFs and their senescent state could be a promising approach to overcoming NAC resistance. [Extracted from the article]

Simple Summary: Selecting and developing effective therapies for distinct epithelial ovarian cancer subtypes necessitates tumor models that accurately recapitulate the individual characteristics and microenvironmental interactions. Patient-derived tumor models offer a promising approach by preserving the tumor's integrity, providing a platform for personalized treatment strategies. Zebrafish embryos could be a useful tool for quickly testing potential treatments in parallel. In this research article, we aimed to evaluate the model using a real-world case study and compare results with existing in vitro and in vivo models. A patient-derived cell line from a low-grade serous ovarian cancer with a KRAS mutation was engrafted in zebrafish embryos. Xenografts were assigned to a five-day treatment with trametinib and/or luminespib, targeting two complementary pathways that have previously shown efficacy in other cancer models of this cell line. The zebrafish model offers several options to analyze the response of the tumor to drug exposure. Here, we evaluated both cell growth and cell death, which showed a significant positive tumor response upon treatment that was amplified further by combining the drugs. Ovarian cancer (OC) is an umbrella term for cancerous malignancies affecting the ovaries, yet treatment options for all subtypes are predominantly derived from high-grade serous ovarian cancer, the largest subgroup. The concept of "functional precision medicine" involves gaining personalized insights on therapy choice, based on direct exposure of patient tissues to drugs. This especially holds promise for rare subtypes like low-grade serous ovarian cancer (LGSOC). This study aims to establish an in vivo model for LGSOC using zebrafish embryos, comparing treatment responses previously observed in mouse PDX models, cell lines and 3D tumor models. To address this goal, a well-characterized patient-derived LGSOC cell line with the KRAS mutation c.35 G>T (p.(Gly12Val)) was used. Fluorescently labeled tumor cells were injected into the perivitelline space of 2 days' post-fertilization zebrafish embryos. At 1 day post-injection, xenografts were assessed for tumor size, followed by random allocation into treatment groups with trametinib, luminespib and trametinib + luminespib. Subsequently, xenografts were euthanized and analyzed for apoptosis and proliferation by confocal microscopy. Tumor cells formed compact tumor masses (n = 84) in vivo, with clear Ki67 staining, indicating proliferation. Zebrafish xenografts exhibited sensitivity to trametinib and luminespib, individually or combined, within a two-week period, establishing them as a rapid and complementary tool to existing in vitro and in vivo models for evaluating targeted therapies in LGSOC. [ABSTRACT FROM AUTHOR]

Purpose: To assess experiences of sexuality and of receiving sexual healthcare in cervical cancer (CC) survivors. Methods: A qualitative phenomenological study using semistructured one-on-one interviews was conducted with 15 Belgian CC survivors recruited in 5 hospitals from August 2021 to February 2022. The interviews were audiotaped and transcribed verbatim. Data were analyzed using inductive thematic analysis. COREQ and SRQR reporting guidelines were applied. Results: Most participants experienced an altered sexuality after CC treatment with often long-term loss/lack of sex drive, little/no spontaneity, limitation of positions to avoid dyspareunia, less intense orgasms, or no sexual activity at all. In some cases, emotional intimacy became more prominent. Physical (vaginal bleeding, vaginal dryness, dyspareunia, menopausal symptoms) and psychological consequences (guilt, changed self-image) were at the root of the altered sexuality. Treatment-induced menopause reduced sex drive. In premenopausal patients, treatment and/or treatment-induced menopause resulted in the sudden elimination of family planning. Most participants highlighted the need to discuss their altered sexual experience with their partner to grow together toward a new interpretation of sexuality. To facilitate this discussion, most of the participants emphasized the need for greater partner involvement by healthcare providers (HPs). The oncology nurse or sexologist was the preferred HP with whom to discuss sexual health. The preferred timing for information about the sexual consequences of treatment was at treatment completion or during early follow-up. Conclusion: Both treatment-induced physical and psychological experiences were prominent and altered sexuality. Overall, there was a need for HPs to adopt proactive patient-tailored approaches to discuss sexual health. [ABSTRACT FROM AUTHOR]

This article explores the impact of hyperthermia on cisplatin tissue penetration and gene expression in peritoneal metastases in ovarian cancer patients. The study examines the effects of hyperthermic intraperitoneal chemoperfusion (HIPEC) with cisplatin on pharmacokinetics, cellular responses, and gene expression. The findings reveal that platinum penetration in tumor tissue varies, with limited uptake after 90 minutes. Hyperthermia triggers a heat shock response in cancer cells and may accelerate the clearance of platinum in the peritoneum. The article provides a comprehensive overview of the study's design, procedure, and statistical analysis. Additionally, it discusses the effects of hyperthermia and HIPEC on the peritoneal and tumor immune contexture in women with recurrent ovarian cancer. The study suggests that hyperthermia enhances the systemic absorption of cisplatin and potentially improves tissue penetration in ovarian cancer. It also induces a heat shock response and up-regulates genes associated with cellular shock. However, further research is necessary to confirm the anticancer effects of hyperthermia. The study was funded by the Flemish Cancer Foundation, and the authors disclose no conflicts of interest. [Extracted from the article]

Extracellular vesicles (EVs) contain a plethora of biomolecules, including nucleic acids, with diverse diagnostic and therapeutic application potential. Although reverse transcription‐quantitative PCR (RT‐qPCR) is the most widely applied laboratory technique to evaluate gene expression, its applicability in EV research is challenged by the lack of universal and stably present reference genes (RGs). In this study, we identify, validate and establish SNRPG, OST4, TOMM7 and NOP10 as RGs for the normalization of EV‐associated genes by RT‐qPCR. We show the stable presence of SNRPG, OST4, TOMM7 and NOP10 in multiple cell lines and their secreted EVs (n = 12) under different (patho)physiological conditions as well as in human‐derived biofluids (n = 3). Enzymatic treatments confirm the presence of SNRPG, OST4, TOMM7 and NOP10 inside EVs. In addition, the four EV‐associated RGs are stably detected in a size‐range of EV subpopulations. RefFinder analysis reveals that SNRPG, OST4, TOMM7 and NOP10 are more stable compared to RGs established specifically for cultured cells or tissues such as HMBS, YWHAZ, SDHA and GAPDH. In summary, we present four universal and stably present EV‐associated RGs to enable normalization and thus steer the implementation of RT‐qPCR for the analysis of EV‐associated RNA cargo for research or clinical applications. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the most lethal gynecologic malignancy, mainly due to late-stage diagnosis, frequent recurrences, and eventually therapy resistance. To identify potentially actionable genetic variants, sequencing data of 351 Belgian ovarian cancer patients were retrospectively captured from electronic health records. The cohort included 286 (81%) patients with high-grade serous ovarian cancer, 17 (5%) with low-grade serous ovarian cancer, and 48 (14%) with other histotypes. Firstly, an overview of the prevalence and spectrum of the BRCA1/2 variants highlighted germline variants in 4% (11/250) and somatic variants in 11% (37/348) of patients. Secondly, application of a multi-gene panel in 168 tumors revealed a total of 214 variants in 28 genes beyond BRCA1/2 with a median of 1 (IQR, 1–2) genetic variant per patient. The ten most often altered genes were (in descending order): TP53, BRCA1, PIK3CA, BRCA2, KRAS, ERBB2 (HER2), TERT promotor, RB1, PIK3R1 and PTEN. Of note, the genetic landscape vastly differed between the studied histotypes. Finally, using ESCAT the clinical evidence of utility for every genetic variant was scored. Only BRCA1/2 pathogenic variants were classified as tier-I. Nearly all patients (151/168; 90%) had an ESCAT tier-II variant, most frequently in TP53 (74%), PIK3CA (9%) and KRAS (7%). In conclusion, our findings imply that although only a small proportion of genetic variants currently have direct impact on ovarian cancer treatment decisions, other variants could help to identify novel (personalized) treatment options to address the poor prognosis of ovarian cancer, particularly in rare histotypes. [ABSTRACT FROM AUTHOR]

Simple Summary: Magnetic resonance imaging (MRI) can be used for the preoperative local staging of endometrial cancer (EC). The purpose of this study was to assess the performance of MRI for the detection of ≥pT1b disease (i.e., tumor invasion in ≥50% of the myometrium, into the cervical stroma or spread outside the uterus) and to evaluate whether tumor size measured via MRI was predictive for ≥pT1b disease, independent of imaging signs of invasion. We found that MRI had good performance for the detection of ≥pT1b disease and that a tumor diameter of ≥40 mm and a tumor volume of ≥20 mL were highly predictive for the presence of ≥pT1b disease. Our results support the use of MRI in the preoperative staging of EC and suggest including size criteria in EC staging guidelines. Magnetic resonance imaging (MRI) can be used for the preoperative local staging of endometrial cancer (EC). The presence of ≥pT1b disease (i.e., tumor invasion in ≥50% of the myometrium, into the cervical stroma or spread outside the uterus) has important prognostic value and implications for the decision to perform lymphadenectomy. The purpose of this study was to assess the performance of MRI for the detection of ≥pT1b disease and to evaluate whether tumor size measured via MRI was predictive for ≥pT1b disease, independent of imaging signs of deep invasion. MRI T-staging and tumor diameter and volume were correlated with histopathology of the hysterectomy specimen in 126 patients. MRI had a sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 70.0%, 83.3%, 79.2%, 75.3% and 77.0%, respectively, for the detection of ≥pT1b disease. A tumor diameter of ≥40 mm and volume of ≥20 mL measured via MRI were predictive for ≥pT1b disease at rates of 78.3% and 87.1%, respectively. An EC size of at least 5 mm upon MRI was predictive for ≥pT1b disease in more than 50% of cases. Our results support the use of MRI in the preoperative staging of EC and suggest including size criteria in EC staging guidelines. [ABSTRACT FROM AUTHOR]

Purpose: To compare sexual/vaginal functioning between early cervical cancer (ECC) and locally advanced cervical cancer (LACC) survivors. Methods: VAMOS was a multicenter, cross-sectional, questionnaire, noninferiority study including ECC patients treated with surgery and, if clinically indicated, adjuvant (chemo)radiotherapy and LACC patients treated with neoadjuvant (chemo)radiotherapy followed by surgery. Patient-reported outcomes (PROs) were assessed using the EORTC QLQ-C30, EORTC QLQ-CX24, and Female Sexual Functioning Index (FSFI) questionnaires. Clinical reported outcomes (ClinROs) consisted of vaginal morbidity scored according to the CTCAE v4.0 scoring system. Results: One hundred forty-three patients were included. Compared to ECC patients (n = 97), LACC patients (n = 46) were significantly less sexually active in the 4 weeks prior to completion of the questionnaires (65% vs. 41%; p =.005). The primary endpoint was not met: LACC patients reported a higher mean score (more problems) for sexual/vaginal functioning than ECC patients, with a non-clinically relevant mean difference of 6.38 ([95% CI: − 6.41, 19.17]; p =.570 for noninferiority). Regarding the secondary endpoints, the prevalence of sexual dysfunction between the two groups did not differ significantly (p = 0.124). Compared to ECC patients, LACC patients did not have significantly more vaginal morbidity (adjusted odds ratio [OR] 1.51 [95% CI: 0.22, 10.29]; p =.674). Moreover, there was poor agreement between any vaginal morbidity and sexual dysfunction (Cohen’s kappa of 0.17). Conclusion: Compared to ECC survivors, LACC survivors were significantly less sexually active and reported equivalent or worse sexual/vaginal functioning, although the proportion of patients with sexual dysfunction was similar. Clinical assessment of vaginal morbidity was poorly correlated with sexual dysfunction. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to compare the difference in survival between invasive ductal (IDC) and lobular carcinoma (ILC). Methods: Data of patients (n = 1843) with a hormone receptor-positive, HER2-negative, pT1-3 IDC or ILC cancer without distant metastasis, treated at the Ghent University Hospital over the time period 2001–2015, were analyzed. Results: ILC represented 13.9% of the tumors, had a higher percentage of pT3 and pN3 stages than IDC, lymphovascular space invasion (LVSI) was less present and Ki-67 was mostly low. 73.9% of ILCs were grade 2, whereas IDC had more grade 1 and grade 3 tumors. Kaplan–Meier curves and log-rank testing showed a significant worse DFS for ILC with pN ≥ 1 than for their IDC counterpart. In a multivariable Cox regression analysis the histologic tumor type, ductal or lobular, was a determinant of DFS over 120 months (IDC as reference; hazard ratio for ILC 1.77, 95% CI 1.08–2.90) just as the ER Allred score (hazard ratio 0.84, 95% CI 0.78–0.91), LVSI (hazard ratio 1.75, 95% CI 1.12–2.74) and pN3 (hazard ratio 2.29, 95% CI 1.03–5.09). Determinants of OS over ten years were age (hazard ratio 1.05, 95% CI 1.02–1.07), LVSI (hazard ratio 3.62, 95% CI 1.92–6.82) and the ER Allred score (hazard ratio 0.80, 95% CI 0.73–0.89). Conclusion: The histologic tumor type, ductal or lobular, determines DFS in hormone receptor-positive, HER2-negative, pT1-3 breast cancer besides the ER Allred score, LVSI and pN3. [ABSTRACT FROM AUTHOR]

Background: The PRIMA/ENGOT‐OV26/GOG‐3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first‐line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. Methods: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first‐line platinum‐based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose. Results: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46–0.76] vs. ISD HR, 0.69 [95% CI, 0.48–0.98]) and the homologous recombination–deficient (FSD HR, 0.44 [95% CI, 0.30–0.64] vs. ISD HR, 0.39 [95% CI, 0.22–0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment‐emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. Conclusions: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen. Results from the phase 3 PRIMA trial of niraparib first‐line maintenance therapy that prospectively evaluated fixed versus individualized dosing support the selection of a niraparib starting dose based on an individual's body weight and platelet count. In prespecified analyses, patients who received the individualized starting dose of niraparib experienced similar progression‐free survival and improved safety outcomes compared with patients who received the fixed starting dose of niraparib. [ABSTRACT FROM AUTHOR]

Simple Summary: The immunological profile of pleomorphic invasive lobular cancer is poorly investigated. pILC is characterized by more aggressive behavior and a worse prognosis; however, this rare subtype lacks a specific treatment approach. Here, we investigated the expression of sTILs and analyzed the PD-L1 expression levels from sixty-six patients with pILC. Moreover, we analyzed the association between sTILs and PD-L1 expression with other prognostic or predictive biomarkers and correlated sTILs and PD-L1 expression with survival outcomes. sTILS (≥1%) was present in 64% of the patients, and 36% of the tumors demonstrated a positive PD-L1 using SP142 (≥1%) and 28% had a positive PD-L1 score of ≥1 using 22C3. We found no differences between the molecular subtypes, the clinicopathological features, and the immune parameters, probably due to the small sample size of the HER2+ and TN subgroups. Larger trials on the immune composition of the subtypes of lobular breast cancer are needed. Background: The prognostic and predictive role of stromal tumor-infiltrating lymphocytes (sTILs) is undetermined in pleomorphic invasive lobular cancer (pILC). The same applies for the expression of PD-1/PD-L1 in this rare breast cancer subtype. Here, we aimed to investigate the expression of sTILs and analyze the PD-L1 expression levels in pILC. Methods: Archival tissues from sixty-six patients with pILC were collected. The sTIL density was scored as a percentage of tumor area using the following cut-offs: 0%; <5%; 5–9%; and 10–50%. The PD-L1 expression was analyzed using IHC on formalin-fixed, paraffin-embedded tissue sections using SP142 and 22C3 antibodies. Results: A total of 82% of the sixty-six patients were hormone receptor positive and 8% of cases were triple negative (TN), while 10% showed human epidermal growth factor receptor 2 (HER2) amplification. sTILs (≥1%) were present in 64% of the study population. Using the SP142 antibody, 36% of tumors demonstrated a positive PD-L1 score of ≥1%, and using the 22C3 antibody, 28% had a positive PD-L1 score of ≥1. There was no correlation between sTILs or PD-L1 expression and tumor size, tumor grade, nodal status, expression of estrogen receptor (ER), or amplification of HER2. Our data did not show any difference in survival between the three molecular subtypes of pILC with respect to sTILs and PD-L1 expression. Conclusion: This study shows that pILCs show some degree of sTILs and PD-L1 expression; however, this was not associated with a survival improvement. Additional large trials are needed to understand immune infiltration in lobular cancer, especially in the pleomorphic subtype. [ABSTRACT FROM AUTHOR]

Background: Extracellular vesicles (EV) are extensively studied in human body fluids as potential biomarkers for numerous diseases. Major impediments of EV-based biomarker discovery include the specificity and reproducibility of EV sample preparation as well as intensive manual labor. We present an automated liquid handling workstation for the density-based separation of EV from human body fluids and compare its performance to manual handling by (in)experienced researchers. Results: Automated versus manual density-based separation of trackable recombinant extracellular vesicles (rEV) spiked in PBS significantly reduces variability in rEV recovery as quantified by fluorescent nanoparticle tracking analysis and ELISA. To validate automated density-based EV separation from complex body fluids, including blood plasma and urine, we assess reproducibility, recovery, and specificity by mass spectrometry-based proteomics and transmission electron microscopy. Method reproducibility is the highest in the automated procedure independent of the matrix used. While retaining (in urine) or enhancing (in plasma) EV recovery compared to manual liquid handling, automation significantly reduces the presence of body fluid specific abundant proteins in EV preparations, including apolipoproteins in plasma and Tamm-Horsfall protein in urine. Conclusions: In conclusion, automated liquid handling ensures cost-effective EV separation from human body fluids with high reproducibility, specificity, and reduced hands-on time with the potential to enable larger-scale biomarker studies. [ABSTRACT FROM AUTHOR]

Background: Chemoradiotherapy (CRT) followed by brachytherapy (BT) is the standard treatment for locally advanced cervical cancer (LACC), but replacement of BT by surgery (CRT-S) could be an acceptable alternative. The main concern is the risk of operative morbidity. The aim is to report on therapeutic morbidity, OS, PC, and LC of CRT-S. Methods: This was a single tertiary center retrospective cohort study in patients treated with CRT-S. A type II Wertheim hysterectomy was performed 6–8 weeks after CRT. Acute and chronic radiotherapy-related and surgical morbidity was classified according to the CTCAE v4.0. OS, and DFS, PC, and LC were calculated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard models were performed to determine variables with a prognostic role. Results: A total of 130 consecutive LACC patients were treated with CRT, and 119 underwent completion surgery. The median follow-up was 53 months. Five-year OS rate, local control, pelvic control, and 5-year DFS rate were 73%, 93%, 90%, and 74%, respectively. The 5-year OS rate was 92%/72%/67%/56% for FIGO (2009) stage I/II/III/IV, respectively. The five-year OS rate was 79% and 71% for adenocarcinoma and squamous cell carcinoma (p > 0.05), respectively. There was no intra- and perioperative mortality. Intraoperative and early postoperative complication rates were 7% and 20% (3% ≥ G3), respectively; they resolved within 3 months. The late postoperative complication rate was 9% (7% ≥ G3). Acute/late radiotherapy-related G3 side effects were 5%/3% for gastrointestinal and 3%/7% for genitourinary side effects. Conclusions: CRT-S is safe with an acceptable rate of complications for both the CRT and completion surgery and shows encouraging outcome data for stage III/IV and adenocarcinoma patients. [ABSTRACT FROM AUTHOR]

Trastuzumab is the cornerstone treatment for HER2-positive breast cancer. While ocular side effects are more commonly described after the use of the antibody-drug conjugate ado-trastuzumab emtansine, we here describe corneal melting in a 79-year-old patient after three cycles of trastuzumab monotherapy. Signs and symptoms persisted with subsequent trastuzumab cycles. The patient showed improvement after treatment with intense lubrication, topical antibiotics, and topical steroids. After tapering of steroids, there was recurrence of epitheliopathy after subsequent trastuzumab treatment, which subsided upon restarting topical steroids. Finally, the patient was kept on a low-dose topical steroid regimen which prevented further epitheliopathy during the next trastuzumab cycles. [ABSTRACT FROM AUTHOR]

Invasive lobular carcinoma (ILC) is the most common histologic subtype of breast cancer after invasive ductal carcinoma (i.e., no special type [NST]). ILC differs from NST in clinical presentation, site-specific metastases and response to conventional therapies. Loss of E-cadherin protein expression, due to alterations in its encoding gene CDH1, is the most frequent oncogenic event in ILC. Synthetic lethality approaches have shown promising antitumor effects of ROS1 inhibitors in models of E-cadherin-defective breast cancer in in vivo studies and provide the rationale for testing their clinical activity in patients with ILC. Entrectinib is a tyrosine kinase inhibitor targeting TRK, ROS1 and ALK tyrosine kinases. Here, the authors present ROSALINE (NCT04551495), a phase II study testing neoadjuvant entrectinib and endocrine therapy in women with estrogen receptor-positive, HER2-negative early ILC. Breast cancer is the most common cancer among women worldwide. Breast cancer is not a unique disease, but rather a heterogeneous disease, with different subtypes. Lobular breast cancer is the second most common histologic subtype of breast cancer after ductal breast cancer. Lobular breast cancer has some peculiar characteristics that make it a distinct entity in the context of breast cancer. Nevertheless, few clinical studies so far have focused specifically on this subtype. ROSALINE is a clinical study aimed to test entrectinib, a new drug that showed promising activity in preliminary research studies, in combination with endocrine therapy in women with lobular breast cancer before surgery. Trial Registration Number: NCT04551495 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

Irradiation induces distinct cellular responses such as apoptosis, necroptosis, irondependent cell death (a feature of ferroptosis), senescence, and mitotic catastrophe. Several of these outcomes are immunostimulatory and may represent a potential for immunogenic type of cell death (ICD) induced by radiotherapy triggering abscopal effects. The purpose of this study is to determine whether intra-tumoral ICD markers can serve as biomarkers for the prediction of patient's outcomes defined as the metastasis status and survival over a 5-year period. Thirty-eight patients with locally advanced cervical cancer, treated with neoadjuvant chemoradiotherapy using cisplatin were included in this study. Pre-treatment tumor biopsy and post-treatment hysterectomy samples were stained for cell death markers and danger associated molecular patterns (DAMPs): cleaved caspase-3 (apoptosis), phosphorylated mixed lineage kinase domain like pseudokinase (pMLKL; necroptosis), glutathione peroxidase 4 (GPX4; ferroptosis) and 4-hydroxy-2-noneal (4-HNE; ferroptosis), high mobility group box 1 (HMGB1) and calreticulin. Although these markers could not predict the patient's outcome in terms of relapse or survival, many significantly correlated with immune cell infiltration. For instance, inducing ferroptosis post-treatment seems to negatively impact immune cell recruitment. Measuring ICD markers could reflect the impact of treatment on the tumor microenvironment with regard to immune cell recruitment and infiltration. [ABSTRACT FROM AUTHOR]

Invasive lobular carcinoma (ILC) is the most common histologic subtype of breast cancer after invasive ductal carcinoma (i.e., no special type [NST]). ILC differs from NST in clinical presentation, site-specific metastases and response to conventional therapies. Loss of E-cadherin protein expression, due to alterations in its encoding gene CDH1, is the most frequent oncogenic event in ILC. Synthetic lethality approaches have shown promising antitumor effects of ROS1 inhibitors in models of E-cadherin-defective breast cancer in in vivo studies and provide the rationale for testing their clinical activity in patients with ILC. Entrectinib is a tyrosine kinase inhibitor targeting TRK, ROS1 and ALK tyrosine kinases. Here, the authors present ROSALINE (NCT04551495), a phase II study testing neoadjuvant entrectinib and endocrine therapy in women with estrogen receptor-positive, HER2-negative early ILC. [ABSTRACT FROM AUTHOR]

Background: With the aim of obtaining more uniformity and quality in the treatment of corpus uteri cancer in Belgium, the EFFECT project has prospectively collected detailed information on the real-world clinical care offered to 4063 Belgian women with primary corpus uteri cancer. However, as data was collected on a voluntary basis, data may be incomplete and biased. Therefore, this study aimed to assess the completeness and potential selection bias of the EFFECT database.Methods: Five databases were deterministically coupled by use of the patient's national social security number. Participation bias was assessed by identifying characteristics associated with hospital participation in EFFECT, if any. Registration bias was assessed by identifying patient, tumor and treatment characteristics associated with patient registration by participating hospitals, if any. Uni- and multivariable logistic regression were applied.Results: EFFECT covers 56% of all Belgian women diagnosed with primary corpus uteri cancer between 2012 and 2016. These women were registered by 54% of hospitals, which submitted a median of 86% of their patients. Participation of hospitals was found to be biased: low-volume and Walloon-region centers were less likely to participate. Registration of patients by participating hospitals was found to be biased: patients with a less favorable risk profile, with missing data for several clinical-pathological risk factors, that did not undergo curative surgery, and were not discussed in a multidisciplinary tumor board were less likely to be registered.Conclusions: Due to its voluntary nature, the EFFECT database suffers from a selection bias, both in terms of the hospitals choosing to participate and the patients being included by participating institutions. This study, therefore, highlights the importance of assessing the selection bias that may be present in any study that voluntarily collects clinical data not otherwise routinely collected. Nevertheless, the EFFECT database covers detailed information on the real-world clinical care offered to 56% of all Belgian women diagnosed with corpus uteri cancer between 2012 and 2016, and may therefore act as a powerful tool for measuring and improving the quality of corpus uteri cancer care in Belgium. [ABSTRACT FROM AUTHOR]

This document provides a summary of results from the article that evaluated the safety and efficacy of the fixed and individualized starting doses of niraparib in the PRIMA study. The original article was published in the journal Cancer in March 2023. The PRIMA study included adult patients with newly diagnosed advanced ovarian cancer who had finished treatment with chemotherapy and surgery. Once patients entered the study, they were treated with an oral (by mouth) medication called niraparib or placebo (substance with no effects that a doctor gives to a patient instead of a drug). The amount of drug (dose) prescribed for patients to take at the start of treatment was determined by the study plan (a document that describes in detail how the study will be performed). Some patients were treated with a fixed starting dose (300 milligrams [mg] once daily), while others were treated with an individualized dose (200 or 300 mg once daily) based on how much they weighed and the results of their blood test. The individualized dose was tested to see if it improved patient safety without changing its efficacy (how well the drug worked). The individualized starting dose of niraparib improved patient safety, with a lower proportion of patients experiencing side effects than the fixed starting dose. The individualized starting dose of niraparib also delayed the cancer from coming back (recurring) or getting worse (progressing) compared with placebo. The delay in the cancer coming back or getting worse with niraparib treatment was generally similar in patients who received the individualized starting dose and those who received the fixed starting dose of niraparib. The results support the use of the individualized starting dose of niraparib, which uses a patient's body weight and blood test results to determine how much drug they should receive at the start of treatment. The study found that the individualized starting dose improved safety compared with the fixed starting dose while still delaying the cancer from coming back or getting worse. Clinical Trial Registration: NCT02655016 (PRIMA study) (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Separating extracellular vesicles (EV) from blood plasma is challenging and complicates their biological understanding and biomarker development. In this study, we fractionate blood plasma by combining size‐exclusion chromatography (SEC) and OptiPrep density gradient centrifugation to study clinical context‐dependent and time‐dependent variations in the biomolecular landscape of systemically circulating EV. Using pooled blood plasma samples from breast cancer patients, we first demonstrate the technical repeatability of blood plasma fractionation. Using serial blood plasma samples from HIV and ovarian cancer patients (n = 10) we next show that EV carry a clinical context‐dependent and/or time‐dependent protein and small RNA composition, including miRNA and tRNA. In addition, differential analysis of blood plasma fractions provides a catalogue of putative proteins not associated with systemically circulating EV. In conclusion, the implementation of blood plasma fractionation allows to advance the biological understanding and biomarker development of systemically circulating EV. [ABSTRACT FROM AUTHOR]

Objective: A significant proportion of adjuvant-treated breast cancer patients experience cognitive decline, challenging the person's ability to return to normal activities after treatment. However, not every patient experiences cognitive problems, and even in patients with impairments, determining clinically important cognitive decline remains challenging. Our objective was to explore differences in neuropsychological performance following adjuvant chemotherapy (CT) in patients with breast cancer. Method: We conducted a prospective observational study in an Oncology Breast Clinic and assessed neuropsychological performance before and after adjuvant CT and in non-CT-treated women with breast cancer and healthy controls (HCs). Standardised between-group differences and regression-based change scores were calculated. Results: CT-treated patients (n = 66) performed significantly different from non-CT-treated patients (n = 39) and HCs (n = 56). There was a significant effect on verbal fluency (p =.0013). CT performed significantly worse than non-CT and HC [effect size (ES) =.89, p <.001 and ES =.61, p ≤.001, respectively] and from HCs with regard to proactive interference (ES =.62, p ≤.001). Regression-based scores revealed more severe cognitive decline in the CT-treated group [24.24% (16/66)] than in the non-CT-treated group [15.20% (6/39)] and HC group [7.14% (4/56)]. Patients who underwent CT and showed cognitive decline were less educated and older, with significantly lower baseline scores. Conclusions: CT-treated patients showed more vulnerability on cognitive control and monitoring than non-CT-treated breast cancer patients and HCs. Older patients with less education and lower baseline cognitive performance represent a group at risk for cognitive decline following CT. Identification of patients at risk for decline could improve targeted support and rehabilitation. [ABSTRACT FROM AUTHOR]

We investigated the potential of tumor‐infiltrating immune cells (ICs) as predictive or prognostic biomarkers for cervical cancer patients. In total, 38 patients treated with (chemo)radiotherapy and subsequent surgery were included in the current study. This unique treatment schedule makes it possible to analyze IC markers in pretreatment and posttreatment tissue specimens and their changes during treatment. IC markers for T cells (CD3, CD4, CD8 and FoxP3), macrophages (CD68 and CD163) and B cells (CD20), as well as IL33 and PD‐L1, were retrospectively analyzed via immunohistochemistry. Patients were grouped in the low score or high score group based on the amount of positive cells on immunohistochemistry. Correlations to pathological complete response (pCR), cause‐specific survival (CSS) and metastasis development during follow‐up were evaluated. In analysis of pretreatment biopsies, significantly more pCR was seen for patients with CD8 = CD3, CD8 ≥ CD4, positive IL33 tumor cell (TC) scores, IL33 IC < TC and PD‐L1 TC ≥5%. Besides patients with high CD8 scores, also patients with CD8 ≥ CD4, CD163 ≥ CD68 or PD‐L1 IC ≥5% had better CSS. In the analysis of posttreatment specimens, less pCR was observed for patients with high CD8 or CD163 scores. Patients with decreasing CD8 or CD163 scores between pretreatment and posttreatment samples showed more pCR, whereas those with increasing CD8 or decreasing IL33 IC scores showed a worse CSS. Meanwhile, patients with an increasing CD3 score or stable/increasing PD‐L1 IC score showed more metastasis during follow‐up. In this way, the intratumoral IC landscape is a promising tool for prediction of outcome and response to (chemo)radiotherapy. What's new? This study explored the effects of (chemo)radiotherapy on the tumor immunome and the potential of tumor‐infiltrating immune cells as predictive or prognostic biomarkers in a unique cervical cancer population treated with (chemo)radiotherapy and subsequent surgery. Analysis of pre‐ and post‐treatment immune cell markers, and their changes during treatment showed correlations with pathological response, survival, and metastasis. The CD8/CD3 ratio, CD8/CD4 ratio, IL33‐tumor cells, IL33‐immune cell/tumor cell ratio, and PD‐L1‐tumor cells may predict pathological complete response and thus radiosensitivity in cervical cancer. Investigation of these markers in future trials may thus lead to more personalized care for cervical cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: The subcutaneous (SC) administration of trastuzumab is highly preferred by patients. At home, administration of trastuzumab SC might further improve patient benefit. The aims of the BELIS study are to evaluate the safety and tolerability of trastuzumab SC when administered at home by a healthcare professional (HCP) and to evaluate patient-reported outcomes for treatment experience of at home cancer therapy. Methods: This open-label phase IIIb study enrolled HER2-positive early breast cancer patients in Belgium and Israel who completed the first six cycles of trastuzumab IV (neo)adjuvant therapy. The study consisted of three consecutive treatment periods: three cycles of trastuzumab IV and SC each at the hospital and six cycles of trastuzumab SC at home. Results: Between November 2013 and December 2014, 23 centres enrolled 102 patients in the intent-to-treat population of which 101 patients entered the safety population. No new safety signals were detected with as expected, more mild administration site events with trastuzumab SC when compared to IV treatment. All patients agreed that they had benefit from at home administration to a large (18/81; 22%) or very large (63/81; 78%) extent. All HCPs (21/21) agreed that SC is the quickest method from start of preparation to finish of administration and that less resource use is needed. Conclusion: The results of the BELIS study support that trastuzumab SC can be safely administered at home by a HCP and all patients considered this setting as beneficial. HCPs consider the SC formulation as the quickest method to administer trastuzumab. Trial registration: EudraCT Identifier: 2013-000123-13. ClinicalTrials.gov Identifier: NCT01926886. [ABSTRACT FROM AUTHOR]

Peritoneal spread indicates poor prognosis in patients with serous ovarian carcinoma (SOC) and is generally treated by surgical cytoreduction and chemotherapy. Novel treatment options are urgently needed to improve patient outcome. Clinically relevant cell lines and patient-derived xenograft (PDX) models are of critical importance to therapeutic regimen evaluation. Here, a PDX model was established, by orthotopic engraftment after subperitoneal tumor slurry injection of low-grade SOC, resulting in an early-stage transplantable peritoneal metastasis (PM)-PDX model. Histology confirmed the micropapillary and cribriform growth pattern with intraluminal tumor budding and positivity for PAX8 and WT1. PM-PDX dissociated cells show an epithelial morphotype with a 42 h doubling time and 40% colony forming efficiency, they are low sensitive to platinum derivatives and highly sensitive to paclitaxel (IC50: 6.3 ± 2.2 nM, mean ± SEM). The patient primary tumor, PM, PM-PDX and derived cell line all show a KRAS c.35 G > T (p.(Gly12Val)) mutation and show sensitivity to the MEK inhibitor trametinib in vitro (IC50: 7.2 ± 0.5 nM, mean ± SEM) and in the PM mouse model. These preclinical models closely reflecting patient tumors are useful to further elucidate LGSOC disease progression, therapy response and resistance mechanisms. [ABSTRACT FROM AUTHOR]

Vaccinating a cancer away: Despite advances in prevention and early detection, cervical cancer remains prevalent worldwide and continues to cause mortality, thus requiring improved therapeutic interventions. One approach being developed for the treatment of cervical cancer is therapeutic vaccination targeting human papillomavirus 16 (HPV16), a key virus associated with the pathogenesis of this cancer. Melief et al. tested this therapeutic vaccine approach in 77 patients with advanced, recurrent, or metastatic cervical cancer who were also receiving standard chemotherapy with carboplatin and paclitaxel. Almost half of the tumors regressed with the combination therapy. The authors characterized the patients' immune responses and correlated them with the likelihood of successful treatment. Therapeutic cancer vaccines have effectively induced durable regressions of premalignant oncogenic human papilloma virus type 16 (HPV16)–induced anogenital lesions. However, the treatment of HPV16-induced cancers requires appropriate countermeasures to overcome cancer-induced immune suppression. We previously showed that standard-of-care carboplatin/paclitaxel chemotherapy can reduce abnormally high numbers of immunosuppressive myeloid cells in patients, allowing the development of much stronger therapeutic HPV16 vaccine (ISA101)–induced tumor immunity. We now show the clinical effects of ISA101 vaccination during chemotherapy in 77 patients with advanced, recurrent, or metastatic cervical cancer in a dose assessment study of ISA101. Tumor regressions were observed in 43% of 72 evaluable patients. The depletion of myeloid suppressive cells by carboplatin/paclitaxel was associated with detection of low frequency of spontaneous HPV16-specific immunity in 21 of 62 tested patients. Patients mounted type 1 T cell responses to the vaccine across all doses. The group of patients with higher than median vaccine-induced immune responses lived longer, with a flat tail on the survival curve. This demonstrates that chemoimmunotherapy can be exploited to the benefit of patients with advanced cancer based on a defined mode of action. [ABSTRACT FROM AUTHOR]

Purpose: Ado-trastuzumab emtansine (T-DM1/Kadcyla®;Genentech) is an antibody-drug conjugate used in the treatment of human epidermal growth factor receptor-2-positive metastasized breast cancer. Few studies report a spectrum of corneal changes in patients treated with this drug. Our aim is to specify the nature and prevalence of corneal features of T-DM1 treatment in order to formulate guidelines as to which findings necessitate systemic treatment cessation or dose reduction. Methods: We performed a cross-sectional, prospective study in all patients currently treated with T-DM1 or recently stopped in Ghent University Hospital, Belgium. Results: A total of 12 patients completed a full ophthalmic workup. Ten patients were currently using T-DM1, and two patients had recently (< 10 weeks) stopped treatment because of clinical non-response. Twenty eyes of 10 patients currently on T-DM1-treatment all exhibited coarse cystoid lesions to the deep corneal epithelial cells, primarily in the midperipheral area, both biomicroscopically and on confocal microscopy. The two patients who stopped treatment, displayed no corneal epithelial changes. Only three patients reported symptoms which were attributed to other ocular factors, likely not to be related to T-DM1 treatment. Conclusions: This case series shows that asymptomatic, low-grade corneal epithelial changes are hallmark features in T-DM1-treatment and should not alarm clinicians. These findings are relatively stationary, reversible and thus do not require ocular treatment or cessation of systemic treatment. [ABSTRACT FROM AUTHOR]

Background: Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature. In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement. We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression.Methods: PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma. Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose. The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity. The primary objective is objective response rate at week 26 according to immune-related response criteria. Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life. Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome.Discussion: In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination.Trial Registration: EU Clinical Trials Register: EudraCT 2016-001569-97 , registered on 19-6-2017. Clinicaltrials.gov: NCT03192059 , registered on 19-6-2017. [ABSTRACT FROM AUTHOR]

Background: Previous studies on cervical cancer reported a worse outcome for adenocarcinoma (AC) compared with squamous cell carcinoma (SCC). Nevertheless, standard treatment remains identical. Insight in the impact of histological types on biological behavior and pathological complete response rates might result in a treatment paradigm shift.Methods: Clinicopathological characteristics, survival rates and relapse patterns were compared between AC (n = 36) and SCC (n = 143) cervical cancer patients. Pathological response to treatment was evaluated in the patient subgroup treated with neo-adjuvant chemoradiation followed by surgery (NA-CRT group; n = 84).Results: In the entire cohort, 5y Disease Specific Survival (DSS) was 97.1 and 84% for AC and SCC respectively (p = 0.150). In the NA-CRT group 5y DSS was 100 and 75.5% for AC and SCC respectively (p = 0.059). Relapse patterns did not differ significantly between AC and SCC in the entire cohort, or in the NA-CRT group. Adenocarcinoma patients treated with NA-CRT showed significantly less pathological complete response compared with SCC patients (AC = 7%, SCC = 43%, p = 0.027).Conclusions: There were no statistically significant differences regarding relapse and DSS rates between SCC and AC in the entire cohort, or the NA-CRT group. However, a trend to better 5y DSS of AC in the NA-CRT group was observed. This analysis showed significant differences in treatment responses after NA-CRT: patients with AC responded remarkably less to chemoradiation, resulting in a significantly lower pathological complete response rate. These findings imply a need for a paradigm shift in the treatment of cervical AC patients. [ABSTRACT FROM AUTHOR]

Background: Definitive chemoradiotherapy is standard of care in locally advanced cervical cancer (LACC). Both toxicity and local relapse remain major concerns in this treatment. We hypothesize that a magnetic resonance imaging (MRI) based redefining of the radiotherapeutic target volume will lead to a reduction of acute and late toxicity. In our center, chemoradiotherapy followed by hysterectomy was implemented successfully in the past. This enables us to assess the safety of reducing the target volume but also to explore the biological effects of chemoradiation on the resected hysterectomy specimen.Methods: The EXIT-trial is a phase II, single arm study aimed at LACC patients. This study evaluates whether a MRI-based exclusion of the non-tumor-bearing parts of the uterus out of the target volume results in absence of tumor in the non-high doses irradiated part of the uterus in the hysterectomy specimen. Secondary endpoints include a dosimetric comparison of dose on normal tissue when comparing study treatment plans compared to treatment of the whole uterus at high doses; acute and chronic toxicity, overall survival, local relapse- and progression-free survival. In the translational part of the study, we will evaluate the hypothesis that the baseline apparent diffusion coefficient (ADC) values of diffusion weighted MRI and its evolution 2 weeks after start of CRT, for the whole tumor as well as for intra-tumoral regions, is prognostic for residual tumor on the hysterectomy specimen.Discussion: Although MRI is already used to guide target delineation in brachytherapy, the EXIT-trial is the first to use this information to guide target delineation in external beam radiotherapy. Early therapy resistance prediction using DW-MRI opens a window for early treatment adaptation or further dose-escalation on tumors/intratumoral regions at risk for treatment failure.Trial Registration: Belgian Registration: B670201526181 (prospectively registered, 26/11/2015); ClinicalTrials.gov Identifier: NCT03542942 (retrospectively registered, 17/5/2018). [ABSTRACT FROM AUTHOR]

Although the prognostic and predictive significance of human epidermal growth factor receptor 2 (HER2) in invasive breast cancer is well established, its role in ductal carcinoma in situ (DCIS) remains unclear. Reports on combined evaluation of both HER2 protein expression and HER2 amplification status in pure DCIS and DCIS adjacent to invasive ductal carcinoma (i.e., admixed DCIS) are scarce. In this study, immunohistochemistry and fluorescence in situ hybridization (FISH) were used to assess HER2 status in 72 cases of pure DCIS, 73 cases of DCIS admixed with invasive ductal carcinoma (IDC), and 60 cases of pure IDC. HER2 copy number-based amplification was present in 49% of pure DCIS, 16% of admixed DCIS, 18% of admixed IDC, and 8% of pure IDC. Amplified pure DCIS with clusters of HER2 signals showed a significantly lower HER2 copy number than amplified admixed DCIS with clusters. Whereas pure DCIS and admixed DCIS presented significant differences, the in situ and invasive component of admixed tumors showed striking similarities regarding mean HER2 and chromosome 17 centromere (CEP17) copy number, grade, and estrogen and progesterone receptor expression. The discrepant prevalence of HER2 amplification among breast cancer subgroups indirectly suggests that HER2 may not play a crucial role in the transition of in situ to invasive breast cancer. The similarities in HER2 amplification status between the in situ and invasive component of admixed tumors hint at a common biological pathway for both components. Our data support the theory that pure DCIS, pure IDC, and admixed lesions have a common progenitor, but can progress as separate lineages. [ABSTRACT FROM AUTHOR]

Background. Standard treatment of stage III and IV advanced ovarian cancer (AOC) consists of primary debulking surgery (PDS) followed by chemotherapy. Since the publication of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial, clinical practice has changed and many AOC patients are now treated with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS).The best option remains unclear. Ovarian cancer is a heterogenic disease. Should we use the diversity in biology of the tumor and patterns of tumor localization to better stratify patients between both approaches? Methods. This analysis was based on results of five phase III randomized controlled trials on PDS and IDS in AOC patients, three Cochrane reviews, and four meta-analyses. Results. There is still no evidence that NACT-IDS is superior to PDS. Clinical status, tumor biology, and chemosensitivity should be taken into account to individualize surgical approach. Nonserous (type 1) tumors with favorable prognosis are less chemo-sensitive, and omitting optimal PDS will lead to less favorable outcome. For patients with advanced serous ovarian cancer (type 2) associated with severe comorbidity or low performance status, NACT-IDS is the preferred option. Conclusion. We propose stratifying AOC patients into five categories according to patterns of tumor spread (reflecting the biologic behavior), response to chemotherapy, and prognosis to make a more rational decision between PDS and NACT-IDS. [ABSTRACT FROM AUTHOR]

Since the discovery of leptin in 1994, our vision of adipose tissue as a static organ regulating mainly lipid storage and release has been completely overthrown, and adipose tissue is now seen as an active and integral organ in human physiology. In the past years, extensive research has tremendously given us more insights in the mechanisms and pathways involved not only in normal but also in 'sick' adipose tissue, for example, in obesity and lipodystrophy. With growing evidence of a link between obesity and several types of cancer, research focusing on the interaction between adipose tissue and cancer has begun to unravel the interesting but complex multi-lateral communication between the different players. With breast cancer as one of the first cancer types where a positive correlation between obesity and breast cancer incidence and prognosis in post-menopausal women was found, we have focused this review on the paracrine and endocrine role of adipose tissue in breast cancer initiation and progression. As important inter-species differences in adipose tissue occur, we mainly selected human adipose tissue and breast cancer-based studies with a short reflection on therapeutic possibilities. This review is part of the special issue on "Adiposopathy in Cancer and (Cardio)Metabolic Diseases". [ABSTRACT FROM AUTHOR]

Purpose: Improved survival after liver resection for breast cancer liver metastases (BCLM) has been proven; however, there is still controversy on predictive factors influencing outcomes. The analysis of factors related to primary and metastatic cancer eventually influencing long-term outcomes and a review of the literature are presented in this report. Methods: Twenty-seven patients diagnosed with metachronous BCLM between 1996 and 2013 were retrospectively reviewed. Patients who had a minimum disease-free interval between primary tumor and liver metastasis of 12 months, no more than 3 liver lesions, no macroscopic extra-hepatic disease and in which systemic therapy showed a good response were included. Results: Twenty-two patients (82%) were initially diagnosed with a stage I-II disease. Twelve patients presented with multiple liver metastases. The 5 years overall survival (OS) rate was 78%, while the 5 years disease-free survival (DFS) rate was 36%. Initial tumor stage III-IV at first diagnosis and number of metastases >1 was significantly associated with a shorter DFS at multivariate analysis (p = 0.03 and p = 0.04 respectively). Patients with multiple lesions had a median DFS of 15 months compared to 47 months in patients with a single lesion (p = 0.03). Conclusions: Resection of single BCLM from primary stage I-II cancer offers very good long-term survival rates and a low morbidity. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study aimed to characterize ductal carcinoma in situ (DCIS) according to human epidermal growth factor receptor 2 (HER2) amplification status and molecular subtype. In addition, we performed a detailed HER2 and CEP17 copy number analysis and we assessed the impact of recent changes in the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on HER2 immunohistochemical (IHC) scores in DCIS. Nuclear grade, extensive comedonecrosis, stromal architecture, stromal inflammation, and progesterone receptor (PR) expression were significantly associated with HER2 amplification status. In multivariate analysis, stromal inflammation and extensive comedonecrosis were the only two features that remained significantly related to HER2 amplification status. The recent changes in ASCO/CAP guidelines resulted in significant upgrading of HER2 IHC score. Remarkably, about one in five non-amplified DCIS presented a 3+ IHC score, regardless of the scoring method. The biological significance of this phenomenon is presently unknown. After categorization according to molecular subtype, luminal A DCIS mainly presented histopathological features associated with good prognosis, whereas luminal B/HER2+ and HER2+ categories displayed a more aggressive phenotype. Overall, our results demonstrate that HER2-amplified DCIS constitute a clearly distinct subgroup which is characterized by histopathological features associated with poor prognosis. Further studies are required to elucidate the biological significance of a 3+ IHC score in non-amplified DCIS, as well as its mechanism. [ABSTRACT FROM AUTHOR]

Aims The incidence of ductal carcinoma in situ ( DCIS) has increased since the introduction of screening mammography. Recurrence prediction is still not accurate, and could be improved by identifying additional prognostic markers. Periductal stroma actively participates in early breast cancer progression. Therefore, the aim of this study was to explore the prognostic potential of stromal characteristics in DCIS. Methods and results Histopathological features and hormone receptor/ HER2 status were analysed in a first cohort of 65 cases of DCIS with a median follow-up of 112 months. Cox regression analysis revealed that myxoid stromal architecture was significantly associated with increased ipsilateral locoregional recurrence ( P = 0.015). Next, we performed immunohistochemical screening of nine stromal proteins in a second cohort of 82 DCIS cases, and correlated their expression with stromal architecture. Because reduced stromal decorin expression correlated most strongly with myxoid stroma ( P < 0.001), it was selected for further analysis in the first cohort. Patients with reduced periductal decorin expression had a higher risk of recurrence ( P = 0.008). Furthermore, HER2 overexpression was significantly associated with invasive but not with in situ recurrence ( P = 0.007). Conclusions Periductal myxoid stroma and reduced periductal decorin expression seem to be prognostic for overall ipsilateral locoregional recurrence in DCIS, whereas HER2 expression might be a more specific biomarker for invasive recurrence. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the clinical and pathobiological significance of distinguishing score 0 and score 1+ within the group of immunohistochemistry (IHC)-negative invasive breast cancers. Methods: We studied HER2 status using both IHC and fluorescence in situ hybridization (FISH) in 150 consecutive breast tumors submitted to our laboratory after a negative IHC result in local testing centers. Results: We were able to discern a group of score 0 tumors that had a lower HER2 copy number than the group consisting of score 1+ tumors. In contrast with the group of score 1+ tumors, HER2 FISH was consistently negative for both copy number-based and ratio-based tumors without equivocal results. Conclusions: In a setting with stringent quality assurance, score 0 and score 1+ tumors emerge as distinct and clinically important subgroups within the HER2 IHC-negative population. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the SARS-CoV-2 pandemic is likely to have created or aggravated mental health symptoms in cancer patients, high-quality longitudinal data on this topic are scarce. The aim of our prospective survey study was to assess cancer patient-reported mental health and quality of life (QOL) at four time points during the first two waves of the pandemic. We found that an important proportion of the 355 participants reported symptoms of COVID-19 peritraumatic distress (34.2% to 39.6%), depression (27.6% to 33.5%), anxiety (24.9% to 32.7%), and stress (11.4% to 15.7%) at any time point during the study period. However, we did not find clinically meaningful mental health and QOL changes during the study period. Additionally, we found no factors associated with better or worse mental health or QOL. In conclusion, the cancer patients who participated in this study showed considerable resilience against mental health and QOL deterioration during the pandemic. Purpose: This longitudinal survey study aimed to investigate the self-reported outcome measures of COVID-19 peritraumatic distress, depression, anxiety, stress, quality of life (QOL), and their associated factors in a cohort of cancer patients treated at a tertiary care hospital during the SARS-CoV-2 pandemic. Methods: Surveys were administered at four time points between 1 April 2020 and 18 September 2020. The surveys included the CPDI, DASS-21, and WHOQOL-BREF questionnaires. Results: Survey response rates were high (61.0% to 79.1%). Among the 355 participants, 71.3% were female, and the median age was 62.2 years (IQR, 53.9 to 69.1). The majority (78.6%) were treated with palliative intention. An important proportion of the participants reported symptoms of COVID-19 peritraumatic distress (34.2% to 39.6%), depression (27.6% to 33.5%), anxiety (24.9% to 32.7%), and stress (11.4% to 15.7%) at any time point during the study period. We did not find clinically meaningful mental health and QOL differences during the study period, with remarkably little change in between the pandemic's first and second wave. We found no consistent correlates of mental health or QOL scores, including cancer type, therapy intention, and sociodemographic information. Conclusion: This cohort of cancer patients showed considerable resilience against mental health and QOL deterioration during the SARS-CoV-2 pandemic. [ABSTRACT FROM AUTHOR]

The secretory Rab27B small GTPase promotes invasive growth and metastasis in estrogen receptor (ER) α-positive breast cancer cells by orchestrating the peripheral targeting of vesicles secreting proinvasive growth regulators. Increased Rab27B expression is associated with poor prognosis in breast cancer patients. The molecular mechanisms of peripheral Rab27B secretory vesicle distribution are poorly understood. Mass spectrometry analysis on green fluorescent protein (GFP)-Rab27B vesicles prepared from GFP-Rab27B transfected MCF-7 human breast cancer cells detected eight subunits of the vacuolar H(+)-ATPase (V-ATPase) and the presence of V0a1 and V0d1 subunits was confirmed by Western blot analysis. Reversible inhibition of V-ATPase activity by bafilomycin A1 or transient silencing of V0a1 or V0d1 subunits demonstrated that V-ATPase controls peripheral localization and size of Rab27B vesicles. V-ATPase expression and activity further controls Rab27B-induced collagen type I invasion, cell-cycle progression and invasive growth in the chorioallantoic membrane assay. In agreement, Rab27B-dependent extracellular heat shock protein90α release and matrix metalloprotease-2 activation is markedly reduced by bafilomycin A1 and transient silencing of V0a1 and V0d1 subunits. Poor prognosis ERα-positive primary breast tumors expressing high levels of Rab27B also expressed multiple V-ATPase subunits and showed a strong cytoplasmic and peripheral V-ATPase V1E expression. In conclusion, inhibiting V-ATPase activity by interfering agents and drugs might be an effective strategy for blocking Rab27B-dependent proinvasive secretory vesicle trafficking in ERα-positive breast cancer patients. [ABSTRACT FROM AUTHOR]

Objective Bone marrow-derived mesenchymal stem cells (BM-MSC) migrate to primary tumours and drive tumour progression. This study aimed to identify the molecular mechanisms associated with these heterotypic cellular interactions and analyse their relevance in colorectal cancer (CRC). Design Paracrine interactions of BM-MSC with CRC cells were studied using collagen invasion assays, cell counts, flow cytometric cell-cycle analysis and tumour xenograft models. The role of neuregulin 1 (NRG1) and the human epidermal growth factor receptor (HER) family pathways were investigated using tyrosine kinase assays, mass spectrometry, pharmacological inhibition, antibody-mediated neutralisation and RNA interference. Transmembrane neuregulin 1 (tNRG1), HER2 and HER3 expression was analysed in primary CRC (n=54), adjacent normal colorectal tissues (n=4), liver metastases (n=3) and adjacent normal liver tissues (n=3) by immunohistochemistry. Results BM-MSC stimulate invasion, survival and tumorigenesis of CRC through the release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signalling cascade in CRC cells. Similarly, tumour-associated mesenchymal cells (T-MC) in CRC demonstrate high tNRG1 expression, which is significantly associated with advanced Union for International Cancer Control stage (p=0.005) and invasion depth (p=0.04) and decreased 5-year progression-free survival (p=0.01). HER2 and HER3 show membrane localisation in cancer cells of CRC tissue. Conclusion Paracrine NRG1/HER3 signals initiated by BM-MSC and T-MC promote CRC cell progression, and high tNRG1 expression is associated with poor prognosis in CRC. [ABSTRACT FROM AUTHOR]

Background: Limited data are available on the use of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (HIPEC) in patients with recurrent stage III ovarian cancer. Methods: Patients with recurrent, heavily pretreated ovarian cancer were enrolled onto a phase II multimodal protocol consisting of extensive cytoreduction followed by HIPEC. Results: Forty-two women were treated from October 2002 until January 2009. Chemoperfusion was performed with cisplatin in 59% and oxaliplatin in 41% of patients. A macroscopically complete resection was achieved in 50% of patients. No mortality occurred, and the major morbidity rate was 21%. After a mean follow-up of 21 months, median overall survival (OS) was 37 months (95% confidence interval 12.2-61.8) and median progression-free survival was 13 months (95% confidence interval 6.9-19.1). In univariate analysis, OS was influenced by completeness of cytoreduction, type of chemoperfusion drug, nodal status, and tumor grade. In a Cox regression model, only completeness of cytoreduction (hazard ratio 0.06-0.8, P = .022) and tumor grade (hazard ratio 1.23-12.6, P = .021) were independent predictors of OS. Conclusions: In selected patients with heavily pretreated recurrent ovarian cancer, cytoreduction combined with HIPEC may provide a meaningful OS with acceptable morbidity. Optimal results are achieved in patients with a macroscopically complete resection and biologically favorable disease. [ABSTRACT FROM AUTHOR]

For premenopausal patients with receptor-positive early breast cancer, administration of tamoxifen for 5 years constitutes the main adjuvant endocrine therapy. During pregnancy, tamoxifen and its metabolites interact with rapidly growing and developing embryonic or fetal tissues. Information about tamoxifen and pregnancy was gathered by searching PubMed. In addition, we had access to the records of the pharmaceutical company AstraZeneca. Because these observations are retrospective and other therapies and diagnostic measures are possible confounders, a causal relationship was not established between tamoxifen treatment and pregnancy outcome. The records from AstraZeneca documented three live births with congenital anomalies and four live births without congenital anomalies related to tamoxifen treatment before pregnancy. Tamoxifen therapy during pregnancy resulted in 16 live births with congenital malformations and a total of 122 live births without malformations. The 122 live births without malformations included 85 patients from a prevention trial that did not record a single anomaly, whereas the AstraZeneca Safety Database alone reported 11 babies with congenital malformations of 44 live births. Additionally, there were: 12 spontaneous abortions, 17 terminations of pregnancy without known fetal defects, six terminations of pregnancy with fetal defects, one stillbirth without fetal defects, two stillbirths with fetal defects, and 57 unknown outcomes. The relatively high frequency of severe congenital abnormalities indicates that reliable birth control during tamoxifen treatment is mandatory. After tamoxifen use, a washout period of 2 months is advisable based on the known half-life of tamoxifen. In case of an inadvertent pregnancy, risks and options should be discussed. [ABSTRACT FROM AUTHOR]